ICERZ INSTITUTE FOR CLINICAL AND ECONOMIC REVIEW Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre- Treated Relapsed and Refractory Multiple Myeloma Final Report May 11, 2021 Updated July 9, 2021 Updated November 22, 2022 Prepared for Y= MIDWEST == CEPAC INET] COMPARATIVE EFFECTIVENESS PUBLIC ADVISORY COUNCIL November 22, 2022 Update: Per ICER's guidelines on the acceptance and use of "In-Confidence" data from manufacturers of pharmaceuticals, academic-in-confidence data that was redacted in the report has been unmasked after 18 months following the date of the public ICER meeting. On November 22, 2022 the manufacturer of belantamab mafodotin (GSK) also announced initiating the process for withdrawal at the request of the FDA, which in turn was based on the negative readout of a confirmatory Phase lll trial earlier this month. As such, this ICER report should be considered no longer current with respect to belantamab mafodotin. New evidence regarding treatments and therapies gets published on an ongoing basis. ICER reached out to key stakeholders included in this review 12 months after the publication of this report giving them an opportunity to submit public comments regarding new relevant evidence or information on coverage that they wish to highlight. Their statements can be found here. ICER has launched ICER Analytics to provide stakeholders an opportunity to work directly with ICER models and examine how changes in parameters would affect results. You can learn more about ICER Analytics here. ICER Staff and Consultants Modeling Team Sei J. Lee, MD, MAS Professor of Medicine University of California, San Francisco Molly Beinfeld, MPH Research Lead, Evidence Synthesis ICER Noemi Fluetsch, MPH Research Assistant, Health Economics and Outcomes Research ICER Melanie D. Whittington, PhD, MS Associate Director of Health Economics ICER Steven D. Pearson, MD, MSc President ICER Daniel A. Ollendorf, PhD Director, Value Measurement & Global Health Initiatives Tufts Medical Center R. Brett McQueen, PhD Assistant Professor, University of Colorado Anschutz Medical Campus Eric Gutierrez, MPH Statistical Analyst, University of Colorado Anschutz Medical Campus Sue Kwon, BS Graduate Research Assistant, University of Colorado Anschutz Medical Campus The University of Colorado was responsible for the development of the cost-effectiveness model, interpretation of results, and drafting of the economic sections of this report; the resulting ICER reports do not necessarily represent the views of the University of Colorado. DATE OF PUBLICATION: May 11, 2021 (Updated July 9, 2021) How to cite this document: Lee SJ, McQueen RB, Beinfeld M, Fluetsch N, Whittington MD, Pearson SD, Ollendorf DA. Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma; Final Evidence Report. Institute for Clinical and Economic Review, May 11, 2021. https://icer.org/assessment/multiple- myeloma-2021/#timeline Sei Lee served as the lead author for the report and wrote the background, other benefits, and contextual considerations sections. Molly Beinfeld led the systematic review and wrote the clinical effectiveness section of the report in collaboration with Noemi Fluetsch and Belén Herce-Hagiwara. Brett McQueen, Eric Gutierrez, and Sue Kwon developed the cost-effectiveness model and authored the corresponding sections of the report. Melanie Whittington provided methods guidance for the cost- effectiveness modeling effort and conducted the potential budget impact analysis. Daniel Ollendorf and Steven Pearson provided methodologic guidance on the clinical and economic evaluations. We would also like to thank Monica Frederick and Liis Shea for their contributions to this report. OInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents About ICER The Institute for Clinical and Economic Review {ICER} is an independent non-profit research organization that evaluates medical evidence and convenes public deliberative bodies to help stakeholders interpret and apply evidence to improve patient outcomes and control costs. Through all its work, ICER seeks to help create a future in which collaborative efforts to move evidence into action provide the foundation for a more effective, efficient, and just health care system. More information about ICER is available at http://www.icer.org. The funding for this report comes from government grants and non-profit foundations, with the largest single funder being the Arnold Ventures. No funding for this work comes from health insurers, pharmacy benefit managers, or life science companies. ICER receives approximately 21% of its overall revenue from these health industry organizations to run a separate Policy Summit program, with funding approximately equally split between insurers/PBMs and life science companies. Life science companies relevant to this review who participate in this program include: GlaxoSmithKline. For a complete list of funders and for more information on ICER's support, please visit http://www.icer-review.org/about/support/. For drug topics, in addition to receiving recommendations from the public, ICER scans publicly available information and also benefits from a collaboration with IPD Analytics, an independent organization that performs analyses of the emerging drug pipeline for a diverse group of industry stakeholders, including payers, pharmaceutical manufacturers, providers, and wholesalers. IPD provides a tailored report on the drug pipeline on a courtesy basis to ICER but does not prioritize topics for specific ICER assessments. About Midwest CEPAC The Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC) - a core program of ICER - provides a public venue in which the evidence on the effectiveness and value of health care services can be discussed with the input of all stakeholders. Midwest CEPAC seeks to help patients, clinicians, insurers, and policymakers interpret and use evidence to improve the quality and value of health care. The Midwest CEPAC is an independent committee of medical evidence experts from across the Midwest, with a mix of practicing clinicians, methodologists, and leaders in patient engagement and advocacy. All Council members meet strict conflict of interest guidelines and are convened to discuss the evidence summarized in ICER reports and vote on the comparative clinical effectiveness and value of medical interventions. More information about Midwest CEPAC is available at https://icer.org/who-we-are/people/independent-appraisal- committees/midwest-comparative-effectiveness-public-advisory-council-m-cepac/. The findings contained within this report are current as of the date of publication. Readers should be aware that new evidence may emerge following the publication of this report that could potentially influence the results. ICER may revisit its analyses in a formal update to this report in the future. The economic models used in ICER reports are intended to compare the clinical outcomes, expected costs, and cost- effectiveness of different care pathways for broad groups of patients. Model results therefore represent average findings across patients and should not be presumed to represent the clinical or cost outcomes for any specific patient. In addition, data inputs to ICER models often come from clinical trials; patients in these trials may differ in real-world practice settings. ®lInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents In the development of this report, ICER's researchers consulted with several clinical experts, patients, manufacturers, and other stakeholders. The following experts provided input that helped guide the ICER team as we shaped our scope and report. It is possible that expert reviewers may not have had the opportunity to review all portions of this report. None of these individuals is responsible for the final contents of this report, nor should it be assumed that they support any part of it. The report should be viewed as attributable solely to the ICER team and its daffiliated researchers. The Expert Reviewers listed below have not reviewed the updated version of this report which was published on July 9. For a complete list of stakeholders from whom we requested input, please visit: http://icerorg.wpengine.com/wp-content/uploads/2020/10/ICER MM_Key Stakeholders 092720.pdf Expert Reviewers Elizabeth Franklin, PhD, MSW President Cancer Support Community The Cancer Support Community receives funding from various pharmaceutical, foundation, and corporate partners. All work is done under CSC's corporate support policy. S. Vincent Rajkumar, MD Edward W. and Betty Knight Scripps Professor of Medicine Associate Editor, Mayo Clinic Proceedings Mayo Clinic Dr. S. Vincent Rajkumar has held a position as a member of the Board of Directors for the International Myeloma Foundation. Ravi Vij, MD, MBA Professor, Department of Medicine Oncology Division, Bone Marrow Transplantation & Leukemia Washington University School of Medicine in St. Louis Dr. Ravi Vij has served on Advisory boards for BMS, GSK and Sanofi. Dr. Vij has also received support for investigator initiated clinical trials for BMS, Sanofi and Takeda. OInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents Table of Contents L =T ol WAV U g o - ES1 1. BACKGIOUNM ... ceiecrc ettt r s s e e e s s s e e e cre e r e s s e n e e s s s s e e e e s s an e e eee s eneas s ssneeesasanneesasnnnaesasnns 1 2. Patient and Caregiver PErspeCtiVves ..........ccciciciiieiierenieeetercseeeseeese st e e ee e e s es e s e e sesen e s neasaameeeanneens 3 3. Comparative Clinical EffeCtiVENESS ......cuvvircrerrircieieerieeerrrrrreerrrscsersrsesneessseessseeesssssessssssnssessssnnensess 5 3.1. MethodSs OVEIVIEW........ccciimiiiieiiiente et s s s e s 5 0 U T 1] PR 9 3.3. Summary and COMMENT ... e e e ee e s e s e s e e e s enes e s e e sesme e s me e e e e enmeesenanens 17 4. LoNg-Term Cost-Eff@CtiVENESS. ... cc.eerrircrerrirrretrrircitiresisesserrerssseeerrssssereressssseeasssssnsessssssnssssessneessesnas 19 4.1. Methods OVEIVIEW......cc.coimiiiiie ettt s s s s 19 4.2. Key Model Assumptions and INPULS ..........coirioriiieiecrre s ccee s e s e e e e 21 I T 1T U] Y 25 4.4, Summary and COMMENT .....coiieieieecirerereeeecee e s e s e e s e e s s ar e s eaeseee s semresaaneseneaenaneasanasenanes 33 5. Potential Other Benefits and Contextual Considerations.............cccecvecccrnernmnnnnnnnn e 34 6. Health Benefit Price BeNChMArks ........ccociiiiiiiiciiinin sttt 36 7. Potential BUAEEt IMPACT ..ottt e e s cr s e s e e s s e en e s e e e mn e s 37 7.1. Overview Of K@Y ASSUMPLIONS .....cccceeeiierieerireeiitenieesetesseesseesssesessesssesasesssseasssasssssansesssassssssnnanas 37 78 V- ] 38 7.3. Affordability and ACCESS AlRIT..........oecieeeereeeccirre et e e s see e e e s seeseae s s sse s seasssesese e s seassnesennenns 42 8. Summary of the Votes and Considerations for POlICY .........cccevereireieenienccinnceee e 43 8.1 About the MidWest CEPAC PrOCESS .......cccccimireierisimiissiitsssissssssssssssssssaesssssassssssssssssssssssssssssssne 43 8.2 VOUING RESUILS ..eevvveeeieeieeireterireeetrrresetsrrseenrreressrsasesssssneessssssssesssssneesssessassssssssseessnssnsnsesssnnseeses 45 8.3 Roundtable Discussion and Key Policy IMpliCations .......cccccveverrirevvieerrciiinmennnsseeeerrssseerssesnseeenes 50 All SEAKENOIEIS ...ttt s s e s ae s s 52 MaANUFACTUFETS ...t e 53 Clinical SPECialty SOCIELIES ......veverrvererrrreieerrircreereeresirnresrssneerrsessereessssnreeseessranessssssresssssnenresssnsraeses 54 P Y LS .. creereeee e e e e e et eeeete ettt eee------------------eeeeeeeeetsasannnnnssnstnseeastaasanananannn 54 Clinical Research CoOmMMUNITY.......cceeceeiiiecceeccecrctrcstirs e s e s seesese s sesn s e e s seesnan e s nesnennnenns 57 Supplemental Materials.......c.ccuvceicereenecieemnerreremnesseremsrerrennsssereenessersanssesssessserennsssessanssssssansssseanas 59 A. Background: Supplemental INformation ........ccccveciciiiniisimrrerrceerrrrreeererccerree s ssrsesssssersesessnseseeenes 60 OInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents AL, D iNTIONS ... eeeecciciccriiisie i e e e s sesesssssssssssssss s e s e s s e e e e e e e e e e e e eeeessassasssssnsnnsseeeeeeeeeeeeennens 60 B. Patient Perspectives: Supplemental INformation..........cceeceieeeeceenccrceeccenne e 63 23 1V T4 T Yo [ R 63 B2. Cancer Support Community Myeloma Registry SUIVEY........ccvvcerrrcrcceerninsineerrrseeersssseeeerecsaenes 64 C. Clinical GUIEIINES ......cciiiceriiiiiii ettt e s s e s s s e snean 67 D. Comparative Clinical Effectiveness: Supplemental Information.........ccccccccunimrninnsencencencseesceenene 69 D1. Detailed Methods ..ot 69 D2. Additional Clinical EVIENCE.......cociiiiiiiiiiiiccense ittt 79 (D1 T VT LT ol I |« T 87 DA. ONGOING STUIES ... eieieiiirieeeie st e s e ee e reer s s s e s sea e s sae e s e sen e s eneaeaae e e snaeaseenenaneasannsananenens 127 D5. Previous Systematic Reviews and Technology Assessments .........cccccceirricencnciencnensceenencenn. 140 E. Long-Term Cost-Effectiveness: Supplemental Information........cccccvcvcevvvecviererirrreenrncreereresseeene. 142 E1l. Detailed Methods........ccccoiiiii e 142 E2. MO INPULS ...ttt r et e s e e et e et e s er e s ea e e ae e s e ea e s eneasaaneeaesanesenenenaneasannsananenenn 144 E3. UNndiscounted RESUILS.........ooouermiieeiiicitrertccnecr e 161 E4. SENSItIVILY ANGIYSES c.uueeieiiricceeerirceerrrrcretrrrrreersr s ressseesrssssse e e rssseressssssesssesssnesessssnsnesssssneessnnns 162 ot =] o P T 37 Vg = L <3 172 E6. Heterogeneity and SUDZIOUPS ......cevvvvciiiiircicciriiinsisnie s ssrr s rsesseeeesesnseessssssssnesssssnseresssssseesennns 173 E7. Model Validation.........ccccoiiiiiceecc e 174 E8. Prior ECONOMIC MOMEIS ......oooeeeiieeiieecerccii e 174 F. Potential Budget Impact: Supplemental INformation.........ccccveevervircivieencccnien e ereseeeenas 176 2] P 177 G. PUDIIC COMMENTS.....iiiiiiiiciiiii e s s a s s s e s a s s ne s s n s 178 H. Conflict of Interest DISCIOSUIES.........ccceiieeriiiiccircirrr et 184 3= =T =T 3Tl SRRSO 187 OInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents List of Acronyms and Abbreviations Used in this Report 95%ClI ADC AE AHRQ AIC BCMA BP CAR CR CRAB CRS D/C DCEP DOR EMD EORTC EPd HR HRQolL IMiD IQR ISS ITT Kcd Ke KPd Mg MM MRD n N N/A NE NICE NR NT OR ORR os 0sDI PCd PFS PI QLQ-Cc30 RRMM SEER TCRMM TINT 95% Confidence Interval Antibody drug conjugate Adverse event Agency for Healthcare Research and Quality Academic in confidence B-cell maturation antigen Bendamustine + prednisone Chimeric antigen receptor Complete response Calcium, renal, anemia, and bone Cytokine release syndrome Discontinuation Dexamethasone + cyclophosphamide + etoposide + cisplatin Duration of response Extramedullary disease European Organization for Research and Treatment of Cancer Elotuzumab + pomalidomide + dexamethasone Hazard ratio Health-related quality of life Immunomodulatory drug Interquartile range Idiopathic subglottic stenosis Intention to treat Carfilzomib + cyclophosphamide + dexamethasone Kilogram Carfilzomib + pomalidomide + dexamethasone Milligram Multiple Myeloma Minimal residual disease Number Total number Not applicable Not estimable National Institute for Health and Care Excellence Not reported Neurotoxicity Odds ratio Overall response rate Overall survival Ocular Surface Disease Index Pomalidomide + cyclophosphamide + dexamethasone Progression free survival Proteasome inhibitor Quality of Life Questionnaire C30 Relapsed or refractory multiple myeloma Survey, Epidemiology, and End Results Program Triple-class refractory multiple myeloma Time to next treatment OInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents Executive Summary Update (Added July 9, 2021) The final evidence report, which contained the full set of analyses, voting summary, and policy roundtable recommendations, was posted on May 11, 2021, following the public meeting of the Midwest CEPAC on April 16, 2021. At the time, the extremely limited evidence available for cilta-cel (i.e., median follow-up of 12 months) was characterized as "preliminary", and the economic model results described as "optimistic." Since the publication of the final report, new evidence has been reported for cilta-cel, based on a median follow-up of 18 months. Data from this longer period of follow-up indicated some worsening of both progression-free and overall survival, which has translated to less favorable findings for cilta-cel's cost-effectiveness. In fact, the revised results now exceed ICER's typical thresholds for fair pricing. We felt that it was critically important to provide these updated findings as a resource to decision- makers and other interested stakeholders, and also as an illustration of the challenges associated with data extrapolations when the evidence available is so limited. The following sections of the report have been updated as of July 9, 2021: e Table ES1 18-month ORR have been added e Section 3.2 Cilta-cel outcomes have been updated e Table 3.3 has been updated e Section 4.3 - base-case results have been updated for cilta-cel e Section 7 - budget impact results for cilta-cel have been updated e Uncertainties and Controversies include updated ORR e Supplement table E.2.5 and all sensitivity analyses ranging from Figure E.4.3 - E.4.4 have been updated; Tables E.4.4 - E.5.1 have been updated e Supplement Table D3.4 detailed outcomes for cilta-cel have been updated ®lInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents Multiple myeloma (MM) is a hematologic cancer of plasma cells, currently estimated to afflict approximately 150,000 Americans. The mainstays of current MM treatment include immunomodulatory agents, proteasome inhibitors and anti-CD38 monoclonal antibodies.! Most patients eventually relapse; these patients with relapsed or refractory multiple myeloma (RRMM) often cycle through different combinations of agents. When a patient's disease is no longer responsive to agents in each of the three classes, the disease is referred to as "triple-class refractory" MM (TCRMM).? ICER reviewed three new treatments targeting the B-cell maturation antigen (BCMA) for heavily pre-treated patients with RRMM who have cycled through numerous previous lines of therapy. Belantamab mafodotin bimf (Blenrep®, GlaxoSmithKline) is an antibody drug conjugate, with a monoclonal antibody to BCMA linked to a cytotoxic drug. Belantamab was studied in patients with heavily pre-treated (6-7 previous lines of therapy) TCRMM (majority quad- and penta-refractory, usually defined as refractory to 4 or 5 agents across all 3 drug classes outlined above). Idecabtagene vicleucel ("ide-cel", Abecma®, Bristol Myers Squibb and bluebird bio) and ciltacabtagene autoleucel ("cilta-cel", Janssen and Legend biotech) are chimeric antigen receptor (CAR) T-cell therapies, involving engineering a patient's own T cells to target BCMA, and were studied in patients who were mostly TCRMM (majority triple- or quad-refractory patients). I" Patients spoke about the burden of symptoms from both MM and its available treatments. Common symptoms of disease include fatigue, which can be overwhelming, and bony pain. Symptoms of the current treatments vary by medication, but frequently mentioned bothersome side effects include neuropathy as well as insomnia and psychosis from dexamethasone. Patients also noted substantial financial burden with annual out-of-pocket costs exceeding $10,000 leading one patient to remark that one had to be a "mathematician" to navigate the costs of being a myeloma patient. Response rates and survival statistics are presented in Table ES1. The CAR T-cell therapies (ide-cel and cilta-cel) appear to be superior to currently available treatment regimens for TCRMM, as estimated from the recent MAMMOTH observational study. In contrast, belantamab appears to be equivalent or slightly superior to the most relevant comparative set from MAMMOTH. OInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents Table ES1. Response Rates and Median PFS for Anti-BCMA Therapies Follow- As Median PFS or Intervention Study Up Treated | ITT ORR os" Toxicity Duration ORR CAR T Population (Triple- or Quad- Refractory, 3+ prior lines of treatment) Ide-cel KarMMa 13.3 73% 63% As-treated PFS | 51% CRS Grade 2+ months = 8.6 months Cilta-cel CARTITUDE- | 18 98% 75% As-treated PFS | 44% CRS Grade 2+ 1 months >18 months 6% Treatment-related deaths Usual Care MAMMOTH | 10.6 - 31% PFS=3.4 Variable months months Belantamab Population (Triple-, Quad- or Penta- Refractory MM, 4+ prior lines of treatment) Belantamab DREAMM-2 | 13 - 32% ITTOS=13.8 18 - 46% Meaningful to months months moderate reversible visual decline {duration 22-33 days) Usual Care MAMMOTH | 10.6 - 28% Triple/quad OS | Variable subcohort' | months =9.2 months Penta OS =5.6 months BCVA: Best Corrected Visual Acuity, CRS: cytokine release syndrome, ITT: intention-to-treat, ORR: overall response rate, OS: overall survival, PFS: progression free survival * Ide-cel and cilta-cel PFS is as-treated. All other PFS and OS data are ITT + MAMMOTH comparator subcohort was defined by weighting the MAMMOTH triple/quad- and penta- refractory cohort proportions to the DREAMM-2 triple/quad- and penta- refractory proportions Toxicities were common with both CAR T-cell therapies and belantamab. For CAR T-cell therapies, Grade 2+ cytokine release syndrome (usually requiring hospitalization) occurred in 51% of patients who received ide-cel and 44% of patients who received cilta-cel. In addition, 6% of patients who received cilta-cel died of treatment-related complications. For belantamab, 18-46% experienced meaningful to moderate decline in vision lasting 22-33 days. Table ES2. ICER Evidence Ratings for Anti-BCMA Therapies Treatment | Comparator | Evidence Rating Triple- or Quad- Refractory MM (3+ prior lines of treatment) Ide-cel Usual Care B+ Cilta-cel Usual Care B+ Ide-cel Cilta-cel | Triple-, Quad- or Penta- Refractory MM (4+ prior lines of treatment) Belantamab | Usual Care P/I* MM: multiple myeloma.*Compared to current treatments, belantamab appears to be comparable to slightly superior. There is a small but nonzero likelihood of slight net harm. Current evidence does not support belantamab being substantially superior to current treatments. OInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents ICER also performed cost-effectiveness modeling and analyses of the new therapies. The base-case findings from our analysis suggest that CAR-T therapies provide clinical benefit in terms of gains in both quality-adjusted and overall survival over current treatment options for triple- or quad- refractory MM patients exposed to three or more lines of therapy. The incremental cost- effectiveness ratios for ide-cel versus the triple- or quad-refractory MM comparator market basket were approximately $319,000 per QALY gained, $250,000 per LY gained, $280,000 per evLYG gained, and $35,000 per additional PFS month gained. Threshold pricing suggests ide-cel would meet the $100,000 per QALY threshold at a price of around $200,000 or a >50% discount from the current list price. Cilta-cel would meet this threshold at a price of around $230,000, but this finding is preliminary and an optimistic estimate given the extremely limited evidence currently available. Base-case findings for belantamab suggest current list pricing is within commonly cited cost- effectiveness thresholds when compared to a triple-, quad-, or penta-refractory MM market basket. However, given uncertainties with the PFS-OS relationship and other parameters in the belantamab model, updated data should be generated and incorporated into future modeling analyses. Small changes in any of the key drivers changed belantamab model findings to a significant extent. Key drivers across all model findings included comparator market basket prices, progression-free survival for the active interventions, and utility of PFS (on or off treatment). Several potential benefits and contextual considerations not fully captured in the economic modeling include the limited treatment options for patients with TCRMM. Since anti-BCMA treatments represent a novel mechanism of action, these treatments may provide efficacy for patients who currently have few alternatives. However, CAR-T therapies are complex and high-cost with significant side effects. Treatments with these characteristics have been underutilized by disadvantaged populations, suggesting that disparities may be worsened. Approximately 43% (ide-cel) and 50% (cilta-cel) of eligible triple- or quad-refractory multiple myeloma patients could be treated within five years before crossing the ICER potential budget impact threshold of $819 million per year. Testimony from clinical experts at the public meeting suggested that the ideal clinical uptake of the CAR-Ts would include the chance for nearly every eligible patient to receive one or the other. Given that efforts to reach this clinical target would create a short-term potential budget impact that exceeds ICER's threshold, ICER is issuing an access and affordability alert for ide-cel and cilta-cel. ICER is not issuing an access and affordability alert for belantamab, because all eligible patients could be treated within five years at its current wholesale acquisition cost. Appraisal committee votes on questions of comparative effectiveness and value, along with key policy recommendations regarding pricing, access, and future research are included in the main report under Summary of the Votes and Considerations for Policy. OInstitute for Clinical and Economic Review, 2021 Final Report- Multiple Myeloma Return to Table of Contents 1. Background Multiple Myeloma (MM) is a hematologic cancer of plasma cells.®> Uncontrolled proliferation of plasma cells can lead to a variety of clinical presentations, including: e Bone pain and fractures due to lytic lesions from plasma cell proliferation in the marrow; e Increased total or monoclonal protein, which can have direct toxic effects on the kidney, resulting in worsening renal function; e Hypercalcemia; e Anemia, due in part to plasma cells suppressing other hematopoietic cell lines and kidney disease. MM is most often diagnosed through a bone marrow biopsy showing >10% plasma cells.* MM is a relatively rare cancer, with an annual incidence of approximately 7 in 100,000 Americans. It is estimated that 32,270 new cases of MM were diagnosed in 2020 and 150,000 Americans are currently living with MM.2 It is primarily a disease of older adults, with a median age at diagnosis of 69. African-Americans appear to be at approximately twice the risk of white Americans, while Asian-Americans appear to be at lower risk.> The rates of MM have been stable without evidence of increasing incidence over six decades.®> The direct medical costs of MM are substantial. A recent analysis of commercial and Medicare claims found that average costs exceeded $250,000 over a 21- month period, and that 60% of these costs were medication-related.® The last 15 years have seen a proliferation of new, approved therapies for MM, resulting in substantial improvements in survival.® In 2000, data from the Survey, Epidemiology, and End Results Program (SEER) suggested that 36% of MM patients achieved 5-year survival while in 2017, SEER models indicated that 56% of patients with MM will survive 5 years.3 Unfortunately, currently-approved therapies are not curative for most patients with MM. While modern combination treatments and autologous stem cell transplant can often lead to effective control with decreased signs and symptoms of MM, over time, most patients will relapse, showing signs and symptoms of renewed, active disease. Patients whose disease does not respond to treatment, or initially respond but are no longer responding to line of treatment are considered refractory. These patients with relapsed or refractory multiple myeloma (RRMM) often cycle through different combinations of agents, which may increase both their clinical and economic burden. Patients with MM whose disease has progressed through three common classes of anti- myeloma medications (monoclonal antibodies such as daratumumab or isatuximab; immunomodulatory drugs or IMiD's such as thalidomide, lenalidomide or pomalidomide; and proteasome inhibitors or PI's such as bortezomib, carfilzomib or ixazomib) are termed "triple class refractory" (TCR) MM. ©Ilnstitute for Clinical and Economic Review, 2021 Page 1 Final Report - Multiple Myeloma Return to Table of Contents Currently, there is no widely accepted preferred ordering of lines of therapy for patients with TCRMM. General principles that guide treatment choice include previous treatments, how patient's disease responded to these previous treatments, comorbidities, and risk stratification. One major consideration is incorporating as many new agents as possible (medications to which the patient has not been previously exposed) into each new line of treatment.? This often results in regimens incorporating newer agents in one of the three major classes of anti-myeloma medications (such as pomalidomide or carfilzomib) as well as agents in other classes such elotuzumab or alkylator based treatments. Even with these treatments, patients with TCRMM unfortunately have limited survival, with overall survival <1 year." These patients with TCRMM represent the population that may potentially benefit from the three medications in this review. For our review, we focused on agents commonly used in the TCR population; thus, some agents, such as Selinexor, were not included as a component of usual care (and comparator to new treatments) due to low rates of use in these patients. Three new treatments, idecabtagene vicleucel ("ide-cel", Abecma®, Bristol Myers Squibb and bluebird bio), ciltacabtagene autoleucel {"cilta-cel" mafodotin-blmf (Blenrep®, GlaxoSmithKline, referred to as belantamab for the remainder of the report) are proposed as the focus for this review. All three treatments target the B-cell maturation antigen (BCMA), which is overexpressed on plasma cells, but appears to be minimally expressed on other cells. In addition, BCMA appears to be essential for the survival of long-lived plasma cells, making BCMA an attractive therapeutic target.® Blenrep is an antibody-drug conjugate, with a , Janssen and Legend Biotech) and belantamab monoclonal antibody specific for BCMA that is linked to a cytotoxic drug. Belantamab is given as an intravenous infusion every 3 weeks. Belantamab received FDA approval in August 2020 for adult patients with relapsed or refractory MM who have received 4 prior lines of therapy including an anti-CD38 monoclonal antibody, a Pl and an IMiD. Ide-cel and cilta-cel are chimeric antigen receptor T (CAR-T) cell therapies, requiring a patient's own T lymphocytes to be obtained via leukapheresis and transduced in the lab with a gene to encode an anti-BCMA antibody. Ide-cel uses a mouse-derived CAR with a single BCMA recognition domain. Cilta-cel uses a camelid CAR with 2 BCMA recognition domains, which theoretically may strengthen the interaction between the CAR and target cells. These genetically modified CAR-T cells are expanded and then infused back into the patient intravenously. Ide-cel received FDA approval in March 2021 for the treatment of adult patients with relapsed or refractory multiple myeloma who previously received four prior lines of treatment, including an IMiD, a Pl and an anti-CD38 monoclonal antibody.® The biologic license application for cilta-cel was submitted December 21, 2020. ©Institute for Clinical and Economic Review, 2021 Page 2 Final Report - Multiple Myeloma Return to Table of Contents 2. Patient and Caregiver Perspectives ICER engaged with patients with MM (including those treated with anti-BCMA medications), representatives from advocacy organizations, and clinical experts to understand the patient perspective of living with MM. We also spoke with two patient advocacy groups who helped us identify patients who could speak to their experiences. We spoke with five patients over five calls. Finally, we also conducted a focus group with four patients, where we heard in depth about their lived experiences. Additional details, including the semi-structured interview guide and questions, are available in the Supplement. Additional details of the patient perspective from a survey of myeloma patients from the Cancer Support Community is available in the Supplement Section B. Patients spoke about the importance of quality of life beyond survival. One patient noted, "l don't want to lie in my bed. | want to meet with friends, go places." In addition, patients mentioned the negative impact of being continually tethered to the health care system. Another patient mentioned, "it's a burden to wake up early, go to the hospital, wait (there's always a delay), then get infused, and not get back home [until after dark]." A second patient summarized, "Visiting the doctor every week or two gets old." Thus, patients reported wanting low side effect treatments that would not require frequent returns to the clinic or hospital. One of the most frequent side effects that patients mentioned was fatigue and weakness. Seventy percent of patients in the Cancer Support Community's (CSC) Myeloma registry reported fatigue within the past week. While some spoke of fatigue as a symptom of poorly controlled MM, for others, it was clearly a side effect of treatment. One patient mentioned, "The fatigue is bad-I find it more on POM [pomalidomide]. | have to take a break from cutting veggies." Others noted, "The weakness is the worst thing...it interferes with your ability to exercise and take care of yourself." Patients also mentioned the impact their disease had on their loved ones and caregivers. One patient mentioned, "My wife was greatly impacted. | couldn't do the grocery shopping anymore and | had to sleep in an office chair because of the pain." One patient mentioned that the irritability caused by dexamethasone led to "a temporary estrangement with my spouse because of my short temper." Thus, MM and its treatments have profound effects on families and caregivers as well as the patients. Several patients reported tremendous financial strain due to MM treatments. One patient stated, "My drugs were about $250,000 a year. That first year | went into debt and had to refinance my home. | was 3 years from paying off my house and | had to start over." Another patient noted, "on top of being filled with cancer, you have to deal with all of these bills." Clinicians noted, "We still see cases where patients decline to take their drugs because the out-of-pocket expenses are so high that they'd have to choose between meds and food/housing." Data from the Cancer Support Community's Multiple Myeloma Specialty Registry indicate that nearly two-thirds of MM patients ©Ilnstitute for Clinical and Economic Review, 2021 Page 3 Final Report - Multiple Myeloma Return to Table of Contents are concerned about the cost of their cancer care and 42% are often or always upset about the cost of their myeloma care. Patients and clinicians mentioned that African American MM patients face additional barriers to effective treatment. One patient noted, "there's a mistrust of medical community [in the African American community] and is a real thing, and not as much awareness and understanding of MM. [African Americans] are wary in participating in trials and refuse stem cell transplant when its offered." A patient advocacy group mentioned, "navigating newer therapies can be like a maze...African Americans and patients with lower socioeconomic status are more like to get lost in that maze." These comments suggest that newer treatments must proactively engage with historically disadvantaged populations; otherwise, these treatments, because of their complexity, may worsen disparities. We spoke with 2 patients who had received CAR T-cell therapies as part of a clinical trial. Both patients described the infusion and subsequent hospitalization as relatively easy ("a piece of cake") but long and monotonous. One patient described CAR-T therapies as "very liberating", since his doctors did not feel like he needed maintenance medications after CAR-T therapies. Thus, the frequency of doctors' visits and laboratory tests have decreased, and he noted, "if it wasn't for COVID [l could] travel to New York or Italy." A second CAR-T therapy patient had a different experience, since he required continued maintenance medications after CAR-T therapy. We also solicited responses from patients who were considering or had been treated with belantamab, but did not receive any replies. We spoke with several patients who were considering CAR T-cell therapies. One patient stated, "I'm afraid of CAR-T." When asked what she was afraid of, she talked about how intensive it sounded and that it "only lasts for about a year." A second patient was more interested in CAR-T therapy, stating that he is currently responding to treatment, but that he would consider it for a future line of therapy. Even a patient who had undergone CAR-T therapy stated that he did so because he felt he had no other options. All patients spoke about the importance of having CAR-T therapy as an option saying, "At some point, we're all going to need this because all combinations eventually seem to stop working." CAR-T therapies appear to be primarily coordinated in larger cancer centers; this was a key consideration for patients, since it would require more frequent, longer drives to doctors' appointments. Our conversations with patients informed our review by reinforcing the importance of specific symptoms including fatigue and weakness. In addition, patient perspectives helped focus our review on the side effects of both current treatments as well as the side effects of the new interventions. Finally, all these issues reinforced the importance of considering health-related quality of life as a primary outcome for our review. ©Ilnstitute for Clinical and Economic Review, 2021 Page 4 Final Report - Multiple Myeloma Return to Table of Contents 3. Comparative Clinical Effectiveness 3.1. Methods Overview Procedures for the systematic review assessing the evidence on ide-cel, cilta-cel, and belantamab for heavily pre-treated relapsed and refractory multiple myeloma are described in the Detailed Methods section of the Report Supplement. Scope of Review This review compares the clinical effectiveness of ide-cel and cilta-cel for the treatment of adults with TCRMM (majority with triple- or quad-refractory disease) who have received at least three prior lines of therapy, as well as belantamab for adults with triple-, quad- or penta-refractory multiple myeloma who have received at least four prior lines of therapy in comparison with usual care (i.e., commonly used regimens for those exposed to 23 and 24 prior lines of therapy respectively). The primary patient-important outcomes included OS, PFS, ORR, and health-related quality of life (HRQoL). The full scope of the review is detailed in the Data Sources and Searches section of the Report Supplement. Evidence Base The clinical evidence is summarized qualitatively for each intervention separately because the key trials were all single arm studies, so quantitative comparisons were not possible. Details of key studies are described below and summarized in Table 3.1. Ide-cel A total of 12 references relating to two single-arm (one Phase |, one Phase Il), open label trials of ide-cel met our inclusion criteria. Data from both trials were obtained from publications, conference abstracts, press releases, and information provided by the manufacturers (Table 3.1). In this report, we will report on the Phase Il trial (KarMMa), but additional details of both trials are included in the Additional Clinical Evidence section of the Report Supplement. KarMMa The KarMMa trial is an ongoing Phase Il multi-center, open-label, single-arm trial being conducted at 24 locations worldwide, including North America, Europe, and Japan.%!! The trial screened 158 adults who had previously been exposed to an immunomodulatory drug (IMiD), a proteasome inhibitor (P1), an anti-CD38 antibody, and were refractory to the last prior therapy and enrolled 149 patients.!? 140 patients underwent leukapheresis and most (88%) received bridging therapy during the manufacturing process, before lymphodepletion with fludarabine and cyclophosphamide five ©Institute for Clinical and Economic Review, 2021 Page 5 Final Report - Multiple Myeloma Return to Table of Contents days prior to infusion (a total of 128 patients, or 86% of the enrolled population, were analyzed). Retreatment with ide-cel was allowed among those who had a recurrence. The primary outcome was ORR. Secondary outcomes were complete response (CR), safety, duration of response (DoR), PFS, OS, pharmacokinetics, and HRQoL (Table 3.1). Cilta-cel A total of 10 references relating to two open-label, single arm trials (one Phase | and one Phase Ib/11) of cilta-cel met our inclusion criteria. At the time of this report, only results from selected sites from the Phase | trial (LEGEND-2) had been published.!® Data from both trials were therefore obtained from a combination of publications, conference abstracts, and press releases (Table 3.1). In this report, we focus attention on the Phase Ib/Il trial (CARTITUDE-1), but additional details of both trials are included in the Additional Clinical Evidence section of the Report Supplement. CARTITUDE-1 CARTITUDE-1 is an ongoing Phase Ib/Il single-arm trial of cilta-cel being conducted in 21 sites in the United States and Japan.'*'> The trial enrolled 126 adults with TCRMM who had progressive disease after at least three prior therapies (including a PI, an IMiD, and anti-CD38 antibody), who are double refractory to an IMiD and P1.1® A total of 113 patients underwent leukapheresis (90% of the enrolled population), 101 underwent lymphodepletion with fludarabine and cyclophosphamide five days prior to infusion (80%), and 97 patients (77% of the enrolled population) were included in the analysis. The primary outcomes were adverse events (AEs) and ORR. Secondary outcomes were 0S, PFS, and minimal residual disease (MRD) (Table 3.1). Belantamab A total of eight references pertaining to one open-label Phase Il clinical trial (DREAMM-2), one conference abstract relating to a pooled post-hoc analysis, and one conference abstract relating to an expanded access program met our inclusion criteria. At the time of this report, two published manuscripts were available for the DREAMM-2 trial,'"-1® which were supplemented with conference abstracts and information provided by the manufacturer. Additional details are available in the Supplement. DREAMM-2 DREAMM-2 is an ongoing Phase I, open-label, global, multicenter trial comparing the efficacy and safety of two doses of belantamab (2.5 mg/kg and 3.4 mg/kg) in adults with TCRMM.Y? In total, 196 patients (97 in the 2.5 mg/arm and 99 in the 3.4 mg/kg arm) who had been treated with at least three prior lines of treatment and who were refractory to an IMiD, a Pl, and refractory to and/or were not able to tolerate an anti-CD38 monoclonal antibody were enrolled in the trial.?" At the time of this report, information on the proportion of patients who are classified as penta-refractory was ©Ilnstitute for Clinical and Economic Review, 2021 Page 6 Final Report - Multiple Myeloma Return to Table of Contents not publicly available (submitted as academic in confidence). In August 2020, the FDA granted accelerated approval to belantamab for the treatment of patients with RRMM with progressive disease after having been treated with four prior lines of therapy. For the purpose of this review, we only present data for the FDA approved dose of 2.5 mg/kg (N=97). The primary outcome assessed was ORR, and secondary outcomes assessed included DoR, time to response, PFS, 0S, and safety. All patients who received at least one dose of belantamab were included in the evaluation of efficacy outcomes (ITT population, N=97). See Supplement for detailed inclusion and exclusion criteria, and definitions of measurable disease and outcomes reported. Table 3.1. Overview of Key Studies of Ide-cel, Cilta-cel, and Belantamab -Received allogeneic SCT - Current corneal epithelial disease Intervention & Trial Inclusion/Exclusion Criteria Outcomes Baseline Characteristics* Ide-cel Inclusion: Primary: - Age, median (range): 61 -Received at least 2 cycles of 23 ORR (33-78) KarMMalL12 prior treatment regimens (incl. P, - Prior lines of therapy, Phase II, open-label single- | IMiD, anti-CD38 antibody) and Secondary: | median (range): 6 (3-16) arm refractory to last regimen CR, OS, - Triple-refractory: 84% PFS, AEs, - Penta-refractory: 26% N=149" Exclusion: HRQoL -EMD: 39% - Previous allogeneic SCT - High-risk cytogenetics: 35% Cilta-cel Inclusion: Primary: - Age, median (range): 61 - Received 23 prior treatment AEs, ORR (43-78) CARTITUDE-161? regimens (incl. PI, IMiD, anti-CD38 - Prior lines of therapy, Phase II, open-label single- | antibody) or are double refractory | Secondary: | median (range): 6 (3-18) arm to a Pl and IMiD OS, PFS, - Triple-refractory: 88% MRD - Penta-refractory: 42% N=126" Exclusion: -EMD: 13% - Allogeneic SCT within 6 months or - High-risk cytogenetics: 23% autologous SCT within 4 months Belantamab Inclusion: Primary: - Age, median (IQR): 65.0 -Received 23 previous lines of ORR (60.0-70.0) DREAMM-2Y7 treatments - Prior lines of therapy, Phase Il, open-label, two- | -Refractory to IMiD and PI, and Secondary: | median (range): 7 (3-21) arm refractory/intolerant to an anti- DoR, time | -Triple-refractory: 100% CD38 therapy to - Penta-refractory: 42% N=97* response, | _ EMD: 23% Exclusion: PFS, AEs - High-risk cytogenetics: 42% AEs: Adverse events, CR: Complete response, DoR: Duration of response, EMD: Extramedullary disease, HRQoL: Health-related quality of life, IQR: interquartile range, MRD: Minimal residual disease, N: total number, ORR: Overall response rate, OS: Overall survival, PFS: Progression free survival, SCT: stem cell transplant. *2.5 mg/kg arm only. + Sample sizes are based on the intention-to-treat population ¥ Baseline characteristics from KarMMa and CARTITUDE-1 are based on the as-treated population OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 7 Return to Table of Contents Usual Care Our systematic literature review did not reveal any prospective studies evaluating the effectiveness of usual care (defined as commonly-used combination regimens described in our research protocol (https://osf.io/3dtr4/) in triple-class refractory patients. The most relevant evidence to support the clinical effectiveness of usual care for triple-class refractory patients to compare with CAR T-cell treatments came from a retrospective observational study (Table 3.2)." The MAMMOTH study was a multi-center US-based retrospective analysis of 275 multiple myeloma patients (data were collected between January 2017 and June 2018), of whom 218 were refractory to at least three lines of therapy (PI, IMiD, and anti-CD38 monoclonal antibody)." 70 (25%) were "penta-refractory" (refractory to two Pls, two IMiDs, and an anti-CD38 monoclonal antibody). Primary outcomes were OS, PFS, and ORR. Two additional retrospective studies were identified and are described in the Additional Clinical Evidence Section of the Report Supplement. Table 3.2. Overview of MAMMOTH Study Study Inclusion/Exclusion Criteria Outcomes Patient Characteristics MAMMOTH? Inclusion: Primary: - Age, median (range): 65 (27-90) Retrospective chart -Refractoryto atleast 1PI,1 | OS, PFS, - Prior lines of therapy, median review IMiD, and 1 anti-CD38 ORR (range): 4 (1-16) N=275 (54% triple/ - Triple- and quad-refractory: 75% quad-refractory, 25% Exclusion: NR - Penta-refractory: 25% penta-refractory) - High-risk cytogenetics: 29% IMiD: Immunomodulatory drug, N: total number, NR: not reported, Pl: Proteasome inhibitor, ORR: Overall response rate, OS: Overall survival, PFS: Progression free survival Key Differences Across Studies See the Report Supplement Table D3.2 for details on baseline characteristics of the key trials of the interventions. Key differences are summarized below. Although the study participants in KarMMa and CARTITUDE-1 were of similar ages (median age 61 in both) and had received a similar amount of pre-treatment {median of 6 prior lines of therapy), patients in the CARTITUDE-1 trial were more likely to be penta-refractory than patients in the KarMMa trial (42% vs 26%), but less likely to have extramedullary disease (EMD, the presence of plasma cells outside the bone marrow, a marker of more aggressive disease) (13% vs 39%), and high-risk cytogenetics (23.7% vs 35.2%).1%%° In KarMMa, 28 patients (22% of the treated population) were retreated with ide-cel after disease progression. At the time of this report, retreatment was not reported in CARTITUDE-1. In DREAMM-2, the patients undergoing treatment with belantamab were typically older {median age 65), had undergone more pre-treatment {(median of seven prior lines of therapy), and were more likely to have high-risk cytogenetics (42.3%);'" the percentage of penta-refractory patients was provided to us as academic in confidence (42%). ©Institute for Clinical and Economic Review, 2021 Page 8 Final Report - Multiple Myeloma Return to Table of Contents A key difference between the pivotal CAR-T therapy trials and DREAMM-2 was the approach for inclusion in the outcomes analysis. KarMMa and CARTITUDE-1 both only included patients who were infused in the analysis (86% and 77% of enrolled and 91% and 86% of leukapheresed patients, respectively) in an as-treated approach, whereas DREAMM-2 reports on the full intention-to-treat (ITT) population. The study populations in MAMMOTH were of similar age (median 60 years) to those in KarMMa and CARTITUDE-1 (median 61 years), but appeared to have received less pre-treatment overall (median of four prior lines of therapy versus six or seven)." For this reason, we report the outcomes for triple and quad-penta-refractory patients separately. Furthermore, the exclusion criteria for MAMMOTH were not reported, making it difficult to interpret differences in study populations relative to the key studies of the interventions. See the Report Supplement Table D3.19 for details on baseline characteristics of the studies of usual care. 3.2. Results Clinical Benefits The primary outcomes that are used in the economic model are PFS and OS as defined in the clinical trials. The key clinical benefits of ide-cel are described first, followed by cilta-cel and belantamab. Additional outcomes are described in the Report Supplement. Ide-cel In the KarMMa trial, with a median follow-up time of 13.3 months (range 0.2-21.2 months) the as- treated median PFS across all target CAR-T therapy doses was 8.8 months, and the as-treated median OS was 19.4 months. Twelve-month as-treated OS and PFS was 78% and 38%, respectively. 11 The as-treated median PFS varied by dose, with the highest dose (450x10° CAR-T cells) achieving the longest median PFS (12.1 months). The as-treated ORR was 73% (94 out of 128 infused patients) and the as-treated stringent complete or complete response rate (sCR or CR) was 33% (42 out of 128) across all doses. The reported outcomes from KarMMa likely represents an optimistic estimate of the results since they are based on patients who received infusion of CAR-T cells, excluding patients who did not receive the therapy due to death prior to infusion, disease progression, or AEs. When calculated on an ITT (that is, including all enrolled patients, including those who were enrolled, leukapheresed but not infused), however, ORR was 63% (94 out of 149 enrolled patients) and sCR or CR was 28% (42 out of 149) (Table 3.3).1¢ 33 patients (26% of the treated population) had MRD-negative status. Importantly, 28 patients (22% of the treated population) were retreated with ide-cel after disease progression, a statistic that was not available until publication of the trial results. Limited data were ©lnstitute for Clinical and Economic Review, 2021 Page 9 Final Report - Multiple Myeloma Return to Table of Contents available on the characteristics of these patients and their associated outcomes; however, PFS in these patients was generally poor, with a median of one month following retreatment.! In the KarMMa trial, HRQoL was assessed using the EQ-5D, EORTC QLQ-C30, and MY20 scales (details on these cancer-specific instruments are available at https://qol.eortc.org/) prior to induction and at day one and nine months post-infusion with ide-cel. Physical functioning, fatigue, pain, and global health sub-scales all improved at nine months compared to baseline {(Table 3.4); however data on only 59 of 111 (53%) patients assessed at day one were available at nine months.?! More details on patient-reported outcomes for ide-cel are available in Table D3.10 of the Report Supplement. Cilta-cel At the time of this report, as-treated median PFS and OS were not reached with a median of 18 months of follow-up (range 1.5-30.5 months) in the CARTITUDE-1 trial. Eighteen-month as-treated 0S and PFS was 81% and 66%, respectively, a decline from 89% and 77% at 12 months. >2° Using an as-treated approach, ORR was 98% (95 out of 97 infused patients) and sCR was 80% (78 out of 97 infused patients had an sCR). However, in an ITT analysis, using the overall enrolled population, ORR was 75% (95 out of 126 enrolled patients) and sCR was 62% (78 out of 126) (Table 3.3).1° 56 patients (58% of the treated population) had MRD negative status. No data were available on whether any patients receiving cilta-cel required retreatment. More details on outcomes data for cilta-cel are available in Table D3.4 of the Report Supplement. In CARTITUDE-1 the EORTC QLQ-C30 was administered prior to induction and at various time points post-treatment. At the time of the report, only data on fatigue and pain sub-domains were available. At 184 days, both fatigue and pain scores improved relative to baseline (Table 3.4), however data were available for only 30 out of the 68 (44%) patients who were assessed at baseline.??2 More details on patient-reported outcomes for cilta-cel are available in Table D3.10 of the Report Supplement. Belantamab At the 13-month follow-up (data cut-off date: January 14 2020), patients treated with 2.5 mg/kg belantamab had a median PFS of 2.8 months and median OS of 13.7 months.?® Please refer to the Report Supplement for OS rates at three, six, nine, and 12 months. PFS rates at three to 12 months were submitted as academic in confidence (42.10%, 32.00%, 27.00%, 22.30%). Thirty-one out of 97 participants (32%) achieved an overall response, with five and two patients achieving CR and sCR, respectively. In DREAMM-2 HRQoL was assessed by means of the EORTC-QLQ-C30, EORTC-QLQ-MY20, and Ocular Surface Disease Index (OSDI) scales. Between weeks 0 to 25, patients' HRQoL was stable ©Institute for Clinical and Economic Review, 2021 Page 10 Final Report - Multiple Myeloma Return to Table of Contents across all domains (disease symptoms, pain, fatigue, role functional, physical functioning, global health status, social functioning, and future perspective). For the 25% of patients who responded to treatment and remained on treatment beyond 25 weeks, there was a trend toward improvement in some of these HRQoL domains.?* However, this trend toward improvement is only applicable to the small minority of patients who remain on therapy beyond 25 weeks. Additional data on HRQolL data for belantamab can be found in Table D3.10 of the Report Supplement. Table 3.3. Key Trial Results of Ide-cel, Cilta-cel, and Belantamab Median Follow-Up As-treated PFS, As-treated OS, ITTORR, n Intervention Trial (N) Duration Median Months | Median Months (%); (95% C1) (95% C1) [95% CI] Ide-cel KarMMat12 13.3 months® 8.8 (5.6, 11.6)% 19.4 (18.2, NE)® 94 (63.0); (N=149)* [NR] Cilta-cel CARTITUDE- 18 months$ Not reached at Not reached at 18 | 95 (75.0); 1151620 18 months?® months$ [NR] (N=126)* Belantamab | DREAMM-2Y/ 13 months 2.8(1.6,3.6)*F 13.7 (9.9, not 31(32.0); (N=97") reached)* [97.5%Cl: 21.7, 43.6] 95%Cl: 95% confidence interval, 97.5%Cl: 97.5% confidence interval, NE: not estimable, NR: not reported, n: number, ORR: Overall response rate, OS: Overall survival, PFS: progression free survival *2.5 mg/kg arm only ¥ Intention-to-treat § Median Follow-up duration, PFS and OS for KarMMa and CARTITUDE-1 are based on the as-treated population Table 3.4. Change from Baseline in Health-Related Quality of Life (Selected EORTC QLQ-C30* Sub- Domains) . . Physical . . Interv.entlon Tlme. from Functioning, Fatigue, Pain, Global Health, (Trial) Baseline (N) Mean (95% Cl) Mean (95% CI)t | Mean (95% CI)T | Mean (95% Cl) Ide-cel¥ 9 months 13.2 -22.8 -23.8 154 (KarMMa)* (N=59) (7.9, 17.9) (-29.1,-17.1) (-30.2,-18.3) (9.8, 20.9) Cilta-celt 6 months NR -9.2 -8.9 NR (CARTITUDE-1)?2 | (N=30) (-16.4, -2.0) (-17.6, -0.3) Belantamab # 6 months -0.1 3.6 2.6 -4.7 (DREAMM-2)2%25 | (N=19) (-5.3,5.3) (-7.6, 14.6) (-6.5, 11.4) (-12.1, 2.8) 95%Cl: 95% confidence interval, N: total number, NR: not reported, ORR: Overall response rate. *EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients tNegative changes indicate a reduction in pain or fatigue $Mean changes from baseline have been digitized and should be interpreted with caution OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 11 Return to Table of Contents Usual Care We identified three retrospective observational studies to inform our comparison of usual care to the interventions."?627 |n this report, we present outcomes from the MAMMOTH study because outcomes are available across various lines of therapy as well as on an overall basis." The majority of patients in the MAMMOTH study were refractory to daratumumab (93%), lenalidomide (77%), bortezomib (68%), and pomalidomide (65%) and a minority were refractory to carfilzomib (47%), ixazomib (12%), and thalidomide (8%). Median PFS was 3.4 months in the overall population but was not separately reported in the triple-quad and penta-refractory populations. Median OS was 9.3 months in the overall population, 9.2 months in the triple-quad population, and 5.6 months in the penta-refractory population. Overall response was 29-31% (Table 3.5). Additional details on the outcomes from MAMMOTH and the additional retrospective studies are provided in Tables D3.15 and D3.16 in the Report Supplement. Table 3.5. Key Results MAMMOTH Study . PFS, Median 0S, Median Study Population (N) Months, (95% CI) | Months (95%cl) | ORr %) MAMMOTH? Overall (N=275) 3.4 (2.8-4.0) 9.3"(8.1, 10.6) 85 (31.0)° Triple- and quad- NR 9.2(7.1, 11.2) 80 (29.0)° refractory (N=148) Penta-refractory (N=70) NR 5.6 (3.5, 7.8) 21 (30.0) 95%Cl: 95% confidence interval, N: total number, n: number, ORR: Overall response rate, OS: overall survival, PFS: progression-free survival. * ORR calculated based on first line of therapy. + PFS and OS on next line after To. Harms Harms of ide-cel, cilta-cel, and belantamab are presented based on the number of study participants who were actually infused/treated ("safety population"). Ide-cel In the KarMMa trial, cytokine release syndrome (CRS) was the most commonly-reported AE, reported by 84% of patients (48% Grade 1; 31% Grade 2) and lasting a median of 5 days.!* Of 107 patients who had CRS with or without neurotoxicity, 19 (17.8%) required intensive care unit admission.?® CRS was most likely to be managed with tocilizumab (52%), followed by corticosteroids (15%). Risk of CRS appeared to be dose-related, reported by 96% of patients in the 450x10° dose compared to 76% in the 300x10° dose. Patients in the 450x10° dose were also more likely to require tocilizumab to manage their CRS than patients in the 300x10° dose (67% vs 43%). Older patients were also more likely to experience CRS; all 20 patients 270 reported CRS across all doses. Other important AEs included neurotoxicity (18%), thrombocytopenia (63%), and ©Ilnstitute for Clinical and Economic Review, 2021 Page 12 Final Report - Multiple Myeloma Return to Table of Contents neutropenia (91%) (Table 3.6). Forty-four (34%) patients died during the study, with 27 (21%) due to progressive disease. Three deaths (2%) were treatment-related AEs within 8 weeks of infusion (CRS, pneumonia, gastrointestinal hemorrhage). An additional treatment-related death from pneumonia was reported within 6 months of infusion.? More information on harms of ide-cel are available in Table D3.11 of the Report Supplement. Cilta-cel In CARTITUDE-1, 95% of patients reported CRS, with most 95% experiencing low to moderate CRS (51% Grade 1 and 39% Grade 2).2° Median time to onset of CRS was seven days (range 1-12) and lasted a median of four days (range 1-97). CRS was most likely to be managed with tocilizumab (69%), followed by corticosteroids (22%) and anakinra (19%). Other important AEs included neurotoxicity (21%), thrombocytopenia (79%), and neutropenia (96%) (Table 3.6). A total of 14 deaths (14.4%) were reported during the study, five due to progressive disease, three due to AEs unrelated to treatment (pneumonia and other cancers), and six due to AEs related to treatment (sepsis, CRS, lung abscess, respiratory failure, neurotoxicity).? More information on harms of cilta- cel are available in Table D3.12 of the Report Supplement. Belantamab In DREAMM-2, AEs were reported by 97.9% of patients treated with belantamab 2.5 mg/g (N=95).% The vast majority of AEs were considered to be related to the study treatment (88.4%). Three patients (3.2%) died during the study due to AEs {(myocardial infarction (n=2), sepsis {n=1)}, with one death being treatment related (sepsis).?> At 6.3 months of follow-up, over three-quarters of the enrolled participants had discontinued study treatment, mainly due to disease progression or death (60.8% and 32.6%, respectively).!" Nine patients (10%) discontinued study treatment due to AEs (one due to keratopathy and one due to blurred vision).?® AEs frequently led to dosing modifications, with over half (54%) experiencing dose delays and over a third (35%) requiring dose reductions. Keratopathy, defined as changes to the corneal epithelium, was reported by 72% of patients; however at 13 months follow-up, 77% had recovered from their first, and 48% from their last corneal event.''"'8 Forty-six percent of patients experienced a moderate decline in vision (Grade 2 toxicity, Best Corrected Visual Acuity), which resolved in most patients at the end of study follow-up. A decline in vision in their better-seeing eye to 20/50 or worse was reported by 18% of patients. The majority, 82%, recovered (improved to 20/40 or better) by the end of the follow-up period. No patients reported permanent vision loss. More information on harms of belantamab are available in Table D3.13 of the Report Supplement. ©Institute for Clinical and Economic Review, 2021 Page 13 Final Report - Multiple Myeloma Return to Table of Contents Table 3.6. Key Harms of Ide-cel, Cilta-cel, and Belantamab Overall Mortality at Intervention Trial (N) Treatment- Important AEs D/C due to Median related SAEs AEs Follow-Up Time Ide-cel KarMMa?! 3.1% - CRS: 84% NR 34% at 13.3 (N=128) - NT: 18% months - Thrombocytopenia: 63% (range 0.2- 21.2) Cilta-cel CARTITUDE- NR - CRS: 95% NR 14% at 12.4 1% -NT: 21% months (N=97) - Thrombocytopenia: 79% (range 1.5- 24.9) Belantamab DREAMM- 11.6% - CRS: 0% 10% 33% at 6.3 21723 -NT: 0% months (IQR (N=95)" - Thrombocytopenia: 38% 3.7-1.7) - Moderate decline in vision in more affected eye (BCVA Grade 2+): 46% - Meaningful decline in vision (20/50 or worse in better eye): 18% AE: adverse event, CRS: cytokine release syndrome, D/C: discontinuation, N: total number, NT: neurotoxicity, SAE: serious adverse event, BCVA: Best Corrected Visual Acuity, IQR: interquartile range * Xi'an site only. T safety population (2.5 mg/kg). Usual Care The retrospective observational studies we selected to represent the effectiveness of usual care did not provide sufficient or consistent information on the harms of the treatment regimens. Therefore, we selected representative prospective trials of commonly used treatments for TCRMM (Elo-Pom-Dex: elotuzumab-pomalidomide-dexamethasone, Car-Cy-Dex: carfilzomib- cyclophosphamide-dexamethasone, Ixa-Len-Dex: ixazomib-lenalidomide-dexamethasone).?%-3! Serious AEs were common, reported by roughly half of the participants. The most commonly reported grade 3 or 4 AEs included neutropenia, anemia, infection, and thrombocytopenia. Discontinuation rates due to AEs varied from 14 to 18% (Table 3.7). Differences in harms between these regimens and that of the interventions should be interpreted with caution, however, as the trials were generally conducted in less heavily pre-treated populations. OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 14 Return to Table of Contents Table 3.7. Harms of Selected Commonly-Used Usual Care Regimens . . Important Grade 3/4 Discontinuation Treatment Trial (N) Serious AEs P AEs / Deaths (all) Due to AEs Elo-Pom-Dex | ELOQUENT-33 53% -Neutropenia: 13% | 22% 18% (N=60) - Anemia: 10% - Infection: 13% Car-Cy-Dex Bringhen 2014%° NR - Neutropenia: 20% | 13% 14% (N=56) -Anemia: 11% -Infection: 5% Ixa-Len-Dex TOURMALINE-MM1% | 46.5% -Neutropenia: 22% | 4% 17% (N=361) - Anemia: 9% -Infection: <1% AE: adverse events, Car: carfilzomib, Cy: cyclophosphamide, Dex: dexamethasone, Elo: elotuzumab, Ixa: Ixazomib, Len: lenalidomide, n: number, N: total number, Pom: pomalidomide. Subgroup Analyses and Heterogeneity Data on efficacy outcomes by subgroups of patients (such as by age, high risk cytogenetics, race/ethnicity, etc.) were not consistently reported. In the KarMMa trial, as-treated median PFS for ide-cel was 8.6 months for patients 65 years or older {n=45) and 10.2 months for 70 or older (n=20), compared to 8.8 months for the overall population.3? As-treated median PFS for the 50 patients in the KarMMa trial who had EMD was 7.9 months, and for the 45 patients with high cytogenetic risk was 8.2 months.3® At the time of this report, efficacy data by subgroups was not available for the CARTITUDE-1 trial. In DREAMM-2, ITT median PFS for belantamab was 2.9 months for patients who had previously been unsuccessfully treated with three to six therapies and 2.2 months for those who had received seven lines of treatment or more.3* ITT median PFS for patients with high cytogenetic risk factors was 2.1 months.3> For those with mild to moderate renal impairment, ITT median PFS was 2.2 and 3.7 months, respectively.3® At 6.3 months of follow up, 43.6% of patients aged 65 to < 75 years achieved an overall response, while only one patient (7.7%) in the age group 75 and above achieved an overall response. 31.6% of White, and 37.5% of Black patients achieved an overall response at 6.3 months of follow-up. ORR at 13 months of follow-up was submitted to ICER as academic in confidence (34.2% (95% Cl: 23.7-46.0) for white patients and 31.3% (95% Cl: 11.0-58.7 for Black patients). Similar to other studies, substantially fewer Black patients were enrolled in this study compared to White patients (16 and 72 patients, respectively).'' Uncertainty and Controversies Several important uncertainties remain in our evaluation of CAR T-cell therapies. First, 9% of the ide-cel patients who were leukapheresed did not receive treatment (14% for cilta-cel) and were not included in the published ORR and PFS estimates. Since manufacturing failures (i.e., inability to OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 15 Return to Table of Contents successfully encode the patients' T-cells) are now rare, most patients who were enrolled but not able to receive treatment likely had more severe or more aggressive disease. Thus, it is likely that accounting for these patients would diminish the benefits seen with ide-cel and cilta-cel; future studies should publish an ITT analysis incorporating these patients. Our calculated ITT analysis decreased the ORR from 73% to 63% for KarMMa and from 98% to 75% for CARTITUDE-1. Second, additional follow-up data are needed for ide-cel and cilta-cel to quantify the median PFS and OS; outcomes data are particularly limited for cilta-cel, as no comprehensive presentations or peer- reviewed publications are available, and the manufacturer did not respond to requests for additional data. Longer-term data may also allow us to definitively determine whether a small minority of patients are able to achieve a long-term, durable response, and to understand whether retreatment with CAR-T therapy might be necessary in others. Third, additional information is needed regarding the specific nature and potential causes of cilta-cel treatment-related deaths (6% in CARTITUDE-1). Fourth, while there is interest in utilizing CAR T-cell therapies earlier in the MM disease course, studies are needed to determine whether these therapies are superior to current therapies for first or second relapse of MM. Uncertainties also remain in our evaluation of belantamab. First, additional studies should examine the median OS with belantamab. Across 22 RCTs in relapsed and refractory patients MM, a meta- analysis found that the ratio between PFS and OS was approximately 3.137; previous meta-analyses have generated comparable results.®® However, in the pivotal DREAMM-2 study, the 2.5mg/kg arm had a median PFS of 2.8 months and a median OS of 13.7 months, for a 4.9 ratio. While it is possible that the OS/PFS ratio would differ substantially for belantamab compared to all other treatments for MM, further studies are needed to confirm or refute the current OS/PFS ratio seen for belantamab. Second, while belantamab was approved as a single-agent treatment, other MM treatments are most effective as doublet or triplet therapies. We await the results of ongoing studies combining belantamab with other treatments to determine whether belantamab would be helpful as a component of novel combination therapies. Lastly, more research is needed to determine a treatment approach best suited for the management of keratopathy, and ultimately to reduce the burden of ocular toxicities on patients, improve patient outcomes and reduce the need for dose adjustments or treatment discontinuation.® ©Institute for Clinical and Economic Review, 2021 Page 16 Final Report - Multiple Myeloma Return to Table of Contents 3.3. Summary and Comment An explanation of the ICER Evidence Rating Matrix (Figure 3.1) is provided in the Supplement. Figure 3.1. ICER Evidence Rating Matrix Level of Certainty in the Evidence Certainty Moderate Certainty Certainty Comparative Clinical Effectiveness High Low Negative Comparable Small Substantial Net Benefit Net Benefit Net Benefit Net Benefit Comparative Net Health Benefit A = "Superior" - High certainty of a substantial (moderate-large) net health benefit B = "Incremental" - High certainty of a small net health benefit C = "Comparable"- High certainty of a comparable net health benefit D= "Negative"- High certainty of an inferior net health benefit B+= "Incremental or Better" - Moderate certainty of a small or substantial net health benefit, with high certainty of at least a small net health benefit C+ = "Comparable or Incremental" - Moderate certainty of a comparable or small net health benefit, with high certainty of at least a comparable net health benefit C- = "Comparable or Inferior" - Moderate certainty that the net health benefit is either comparable or inferior with high certainty of at best a comparable net health benefit C++ = "Comparable or Better" - Moderate certainty of a comparable, small, or substantial net health benefit, with high certainty of at least a comparable net health benefit P/I = "Promising but Inconclusive" - Moderate certainty of a small or substantial net health benefit, small likelihood of a negative net health benefit = "Insufficient" - Any situation in which the level of certainty in the evidence is low ©lnstitute for Clinical and Economic Review, 2021 Page 17 Final Report - Multiple Myeloma Return to Table of Contents Our systematic review of the evidence suggests that CAR T-cell therapies for patients with triple-or quad- refractory MM likely provides small to substantial net health benefits over current usual care. Benefits included longer survival as well as improved quality of life. Counterbalancing these benefits were the harms, including CRS, which is temporary but often requires hospitalization and intensive care unit level care. Our systematic review of cilta-cel and ide-cel suggests that the evidence is insufficient to determine whether one agent is superior to the other. There are no studies comparing these agents directly, nor sufficient data to perform quantitative indirect comparisons. We conclude that belantamab is promising but inconclusive compared to usual care for patients with triple-, quad- and penta- refractory MM exposed to 4+ prior lines of treatment. The ORR and OS suggests a possible small net benefit. However, the frequency and severity of visual impairment and lack of demonstrated improvement in HRQolL suggests that any net benefits are likely to be modest. The current evidence precludes a substantial benefit; additional data is required to preclude small overall net harm. Table 3.8. Evidence Ratings Treatment | Comparator Evidence Rating Triple- or quad- refractory MM (3+ prior lines of treatment) Ide-cel Usual Care B+ Cilta-cel Usual Care B+ Ide-cel Cilta-cel I Triple-, quad- or penta- refractory MM (4+ prior lines of treatment) Belantamab | Usual Care | P/1 MM: multiple myeloma ©Ilnstitute for Clinical and Economic Review, 2021 Page 18 Final Report - Multiple Myeloma Return to Table of Contents 4. Long-Term Cost-Effectiveness 4.1. Methods Overview The primary aim of this section of the review was to assess the lifetime cost-effectiveness of ide-cel, cilta-cel, and belantamab as compared to relevant comparator treatments. We developed a de novo decision analytic model for this evaluation, informed by key clinical trials and prior relevant economic models.3%40 Specific to CAR-T therapies, an initial decision tree was used to calculate the costs and consequences from treatment initiation (i.e., leukapheresis) to T-cell infusion. We note this differs somewhat from our reporting of "intent to treat" results based on all enrolled trial patients, but better fits the purpose of the model, which is to reflect costs and outcomes following the initiation of the CAR-T therapy process. The decision tree included patients who were eligible for CAR-T therapy and who had undergone leukapheresis. After initiating leukapheresis, patients could continue to receive the infusion of the engineered T-cells; discontinue (before infusion but after leukapheresis) because of disease progression, adverse events, or manufacturing failures; or die before receiving the infusion. Those who discontinued prior to T-cell infusion received the costs, benefits, and risks of the market basket of triple- or quad-refractory comparators. The cohort of patients were assigned to three mutually exclusive and exhaustive health states in a partitioned survival model (Figure 4.1). Health states included 1) alive and progression free or responding to therapy, 2) alive and not responding to therapy/subsequent relapse, and 3) dead from multiple myeloma-related complications or other causes. We accounted for on/off therapy through application of differential utilities within a health state. At the end of each cycle, patients in the alive and progression free or responding to therapy health states did not transition treatments. Those in the alive and not responding to therapy/subsequent relapse health state transitioned to a progressed state that included a market basket of subsequent therapies. Patients remained in the model until they died. Health state occupancy was derived using partitioned survival techniques that included the direct extrapolation of progression-free survival (PFS) and overall survival (OS) Kaplan-Meier curves. A detailed description of curve digitization is available in Supplement Section E2. Model outcomes included total life years {LYs) gained, quality-adjusted life years (QALYs) gained, equal-value life years gained (evLYG), time progression free/responding to treatment, and total costs for each intervention over a lifetime time horizon discounted at 3% per annum. Supplement Table E.3.1-E.3.3 present undiscounted results. ©Ilnstitute for Clinical and Economic Review, 2021 Page 19 Final Report - Multiple Myeloma Return to Table of Contents Figure 4.1. Model Structure Idecabtagene vicleucel* -a Triple- or quad-refractory regimens Alive and Responding to Treatment Ciltacabtagene autoleucel* e T N Triple- or quad-refractory regimens Alive and not Responding to Treatment Belantamab - -0 ~_ Triple-, quad- or penta- refractory regimens *Includes up-front decision tree to account for patient disposition from leukapheresis and through CAR-T infusion. Target Population The model focused on an intention-to-treat analysis, with a hypothetical cohort of heavily pre- treated patients with MM beginning at age 60. The CAR-T trials' enrollment criteria required patients to have been treated with at least 3 previous lines of therapy. However, enrolled patients had received a median of 6 previous lines of therapy and were 84% - 88% TCRMM. For belantamab, 100% were at least triple class-refractory and enrolled patients had received a median of 7 previous lines of therapy. Cohort characteristics for each treatment group are described in Supplemental Table E.1.2 and E.1.3. Treatment Strategies Interventions The list of interventions was developed with input from patient organizations, clinicians, manufacturers, and payers on which treatments to include. The full list of interventions is as follows: e Idecabtagene vicleucel (Abecma®, Bristol Myers Squibb, bluebird bio, Inc.) e Ciltacabtagene autoleucel (Janssen, Legend Biotech) e Belantamab mafodotin-bimf (Blenrep®, GlaxoSmithKline) ©Institute for Clinical and Economic Review, 2021 Page 20 Final Report - Multiple Myeloma Return to Table of Contents Comparator Treatments Given the numerous available therapies used by clinicians at various lines of therapy, a market basket approach was used to compare to each intervention based on level of pretreatment using the MAMMOTH study and a recent conference proceeding that estimated the distribution of treatments by line of therapy."?" The market basket composition was approximated by both broad- therapy and specific-therapy estimations. PFS and OS curves were either directly informed by the MAMMOTH study or derived as described in the model structure section." Supplement Tables E.2.3 and E.2.4 provide dosing, administration schedules, and unit costs for each market basket of comparators. 4.2. Key Model Assumptions and Inputs Our model includes several key assumptions described in Table 4.1. Table 4.1. Key Model Assumptions Assumption Rationale For CAR-T therapies, patients received at least one full single course of therapy. A proportion of patients were re-treated and assigned the full costs associated with CAR-T, including infusion and other resource utilization. A proportion of patients in the KarMMa trial were re- treated and we assume the cost of re-treatment would be incurred for the infusion and other resources during and after infusion. In the absence of data from CARTITUDE-1 on retreatment, we assumed the same percentage across CAR-Ts and tested this in a scenario analysis. Subsequent treatments received after progression are uniform within each population/line of therapy. Patients progressing but still alive are assumed to receive subsequent therapy consistent with the line of therapy by population. Parametric curve functions were fit separately for each population/treatment and used to extrapolate the data over a lifetime horizon. Given different populations and lines of treatment, an indirect treatment comparison with the same baseline comparator across populations/treatments was not feasible. Recent observational evidence on patients using a mix of therapies was used to estimate PFS and OS of relevant comparators. There is wide variation in therapies used by line of therapy; we used a population with a mix of the most recently used therapies to reflect survival under conditions of current practice in RRMM. In cases with immature survival data, calibration methods were used to adjust the relationship between PFS and OS based on prior evidence in multiple myeloma. In some cases, OS data were immature and to calculate health outcomes, we used calibration methods to adjust relationships between PFS and OS. Patients who discontinue CAR-T therapy due to an AE, or manufacturing failure before receiving the T- cell infusion received comparator treatment benefits, risks, and costs; those who died were accounted for prior to CAR-T infusion. Patients with MM often receive some level of therapy or intervention until death and therefore patients that discontinued received a market basket of subsequent therapies consistent between each arm of the model. OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 21 Return to Table of Contents The model included only grade 3/4 adverse Less severe adverse events are not expected to events and specific toxicities as well as all grades significantly impact patient health outcomes or costs, of cytokine release syndrome. although there is evidence to suggest an impact of cytokine release syndrome and keratopathy on outcomes and cost across all grades. 95%Cl: 95% confidence interval, CAR-T: chimeric antigen receptor T-cell, MM: multiple myeloma, OS: overall survival, PFS: progression-free survival Model inputs were estimated from the clinical review, published literature, and information from expert stakeholders. Model inputs included PFS, OS, occurrence of adverse events, quality-of-life utility values, and health care costs. We note that data on PFS are extremely limited for cilta-cel; we used reported data for PFS from CARTITUDE-1 and used prior estimates of the relationship between PFS and OS to estimate the median OS. Probabilities, costs, and other inputs differed between treatments to reflect varying effectiveness between interventions. Health state utility values were consistent across interventions within the same disease, although different utilities were applied for patients in the progression-free state depending on whether they were on or off therapy. Key model inputs are described in Tables 4.2 and 4.3 for interventions in the triple- or quad-refractory population and for interventions in the triple-, quad-, or penta-refractory population, respectively. ©Ilnstitute for Clinical and Economic Review, 2021 Page 22 Final Report - Multiple Myeloma Return to Table of Contents Table 4.2. Key Model Inputs for Population with Triple- or Quad-Refractory MM (3+ prior lines of treatment) CAR-T Parameter Ide-Cel Cilta-Cel Comparator Market Basket Progression-Free Survival, 8.8 Months Not reached; 12 3.4 Months Median and 18 month % PFS used Overall Survival, Median 19.4 Months NR; 18 month % 9.2 Months OS used Progression-Free on Therapyand | 0.78 Responding Utility Progression-Free Off Therapy 0.82 0.82 N/A and Responding Utility Progressed Disease/Not 0.71 Responding to Therapy Utility Proportion of patients infused 91% 86% N/A {CAR-T specific) Proportion of patients re-treated | 22% of those initially infused 22% of those N/A (CAR-T specific) initially infused Treatment Acquisition Price" $419,500 $419,500 $24,829 per (assumption based | cycle applied on ide-cel list until price) progression Administration, Monitoring, and | $18,500 (CRS grade 1) - $18,500 (CRS $4,661 Adverse Event Management $121,500 (CRS grade 4); other AE | grade 1) - Costs Applied in First Model costs and monitoring included in $121,500 (CRS Cycle' decision tree grade 4); other AE costs and monitoring included in decision tree Other Management-Related $540 Costs per Model Cycle Key Sources (see inputs section Delforge et al 2020%%;Hari et al, Delforge et al Gandhi et al, and supplement for all sources) | 2020%%;Munshi et al, 202111 2020*4Hari et al, 2019*%;Gandhi 20202%8;Madduri et al, etal, 2020520 20197;Mehra et al, 2020% CAR-T: chimeric antigen receptor T-cells, N/A: not applicable, NR: not reported. *Comparator market basket price assumes 15% discount for oral therapies based on Federal Supply Schedule pricing ¥ For ide-cel approximately 80% had a grade 1-4 CRS event, whereas for cilta-cel approximately 95% had a grade 1- 4 CRS event OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 23 Return to Table of Contents Table 4.3. Key Model Inputs for Population with Triple-, Quad-, or Penta- Refractory MM (4+ prior lines of treatment) Belantamab Comparator Parameter Belantamab Market Basket Progression-Free Survival, Median 2.8 Months 2.6 Months Overall Survival, Median 13.7 Months 7.7 Months Progression-Free on Therapy and Responding Utility 0.78 Progressed Disease/Not Responding to Therapy Utility 0.71 WAC Price per Treatment Cycle* $8,277 per vial $20,434 Administration and Monitoring Costs per Model Cycle $355 $1,301 Adverse Event Management Costs for First Two Model $2,565 $1,259 Cycles Other Management-Related Costs per Model Cycle $540 Key Sources (see inputs section and supplement for all | Delforge et Gandhi et al, 20194%;,Gandhi et sources) al, 20202 Lonial et al, al, 20197;Mehra et al, 2020%7 202043 *Belantamab dosing based on weight distribution from trial with proportion of patients receiving 2 or 3 vials; comparator market basket price assumes 15% discount for oral therapies based on Federal Supply Schedule pricing Clinical Inputs Base-case survival was derived from parametric fits to each intervention's available PFS and OS Kaplan-Meier curves.*#34 Tables E.2.5 and E.2.6 delineate the evidence that was used to calculate transition probabilities. The model included any grade 3/4 adverse event that occurred in at least 5% of patients for any of the treatments and comparators. Given the potentially significant impact of cytokine release syndrome on health care resource utilization and quality of life, we included all grades 1-4 for these adverse events and adjusted costs and quality of life estimates accordingly. The costs and disutility of adverse events were applied to the first two model cycles for each intervention and comparator. After cycle 2 of the model, we applied a dose adjustment factor, assuming adverse events would be resolved with lower dosing of each therapy. Supplement Table E.2.8 lists the adverse events considered. Health state utilities were applied for each model health state to adjust for quality-of-life changes over time. Utilities were derived from publicly available sources.*? Tables 4.2 and 4.3 show health utility values by line of therapy. Supplement Table E.2.9 describes the adverse event disutilities. Economic Inputs All costs used in the model were updated to 2020 US dollars using methods following the ICER reference case. The unit cost for each treatment is reported in Supplement Table E.2.10. The regimens used for each comparator treatment can be found in Supplement Table E.2.3 and E.2.4. We used the list price for ide-cel and, in the absence of any available market projection or other data, assumed the same price for cilta-cel. The wholesale acquisition cost for belantamab was used.** Comparator therapy pricing was based on WAC pricing with 15% discounts on oral therapies based on the Federal Supply Schedule. Costs associated with additional health care ©Ilnstitute for Clinical and Economic Review, 2021 Page 24 Final Report - Multiple Myeloma Return to Table of Contents utilization that occurred from administration and monitoring, and post-treatment were included in the model. Supplement Table E.2.12 details the health care utilization unit costs used in the model and the evidence sources. AE costs were derived from reasonable treatment assumptions used in previous analyses mentioned as evidence sources in Supplement Table E.2.14. 4.3. Results Base-Case Results The total discounted costs, life years (LYs), quality-adjusted life years (QALYs), and equal value of life years gained (evLYG) over the lifetime time horizon are detailed in Tables 4.4, 4.5, and 4.6. In the triple- or quad- refractory cohort of patients treated with three or more lines of therapy, ide-cel had a total discounted cost of $646,000 with discounted LYs, QALYs, and evLYG gained of 2.97, 2.24, and 2.40, respectively. Cilta-cel had a total discounted cost of $609,000 with discounted LYs, QALYs, and evLYGs gained of 3.10, 2.39, and 2.54, respectively. The CAR-T therapy comparator market basket cohort had a total discounted cost of $276,000 with discounted LYs, QALYs, and evLYGs gained of 1.50, 1.08, and 1.08, respectively. In the triple-, quad-, or penta-refractory cohort of patients treated with four or more lines of therapy, the belantamab arm had a total discounted cost of approximately $254,000 with discounted LYs, QALYs, and evLYGs gained of 1.60, 1.15, 1.19, respectively. The belantamab comparator market basket had a total discounted cost of $218,000 with discounted LYs, QALYs, and evLYGs gained of 1.08, 0.78, and 0.79, respectively. We note that cost differences between belantamab and its comparator were mitigated by dose reduction and/or discontinuation due to adverse events for belantamab. Table 4.4. Results for the Base-Case for Ide-cel Compared to Triple- or Quad- Refractory MM Comparator Market Basket (3+ prior lines of treatment) Intervention Other non- Time Spentin Life Treatment intervention Total Cost PFS State QALYs evLYGs Cost Years costs™ {months) Ide-Cel $466,000 $180,000 $646,000 16.24 2.24 297 | 240 CAR-T $153,000 $123,000 $276,000 5.75 1.08 150 | 1.08 Comparator Market Basket CAR-T: chimeric antigen receptor T-cells, evLYG: equal-value of life years gained, QALYs: quality-adjusted life years gained, PFS: progression-free survival. *Other non-intervention costs include costs for monitoring, progressed treatment costs, physician visits, adverse event management (first two cycles only) and monthly laboratory costs for complete blood count and liver testing OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 25 Return to Table of Contents Table 4.5. Preliminary Base-Case Results for Cilta-cel Compared to Triple- or Quad- Refractory MM Comparator Market Basket (3+ prior lines of treatment) Intervention Other non- Time spent Life Treatment intervention Total Cost in PFS State QALYs evLYGs Cost Years costs* {months) Cilta-Cel' $445,000 $164,000 $609,000 25.82 2.39 3.10 2.54 (preliminary) CAR-T $153,000 $123,000 $276,000 5.75 1.08 1.50 1.08 Comparator Market Basket CAR-T: chimeric antigen receptor T-cells, evLYG: equal-value of life years gained, QALYs: quality-adjusted life years gained, PFS: progression-free survival. *Other non-intervention costs include costs for monitoring, progressed treatment costs, physician visits, adverse event management (first two cycles only) and monthly laboratory costs for complete blood count and liver testing *Using placeholder price for cilta-cel Table 4.6. Results for the Base-Case for Belantamab Compared to Triple-, Quad-, or Penta- Refractory MM Comparator Market Basket (4+ prior lines of treatment) Intervention Other non- Total Time Spent in Treatment intervention PFS State QALYs | Life Years evLYGs Cost * Cost costs {months) Belantamab | $152,000 $102,000 $254,000 | 6.7 1.15 1.60 1.19 Belantamab $118,000 $99,000 $218,000 | 4.7 0.78 1.08 0.79 Comparator Market Basket evLYG: equal-value of life years gained, QALYs: quality-adjusted life years gained, PFS: progression-free survival. *Other non-intervention costs include costs for monitoring, progressed treatment costs, physician visits, adverse event management (first two cycles only) and monthly laboratory costs for complete blood count and liver testing Table 4.7 presents the incremental results from the base-case analysis, which include incremental cost-effectiveness ratios for the incremental cost per LY gained, incremental cost per QALY gained, and incremental cost per evLYG gained. In the triple- or quad- refractory cohort of patients treated with three or more lines of therapy, total costs for ide-cel were approximately $370,000 greater than total costs for the comparator arm; gains in LYs, QALYs, and evLYGs were 1.47, 1.16, and 1.32 in relation to the comparator arm. This resulted in an incremental cost-effectiveness ratio of approximately $319,000 per QALY gained, $250,000 per LY gained, $280,000 per evLYG gained, and $35,000 per additional PFS month gained for ide-cel versus the comparator arm. In the triple- or quad- refractory cohort of patients treated with three or more lines of therapy, total costs for cilta- cel were approximately $332,000 greater than total costs for the comparator arm; gains in LYs, QALYs, and evLYGs were 1.60, 1.31, and 1.46, respectively. This resulted in an incremental cost- effectiveness ratio of approximately $253,000 per QALY gained, $207,000 per LY gained, $228,000 per evLYG gained, and $17,000 per additional PFS month gained for cilta-cel versus the comparator OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 26 Return to Table of Contents arm. However, we note results for cilta-cel are based on very limited clinical and economic evidence and should be considered preliminary for the purposes of this analysis. Among other key inputs missing, there was no publicly available overall survival curve to inform survival extrapolations and the price of cilta-cel is a placeholder based on the price of ide-cel. In the triple-, qguad-, or penta-refractory cohort treated with four or more lines of therapy, total costs for the belantamab arm were approximately $36,000 greater than total costs for the comparator arm; gains in LYs, QALYs, and evLYGs were more than 0.52, 0.37, and 0.40 than that of the comparator arm. This resulted in an incremental cost-effectiveness ratio of approximately $98,000 per QALY gained, $70,000 per LY gained, $93,000 per evLYG gained, and $18,000 per additional PFS month gained for belantamab versus the comparator arm. As mentioned above, cost differences are relatively low for this comparison due to high rates of discontinuation in the belantamab arm. ©lnstitute for Clinical and Economic Review, 2021 Page 27 Final Report - Multiple Myeloma Return to Table of Contents Table 4.7. Incremental Cost-Effectiveness Ratios for the Base Case . Cost per Treatment Comparator Cost pfer QALY Cost per- Life Cost po._er additional PFS Gained Year Gained evlLYG gained . month gained Ide-Cel CAR-T $319,000 $250,000 $280,000 $35,000 Comparator Market Basket Cilta-cel CAR-T $253,000 $207,000 $228,000 $17,000 (preliminary)* Comparator Market Basket Belantamab Belantamab $98,000 $70,000 $93,000 $18,000 Comparator Market Basket evLYG: equal-value of life years gained, QALY: quality-adjusted life year, LY: life years. *Using placeholder price for cilta-cel Threshold Analyses Tables 4.8 and 4.9 present the unit price needed for each therapy to reach commonly cited cost- effectiveness thresholds. The price needed to achieve these thresholds would be inclusive of both the manufacturer price and any potential hospital mark-up that may be applied. As above, we note that threshold prices differ substantially between the CAR-T therapies in part because of a paucity of available data on PFS and OS for cilta-cel. Table 4.8. QALY-Based Threshold Analysis Results Unit Price to | Unit Price to | Unit Price to | Unit Price to WAC per Net Price Achieve Achieve Achieve Achieve Unit per Unit $50,000 per $100,000 $150,000 $200,000 QALY per QALY per QALY per QALY Ide-Cel $419,500 N/A $140,000 $192,000 $245,000 $295,000 Cilta-cel N/A N/A $168,000 $230,000 $292,000 $354,000 (preliminary)* Belantamab $8,277 B 5730 $8,300 $9,300 $10,400 N/A: not available, evLYG: equal-value life years gained, QALY: quality-adjusted life years gained, WAC: wholesale acquisition cost. *Using placeholder price for cilta-cel OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 28 Return to Table of Contents Table 4.9. evLYG-Based Threshold Analysis Results Unit Price to | Unit Price to | Unit Price to | Unit Price to WAC per Net Price Achieve Achieve Achieve Achieve Unit per Unit $50,000 per $100,000 $150,000 $200,000 evLYG per evLYG per evLYG per evLYG Ide-Cel $419,500 N/A $146,000 $206,000 $265,000 $324,000 Cilta-cel N/A N/A $175,000 $244,000 $312,000 $381,000 (preliminary)* Belantamab $8,277 B 300 $8,400 $9,500 $10,600 mafodotin N/A: not available, evLYG: equal-value life years gained, QALY: quality-adjusted life years gained, WAC: wholesale acquisition cost. *Using placeholder price for cilta-cel Sensitivity Analyses To demonstrate effects of uncertainty on both costs and health outcomes, we varied input parameters using available measures of parameter uncertainty (i.e., standard errors or plausible parameter ranges). Figure 4.2 presents an example tornado diagram resulting from the one-way sensitivity analysis for ide-cel versus the triple- or quad-refractory comparator market basket. When varying PFS, we assumed the same proportional relationship in terms of gains in OS. At lower PFS (6 months) the ICER was well above commonly cited cost-effectiveness thresholds while the upper PFS (12 months) generated an ICER of approximately $212,500. Key drivers across all model findings included the unit price of the comparator market basket of therapies, progression-free survival for the active interventions, and utility of PFS (on or off treatment). The belantamab model in particular was extraordinarily sensitive. Small changes in any of the key drivers listed above changed model findings to a significant extent. Please see Supplement Section E4 for additional results from the one-way sensitivity analyses, including tornado diagrams for cilta-cel and belantamab . Figure 4.2, Tornado Diagram for Ide-Cel Ide-Cel progression-free survival N Unit price of comparator basket I - Utility of PFS (off treatment) | Froportion re-treated with CAR-T - Utility in progressed state || Utility of PFS (on treatment) um Dose intensity for comparator . Cost to manage grade 1 CRS n Cost to manage grade 2 CRS I Cost to manage CRS and NE <=2 I $200,000 $300,000 $400,000 $500,000 $600,000 $700,000 $800,000 Incremental $/QALY ©Institute for Clinical and Economic Review, 2021 Page 29 Final Report - Multiple Myeloma Return to Table of Contents With noted uncertainty outside of that modeled, a probabilistic sensitivity analysis was conducted to assess variation across all model inputs with quantified uncertainty simultaneously and to vary the results over 5,000 iterations. Tables 4.10 and 4.11 present the probability of reaching certain willingness-to-pay thresholds for ide-cel. A total of 3% of the iterations for ide-cel versus the comparator were beneath a threshold of $150,000 per QALY gained. Similarly, 6% of the iterations for ide-cel versus the comparator were beneath a threshold of $150,000 per evLYG gained. Sensitivity analyses for cilta-cel and belantamab are available in Supplement Section E4. Table 4.10. Probabilistic Sensitivity Analysis Cost per QALY Gained Results: Ide-Cel versus Triple- or Quad- Refractory MM Comparator Market Basket {3+ prior lines of treatment) Cost Effective at $50,000 per QALY Cost Effective at $100,000 per QALY Cost Effective at $150,000 per QALY Cost Effective at $200,000 per QALY Ide-cel <1% <1% 3% 15% Table 4.11. Probabilistic Sensitivity Analysis Cost per evLYG Gained Results: Ide-Cel versus Triple- or Quad- Refractory MM Comparator Market Basket {3+ prior lines of treatment) Cost Effective at $50,000 per evLYG Cost Effective at $100,000 per evLYG Cost Effective at $150,000 per evLYG Cost Effective at $200,000 per evlYG Ide-cel <1% <1% 6% 24% Scenario Analyses We ran three main scenario analyses: 1) a scenario that assumes no retreatment costs for each CAR-T product; 2) a modified societal perspective (results presented in supplement section E5); and 3) a scenario analysis that adjusts the proportional relationship between PFS and OS for belantamab to be within a similar range to that suggested by a recent synthesis of the evidence (results presented in supplement section E5). The base-case model assumed 22% of patients were re-treated with CAR-T as reported in KarMMa.!! In this scenario analysis, we assume no additional retreatment charge for each CAR-T product. We include all other costs related to re-treatment for the 22% re-treated, including adverse events (i.e., hospitalizations) and monitoring. This scenario suggests re-treatment as a driver of the model results with, reductions in the incremental cost-effectiveness ratio of approximately -25% (Table 4.12). OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 30 Return to Table of Contents Table 4.12. Incremental Cost-Effectiveness Ratios for Scenario Analysis 1 . Cost per Treatment Comparator Cost p.er QALY Cost per. Life Cost per Month of PFS Gained Year Gained evLYG . Gained Ide-cel CAR-T $247,000 $194,000 $217,000 $27,000 Comparator Market Basket Cilta-cel CAR-T $189,000 $155,000 $170,000 $12,000 (preliminary)* Comparator Market Basket evLYG: equal-value of life years gained, QALY: quality-adjusted life year, LY: life years *Using placeholder price for cilta-cel Model Validation We used several approaches to validate the model. First, we attempted multiple survival extrapolation techniques and compared estimates to findings from each intervention's most recent published paper or abstract to ensure outcomes were consistent with clinical evidence. Second, we presented preliminary results to manufacturers and clinical experts, and based on feedback from these groups, we refined data inputs or extrapolations as needed. During the model transparency process, manufacturers noted we underestimated survival for ide-cel and the CAR-T comparator market basket (which also impacted a percentage of the comparator to belantamab). These changes were reflected in the final model calculations. Third, we varied model input parameters to evaluate face validity of changes in results. Finally, we compared model results to other cost- effectiveness findings in this therapy area. Uncertainty and Controversies There were important uncertainties relevant to generating model outcomes. Given that evidence was abstracted from single-arm studies, there were challenges when selecting the most appropriate comparator. In order to calculate incremental costs, risks, and benefits, we compared each therapy to a contemporaneous population of RRMM patients within the MAMMOTH observational study, i.e., a triple-/quad-refractory cohort as a comparator to CAR-T therapies and a weighted average cohort of triple-, quad-, and penta-refractory treated patients as a comparator to belantamab. Advantages of using the MAMMOTH population as a comparator include generalizability to the academic medical center setting and use of currently-recommended regimens; these settings are likely to be the same ones that will provide CAR-T and belantamab therapy. This allowed us to include not only survival evidence but also the mix of therapies used to estimate a monthly cost for each comparator. However, given that the treatment landscape changes dramatically over short time periods in RRMM, and the lack of a quantitative indirect treatment comparison to inform these analyses, caution should be used when interpreting cost-effectiveness estimates. A further complication in identifying a relevant comparator to belantamab was the mix of patients exposed to OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 31 Return to Table of Contents three or more lines of therapy and four or more lines of therapy, respectively. To address this limitation, we assumed a population mix from MAMMOTH to estimate weighted average outcomes and costs. Moreover, comparisons across the interventions of interest were not feasible given differences in populations from each single-arm study. We acknowledge the challenge of interpreting incremental cost-effectiveness ratios for recently approved or investigational therapies when they are compared to existing high-cost comparators. Model outcomes were sensitive to the price of comparators as well as future health care costs for survivors. In sensitivity analyses, we varied the price of the market basket by the minimum and maximum estimated combination regimen in the market basket {which varied from approximately $17,000 to $37,000 per cycle of therapy). Therefore, interpretation of the cost-effectiveness of each therapy should include review of the one-way sensitivity analyses. Not surprisingly, we generally found that lower comparator prices led to less favorable cost-effectiveness estimates for the interventions. The relationship between PFS and OS for each therapy was fairly consistent with prior meta-analysis evidence that suggests for every one month in PFS, patients gain approximately 2.5-3 months of 0S.37:38 However, we observed a different pattern in the DREAMM-2 belantamab trial. The single arm study suggested that relationship was closer to a 5-month gain in OS for every 1-month gain in PFS. The resulting model was quite sensitive; small changes in this relationship as well as other key parameters resulted in relatively large swings in our cost-effectiveness estimates. To address this limitation and the uncertainty around these estimates, we adjusted the relationship between PFS and OS for the belantamab arm to be consistent with the most recent meta-analysis evidence in a scenario analysis.3" In this scenario, belantamab was dominated (i.e., more costly, less effective) by the market basket of comparators. This suggests that as new evidence emerges, cost-effectiveness findings should be updated. After our draft report was published, new data emerged in a recent publication of the results of the KarMMa trial, suggesting that >20% of ide-cel patients received a second CAR-T infusion. While these patients were treated with T cells that had already been harvested and engineered, there is uncertainty around whether there would be a second "charge" for retreatment; it is certainly the case that hospitals delivering a second infusion would incur costs of infusion, monitoring, and management of side effects. We assumed that a second charge would be levied in our base-case analyses (for both ide-cel and cilta-cel) and removed this second charge this in a scenario analysis. Our findings suggested that this would have a significant impact on the price that could be charged to achieve a $100,000 per QALY threshold (e.g., $191,000 vs. $233,000 for ide-cel with and without a second charge, respectively). In addition, one of the CAR-T recipients we spoke with indicated that he was receiving high-priced maintenance medication after his infusion even though he remained in response to CAR-T, suggesting that other treatment decisions following an initial CAR-T infusion may have a significant impact on the estimated cost-effectiveness of these therapies. ©lnstitute for Clinical and Economic Review, 2021 Page 32 Final Report - Multiple Myeloma Return to Table of Contents Specific to cilta-cel, interpretation of the cost-effectiveness findings should be noted as a very preliminary and somewhat optimistic scenario. The evidence used in the model relies on limited clinical study evidence with a PFS estimate that has yet to reach its median and OS evidence based on 18 months of follow-up. The only study with longer follow-up data available to us was the Phase 1 LEGEND-2 study, which focused on a younger population with fewer previous lines of treatment. Therefore, extrapolations of survival are likely overestimates of the benefit of cilta-cel. We found through sensitivity analyses that at lower PFS and OS levels, the incremental cost-effectiveness ratios became less favorable. In addition, while dosing of cilta-cel ranged in the CARTITUDE-1 study, there have been no reports of whether retreatment was necessary. In the absence of any reported data, a study publication, or input from the manufacturer, we assumed the same rate of retreatment as observed in the ide-cel KarMMa study. Finally, we found no indication of the likely price of cilta-cel and relied instead on the ide-cel price as a placeholder. Survival curve fitting relies on assumptions that may differ substantially between parametric models (see Figures E.2.1 to E.2.4 for modeled survival extrapolations). Scenario analyses around alternative extrapolations found large variation in incremental cost-effectiveness ratios. There are further limitations to piecewise modeling approaches, such as seemingly arbitrary cut-point intervals and modeled "jumps" in the hazard that may appear clinically unjustifiable.*®* We ensured our assumptions did not lead to invalid and unrealistic survival estimates, for example the tail of the extrapolated PFS curve crossing the tail of the OS curve. We relied on reported estimates of percentage alive and in PFS and OS states in addition to fit statistics. Survival estimates were sensitive to base-case findings as shown in the one-way sensitivity analyses. 4.4. Summary and Comment The base-case findings from our analysis suggest that CAR-T therapies provide clinical benefit in terms of gains in QALYs and LYs over current treatment options for patients exposed to three or more lines of therapy. However, the benefits of ide-cel and cilta-cel should be reviewed separately given that evidence is still emerging. Threshold pricing suggests ide-cel would meet the $100,000 per QALY threshold at a price of around $200,000, which represents a discount of >50% from the list price of $419,500. Cilta-cel would meet this threshold at a price of around $230,000, but as noted above this is likely an optimistic estimate given the limited evidence currently available. Base-case findings for belantamab suggest current list pricing is within commonly cited cost- effectiveness thresholds. However, given uncertainties with the PFS-0OS relationship and other parameters in the belantamab model, updated data should be generated and incorporated into future modeling analyses. Model findings across all interventions were sensitive to the cost of comparators, PFS and OS estimates, utility of PFS {on and off treatment), and overall health care costs for multiple myeloma patients. ©lnstitute for Clinical and Economic Review, 2021 Page 33 Final Report - Multiple Myeloma Return to Table of Contents 5. Potential Other Benefits and Contextual Considerations Our reviews seek to provide information on potential other benefits offered by the intervention to the individual patient, caregivers, the delivery system, other patients, or the public that was not available in the evidence base nor could be adequately estimated within the cost-effectiveness model. These elements are listed in the table below, with related information gathered from patients and other stakeholders. Following the public deliberation on this report the appraisal committee will vote on the degree to which each of these factors should affect overall judgments of long-term value for money of the intervention(s) in this review. Table 5.1. Categories of Contextual Considerations Contextual Considerations Relevant Information Acuity of need for treatment of individual patients based on the severity of the condition being treated The acuity of need for treatment is high. Patients with heavily pre-treated MM have relatively short life expectancy without treatment, and their treatment options are currently limited. Magnitude of the Jifetime impact on individual patients of the condition being treated MM has a moderate lifetime impact on individual patients. The disease has a tremendous effect on the quality and quantity of life for affected patients. However, the median age at diagnosis is 69; thus, most patients diagnosed with MM have lived many decades without myeloma. Thus, unlike diseases such as cystic fibrosis which has a large effect on a patient's entire lifespan, MM has a large effect on a proportion of a patient's lifespan, leading to our assessment of moderate lifetime impact. New mechanism of action may provide benefits for patients who are unresponsive to current therapies Anti-BCMA activity of both CAR-T therapies and belantamab suggests that these treatments may be efficacious for patients who are unresponsive to other treatments. ©Institute for Clinical and Economic Review, 2021 Page 34 Final Report - Multiple Myeloma Return to Table of Contents Table 5.2. Categories of Potential Other Benefits Patients' ability to achieve major life For CAR-T therapy, suppressing the symptoms of MM goals related to education, work, or appears to support patients' ability to achieve life family life goals. For belantamab, substantial side effects of treatment balance the decrease in disease effects, making it less clear whether belantamab supports patients' ability to achieve life goals. Caregivers' quality of life and/or ability to | For CAR-T therapy, suppressing the symptoms of MM achieve major life goals related to appears to support caregivers' ability to achieve life education, work, or family life goals. For belantamab, substantial side effects of treatment balance the decrease in disease effects, making it less clear whether belantamab supports caregivers' ability to achieve life goals. Patients' ability to manage and sustain For CAR-T therapy, patient burden may be treatment given the complexity of substantially less since much of the monitoring is regimen done immediately after infusion and many patients appear to need no maintenance therapy. For belantamab, patient burden may be less since the studies focused on monotherapy. However, studies are underway focusing on combining belantamab with other treatments, which may negate patient burden advantages with belantamab. Society's goal of reducing health Anti-BCMA therapies have the potential to worsen inequities existing disparities. Therapies with high cost or high side effect burden (such as the current anti-BCMA therapies), as well as those requiring treatment at specialized centers, are often utilized at lower rates among historically disadvantaged populations. ©Institute for Clinical and Economic Review, 2021 Page 35 Final Report - Multiple Myeloma Return to Table of Contents 6. Health Benefit Price Benchmarks The ICER health benefit price benchmark (HBPB) is a price range suggesting the highest price a manufacturer should charge for a treatment, based on the amount of improvement in overall health patients receive from that treatment, when a higher price would cause disproportionately greater losses in health among other patients due to rising overall costs of health care and health insurance. Inshort, it is the top price range at which a health system can reward innovation and better health for patients without doing more harm than good. Unit prices for ide-cel, cilta-cel, and belantamab that would achieve incremental cost-effectiveness ratios of $100,000 and $150,000 per QALY or evLYG are presented in Table 6.1. We arrive at a range of HBPB of approximately $192,000 - $265,000 for ide-cel, $230,000 - $312,000 for cilta-cel, and $8,300 - $9,500 for belantamab. Table 6.1. Cost-Effectiveness Threshold Prices for Ide-cel, Cilta-cel, and Belantamab Unit Price at Unit Price at Discount from WAC per Unit $100,000 $150,000 WAC to Reach Threshold Threshold Threshold Prices Ide-cel QALYs Gained $419,500 $192,000 $245,000 42%-54% evlLYG $419,500 $206,000 $265,000 37%-51% Cilta-cel {preliminary) QALYs Gained $419,500 $230,000 $292,000 30% - 45% (placeholder) evLYG $419,500 $244,000 $312,000 26% - 42% (placeholder) Belantamab QALYs Gained $8,277 per vial $8,300 $9,300 No discount evLYG $8,277 per vial $8,400 $9,500 No discount QALY: quality-adjusted life year, WAC: wholesale acquisition cost "WAC as of March 2021 ©Institute for Clinical and Economic Review, 2021 Page 36 Final Report - Multiple Myeloma Return to Table of Contents 7. Potential Budget Impact 7.1. Overview of Key Assumptions Using results from the cost-effectiveness model, we estimated the potential budgetary impact of each B-cell maturation antigen CAR-T cell and antibody drug conjugate therapy for refractory multiple myeloma. We used the price from the base-case analysis and three threshold prices (at $50,000, $100,000, and $150,000 per QALY) for each intervention. Potential budget impact is defined as the total differential cost of using each new therapy rather than the relevant existing therapy for the treated population, calculated as differential health care costs (including intervention costs) minus any offsets in these costs from averted health care events. All costs were undiscounted and estimated over a five-year time horizon. The analysis included the estimated number of individuals in the US who would be eligible for each treatment. To estimate the size of the potential candidate populations for each intervention, we used the total number of adults 18 years and older with at a minimum triple-class refractory multiple myeloma. It is estimated that 140,000 Americans are living with MM.3 Patients with MM are treated with CD38-targeting antibodies which are generally well tolerated and result in a response in approximately 30% of patients with MM. Thus, we assumed that 70% of patients with MM are refractory to CD38-targeted antibodies. Further, among MM patient's refractory to CD38- targeting antibodies, 54% are triple and quad-refractory and 25% are at least penta-refractory.' Therefore, we estimated approximately 98,000 MM patients are refractory to CD38-targeting antibodies, with approximately 52,900 classified as triple or quad-refractory and 24,500 classified as at least penta-refractory in the US. We assumed that 20% of these patients would initiate treatment in each of the five years, or approximately 10,580 patients eligible for CAR-T therapy and 4,900 eligible for belantamab each year. Because the CAR-T therapies will be launched (if cilta-cel is approved) within a short period of each other, the eligible population of approximately 10,580 triple or quad-refractory patients per year was split in half between the two interventions (approximately 5,290 per year per CAR-T therapy). The aim of the potential budgetary impact analysis was to document the percentage of patients who could be treated at select prices within 5 years without crossing a potential budget impact threshold that is aligned with overall growth in the US economy. For reports begun in 2019-2020, the five-year annualized ICER potential budget impact threshold that should trigger policy actions to manage access and affordability is approximately $819 million per year for new drugs. More detail on these methods can be found in the Section F of the Report Supplement. ©lnstitute for Clinical and Economic Review, 2021 Page 37 Final Report - Multiple Myeloma Return to Table of Contents 7.2. Results Belantamab Figure 7.1 depicts the cumulative per-patient potential budget impact calculations for belantamab as compared to the market basket comparator, based on the wholesale acquisition cost. The average potential budgetary impact for belantamab was approximately $5,610 per patient in year one, with cumulative net cost increasing in years two and three and beginning to plateau at year four, reaching approximately $39,210 per patient in year five. Figure 7.1. Cumulative Net Cost per Patient Treated with Belantamab at Wholesale Acquisition Cost $45,000 - $40,000 1 $35,000 $30,000 1 $25,000 1 $20,000 1 $15,000 1 $10,000 $5,000 | . s0 1 2 3 4 5 Assuming the wholesale acquisition cost (unit price of approximately $8,280), all eligible patients could be treated within five years (assuming 20% uptake each year), reaching 18% of the ICER budget impact threshold of $819 million per year over five years. Similarly using the prices to reach $150,000, $100,000, and $50,000 per QALY (unit prices of approximately $9,340, $8,310, and $7,290, respectively), all eligible patients could be treated within five years (assuming 20% uptake each year) without crossing the ICER budget impact threshold. Idecabtagene vicleucel Figure 7.2 depicts the cumulative per-patient potential budget impact calculations for ide-cel as compared to the market basket comparator, assuming the list price of $419,500. The average potential budgetary impact was approximately $354,340 per patient in year one, which remained relatively constant through year five where it reached approximately $364,120 per patient. ©Institute for Clinical and Economic Review, 2021 Page 38 Final Report - Multiple Myeloma Return to Table of Contents Figure 7.2. Cumulative Net Cost per Patient Treated with Ide-cel at List Price $400,000 1 $350,000 $300,000 $250,000 $200,000 $150,000 $100,000 $50,000 ] 50 1 2 3 4 5 Assuming the list price ($419,500), only 43% of the eligible patients could be treated within five years (assuming 20% uptake each year), before crossing the ICER budget impact threshold of $819 million per year. Similarly using the price to reach $150,000 per QALY (price of approximately $245,000), 95% of the eligible patients could be treated within five years (assuming 20% uptake each year) before crossing the ICER budget impact threshold. All eligible patients could be treated within five years without crossing the ICER budget impact threshold at the price to reach either $100,000/QALY and $50,000/QALY. Figure 7.3 depicts the potential budgetary impact of idecabtagene vicleucel. ©Institute for Clinical and Economic Review, 2021 Page 39 Final Report - Multiple Myeloma Return to Table of Contents Figure 7.3. Potential Budgetary Impact of Ide-Cel in Triple- or Quad-Refractory Multiple Myeloma $450,000 @ _Base Case $400,000 Sso $350,000 ~ $300,000 e Seae 5330,000/QALY - - $250,000 $200,000 Annual Price $150,000 $100,000 $50,000 S0 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Percentage of Eligible Patients Treated by Year 5 Without Crossing Bl Threshold Ciltacabtagene autoleucel Figure 7.4 depicts the preliminary cumulative per-patient potential budget impact calculations for cilta-cel as compared to the market basket comparator, assuming the placeholder price of $419,500. The average potential budgetary impact was approximately $289,700 per patient in year one, with a small increase each year to approximately $330,300 per patient in year five. ©lnstitute for Clinical and Economic Review, 2021 Page 40 Final Report - Multiple Myeloma Return to Table of Contents Figure 7.4. Cumulative Net Cost per Patient Treated with Cilta-cel at Placeholder Price (Preliminary) $350,000 $300,000 $250,000 $200,000 $150,000 $100,000 $50,000 S0 1 2 3 4 5 Assuming the placeholder price of $419,500, only 50% of the eligible population could be treated within five years (assuming 20% uptake each year) before reaching the ICER potential budget impact threshold of $819 million per year. At the price to achieve a threshold of $150,000/QALY (approximately $290,000), only 90% of the eligible population could be treated within five years (assuming 20% uptake each year) before reaching the ICER potential budget impact threshold of $819 million per year. All eligible patients could be treated at the price to reach a threshold of $100,000/QALY and $50,000/QALY without reaching the ICER potential budget impact threshold. Figure 7.5 depicts the potential budgetary impact of ciltacabtagene autoleucel. ©lnstitute for Clinical and Economic Review, 2021 Page 41 Final Report - Multiple Myeloma Return to Table of Contents Figure 7.5. Potential Budgetary Impact of Cilta-Cel in Triple- or Quad-Refractory Multiple Myeloma (Preliminary) $450,000 @ _Base Case $400,000 S e $350,000 S Sso $150,000/QALY $300,000 - $250,000 $200,000 Annual Price $150,000 $100,000 $50,000 S0 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Percentage of Eligible Patients Treated by Year 5 Without Crossing Bl Threshold Additional net costs per year are presented along with cumulative net costs in Section F of the supplement for each of the three treatments. 7.3. Affordability and Access Alert Approximately 43% (ide-cel) and 50% (cilta-cel) of eligible triple- or quad-refractory multiple myeloma patients could be treated within five years before crossing the ICER potential budget impact threshold of $819 million per year. Testimony from clinical experts at the public meeting suggested that the ideal clinical uptake of the CAR-Ts would include the chance for nearly every eligible patient to receive one or the other. Given that efforts to reach this clinical target would create a short-term potential budget impact that exceeds ICER's threshold, ICER is issuing an access and affordability alert for ide-cel and cilta-cel. The purpose of an ICER access and affordability alert is to signal to stakeholders and policy makers that the amount of added health care costs associated with a new service may be difficult for the health system to absorb over the short term without displacing other needed services, creating pressure on payers to sharply restrict access, or causing rapid growth in health care insurance costs that would threaten sustainable access to high-value care for all patients. ICER is not issuing an access and affordability alert for belantamab, because all eligible patients could be treated within five years (assuming 20% uptake each year) at the wholesale acquisition cost for belantamab. ©lnstitute for Clinical and Economic Review, 2021 Page 42 Final Report - Multiple Myeloma Return to Table of Contents 8. Summary of the Votes and Considerations for Policy 8.1 About the Midwest CEPAC Process During Midwest CEPAC public meetings, the Midwest CEPAC Panel deliberates and votes on key questions related to the systematic review of the clinical evidence, an economic analysis of the applications of treatments under examination, and the supplementary information presented. Panel members are not pre-selected based on the topic being addressed and are intentionally selected to represent a range of expertise and diverse perspectives. Acknowledging that any judgment of evidence is strengthened by real-life clinical and patient perspectives, subject matter experts are recruited for each meeting topic and provide input to Midwest CEPAC Panel members before the meeting to help clarify their understanding of the different interventions being analyzed in the evidence review. The same clinical experts serve as a resource to the Midwest CEPAC Panel during their deliberation, and help to shape recommendations on ways the evidence can apply to policy and practice. After the Midwest CEPAC Panel votes, a policy roundtable discussion is held with the Midwest CEPAC Panel, clinical experts, patient advocates, payers, and when feasible, manufacturers. The goal of this discussion is to bring stakeholders together to apply the evidence to guide patient education, clinical practice, and coverage and public policies. Participants on policy roundtables are selected for their expertise on the specific meeting topic, are different for each meeting, and do not vote on any questions. At the April 16, 2021 meeting, the Midwest CEPAC Panel discussed issues regarding the application of the available evidence to help patients, clinicians, and payers address important questions related to the use of belantamab, ide-cel and cilta-cel for multiple myeloma. Following the evidence presentation and public comments (public comments from the meeting can be accessed here, the Midwest CEPAC Panel voted on key questions concerning the comparative clinical effectiveness, comparative value, and potential other benefits and contextual considerations related to belantamab, ide-cel and cilta-cel. These questions are developed by the ICER research team for each assessment to ensure that the questions are framed to address the issues that are most important in applying the evidence to support clinical practice, medical policy decisions, and patient decision-making. The voting results are presented below, along with specific considerations mentioned by the Midwest CEPAC Panel members during the voting process. ©lnstitute for Clinical and Economic Review, 2021 Page 43 Final Report - Multiple Myeloma Return to Table of Contents In its deliberations and votes related to value, the Midwest CEPAC Panel considered the individual patient benefits, and incremental costs to achieve such benefits, from a given intervention over the long term. There are four elements to consider when deliberating on long-term value for money (see Figure 8.1 below): 1. Comparative clinical effectiveness is a judgment of the overall difference in clinical outcomes between two interventions (or between an intervention and placebo), tempered by the level of certainty possible given the strengths and weaknesses of the body of evidence. Midwest CEPAC uses the ICER Evidence Rating Matrix as its conceptual framework for considering comparative clinical effectiveness. 2. Estimated incremental cost-effectiveness is the average incremental cost per patient of one intervention compared to another to achieve a desired "health gain," such as an additional stroke prevented, case of cancer diagnosed, or gain of a year of life. Alternative interventions are compared in terms of cost per unit of effectiveness, and the resulting comparison is presented as a cost-effectiveness ratio. Relative certainty in the cost and outcome estimates continues to be a consideration. As a measure of cost-effectiveness, the Midwest CEPAC voting panel follows common academic and health technology assessment standards by using cost per quality-adjusted life year (QALY), with formal voting on "long- term value for money". 3. Potential other benefits refer to any significant benefits or disadvantages offered by the intervention to the individual patient, caregivers, the delivery system, other patients, or the public that would not have been considered as part of the evidence on comparative clinical effectiveness. Examples of potential other benefits include better access to treatment centers, mechanisms of treatment delivery that require fewer visits to the clinician's office, treatments that reduce disparities across various patient groups, and new potential mechanisms of action for treating clinical conditions that have demonstrated low rates of response to currently available therapies. Other disadvantages could include increased burden of treatment on patients or their caregivers. For each intervention evaluated, it will be open to discussion whether potential other benefits or disadvantages such as these are important enough to factor into the overall judgment of long-term value for money. There is no quantitative measure for potential other benefits or disadvantages. ©Ilnstitute for Clinical and Economic Review, 2021 Page 44 Final Report - Multiple Myeloma Return to Table of Contents 4. Contextual considerations include ethical, legal, or other issues {but not cost) that influence the relative priority of illnesses and interventions. Examples of contextual considerations include whether there are currently any existing treatments for the condition, whether the condition severely affects quality of life or not, and whether there is significant uncertainty about the magnitude of benefit or risk of an intervention over the long term. There is no quantitative measure for contextual considerations. Figure 8.1. Conceptual Structure of Long Term Value for Money Long-Term Value for Money Other Benefits or Contextual Disadvantages Considerations 8.2 Voting Results 1. Given the currently available evidence, is the evidence adequate to demonstrate that the net health benefit of belantamab mafodotin is superior to that provided by usual care? | Yes: 5 votes | No: 10 votes | Comments: The panel concluded that further evidence, including on the relationship between progression-free and overall survival as well as ocular toxicity, is required to demonstrate superiority of belantamab over standard treatments in the target population. ©lnstitute for Clinical and Economic Review, 2021 Page 45 Final Report - Multiple Myeloma Return to Table of Contents 2. Given the currently available evidence, is the evidence adequate to demonstrate that the net health benefit of idecabtagene vicleucel (ide-cel) is superior to usual care? | Yes: 15 votes | No: 0 votes | Comments: The panel found that the evidence suggests that ide-cel provides a net health benefit over current usual care. The panel emphasized benefits such as improved survival and quality of life. There is uncertainty, however, in whether the benefit is small or substantial. 3. Given the currently available evidence, is the evidence adequate to demonstrate that the net health benefit of ciltacabtagene autoleucel (cilta-cel) is superior to usual care? | Yes: 13 votes | No: 2 votes | Comments: Similar to ide-cel, the panel found that cilta-cel could potentially provide a net health benefit over current usual care. In this case, however, a greater level of concern was raised on the immaturity of the available data, particularly on survival, and the lack of published evidence. 4. Is the evidence adequate to distinguish the net health benefit of idecabtagene vicleucel (ide-cel) from ciltacabtagene autoleucel (cilta-cel)? | Yes: 0 votes | No: 15 votes | Comments: The panel found that current evidence is insufficient to determine whether one CAR-T therapy is superior to the other. Panel members highlighted that there are no studies comparing these agents directly, nor sufficient data to perform quantitative indirect comparisons. 5. When making judgments of overall long-term value for money, what is the relative priority that should be given to any effective treatment for triple-class refractory multiple myeloma, on the basis of the following contextual considerations: Acuity of need for treatment based on the severity of the condition being treated Very low priority: 0 Low priority: 0 Average priority: 2 High priority: 9 Very high priority: votes votes votes votes 4 votes Comments: The panel found that high priority should be given to any new treatments since the acuity of need for treatment in these specific populations is high. Patients with heavily pre-treated MM have relatively short life expectancy without treatment, and their treatment options are currently limited. ©lnstitute for Clinical and Economic Review, 2021 Page 46 Final Report - Multiple Myeloma Return to Table of Contents 1. When making judgments of overall long-term value for money, what is the relative priority that should be given to any effective treatment for triple-class refractory multiple myeloma, on the basis of the following contextual considerations: Magnitude of the lifetime impact of the condition being treated Very low priority: 0 Low priority: 0 Average priority: 8 High priority: 7 Very high priority: votes votes votes votes 0 votes Comments: Based on the report findings and the patient testimonies presented at the public meeting, the panel voted that based on the magnitude of the lifetime impact of myeloma, average or high priority should be given to any effective treatment. During the public meeting, patient testimonies highlighted that even though the median diagnosis is at age 69, once diagnosed with multiple myeloma, the disease has a tremendous effect on the quality and quantity of life for patients. 2. What are the relative effects of belantamab mafodotin versus usual care* on the following outcomes that inform judgment of the overall long-term value for money of belantamab mafodotin? Patients' ability to achieve major life goals related to education, work, or family life Major negative Minor negative No difference: 11 Minor positive Major positive effect: 0 votes effect: 1 vote votes effect: 3 votes effect: 0 votes Comments: Since for belantamab the potential substantial side effects of treatment balance the clinical improvement, it is less clear whether belantamab supports patients' ability to achieve life goals. Therefore, the panel voted that belantamab would have no difference in patients' ability to achieve major life goals, compared to usual care. 3. What are the relative effects of belantamab mafodotin versus usual care* on the following outcomes that inform judgment of the overall long-term value for money of belantamab mafodotin? Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life Major negative Minor negative No difference: 8 Minor positive Major positive effect: 0 votes effect: 6 votes votes effect: 1 vote effect: 0 votes ©lnstitute for Clinical and Economic Review, 2021 Page 47 Final Report - Multiple Myeloma Return to Table of Contents Comments: Based on similar reasoning as the previous voting question, the panel voted that belantamab would have either no difference or potentially a minor negative effect in caregivers' ability to achieve major life goals, compared to usual care. 4. What are the relative effects of belantamab mafodotin versus usual care* on the following outcomes that inform judgment of the overall long-term value for money of belantamab mafodotin? Society's goal of reducing health inequities Major negative effect: 2 votes Minor negative No difference: 8 effect: 5 votes votes Minor positive effect: 0 votes Major positive effect: 0 votes Comments: Anti-BCMA therapies {which include belantamab) have the potential to worsen existing health disparities. Therapies with high cost or high side effect burden are often utilized at lower rates among historically disadvantaged populations. Therefore, the panel voted that belantamab would have either no difference or a minor negative effect to society's goal of reducing health inequities. 5. What are the relative effects of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) versus usual care* on the following outcomes that inform judgment of the overall long-term value for money of ide-cel and cilta-cel? Patients' ability to achieve major life goals related to education, work, or family life Major negative effect: 0 votes Minor negative effect: 0 votes No difference: 1 vote Minor positive effect: 8 votes Major positive effect: 6 votes Comments: Based on the report findings and patient testimonies, the panel voted that the CAR-T therapies would have a minor or major positive effect on the patients' ability to achieve major life goals based on how the therapies suppress the symptoms of MM and offer potential for a substantial period of time free from maintenance treatment. OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 48 Return to Table of Contents 6. What are the relative effects of idecabtagene vicleucel {ide-cel) and ciltacabtagene autoleucel (cilta-cel) versus usual care* on the following outcomes that inform judgment of the overall long-term value for money of ide-cel and cilta-cel? Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life Major negative effect: 0 votes Minor negative No difference: 0 effect: 0 votes votes Minor positive effect: 13 votes Major positive effect: 2 votes Comments: Based on the report findings and patient testimonies, the panel voted that the CAR-T therapies would have a minor positive effect on the caregivers' quality of life based on how the therapies suppress the symptoms of MM and offer potential for a substantial period of time free from maintenance treatment. 7. What are the relative effects of idecabtagene vicleucel {ide-cel) and ciltacabtagene autoleucel (cilta-cel) versus usual care* on the following outcomes that inform judgment of the overall long-term value for money of ide-cel and cilta-cel? Patients' ability to manage and sustain treatment given the complexity of regimen Major negative effect: 0 votes Minor negative effect: 0 votes No difference: 1 vote Minor positive effect: 12 votes Major positive effect: 2 votes Comments: Based on patient testimonies and the evidence presentation, the panel voted that CAR-T therapies would have a minor positive effect on the patients' ability to manage and sustain treatment. For CAR-T therapies, monitoring is done immediately after infusion and many patients appear to need no maintenance therapy. 8. What are the relative effects of idecabtagene vicleucel {(ide-cel) and ciltacabtagene autoleucel (cilta-cel) versus usual care* on the following outcomes that inform judgment of the overall long-term value for money of ide-cel and cilta-cel? Society's goal of reducing health inequities Major negative effect: 5 votes Minor negative effect: 9 votes No difference: 1 vote Minor positive effect: 0 votes Major positive effect: 0 votes Comments: The panel voted that the CAR-T therapies could have a minor or major negative effect on reducing health inequities due to these being therapies with high cost and a high side effect burden. Furthermore, CAR-T therapies require treatment at specialized academic medical centers which are often utilized at lower rates among historically disadvantaged populations. OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 49 Return to Table of Contents 9. Given the available evidence on comparative effectiveness and incremental cost-effectiveness, 10. and considering other benefits, disadvantages, and contextual considerations, what is the long- term value for money of treatment at current pricing with belantamab mafodotin versus usual care*? Low long-term value for Intermediate long-term value High long-term value for money at current prices: 8 for money at current prices: 6 money at current prices: 1 votes votes vote Comments: The majority of the panel voted that belantamab represents "low" long-term value for money. The incremental cost-effectiveness ratio for belantamab using the base case was $98,000 per QALY. Although the cost-effectiveness results for belantamab were relatively favorable, the panel found that these results could have been impacted by patients discontinuing therapy because of side effects, as well as the high prices for the three-drug alternative regimens. Given the available evidence on comparative effectiveness and incremental cost-effectiveness, and considering other benefits, disadvantages, and contextual considerations, what is the long- term value for money of treatment at current pricing with idecabtagene vicleucel (ide-cel) versus usual care*? Low long-term value for Intermediate long-term value High long-term value for money at current prices: 9 for money at current prices: 5 money at current prices: 0 votes votes votes Comments: The majority of the panel voted that ide-cel represents "low" long-term value for money. The incremental cost-effectiveness ratio for ide-cel using the base case was $319,000 per QALY. ICER's recommended health-benefit price benchmark (HBPB) range for ide-cel is between $192,000-5265,000 per dose, which would require a 37-54% discount off the treatment's recently announced wholesale acquisition cost (WAC) of $419,500. 8.3 Roundtable Discussion and Key Policy Implications Following its deliberation on the evidence, the Midwest CEPAC Panel engaged in a moderated discussion with a policy roundtable about how best to apply the evidence on CAR-Therapies and belantamab for TCRMM to policy and practice. The policy roundtable members included two patients, two clinical experts, two payers and one representative from a pharmaceutical manufacturer. The discussion reflected multiple perspectives and opinions, and therefore, none of the statements below should be taken as a consensus view held by all participants. The names of the Policy Roundtable participants are shown below, and conflict of interest disclosures for all meeting participants can be found in Supplement G. ©lnstitute for Clinical and Economic Review, 2021 Page 50 Final Report - Multiple Myeloma Return to Table of Contents Table 8.1 Policy Roundtable Members Policy Roundtable Member Conflicts of Interest Tom Bellfort, Patient Expert No conflicts to disclose. Harold Carter, PharmD, Vice President, Pharma Harold Carter is a full-time employee of Express Scripts. Contracting, Strategy & Wholesale Markets, Express Scripts Anita D'Souza, MD, MS, Associate Professor of Anita D'Souza has received institutional research funding Medicine, Medical College of Wisconsin from Sanofi, TeneoBio, Takeda, and Caelum. D'Souza reports advisory board roles with Akcea, Imbrium Therapeutics and Pfizer and received consulting honoraria from Janssen. Ira Gupta, MD, Vice President & Medicine Ira Gupta is a full-time employee of GSK. Development Leader, GlaxoSmithKline R&D, Oncology David Mitchell, Patient Expert David Mitchell is on the Board of Directors of Friends of Founder, Patients For Affordable Drugs Cancer Research which receives grants from BMS, bluebird Bio, and Janssen. He received honoraria from the FDA for his service on the Oncologic Drugs Advisory Committee and was part of a class action suit against Celgene to which he received a service award. S. Vincent Rajkumar, MD, Edward W. and Betty Knight | S. Vincent Rajkumar has held a position as a member of Scripps Professor of Medicine, Mayo Clinic, Rochester, | the Board of Directors for the International Myeloma MN Foundation. Melissa Pozotrigo, PharmD, BCOP Melissa Pozotrigo is a full-time employee of Oncology Senior Clinical Oncology Pharmacist, Oncology Analytics. Analytics Inc. The following policy recommendations reflect the main themes and points made during the Policy Roundtable discussion at the April 16, 2021 Midwest CEPAC public meeting on the use of anti-BCMA therapies for the treatment of heavily pre-treated multiple myeloma. At the meeting, ICER presented the findings of its revised report on these treatments and the Midwest CEPAC voting council deliberated on key questions related to their comparative clinical effectiveness, potential other benefits and contextual considerations, and long-term value for money at current prices. Following the votes, ICER convened a Policy Roundtable of two patients, two clinical experts, two payers, and one representative from a pharmaceutical manufacturer to discuss how best to apply the evidence and votes to real-world practice and policy. The discussion reflected multiple perspectives and opinions, and therefore, none of the statements below should be taken as a consensus view held by all participants. A recording of the conversation can be accessed here, and a recording of the voting portion of the meeting can be accessed here. More information on Policy Roundtable participants, including conflict of interest disclosures, can be found in the appendix of this document. ICER's report on these treatments, which includes the same policy recommendations, can be found here. ©Ilnstitute for Clinical and Economic Review, 2021 Page 51 Final Report - Multiple Myeloma Return to Table of Contents The roundtable discussion was facilitated by Dr. Steven Pearson, MD, MSc, President of ICER. The main themes and recommendations from the discussion are organized by audience and summarized below. All Stakeholders All stakeholders have a responsibility and an important role to play in ensuring that effective new treatment options for patients with multiple myeloma are introduced in a way that will help reduce health inequities. African Americans are at a higher risk of developing multiple myeloma. Unfortunately, these individuals are also at a higher risk of not receiving adequate education about their condition, face a longer time between diagnosis to initiation of any therapy, are often late to receive guidance regarding new treatment options, and may have trouble accessing highly specialized therapies such as those that are the focus of this review. All stakeholders should accept and act upon their responsibility to address these disparities. e Manufacturers should engage with a variety of people from diverse communities to help inform the design and implementation of clinical trials, ensure that patients enrolled in pivotal trials are fully representative of people of color and those from less advantaged backgrounds. Relying solely on patient organizations and representatives already engaged in ASH and ASCO meetings may provide a skewed view of the diversity of patient perspectives. Active and broad outreach should be conducted to historically underserved patient populations. In addition, manufacturers should moderate new treatment pricing. Even with insurance coverage, cost is a tremendous driver of health inequities; thus, pricing that exceeds reasonable proportions to the added clinical and contextual benefits for patients will likely exacerbate health inequities, while pricing that is viewed as responsible may provide opportunities for improved access to patients facing financial barriers to care. e Payers should recognize that, in addition to often steep out-of-pocket costs for the treatments themselves, there are often ancillary costs which can become real barriers to care and exacerbate inequities. Specifically, these treatments may require travel to specialized centers, with the attendant travel costs and lost wages for accompanying caregivers. Payers should develop coverage that creates a broader package of benefits so that patients who face financial or logistical hurdles can have equal access to specialized care at Centers of Excellence, if desired. Another way to accomplish this goal is by expanding telemedicine coverage and creating parity (e.g., in out-of-pocket costs) between in-person and remote care, which can help patients receive care in their own communities while receiving input and second opinions from leading experts in other locations. Through one or multiple mechanisms, patients from rural and inner-city neighborhoods need broader benefit designs to give them the equal access they deserve. ©lnstitute for Clinical and Economic Review, 2021 Page 52 Final Report - Multiple Myeloma Return to Table of Contents e (Clinicians and clinical societies should conduct (or continue to conduct) active outreach and education to underserved communities and the general oncologists and other members of the health care team serving those communities to get new, effective treatments to those patients who would benefit most. Given the difficult trade-off decisions necessary in the choices for multiple myeloma treatment, clinicians should actively engage in and encourage shared decision-making to ensure that the values of patients with diverse needs and perspectives on risks and benefits of different treatments are at the heart of all treatment decisions. e Patient organizations for people with multiple myeloma should seek (or continue to seek) to represent diverse perspectives, requiring outreach to patients who may not be engaged by academic health systems, manufacturers, payers, policymakers, or other stakeholders. Patient groups should collaborate with organizations and people in diverse communities to build lasting relationships and trust. Patient organizations should also embrace their responsibility to address the impact of pricing of new treatment options on the ability of patients to access care. The patient voice should always be present as society wrestles with how to find the difficult balance between incentives for innovation and affordability. e We propose that these principles and individual considerations, explored throughout the ICER public meeting, should be the focus of a more comprehensive Multiple Myeloma Therapy Access Summit. With all stakeholders at the table, this Summit would develop these goals and specific actions further and forge them into a coordinated action plan for improvement. One element of such a plan should be transparent targets for improvement by which manufacturers, payers, clinical specialty groups, and patient advocacy groups would hold themselves and each other accountable in addressing the substantial inequities that our current health care system - and society - have allowed to persist. Manufacturers Manufacturers should seek to set prices that will foster affordability and good access for all patients by aligning prices with the patient-centered therapeutic value of their treatments. In the setting of these new interventions for multiple myeloma, while there is considerable hope associated with the promise of the therapies, there also remains substantial uncertainty regarding their longer-term safety and effectiveness, and the platform on which they are based has been funded in part with taxpayer money. Manufacturer pricing should also reflect these considerations in moderating launch pricing. Drug prices that are set well beyond the cost-effective range cause not only financial toxicity for patients and families using the treatments, but also contribute to general health care cost growth ©lnstitute for Clinical and Economic Review, 2021 Page 53 Final Report - Multiple Myeloma Return to Table of Contents that pushes families out of the insurance pool, and that causes others to ration their own care in ways that can be harmful. Manufacturers should therefore price novel treatments in accordance with the demonstrated benefits to patients. In settings of substantial uncertainty, initial pricing should err on the side of being more affordable. This would allow more patients access, generating additional data on the real-world effectiveness of novel treatments that could be used in future assessment updates. With accumulation of evidence of substantial patient benefit, manufacturers should be allowed to increase pricing in accordance with benefit. The initial developmental science underpinning anti-BCMA chimeric antigen receptor T-cells was conducted at the National Cancer Institute. Manufacturers should propose lower prices, particularly for public payers, in situations when a substantial part of the initial risk of drug development is borne by taxpayers. Clinical Specialty Societies Clinical specialty societies should advance education, policy, and practice mechanisms that facilitate awareness of treatment costs and financial burdens for patients as part of shared decision-making for individual patients. Given the huge impact of treatment costs on both society and patients, clinicians should be aware of the costs of the treatment options they are recommending to patients and develop the tools to incorporate patients' own financial considerations into transparent shared decision-making. As a general principle, when efficacy is similar between two treatment options, and patient preferences for different side effect profiles has been fully discussed, clinicians should recommend the less expensive option. Payers Payers should use the FDA label as the guide to coverage policy and engage clinical experts and diverse patient representatives in considering how to address coverage issues for which there is limited or no evidence at the current time. Given the significant uncertainty that remains about anti-BCMA therapy, it is reasonable for payers to use prior authorization as a component of coverage. Prior authorization criteria should be based on the FDA label, clinical evidence, specialty society guidelines, and input from clinical experts and patient groups. The process for authorization should be clear and efficient for providers and patients. Options for specific elements of coverage criteria within insurance coverage policy are discussed below. ©lnstitute for Clinical and Economic Review, 2021 Page 54 Final Report - Multiple Myeloma Return to Table of Contents Coverage Criteria: General Payers should offer alternatives to prior authorization protocols such as programs that give feedback on prescribing patterns to clinicians or exempt them from prior authorization requirements ("gold carding") if they demonstrate high fidelity to evidence-based prescribing. Patients should be provided information on the incentives and guidelines that clinicians consider when recommending a course of treatment. Payers should document at least once annually that clinical eligibility criteria are based on high quality, up-to-date evidence, with input from clinicians with experience in the same or similar clinical specialty. Clinical eligibility criteria should be developed with explicit mechanisms that require payer staff to document using an open and transparent process that is readily accessible to the public that they have: o Considered limitations of evidence due to systemic under-representation of minority populations and sought input from clinical experts on whether there are distinctive benefits and harms of treatment that may arise for biological, cultural, or social reasons across different communities; o Confirmed that clinical eligibility criteria have not gone beyond reasonable use of clinical trial inclusion/exclusion criteria to interpret or narrow the FDA label language in a way that disadvantages patients with underlying disabilities unrelated to the condition being treated. Drug-Specific Considerations: belantamab FDA Label: Adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Coverage Criteria: Diagnosis: Per clinician attestation Patient Eligibility Criteria: As per the FDA label, with no need for definition of clinical terms. Key inclusion criteria in pivotal trials included ECOG status of 0-2, and ineligibility for autologous stem cell transplantation or transplantation > 100 days prior. Clinical experts did not feel these criteria were needed for inclusion in coverage language in order to prevent inappropriate use. ©lnstitute for Clinical and Economic Review, 2021 Page 55 Final Report - Multiple Myeloma Return to Table of Contents Step Therapy: Besides the FDA label clinical requirements, there is no other treatment that could be considered a first-step treatment prior to eligibility for belantamab. Exclusion Criteria: Pivotal trials excluded patients with prior BCMA therapies or those who are on systemic high-dose corticosteroids, and those who have received allogeneic SCT. There is no evidence on the use of belantamab in patients who have had inadequate response or have recurrence following CAR-T treatment. Many payers are likely to restrict coverage pending clinical research on the risks and benefits of retreatment with anti-BCMA therapies. Duration of Therapy and Renewal of Coverage: N/A Provider Criteria: The therapy should be prescribed by an oncologist. Drug-Specific Considerations: CAR-T (ide-cel) FDA Label: Adult patients with relapsed or refractory multiple myeloma after 4 or more prior lines of therapy, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Coverage Criteria: Diagnosis: Per clinician attestation Patient Eligibility Criteria: As per the FDA label, with no need for definition of clinical terms. Key inclusion criteria in pivotal trials included ECOG status of 0-1. Clinical experts did not feel these criteria were needed for inclusion in coverage language in order to prevent inappropriate use. Step Therapy: Besides the FDA label clinical requirements, there is no other relevant treatment that could be considered a first-step treatment requirement prior to eligibility for CAR-T. The risks and benefits of belantamab are so different from those of CAR-T that it does not meet criteria for reasonable consideration of step therapy. Exclusion Criteria: Pivotal trials excluded patients who have received allogeneic SCT. There is no evidence on the use of CAR-T in patients who have had inadequate response or have recurrence following an anti-BCMA therapy such as belantamab. Many payers are likely to restrict coverage pending clinical research on the risks and benefits of retreatment with anti-BCMA therapies. Similarly, until further evidence is developed, payers are likely to restrict coverage to repeat CAR-T, whether a second round with the same CAR-T or a trial of ©lnstitute for Clinical and Economic Review, 2021 Page 56 Final Report - Multiple Myeloma Return to Table of Contents a different CAR-T. Clinical experts suggested, however, that requests for consideration of repeat CAR-T are likely and will require case-by-case consideration. e Duration of Therapy and Renewal of Coverage: N/A e Provider Criteria: The therapy should be prescribed by an oncologist. Medicare should consider new reimbursement strategies, including enhanced new technology add-on payments or demonstration projects that carve out pricing and payment for cell and gene therapy, to improve the chances that hospitals and clinics can provide the necessary services to deliver these novel therapies to patients safely. The early experience with CAR-T for lymphoma demonstrated the inefficiency of the existing Medicare payment structures for novel one-time therapies with high costs. Hospitals struggled to provide CAR-T without adequate reimbursement, leading to barriers to access for many patients. Medicare should consider changes to its reimbursement system to avoid such bottlenecks in the future. Approaches that should be considered include: a. Increasing the new technology add-on payment to 80% b. Consider a new demonstration project where cell and gene therapies are carved out, allowing CMS to buy directly from manufacturers and negotiate a value-based payment that includes outcomes-based measures. Clinical Research Community The clinical research community should move rapidly to address key gaps in evidence for treatments for multiple myeloma. These gaps include whether patients can stop therapy while in response, how well the clinical trial populations reflect the target populations for treatment, data on preferences and patient-reported outcomes in historically disadvantaged populations, and the clinical characteristics of the disease and its affected populations that may be predictive of response. Numerous important research questions remain regarding treatment options for multiple myeloma. First, nearly all studies conducted to date focus on continuing treatment until progression. Thus, it is unclear whether patients can safely stop therapy. Since therapies often expose patients to side effects and impose substantial financial costs, non-inferiority studies comparing a fixed duration of treatment to indefinite treatment until progression should be conducted. Since these studies will provide the evidence base for less drug use, manufacturers will not support these studies and public funding through entities such as the NIH will be necessary. ©lnstitute for Clinical and Economic Review, 2021 Page 57 Final Report - Multiple Myeloma Return to Table of Contents Second, the FDA should work with manufacturers to ensure that the studied population for any disease is representative of the population with disease. For example, the anti-BCMA studies were conducted in populations that were substantially younger and which included fewer African Americans than the US population of multiple myeloma patients, injecting additional uncertainty on whether the benefits seen in the studies will be replicated when these therapies are used in clinical practice. Third, additional research needs to be conducted regarding patient preferences and patient- reported outcomes in African American and other historically disadvantaged populations, to better inform accurate characterization of the impact of multiple myeloma in these groups and the potential benefits of new treatments. Finally, additional research is needed to determine which patient characteristics predict response, so that these costly, high side effect therapies can ideally be targeted to those patients most likely to benefit. ©lnstitute for Clinical and Economic Review, 2021 Page 58 Final Report - Multiple Myeloma Return to Table of Contents Supplemental Materials ©Institute for Clinical and Economic Review, 2021 Page 59 Final Report - Multiple Myeloma Return to Table of Contents A. Background: Supplemental Information Al. Definitions Disease Definitions: Triple-Class Refractory Multiple Myeloma: Multiple myeloma that has become refractory to the three common classes of myeloma medications: immunomodulators (l.e., lenalidomide), proteasome inhibitors (l.e., bortezomib) and a monoclonal antibody (l.e., daratumumab). Quad Refractory Multiple Myeloma: Multiple myeloma that has become refractory to 4 commonly used myeloma medications. Most commonly, quad-refractory disease is refractory to: 1 anti-CD38 monoclonal antibody (most often daratumumab), 1 or 2 immunomodulators (most often lenalidomide +/- pomalidomide) and 1 or 2 proteasome inhibitors (most often bortezomib +/- carfilzomib). Penta Refractory Multiple Myeloma: Multiple myeloma that has become refractory to 5 commonly used myeloma medications. Most commonly, penta-refractory disease is refractory to 2 immunomodulators {most often lenalidomide and pomalidomide), 2 proteasome inhibitors (most often bortezomib and carfilzomib) and an anti CD38 monoclonal antibody {most often daratumumab). Extramedullary disease: Multiple myeloma in which plasma cells form tumors outside of the bone marrow. Extramedullary disease is a sign of more aggressive myeloma and portends a worse prognosis. High-risk Cytogenetics: A chromosomal abnormality which has been shown to increase the risk of more aggressive disease. Intervention Definitions: CAR T-cell therapy: Chimeric antigen receptors {(CARs) are artificial fusion proteins constructed to recognize specific antigens. CAR T-cells are T-cell ymphocytes that have been genetically modified to express these CAR's, so that these T-cells can identify and to marshal an immune response against cancer cells that produce these antigens. The focus of this review, ide-cel and cilta-cel utilize CAR T-cells that recognize the B-cell Maturation Antigen which appears to be expressed on most malignant plasma cells. CAR T-cell therapy starts with 1) harvesting of the patient's lymphocytes with leukapheresis. 2) Lymphocytes are then modified in the laboratory to express the CAR protein. 3) These modified lymphocytes are expanded to sufficient numbers and 4) the modified, expanded lymphocytes are reinfused back into the patient. ©lnstitute for Clinical and Economic Review, 2021 Page 60 Final Report - Multiple Myeloma Return to Table of Contents Ide-cel: Idecabtagene vicleucel is a chimeric antigen receptor (CAR) T-cell therapy based on the first anti-BCMA CAR developed at the National Cancer Institute (11D5-3-CD828Z), using a mouse origin anti-BCMA moiety. CARs are artificial fusion proteins that combine a BCMA-recognition domain with a costimulatory domain*'. When reinfused into the patient, the genetically modified lymphocytes with the CAR proteins triggers a multi-pronged immune response, resulting in the destruction of cancer cells. Cilta-cel: Ciltacabtagene autoleucel is a chimeric antigen receptor (CAR) T-cell therapy based on the camelid heavy chain only anti-BCMA CAR. The camelid heavy chain (LCAR-B38M) incorporates 2 BCMA recognition domains, which theoretically should increase the specificity for BCMA. Otherwise, cilta-cel has a similar mechanism of action and treatment logistics to ide-cel.*' Belantamab mafodotin: a first-in-class, antibody-drug immunoconjugate consisting of an anti-BCMA monoclonal antibody and an anti-cancer drug. Belantamab mafodotin (referred to as belantamab for the remainder of the supplement) binds to BCMA-antigens and kills multiple myeloma cells via a multimodal mechanism. Belantamab induces cell apoptosis in addition to antibody-dependent cellular cytotoxicity (ADCC).%849 Outcome definitions; Studies rely on the International Myeloma Working Group (IMWG) Uniform Response Criteria definitions for outcomes.*° Complete Response (CR): Negative immunofixation on serum and urine AND disappearance of any soft tissue plasmacytomas AND <5% plasma cells in the bone marrow. Stringent Complete Response (sCR): Meets CR criteria AND normal free light chain ratio AND absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. Partial Response (PR): 2 50% reduction of serum M-protein AND reduction in 24-hour urinary M-protein by = 90% or to <200 mg/24 h If the serum and urine M-protein are unmeasurable, a 2 50% decrease in the difference between involved and uninvolved free light chain levels is required in place of the M-protein criteria. If serum and urine M-protein are not measurable and serum free light chain assay is also not measurable, = 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was 2 30%. In addition to the above criteria, if present at baseline, a =2 50% reduction in the size of soft tissue plasmacytomas is also required. ©lnstitute for Clinical and Economic Review, 2021 Page 61 Final Report - Multiple Myeloma Return to Table of Contents Very Good Partial Response (vgPR}: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 2 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h Overall Response Rate (ORR): Proportion of patients treated who had a partial response to treatment or better (PR + vgPR + CR + sCR) Minimal Residual Disease {MRD): Small number of cancer cells that can remain after treatment. MRD status predicts relapse. In MM, MRD is assessed in patients with CR, via sensitive techniques such as next-generation flow cytometry or next-generation sequencing.®! ©lnstitute for Clinical and Economic Review, 2021 Page 62 Final Report - Multiple Myeloma Return to Table of Contents B. Patient Perspectives: Supplemental Information B1l. Methods ICER conducted a wide-ranging effort to engage patients and advocacy groups to develop an understanding of perspectives of patients with MM. We drew on experience from the prior ICER review of MM therapies in 2016, reaching out to patient advocacy groups and individual patients engaged in the previous review. Specifically, we had a series of conversations with the Cancer Support Community, who were able to provide us with invaluable insights into the experience of MM patients within their community. They also helped us engage with individual patients who were able and willing to speak with us. We also engaged with Patients for Affordable Drugs, who also helped us identify patients we could speak to about their experience. We purposefully tried to engage African American patients to elicit their experiences, since they are overrepresented in the MM population and may face disparities in diagnosis and access to care. We contacted the International Myeloma Foundation and the Black Women's Health Imperative for further guidance on reaching out to specific myeloma patients and advice on any relevant data resources to assess racial disparities in myeloma care. We connected with the Association of Community Cancer Centers and spoke with an expert who commented on the differences in access to new myeloma treatments between large academic medical centers and community cancer centers. We had a series of conversations with individual patients with MM, as well as one focus group discussion. Conversations were informed by a semi-structured interview guide which focused the conversation on several themes, including: 1. What is your experience with different treatments that you have tried? o What has worked, what has not? o Side-effects o Impact on daily life, family, work 2. What are the financial aspects of the treatments you have tried? o Any issues with insurance, paying for the treatment 3. Where have you received care (in what type of hospital), what doctors have you seen? 4. What are you hoping to get from any new treatments that become available? ©Institute for Clinical and Economic Review, 2021 Page 63 Final Report - Multiple Myeloma Return to Table of Contents 5. What do you think are some key issues about patients' experience with multiple myeloma that are not being captured in major clinical studies or trials, including: Symptoms and complications of disease Impact of disease on function and quality of life Side effects of treatment Effects on caregivers and family members Any other issues O O O 0O O 6. For patients who have experience with CAR-T therapies: How well did it work for you? What were the side effects? What was the impact like on daily life, family, work? How was it like finding these treatments, how available or accessible do you think these are for patients? Compared to other treatments you have received for multiple myeloma, what was your experience like? Specifically, how did it feel to be "off" treatment after you received the CAR-T infusion? o Have you required any follow-up after CAR-T infusion? If so, is this routine follow-up or for complications of treatment? O O O O O We had an iterative process, where emerging themes were incorporated into subsequent conversations to determine whether these themes were universally felt by all (or most) patients or were idiosyncratic to a single (or few) patient(s). Furthermore, patients submitted individual feedback and shared their experiences via the Patient Input Questionnaire on ICER's website. After each of these conversations, patient comments were transcribed, collated, organized, and summarized. We drew upon the themes that emerged from our conversations and our summaries for the patient perspective sections of this report. B2. Cancer Support Community Myeloma Registry Survey Cancer Support Community (CSC) is an international nonprofit organization that provides support, education and hope to people impacted by cancer. CSC has conducted surveys of over 14,000 cancer patients across a wide variety of cancers, including multiple myeloma. We believe that these responses provide additional insight into the patient experience with myeloma and complement the qualitative responses provided in the report. We are indebted to the CSC for allowing us access to the following data. Table B1 highlights that side effects may be even more common than reported, as 25% of respondents reported not mentioning side effects because they didn't believe anything could be done. ©lnstitute for Clinical and Economic Review, 2021 Page 64 Final Report - Multiple Myeloma Return to Table of Contents Table B1. CSC Multiple Myeloma Specialty Registry Findings: Physical Symptoms and Side Effects Physical Symptoms and Side Effects Concerns Findings Respondents who did not report side effects because they didn't believe 5% anything could be done about their side effects Comfort level with speaking to their doctor about side effects and symptoms >99% positive Always: 5% Often: 9% Side effects impacted patients' decisions about treatments... Sometimes: 28% . . Very much: 33% How well respondents felt their health care team prepared them to manage side Quite a bit: 26% effects Somewhat: 22% Table B2 highlights the high prevalence of fatigue in multiple myeloma. Over half of survey respondents experience fatigue often or always and for over one-third of respondents, fatigue interfered with their daily lives "quite a bit" or "very much". Table B2. CSC Multiple Myeloma Specialty Registry Findings: Fatigue Fatigue Concerns Findings Respondents experiencing fatigue in the past 7 days 70% Always: 20% Often: 32% Respondents experienced fatigue... Sometimes: 29% Very much: 16% Quite a bit: 21% Somewhat: 26% Very much: 8% Quite a bit: 19% Somewhat: 25% Pain interfered with their daily lives... Pain interfered with respondents' ability to participate in social activities... Table B3 shows that pain is also a significant concern. One-third of respondents had pain often or always and 23% reported pain interfering with their daily lives "quite a bit" or "very much". Table B3. CSC Multiple Myeloma Specialty Registry Findings: Pain & Bone Pain Pain & Bone Pain Concerns Findings Respondents experiencing bone pain in the past 7 days | 48% Always: 19% Often: 15% Respondents experienced pain... Sometimes: 25% Very much: 13% Pain interfered with their daily lives... Quite a bit: 10% Somewhat: 18% . . ) L .. Very much: 8% Pain interfered with respondents' ability to participate Quite a bit: 11% in social activities... Somewhat: 12% Page 65 OInstitute for Clinical and Economic Review, 2021 Return to Table of Contents Final Report - Multiple Myeloma Table B4 highlights to importance of financial concerns to patients. Forty-two percent of respondents were always or often upset about the cost of care. Fifty-six percent of respondents felt overwhelmed by the demands of paying for care at least some of the time. Table B4. CSC Multiple Myeloma Specialty Registry Findings: Financial Concerns Financial Concerns Findings Respondents received financial assistance related to their multiple myeloma 63% Always: 19% Respondents felt upset about money and the cost of care... Often: 23% Sometimes: 21% Always: 8% Respondents felt overwhelmed by the demands of paying for medical care... Often: 19% Sometimes: 29% Always: 9% Respondents worried they won't be able to leave assets to their families Often: 13% Sometimes: 22% ©lnstitute for Clinical and Economic Review, 2021 Page 66 Final Report - Multiple Myeloma Return to Table of Contents C. Clinical Guidelines Due to the number of treatments that have recently become available, we focus on guidelines that have been published in the last 2 years. National Comprehensive Cancer Network (NCCN) Multiple Myeloma, V5, March 202152 The NCCN convened a panel of nationally recognized expert clinicians in the care of MM to develop a consensus statement on currently accepted approaches to treatment. While there are not specific recommendations for the triple/quad/penta refractory population that is the focus of our current review, they do provide recommendations on relapsed or refractory MM. Recommendation 1 (MYEL-7): For relapsed patients, consider a) treatments for previously treated myeloma, b) clinical trial and c) allogeneic stem cell transplant. Recommendation 2 (MYEL-7): For patients with refractory disease and lack of treatment options, refer to palliative care. Recommendation 3 (MYEL-F, 3 of 3): The NCCN listed a wide range of therapeutic options for patients with relapsed, previously treated MM, representing the lack of clear evidence on the preferred ordering of treatments. Specifically, they listed 9 preferred regimens, 19 other recommended regimens and 17 regimens listed as "useful in certain circumstances". Most were triplet regimens and nearly all regimens included dexamethasone. In addition, bortezomib, pomalidomide, carfilzomib, daratumumab, ixazomib, elotuzumab, selinexor and panobinostat were common components of listed regimens. American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) Joint Clinical Practice Guideline for Multiple Myeloma, Apr 2019 The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel of medical oncologists, surgeons, radiation oncologists, and patient advocates to conduct a review of the literature to develop evidence-based guidelines. While they did not address triple-class refractory patients, they did produce recommendations for myeloma patients with a first relapse. Recommendation 7.3: Triplet therapy (3 agents including a steroid, and 2 of the following 3 classes: proteasome inhibitor, immunomodulator and monoclonal antibody) is preferred. While toxicity appears to be increased with triplet vs doublet therapy, triplet therapy leads to improved PFS, ORR and OS, even in older adults. ©lnstitute for Clinical and Economic Review, 2021 Page 67 Final Report - Multiple Myeloma Return to Table of Contents Recommendation 7.5: Prior therapies should be taken into consideration when selecting the treatment in patient with relapsed multiple myeloma. Patients who have been off of a particular medication for >1 year are likely to respond to a repeat course of that medication. However, patients who relapse <1 year after exposure to a medication are less likely to respond; thus, novel medications are recommended in these situations. ©lnstitute for Clinical and Economic Review, 2021 Page 68 Final Report - Multiple Myeloma Return to Table of Contents D. Comparative Clinical Effectiveness: Supplemental Information D1. Detailed Methods PICOTS Population The population of focus for the review is patients who have at a minimum triple-class refractory MM, defined as disease that has progressed while on an anti-CD38 antibody (e.g., daratumumab), immunomodulatory drugs (e.g., lenalidomide), and a proteasome inhibitor {e.g., bortezomib). The indication for belantamab involves a population subset with somewhat more advanced disease (at least four prior lines of treatment, triple-, quad-, or penta-refractory patients) than those in the current Ide-cel and Cilta-cel trials (at least three prior lines, mostly triple- or quad-refractory). (lde- cel was recently approved for patients with 4+ prior lines of therapy.) We therefore did not make any explicit comparisons between belantamab and Idecabtagene vicleucel and Ciltacabtagene autoleucel, and we summarized evidence on relevant comparator therapies to match these population differences (see below). Data permitting, we included evidence across relevant subgroups, such as patients with genetic factors that put them at particularly high risk as well as subgroups defined by race. Interventions The full list of interventions is as follows: e |decabtagene Vicleucel (Ide-cel, Abecma®, Bristol Myers Squibb and bluebird bio) ¢ Ciltacabtagene Autoleucel (Cilta-cel, Janssen and Legend biotech) e Belantamab mafodotin (Blenrep®, GlaxoSmithKline) Comparators We used the characteristics of patients enrolled in each of the pivotal studies of the drugs under consideration to guide the most appropriate comparator treatments (i.e., the regimens patients would have received if the drugs under consideration were not an option). Since the belantamab study focused on a more heavily pre-treated population, the comparator cohort for belantamab differs from the comparator cohort for Ide-cel and Cilta-cel. ©Institute for Clinical and Economic Review, 2021 Page 69 Final Report - Multiple Myeloma Return to Table of Contents We compared the selected interventions to commonly used regimens in triple-class refractory populations as well as to palliative care (no active anti-cancer therapy). The comparator regimens include: ¢ Carfilzomib + cyclophosphamide + dexamethasone (KCd) e Pomalidomide + cyclophosphamide + dexamethasone (PCd) e Carfilzomib + pomalidomide + dexamethasone (KPd) ¢ Elotuzumab + pomalidomide + dexamethasone (EPd) Outcomes The outcomes of interest are described in the list below. - Patient-Important Outcomes Overall survival (OS) Quality of life Complete response rate Progression-free survival (PFS) Durability of response Pain and function O O O 0O 0O 0 O O Treatment burden Bone fractures Adverse events including: cytokine response syndrome fatigue/sleep disturbance infection peripheral neuropathy ocular toxicity anemia gastrointestinal toxicity thromboembolism death e Other Outcomes o Overall response rate O O O Partial response rate Minimal residual disease Blood and urine markers of disease OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 70 Return to Table of Contents Timing Evidence on intervention effectiveness and harm was derived from studies of any duration. Settings Evidence from all relevant settings were considered. ©lnstitute for Clinical and Economic Review, 2021 Page 71 Final Report - Multiple Myeloma Return to Table of Contents S1U9U0) JO 3|qe] O} uin3ay 7L 98ed ewo|aA a|di|ny - Hoday jeuld 10T 'M3IASY J1WOU0DT pue [eJIUI[D 10§ 3INISUIQ S1INS3H 'paynads-aid asam yaym uneoipui 'suop Ji '(uoissasdal-elaw 'sasAjeue dnoadqns Jo AlAINSUDS ""8°9) sasAjeue |euonlippe JO Spoylsw aqaasaqg 9T sasAjeue [euollippy "(se1pnis ulyum sajpnis Buiodau aapoa|as 'seiq uonesiignd "8:9) 93uUspIAS SAIIEINWIND 3Y3 133 Aew eyl seiq Jo ysi Jo Juawssasse Aue Ajpads ST ssoJoe seiq Jo )ySiy 'sisAjeue-e1aw yoea Joj (| g-a) Aduaisisuod o saunseaw Suipnjoul 'auop i 'salpnls Jo sy nsaJ Sujuiquod pue elep Sujjpuey Jo spoyldw ayl aquasaq | YT S}|NS3. JO SISOYIUAS *(sueaw uj 33UBBIP 'Ol1ed ysi 8 9) sainseaw Asewwns |edpupd oy ajels €T sainseaw Alewwns *SIS3YJUAS elep Aue uj pash 8q 03 S| UOIIBWLIOJUI SIY] MOY PUB '(|9A3] 3W023N0 4o Apnls 3y} S9IpNis |enpiAIpul 1e SUOp Sem SIY3 JaYlaym Jo uolieayydads Suipnjaul) saipnis [enplAlpu] JO seiq JO Ysil Sujssasse 1o} pash spoylsw aquasaq | T uj sejyq Jo sy 'apew suolesylidwis pue suopndwnsse Aue pue (s32.4n0s Sujpuny 'SOJId "8°3) IYBnos auam eilep Ydiym o) sa|qeleA [|e suyap pue sl | TT swayl ejeq *s101e31359AU] WoJj eyep Sulwujuod pue Sujuieiqo Joy} sassado.d Aue pue (a3ediidnp uj 'Ajpuspuadapul 'swuoy pajojid ~8'9) spodas wody uondeIIXS Blep JO poyIaw 3q14asaq OT | ss@20.d uo)3d39jj03 elRQ *(sisAjeue-elaw ay3 u| papnjaul 'O|qedijdde Ji 'pue 'malnal d11ewd1sAs ul papnpoul 'Al|iqiBija 'Buiuaauds "a°1) saipnis S8ul109]as 104 ssa204d ay) a1els 6 uond3|as Apnis 'pajeadal aq pinod M 1eyil yons 'pasn sywi| Aue Suipnpul 'oseqejep suo 1sed) je 10} ASd1eJls Yoaeas J1U041II|I [N} JUDSDId 8 ydueas 'payd.eas 1se| a1ep pue yaiess ayl uj (saipnis |euolyippe Ajluspi 03 sioyine Apnis YHm 10e1u0d '98eI3A02 JO s3ep YUMm saseqelep "8'9) s82unos uonew.ojul [|e aqiasaq L $92.n0s uolnew.oju| *9leuoinles SulAI8 'AJIgi81[9 Joy Bl Se pash (shiels uonediignd '98en3ue| 'pasapisuod sieah "§'9) sonsualoeleyd podas pue (dn-mojjo4 Jo Y18ua| 'SOIId "3'9) sansualaeseys Apnis Ajidads 9 enaa Aupqisig -19quinu uoneJisi8au Suipnpul uonew.oyul uoneslsi8al uoneJysidau apiaoud 'a[ge|ieAe J| 'pue '(ssauppe gap "8'8) passadie aq ued } 9JaYm pue Ji 's3SI |03030.d maIA3I B J 91eI]pU| S pue [03010.d SAOH13IN '(SODId) uBisap Apnis pue 'sawo021no 'suosiiedwod 'suojjudanialul 'syuedidipied 03 33ud493. YIm passalppe Suiaq suoiisanb Jo Juswaiels Hd1dxa ue apinoid v saAnddiqo 'umouy| ApeaJje S| Jeym JO IX3JU0D By} Ul MIIADI dY] JOJ DBUOIIRI DY} 9qIIISdQ € djeuoney NOILONAOYLNI "1aquinu uoljesi8al malaal a1jewd)sAs sBulpuly Aoy JO suojedidwi pue suoIsnpUOd {suoijenwl| {s3nsaJ 'spoylaw sisayjuAs pue |esiesdde Apnis {suoiusariiul pue 'syuedpiped 'eld ANIqiBia Apnis {S924nos elep (saAld3(qo 'punodydeq :ajqedijdde se 'Buipnjpul Alewiwins painidniis e IpIAcd Z Atewwins painidnas 1ovdisay *y1oq Jo 'sisAjeue-e1aw 'malAal d1lewsAs e se podad syl Ajiuap) _ T _ L ILIL sway| 1siI3Y) | ISIPI9Y) 600Z VIWSINC T°T1d @Iqel SJUDIUO) JO 9|qe] 0} UIN1ayY ewo|aA a|di|ny - Hoday jeuld €/ 98ed TTOC 'M3IA9Y d1WOU0d3] pue |edjul[) JO} 91NUISUIQ £60000Tpawd|ewinol/T/ET°0T:I0P "Z60000T? :(9)9 PAIN SOTd "IUSWS1LIS VINSIYd 9y :sasAjeuy-e19|N pue SMaIAdY J11eW]SAS 10y swal| Suiuoday patssyald (600¢) dnolo YINSING YL "DQ Uewlly 'r Jejz1a] 'v 11elaqi] 'g 4124o wou4 "MBIABJ J131BWDISAS ayz1 Joy s1apuny jo ajou (erep jo Ajddns "8'a) 1ioddns Jaylo pue malaal d11eWI1SAS BY] 40} Sulpuny Jo $92INOS 3qLIISAQ] LT Suipun4 ONIGNNd *YoJeasal aunjny 1o} suoiiedijdwl pue '92uspiAd JBY10 JO IXDIU0D 3Y) U] S} NSaU 3y} Jo uoneidudiaiul |essusd e aplnold | 9z suoisnpuo) *(seiq Sujpodal 'Yoseasau paljlluapl Jo |eAal1aa 919|dwodul "3:9) |9ASI-MIIABI 1B pue '(selq Jo sl "8'9) [9A9] WodINo pue Apnis je suoneywl| ssnasiq | ¢ suonejywi] '(s4a)ew Adjjod pue 'siasn 'siapiroad ased yijesy "8-s) sdnoud A3y 01 3dUBA3|31 J19Y3} JAPISUOD DLIOIINO UIRW YIBD J0) 3JUBPIASI Jo Yy18uals ayl Buipnpui sSuipulj uilew ayy azuewwns | 4z 2JUIPIAD Jo Alewwng NOISSNJsia ([9T wa}| 935s] uoissaidas-e1ow 'sasAjeue dnoadqns Jo AlAINSUSS "8°9) suop I 'sosAjeue |BUOIIIPPE JO S} NSDJ DAID €2 sisAjeue jeuolippy sa|pnis *(GT Wy 935) SaIpPNIS SSOJIE SElq JO YSIJ JO JUBISSASSE AU JO S} nsau Juasald | Z¢ SS0.JE selq Jo )siy *AoUd351SU0D JO SINSESW pue S|eAISIUI DIUDPIIUOI Bulpn[aul 'Buop sisAjeue-e1aw yoea Jo S3jnsal Juasald | T S3|nsaJ JO SISOYIUAS *10|d 15940J B UM A||E3pI 'S|EAID]UI DIUIPIIUOD pue SD1BeW|1SD 1039 (q) dnoud saIpnis UOJIU3AIRIUI Yoea Jo) erep Atewwns ajdwis (e) :Apnis Ydes 1o} 'Juasald '(swJiey Jo SHJauUsq) paiapisuod sswodlno |eJod | 0F |enpiAlpul Jo s1nsay sa|pnis '(2T wall 99s) JUBWISSISSE [9A3] 3WO0IINO0 Aue 'B|qe|IBAR JI 'pUB ApN3S UIEa JO Seiq JO )SIJ Uo Blep Juasald | 61 UIYHMm selq Jo ysiy *suoneld ayl apinoud pue (polad dn-moj||0} 'SODId '9zIs Apnis "8°9) poldeJIXa dJ9M BIep YdIYM Joy} sanlsialoeleyd Juasald 'Apnis yoes Jo4 8T sansaeIeyd Apnis 'weJde|p moyj) e yum Ajjeapi 'a8e3s Yoea 1e SUoISN|oXa 10} SUOSEDS YUM 'MBIASI BY3 Ul papn|dul pue 'A}|1qIS1|2 Jo) passSasse 'pauaalds SAIPNIs JO SIBqUINUBAID | /T uo3|as Apnis Data Sources and Searches Procedures for the systematic literature review assessing the evidence on new therapies for relapsed and refractory multiple myeloma followed established best research methods.'*>> We conducted the review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.® The PRISMA guidelines include a checklist of 27 items, which are described further in Supplemental Table D1.1. We searched MEDLINE and EMBASE. Each search was limited to English-language studies of human subjects and excluded articles indexed as guidelines, letters, editorials, narrative reviews, case reports, or news items. We included abstracts from conference proceedings identified from the systematic literature search. All search strategies were generated utilizing the Population, Intervention, Comparator, and Study Design elements described above. The proposed search strategies included a combination of indexing terms {MeSH terms in MEDLINE and EMTREE terms in EMBASE), as well as free-text terms. To supplement the database searches, we performed manual checks of the reference lists of included trials and systematic reviews and invited key stakeholders to share references germane to the scope of this project. We also supplemented our review of published studies with data from conference proceedings, regulatory documents, information submitted by manufacturers, and other grey literature when the evidence met ICER standards (for more information, see https://icer.org/policy-on-inclusion-of-grey-literature-in-evidence-reviews/) Where feasible and deemed necessary, we also accepted data submitted by manufacturers "in-confidence," in accordance with ICER's published guidelines on acceptance and use of such data https://icer.org/guidelines-on-icers-acceptance-and-use-of-in-confidence-data-from- manufacturers-of-pharmaceuticals-devices-and-other-health-interventions/) ©lnstitute for Clinical and Economic Review, 2021 Page 74 Final Report - Multiple Myeloma Return to Table of Contents Table D1.2. Search Strategies for Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Versions(R) 1946 to Present* # Search Term 1 | Exp Multiple Myeloma/ ("Multiple Myeloma" or "Multiple Myelomas" or "Myeloma, Multiple" or "Myeloma, Plasma cell" or "Plasma cell myeloma" or "Plasma cell myelomas" or "Myelomatosis" or "Kahler Disease" or "Myeloma" or "Myelomas").ti,ab OR (("relapsed" or "refractory" or "pretreated" or "high risk") and ("multiple myeloma")).ti,ab 3 (1or2 ("CAR T" or "CAR-T" or "chimeric antigen receptor" or "CAR-T cell" OR "Anti BCMA" or "anti-BCMA" or "CMA CAR-T" or "b-cell maturation antigen" OR "anti b-cell maturation antigen" OR "CD269").ti,ab ("blenrep" or "belantamab" or "belantamab mafodotin" OR "belantamab mafodotin-bimf" or "GSK2857916" or "GSK 2857916" OR "GSK-2857916" OR "gsk916" OR "gsk 916" or "gsk-916").ti,ab. 6 | ("bb2121" or "bb-2121" OR "bb 2121" or "idecabtagene vicleucel" or "ide-cel" OR "ide cel").ti,ab. ("JNJ-68284528" OR "JNJ68284528" OR "JNJ 68284528" OR "JNJ4528" OR "JNJ 4528" OR "LCAR-B38M" OR "cilta-cel" OR "cilta cel" OR "ciltacabtagene autoleucel").ti,ab. {{{"pomalidomide"" or "pomalyst"} and ("Cyclophosphamide" or "Cytoxan") and ("dexamethasone" or "decadron" or "Dexamethasone Intensol" or "Dexpak Taperpak" or "prednisone")) or {("Carfilzomib" or "Kyprolis") and ("pomalidomide" or "pomalyst") and ("dexamethasone" or "decadron" or "Dexamethasone Intensol" or "Dexpak Taperpak" or "prednisone")) OR {("Elotuzumab" OR "Empliciti") AND ("pomalidomide" OR "pomalyst") AND ("dexamethasone" OR "decadron" OR "Dexamethasone Intensol" OR "Dexpak Taperpak" or "prednisone")) OR {("Carfilzomib" OR "Kyprolis") AND ("Cyclophosphamide" OR ""Cytoxan") AND ("dexamethasone" OR "decadron" OR "Dexamethasone Intensol" OR "Dexpak Taperpak" or "prednisone"))).ti,ab. 9 |4orS5or6or7o0r8 10 | 3and 9 11 | animals not (humans and animals).sh. 12 [ 10not 11 13 | limit 12 to English language 13 and ("chapter" OR "comment" OR "editorial" OR "letter" OR "note" OR "short survey" OR "review" OR "opinion").pt 15 | 13 not 14 * Search last updated on March 08, 2021. 14 ©lnstitute for Clinical and Economic Review, 2021 Page 75 Final Report - Multiple Myeloma Return to Table of Contents Table D1.3. Search Strategy for EMBASE* # Search Term #1 | 'multiple myeloma'/exp ('multiple myeloma' OR 'refractory multiple myeloma' OR 'relapsed multiple myeloma' OR 'Kahler " disease' OR 'morbus Kahler' OR 'myeloma multiplex' OR 'Myelomatosis' OR 'Myeloma' OR 'Myelomas' OR 'plasma cell myeloma' OR {('relapsed' OR 'refractory' OR 'pretreated' OR 'high risk') and 'multiple myeloma')):ti,ab #3 | #lor#2 a1 ('car t' OR 'CAR-T' OR 'chimeric antigen receptor' OR 'anti-BCMA' OR 'anti bcma' OR 'b cell maturation antigen' OR 'anti b-cell maturation antigen' OR 'CD269'):ti,ab #5 | 'belantamab mafodotin'/exp OR 'belantamab'/exp 46 ('gsk2857916' OR 'gsk 2857916' or 'gsk-2857916' or 'gsk916' or 'gsk 916' OR 'gsk-916' OR 'belantamab' or 'belantamab mafodotin' or 'belantamab mafodotin-bimf' or 'blenrep'):ti,ab #7 | #5 OR#6 #8 | 'idecabtagene vicleucel'/exp #9 | ('bb2121'OR 'bb 2121' OR 'bb-2121' OR 'ide-cel' OR 'idecabtagene vicleucel' OR 'ide cel'):ti,ab #10 | #8 OR#9 #11 | 'jnj 68284528'/exp or 'ciltacabtagene autoleucel'/exp #12 | ('jnj 4528' OR 'jnj68284528' OR 'Icar-b38m' or 'cilta-cel' or 'cilta cel' or 'ciltacabtagene autoleucel'):ti,ab #13 | #11 OR #12 ({{'pomalidomide') AND ('cyclophosphamide') AND {'dexamethasone' OR 'prednisone'})) OR ('carfilzomib' #14 AND 'pomalidomide' AND ('dexamethasone' OR 'prednisone'})) OR ('elotuzumab' AND ' pomalidomide' AND ('dexamethasone' or 'prednisone')) OR ('carfilzomib' AND 'cyclophosphamide' AND ('dexamethasone' OR 'prednisone'))):ti,ab #15 | #3 AND (#4 OR #7 OR #10 OR #13 OR #14) #16 | ('animal'/exp OR 'nonhuman'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT 'human'/exp #17 | #15 NOT #16 #18 | #17 AND [English]/lim #19 #18 AND ('chapter'/it or 'comment'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it OR 'short survey'/it OR 'review'/it OR 'opinion'/it) #20 | #18 NOT #19 * Search last updated on March 08, 2021. ©lnstitute for Clinical and Economic Review, 2021 Page 76 Final Report - Multiple Myeloma Return to Table of Contents Figure D1. PRISMA flow Chart Showing Results of Literature Search for Idecabtagene vicleucel, Ciltacabtagene autoleucel, and Belantamab mafodotin 979 references identified 18 references identified through literature search through other sources v 966 references after duplicate removal 966 references screened 856 citations excluded e N\ 75 citations excluded 110 references assessed > 29 Duplicates for eligibility in full text 15 Intervention 14 Outcomes - 9 Study Design l 8 Population /-\ 35 total references 0 RCTs \- ©Ilnstitute for Clinical and Economic Review, 2021 Page 77 Final Report - Multiple Myeloma Return to Table of Contents Study Selection We performed screening at both the abstract and full-text level. Two investigators screened all abstracts identified through electronic searches according to the inclusion and exclusion criteria described earlier. We did not exclude any study at abstract-level screening due to insufficient information. For example, an abstract that did not report an outcome of interest would be accepted for further review in full text. We retrieved the citations that were accepted during abstract-level screening for full text appraisal. Two investigators reviewed full papers and provided justification for exclusion of each excluded study. We also included FDA documents related to belantamab and ide-cel. These included the manufacturer's submission to the agency, internal FDA review documents, and the transcript of Advisory Committee deliberations and discussions. All literature that did not undergo a formal peer review process is described separately. Data Extraction and Quality Assessment Because we did not identify any comparative trials of the interventions, we did not assess the quality of the individual trials. Assessment of Level of Certainty in Evidence We used the ICER Evidence Rating Matrix to evaluate the level of certainty in the available evidence of a net health benefit among each of the interventions of focus (see Figure 3.1 of the main report).>'~8 Assessment of Bias As part of our quality assessment, we evaluated the evidence base for the presence of potential publication bias. We performed an assessment of publication bias for Ide-cel, Cilta-cel and belantamab using the clinicaltrials.gov. We scanned the site to identify studies completed more than two years ago that would have met our inclusion criteria and for which no findings have been published and did not find any evidence of publication bias. The primary concern is the lack of peer-reviewed, published data for the KarMMa and CARTITUDE-1 trials as well as the lack of head- to-head trials of the interventions compared to usual care. Data Synthesis and Statistical Analyses Data on relevant outcomes were summarized in evidence tables (See Supplement D3) and synthesized qualitatively in the body of the review. Due to differences in study populations and limitations of study design (single-arm trials), outcomes are described for each trial separately. ©lnstitute for Clinical and Economic Review, 2021 Page 78 Final Report - Multiple Myeloma Return to Table of Contents D2. Additional Clinical Evidence Evidence Base Ide-cel In addition to the pivotal phase Il KarMMa trial described in the main report, we also identified a phase | trial of bb2121 (ide-cel), CRB-401.5%5° CRB-401 was a phase 1 open-label single-arm dose- escalation and dose-expansion, multi-center US-based trial. The trial enrolled 62 adults (21 in the dose-escalation and 41 in the dose-expansion phase) who had previously received three lines of therapy {including an IMiD and a PI), or were refractory to both classes. The dose-expansion phase also required exposure to daratumumab and that patients be refractory to the last line of therapy. Patients underwent leukapheresis, bridging therapy during manufacturing, and lymphodepletion with fludarabine and cyclophosphamide prior to infusion with 50, 150, 450, or 800x10° CAR-T cells in the dose-escalation phase and 150 to 450x10° CAR-T cells in the expansion phase. 33 patients were analyzed in the original publication and 62 patients were analyzed in the updated analysis as of January 2020. %% The primary outcome was safety. Secondary outcomes were overall response rate (ORR) and duration of response. More details on both KarMMa and CRB-401 are provided in Table D3.1. Cilta-cel In addition to the pivotal phase Ib/Il CARTITUDE-1 trial described in the main report, we also identified a phase | trial of cilta-cel (LEGEND-2). LEGEND-2 is a Phase | single-arm trial conducted at four sites in China.136%62 The trial enrolled 74 adults with TCRMM who had progressive disease after at least 3 prior therapies (including a Pl, an IMiD, and anti-CD38 antibody). The trial explored the differences between a single and three CAR-T cell infusion approach with varying doses (0.2-2.0x108 CAR-T cells/kg) as well as cyclophosphamide alone versus in combination with fludarabine during conditioning. For this report, we will include data from the largest study site (Xi'an, N=57) because data was not aggregated across all four sites. The primary outcome was AEs; the secondary outcome was CR. More details on both trials are provided in Table D3.1. Belantamab In addition to the pivotal phase I, open-label, two-arm, multicenter trial of belantamab (DREAMM- 2), we identified a pooled post-hoc analysis of DREAMM-1 and DREAMM-2 and one expanded access study. Neither of the two additional studies had been published at the time of this report, and data was only available in form of conference abstracts/posters. ©lnstitute for Clinical and Economic Review, 2021 Page 79 Final Report - Multiple Myeloma Return to Table of Contents DREAMM-2: DREAMM-2, the pivotal trial of belantamab in adults with triple-class refractory multiple myeloma, is an ongoing global, open-label, phase Il randomized multicenter trial comparing the efficacy and safety of two doses of belantamab (2.5 mg/kg and 3.4 mg/kg).'' Patients were treated with intravenous belantamab every three weeks until disease progression, or unacceptable toxicity occurred. Dosing delays or reductions were permitted for the management of adverse events. Efficacy and safety outcomes were assessed every three weeks after the first course of treatment had been administered.'" Due to the risk for ocular toxicity of belantamab, ophthalmic testing was required prior to each round of treatment.'" To further mitigate corneal events, patients were administered prophylactic corticosteroid eye drops as well as artificial tears. Pooled post-hoc analysis: Trudel 2020 presented pooled tolerability and safety data from the DREAMM-1 and DREAMM-2 trials.?* DREAMM-1 was an open-label phase I trial and included adult patients with RRMM, who had previously failed 3 or more lines of treatment, and were refractory to an alkylator, PI, and IMiD. DREAMM-2 has been described previously in this report. A total of 264 patients were randomized to either 2.5 mg/kg (N=103) or 3.4 mg/kg (N=161) every three weeks.5 For the purpose of this review, we will only discuss the arm that received the FDA approved dose of 2.5 mg/kg. The median age of patients was 65 years and 50% of the randomized patients were male. The study population also included a subset of RRMM patients at higher risk of more aggressive disease, including 40% with ISS stage lll, 20% who exhibited extramedullary disease (EMD), and 27% with high-risk cytogenetic features. The median number of prior lines of therapy was 7 (range 3 to 21). Expanded Access Program: This multicenter, observational study included 32 patients with RRMM who were treated under the expanded access compassionate care program at 6 Israeli multiple myeloma centers.5* The primary outcome assessed was progression-free survival. Secondary outcomes included overall response rate, overall survival, as well as safety and tolerability. Between July 2019 and February 2020, 32 patients were treated with at least one dose of belantamab (median 3; range 1-11) and identified for inclusion in this study. Median follow-up duration was 5.7 months (range 0.5 - 13.8 months) and data were obtained from medical charts. A total of 13 patients received the 2.5 mg/kg dose, and 17 patients received the 3.4 mg/kg dose, respectively. Of note, this study did not present stratified results of the two separate doses, and therefore, the results presented contain both doses. Thus, these results should be synthesized cautiously with other studies which focused solely on patients receiving the FDA approved 2.5 mg/kg dose. Patients included had a median age of 70 years, over half were male (59%), and roughly 20% were considered to have high-risk cytogenetics. The heavily pre-treated patients had received a median of 6 prior lines of treatments {range 3-11), with a majority having been previously exposed to bortezomib (94%), carfilzomib (74%), lenalidomide (91%), pomalidomide (87%), or daratumumab ©lnstitute for Clinical and Economic Review, 2021 Page 80 Final Report - Multiple Myeloma Return to Table of Contents (97%). The overwhelming majority of included participants (97%) had also received an autologous stem-cell transplant. Usual Care The main report discusses the primary source of outcomes data to inform our comparison of the interventions to usual care, the MAMMOTH study." Two additional retrospective studies were identified with sufficient numbers of triple-class refractory patients (Mehra 2020 and Goldsmith 2020). In Mehra 2020, patient data were abstracted from a US-based electronic health record system from January 2011 to October 2019.?7 A total of 251 patients with at least triple-class refractory multiple myeloma were included in the analysis. Of those, 73 (29%) were "penta- refractory". Primary outcomes were overall survival (OS), progression free survival (PFS}), and time to next treatment (TTNT). In Goldsmith 2019, data from 58 patients were abstracted from health records at a single US-based academic center from January 2013 and August 2018.%% Patients were either quad or penta-refractory and treated with at least one cycle of bendustamine/prednisone (BP) or dexamethasone, cyclophosphamide, etoposide, cisplatin (DCEP). Primary outcomes were PFS and OS. Additional information on the study design of the usual care studies are available in Table D3.18 and baseline characteristics are available in Table D3.19. Effectiveness Ide-cel Outcomes from the pivotal phase Il trial of ide-cel (KarMMa) are described in the main report. In the phase 1 dose-escalation/expansion trial, CRB-401 {(n=62), as of January 2020, median follow-up was 14.7 months, as-treated median PFS was 8.8 months (95% Cl: 5.9-11.9 months), and as-treated median OS was 34.2 months (95% Cl: 19.2-not estimable). As-treated ORR was 75.8% and as- treated stringent or complete response (sCR or CR) was 38.7%. As with KarMMa, ORR appeared to be dose-related in CRB-401. As-treated ORR in the higher dose (450x10°) was 90% compared to 50% in the lower dose (150x10°). As-treated median duration of response was 10.3 months overall (95% Cl: 7.7-13.7 months).%° More detailed outcomes from both the KarMMa and CRB-401 trial are provided in Table D3.3. Details on HRQoL outcomes from KarMMa are provided in Table D3.10. ©Ilnstitute for Clinical and Economic Review, 2021 Page 81 Final Report - Multiple Myeloma Return to Table of Contents Cilta-cel The main report provides outcomes from the pivotal phase Ib/Il trial (CARTITUDE-1) In the Phase | trial (LEGEND-2, Xi'an study site), with a median follow-up time of 25 months, median PFS was 19.9 months, median OS was 36 months, and ORR was 87.7%.5>%¢ Because all patients in LEGEND-2 who were enrolled were leukapheresed and underwent infusion, an ITT analysis was not applicable, however comparisons based on data from LEGEND-2 should be interpreted with caution due to differences in the patient population. Detailed outcomes from both trials are provided in Table D3.4. Details on HRQoL outcomes from CARTITUDE-1 are provided in Table D3.10. Belantamab DREAMM-2: The DREAMM-2 study reported ITT results; thus, the following results are all calculated on an ITT basis. At 13-month follow-up (data cut-off date: January 2020), 13 and 11 patients treated with 2.5 mg/kg belantamab achieved PR and vgPR, respectively. The median duration of response was 11 months (95% Cl: 4.2 to not reached). Time to initial response and time to CR was not reported.?® Out of 97 participants, 59 had progressive disease at 6.3 months of follow-up.'' More detailed outcomes from DREAMM-2 are provided in Table D3.5 and for additional data on HRQoL please refer to Table D3.10. Expanded Access Program: Overall, the median duration of PFS achieved by DREAMM-2 trial participants was 2.6 months. Twelve out of 29 patients who were evaluable, achieved an ORR (with 3 participants achieving PR, 8 achieving VGPR, and one participant achieving CR). OS at 6 months was 68%. Statistical analyses were not reported. A subgroup analysis showed that ORR and PFS were comparable between patient who had been previously treated with <5 prior lines of treatments, and those who had previously received more than 5. More detailed outcomes from the Expanded Access Program can be found in Table D3.17. Usual Care Outcomes from the retrospective MAMMOTH study are discussed in the main report." We also identified two additional retrospective studies (Goldsmith 2020 and Mehra 2020) to inform our comparison of usual care to the interventions. In these trials, median PFS varied from 1.4 months to 4.8 months, median OS varied from 6.2 months to 11.0 months, and ORR was around 31%2%%7, The patient populations of these studies varied, particularly in the percentage of patients with penta-refractory disease (29% in Mehra and 78% in Goldsmith). Additional outcomes data for the MAMMOTH study is available in Table D3.20 and for the two additional retrospective studies is available in Table D3.21. ©lnstitute for Clinical and Economic Review, 2021 Page 82 Final Report - Multiple Myeloma Return to Table of Contents Harms Ide-cel AEs from the pivotal phase Il trial of ide-cel (KarMMa) are described in the main report. In the phase 1 dose-escalation/expansion trial, CRB-401 (n=62), the most frequent grade three or higher AEs were neutropenia (92%), leukopenia (61%), anemia (57%), and thrombocytopenia {(57%). CRS was also common, occurring in 76% of patients and requiring tocilizumab in 21%. Sixty-nine percent had low to moderate (Grade 1 or 2) CRS, 7% had severe (Grade 3) CRS, and none had a grade 4 CRS. As in the KarMMa trial, risk of CRS in CRB-401 was dose-related. 92% of patients in the higher dose group (450x10°) reported any grade CRS compared to 11% in the lower dose group (150x10°). 82% of patients 265 experienced any grade CRS. As of the January 2020 cutoff date, 49 (79%) had discontinued due to progressive disease (58%), withdrawal by patient (10%), or death (10%).%" More detailed safety data from both the KarMMa and CRB-401 trials are provided in Table D3.11. Cilta-cel The main report provides adverse events from the pivotal phase 1b/Il trial of cilta-cel (CARTITUDE- 1). In the phase | trial (LEGEND-2, Xi'an site) of cilta-cel, CRS was common (89.5%) and with 25 months of follow-up, 17 deaths (29.8%) were reported, 14 (24.6%) due to progressive disease and 2 (3.5%) due to AEs. Other important AEs included thrombocytopenia (49.1%) and neurotoxicity (1.8%).55%5 Detailed safety data from both trials are provided in Table D3.12. Belantamab DREAMM-2: Most dose delays, as well as dose reductions were due to keratopathy (45/51 and 24/33 patients, respectively).? Adverse events grade 3 or above were reported by 84% of patients treated with belantamab, and the most commonly reported events were keratopathy (46%), thrombocytopenia (22%), and anemia (21%). Median time to onset of the first corneal event was 37 days and lasted for a median duration of 86.5 days.!® The occurrence of ocular toxicities increased with increasing number of doses; 25% of patients reported ocular toxicities after the first dose, 69% reported their first corneal event after by the fourth dose. Only two patients developed a corneal event subsequent to having received 4 doses. Overall, 24 patients reported experiencing blurred vision and 14 patients experienced dry eyes. CRS or neurotoxicity was not reported by any patient in the DREAMM-2 trial. Please refer to Table D3.13 for a more detailed description of safety data. Pooled Analysis: Patients received a median of 3 courses of treatment with 2.5 mg/kg belantamab (range 1- 15). Most patients (98%) experienced at least one AE, of which 90% were considered treatment related. Serious adverse events (SAEs) were reported by 42 participants, with 13 ©lnstitute for Clinical and Economic Review, 2021 Page 83 Final Report - Multiple Myeloma Return to Table of Contents reporting SAEs related to the study treatment. One participant died due a treatment-related SAE (sepsis). Keratopathy, which was only assessed in the DREAMM-2 trial, was the most commonly reported AE of any grade (66%), followed by anemia (26%) and thrombocytopenia (23%). Blurred vision and dry eye were reported by 20 and 12 patients, respectively. Grade 3/4 adverse events most frequently experienced by patients were keratopathy (27%), anemia {(18%) and thrombocytopenia (17%). Four patients experienced grade 3/4 blurred vision, and no patients reported experiencing grade 3/4 dry eye. Generally, adverse events were managed by means of dose reductions (32%) and/or delays in treatment administration (51%). Keratopathy was the most frequently cited reason for delays or reduction in dosing by 45% and 24% of patients, respectively, as well as for treatment discontinuation (2%). Expanded Access Program: Seventeen study participants (53%) were still receiving treatment at the time of data cut-off, while the remaining 15 had discontinued treatment. The most commonly cited reason for treatment discontinuation was progression or death (13 patients). Twenty out of 31 evaluable patients experienced ocular toxicity (keratopathy) of any grade, and eight reported grade 23 keratopathy. 62.5% of patients who experienced grade 23 ocular toxicity reported an improvement to grade <2 ocular toxicity, and one person discontinued treatment. Other adverse events commonly reported by 2 20% of study participants were thrombocytopenia (30%), neutropenia (22%), and infections (22%). Thrombocytopenia, neutropenia, and infections grade 3 or higher were reported by three, four, and three patients, respectively. Adverse events were managed by means of dosing delays (13 patients) and dosing reductions (11 patients). Ocular toxicity was most commonly cited as requiring dosing delays or reductions (9 patients). Please refer to Table D3.17 for a more detailed description of safety data for the Pooled Analysis and Expanded Access Program. Subgroup Analyses Ide-cel Subgroup data from the pivotal phase Il trial of ide-cel (KarMMa) are described in the main report. In the phase 1 dose-escalation/expansion trial, CRB-401, subgroup efficacy data was only available from the original publication (n=33).5° At a median of 11.3 months of follow-up, as-treated ORR was 85% (28 patients had a response out of 33 infused). Response appeared to be dose-related, with the highest dose (>150x10° CAR-T cells) achieving the highest as-treated ORR (96%). Those with high cytogenetic risk (n=15) had a lower as-treated ORR (73%).%° More detailed subgroup data from both the KarMMa and CRB-401 trial are provided in Tables D3.6 and D3.7. ©lnstitute for Clinical and Economic Review, 2021 Page 84 Final Report - Multiple Myeloma Return to Table of Contents Cilta-cel At the time of the report, subgroup data from the pivotal phase Ib/Il trial (CARTITUDE-1) of cilta-cel was not available. In the Phase | trial (LEGEND-2, Xi'an site), as-treated median PFS for cilta-cel for patients with EMD was significantly lower {8.1 months) than for patients without EMD (25 months, p<0.001).58 Additional subgroup data is presented in Table D3.8. Belantamab In DREAMM-2 the probability of PFS reaching a duration of 6 months or more was 35% for patients who had received 3 to 6 prior lines of treatment, and 30% for both those who had received 7 prior lines of therapy or more, and for patients with high-risk cytogenetics. Median OS, which was only reported for the subgroup considered to have high-risk cytogenetics, was 9.4 months. The probability of OS at 12 months was 45%. At 12.4 months of median follow up time, 34% of the patients who had received three to six prior treatments achieved an overall response compared to 30% of patients who had received seven prior lines of treatments or more. Very good partial response was achieved by 17% of those who had received three to six prior lines of therapies and by 20% of those who had received seven or more. ORR at nine months was achieved by 27% who had a high-risk cytogenetic risk profile, with 22% achieving a vgPR. Of the patients who had mild to moderate renal impairment, ORR was achieved by 31.3% and 33.3%, respectively. The median duration of response achieved by patients who had been treated with three to six prior lines of therapy was 11 months versus 13.1 months for those who had received seven or more. The probability of a response lasting six months or longer was 63% and 73%, respectively. At nine months of follow-up, the median duration of response for the high-risk cytogenetics and renal impairment subgroups had not yet been reached. The probability of a response lasting for six months or more was 52% for the high-risk cytogenetics subgroup. For the renal impairment subgroups (mild to moderate), the probability of a duration of response of six months or more was not reported. More patients with moderate renal impairment experienced serious adverse events (50%) compared to those with mild renal impairment (33.3%). Of those with high-risk cytogenetics, 46.3% reported experiencing SAEs. For more information regarding subgroup safety outcomes refer to Table D3.13. Usual Care As discussed in the main report, the retrospective studies we selected to represent the effectiveness of usual care did not provide sufficient information on the harms of the treatment regimens. See Table D3.22 for what safety data was available in two of the retrospective studies.":? ©lnstitute for Clinical and Economic Review, 2021 Page 85 Final Report - Multiple Myeloma Return to Table of Contents Therefore we selected representative prospective trials of commonly used treatments that make up components of the market basket of therapies in the economic model (Elo-Pom-Dex: elotuzumab- pomalidomide-dexamethasone, Car-Cy-Dex: carfilzomib-cyclophosphamide-dexamethasone, Ixa- Len-Dex: ixazomib-lenalidomide-dexamethasone).?*3! In these prospective trials, treatment-related AEs were reported by 7-8% of patients. Discontinuation rates varied from 14 to 18%. Grade 3 or 4 AEs were common (57-74%). The most common grade 3 or 4 AEs were neutropenia (13-22%), anemia {9-11%), and thrombocytopenia (4-19%). Mortality ranged from 4.2% to 21.7%, however follow-up time varied (median 9 to 23 months). Deaths were most likely due to progressive disease (3.6-13.3%) followed by AEs (7.1-8.3%). Differences in harms between these regimes and that of the interventions should be interpreted with caution, however, as the trials were generally conducted in less heavily pre-treated populations (median of 2-3 prior therapies). See Table D3.23 for more details on harms of the usual care treatment regimens. ©Institute for Clinical and Economic Review, 2021 Page 86 Final Report - Multiple Myeloma Return to Table of Contents S1U9U0) JO 3|qe] O} uiniay L8 98ed ewo|aA a|di|ny - Hoday |euld TZ0T 'M3IASY JJWIOUODT PUE [BJIUI]D 0} SINHISUIQ Suninbau ejwylAydie JBJNJLIIUSA 1O 'UolIdIeu| |eipiesoAw 'euiBue 3jqejsun 'AyjedoAwoipies S1WaYISI-UoU JO 4HD Al 4O ||| SSe|d Jo AJOISIH - uojssjwal 213|dwoa uj Jou S| Io siedA ¢ 1se| ay31 ul Adesayl padinbaa sey Adueusijew puodas ay3 §| ewoldAw 0} uonippe uj sapueusien - SINOY 7/ UIYHM UOI}I9)Ul SAINO. JO 9IUasSald - uoIpuny mollew auoq '|euas 'anedsy alenbapeu| - 9SEISIp SND umou)| - s||92 ewse|d MOJIBW dUOq %0€ Ueys 2JowW Jo 3sess|p 3|qeinsedN - T-0J0 smeis DOd3 - (aiNI pued e Suipnjpu) Adesays Jo saul| €2 - J9p|o pue 28e Jo s1edA 8T - pa32p43sqp J0U aiam suup By/si132 | +4VD 90T X 008 PUb 40T X 0Sx 34/51190 L +¥VD 40T X 0S¥ - BY/s1199 L +¥VD 40T X 06T - (T2=N) oseyd uolje|edsa-29s0Qg sajes pajlun :UOREIo] ¢9=N [Bl} J2UI}NW 'dno.g -9|8uls '|aqge| -uado '| aseyd (6268592Z0.1ON) 69'2965 LOV-GHD ewojoAw 0} uojlppe uj sapueudijew Alepuodas - syjuow g snojadud ay3 uiyum eILWYIAYJIe JBINDLIJUSA JO 'UOIIdJRU |BIPJEDOAW 'eujdue a|geisun '@jo.3s jo Aloisiy 'AyzedoAwolpied 3|WAYIS|-UoU UBA3S 10 {HD 'Al 40 ||| ssepd jo AIoISIH - D siizeday 'g sizeday 'AlH - Adesayy paysBiel yIADg 10 J3oued 1o} Adesayy Jejn||2 jeuonesd|3ssaul 10 J3dued Joj Adesayy paseq-Adessays auad Aue yim juswiealy Jo {17 onslodojeway d1auadoj|e snojAsld - sjuessaiddnsounwwii 21UOJYD Yy3im Juawieay Sujo8up - uoi3ounj uedio ajenbapeu| - 9SEASIp 9|geJINSEIW JO ADUSPIAS J2YIO0 1NOYUM ewojaAw Al03a403s-uou Jo sewojhdewsed Aseyjos - e|wayna| |99 ewseld jo A101S1Y 10 dAIDY - aseasip a|geinseaw aAeY Isnw sp3[gns - T-0 Jo snie1s oD - uawisal Juaweal 1se| 01 AJoyoeujal 9q ISNN - usw|8ai yoes 1o} S9J2AD 1UBWIILAIY BAIINIASUOD ¢< duo8iapun aaey SNy - Apoqnue 8€QD-11ue Ue pue 'Qi| 'Id & 8uipn)pu) 'sudwi8al juswleal) Joud € 2 paAIaIay - ewoaAw sjdiynw uoisnfui ajbuis BY/s1199 L +¥VD 40T X 061 - [eqo|D) :UOEIOT] 8ZT = (paiean) N ot = (pasasaydena)) N 6vT = (p3|joJud) N [eL} JajusdInw 'wae-9|3uls A3ojoyred jo sisougelp pajuawindog - | /5|33 L +¥VD ;0T X00E- | "Med-om1 '|9qe| | (87ZTIEE0LIN) Wa3SAS SNOAJBU |BJIIUSD JUBRAS|RJ Ajjedtuld jo AIOlSIH - a8e JosiesA 8T 2 - | /5|82 L +4VD 40T X OST - uado '|| aseyd zrotCININIE)Y 192-3p| eHI}I4D) UoISn|IXx3 eLJ9314) uojsnjouj judswneall vonesot (1LON) 1enL 3 udisag Apmis suonuanIdu| :usisag Apnis "1°€Q |qel SUOJ3U3AIDIU| sd|qel Ju3pIn] "€d SJUdIUO) JO 9|qE] 0} uinldy 88 98ed ewo|aA a|di|ny - Hoday jeuld TZ0T 'M3IASY IWIOUODT PUE [BJ1UI]D 0} SINHISUIQ 108 o19ua8oj|e panaday $)Y99M ZT UIYUM | DS ShoSojoine paniaday S)93M g UIYUM (p10J3]S0DI11I0D JdYyloue Jo 9s0p 1uajeainbs 10) auosjupaud jo Aep/3w S uey} 493e243 Jo Adelayl p10Ja1SOI1H02 IIWISAS (%S> 43A17) uonduny aeipaed padiedw) adoouAs paulejdxaun Jo ejwylAiie Jend1UdA Jo AIOISIH Joud syjuow 95 ngyd Jo 'uoidieyul |eipaesoAw 'AHD Al-lIl 9881S VHAN ZT ulyum/unnp uoissaidoad asessip pauawnioq - (amAll Jo/pue |d "|pul) ewolaAw a|diynw Joj juswieasy Jo sauj| Joud g 1Sea| 1e paAIaIRy - 8ujuaauds 1e 3seas|p s|qelnsea|N - el491.2 J11soude|p DMIAII 03 Suipaodde ewo|sAw 3jdi3jnw jo sisouSelp |e1jul pajuawWwNdoq - 98e Jo suedA g/-8T - (asop -91buis auo uf JuawIna 3Y31 paJaisiuiuipo 334s [D21UI[2 3UQ) SAPP £ ulyum suoisnfui a10ipdas € ?Afs|199 L +4VD 0T X £°0- :950p uesy (Soms ulliny nsauelf 'suayzsuey) (50T x T'2 - £0°0 :98uey) /51190 L +¥VD 40T X S0 - :9S0p UBIPIA (9¥IS UB,IX euly) :UOREI0] vL=N [BL} J2UdI}NW 'dnou8 -918uis '|age| -uado '| aseyd (6S9060€E0LDN) on.Nlefi N3931 ewojsAw 3jdijnw JO JudWdAjoAU] [eSSulUaW 4O SuSIs |eajul[d JO JUBWSAJOAUL SND Jo AlO1SIH S)3aM ZT UlyuMm DS snoSojoine Ue JO SYJUOW 9 UIyHM 1) d1uaSo||e ue paAadaYy Adesoyy 1U323J 1SOW JO Syuow CT UlyUm Jo eusiid HMINI Jad aseas|p aaissa180.ad uoisnfui ajbuis sa1e35 payiun 'ueder :UONEIO] L6=(pa1ean) N 13 udisag Apnis sisaJayde 03 Jond 40 3dUsplAd pajuawndoqg - (0T X S6'0 sAep 7/ ulyum suosiupald jo 8w g7 =< 03 JuadjeAinba Id PUe qIN| ue -15°0 :28uey) 3y/s|192 €11 SP10J31S031103 JO 3SOP SAIIR|NWND B PIAISIJY - 01 Alo1oRJ 3. 3|gNOp 3Je U0 L1+YVO 0T XTL 0~ = (pasaJsayde) N uolouny Jeipaed padiedw 'AyredoAwolpien (Adesayy Apoqnue gegd-laue :9s0(Q uUelpaN 97T 2IWAYISI-UOU 2JaABS JO AIOlslY '@doduAs '@Al 1d Buipnjoun) saidelayy = (pajjoJua) N paujejdxaun Jo elWylAYdie JeNJLIIUSA Juedludis € 2 paniadal Ajsnoinald - Ajleaiuy)d jo Aioisiy 'syjuow g uIyum ogyd 9seasip d|qeinseaiy - Apnis Jo uoppJeyul [eipJedcAw (JHD Al JoO ||| 93e3s YHAN - 15> snmeis ood3 - (0T x 191U NW (vDg) ussnue eI} DM Jod 0°T-5°0 -28uey) 8%/s|192 '[oqe-uado | (£0Z8¥SEOLON) uolleinlew [|93-g 03 palasies s| Jeyy Adesayy Jolud - sisou8elp NNl paiuawndoq - L+4VD 40T xGL0- 'dnou8-a|8uis oz'orl 1981e3 AUk 3B pa3dalIp JUBWIESI} |-HYD Jold - a8e josiesAgT 2 - :3sop 1981e] 'l1/91 @seyd -3aN.LILYVYD 19%-e341d sisopiojAwe JuedlusIs Ajjeajulpd Jo ejuayna| |22 ewseld - AH - 8%/51199 L +4VD 40T X 0S¥ - syjuow g snoinaid 84/s1199 1 +¥VD 40T X 0ST - Y3 UIY}M |0JIUOD |BDIUBYIDW JO Uolledipaw {(T=N) 9seyd uojsuedx3 uones'o eld)IM) uoIsSn)Ix3 eI uoisnjpu| judwieas) (1ON) enL SJUDIUO) JO 9|qe] 0} UIN1ayY ewo|aA a|di|ny - Hoday jeuld 68 98ed TTOC 'M3IAJY dlWOU0I] pue |edjul|) JO) 91NUISUIQ jue|dsues) |92 wa3ls :1)S 'sa8ueyd upjs pue 'uiayosd ewojaAw 'Ayjedoursdopua 'AjeS8awouesio 'Ayzedounaudjod (SN0 "J0qIYul dWOsed104d :|d 'UOIIRIDOSSY LEIH JIOA MBN WHAN '4aquuinu [e103 :N 'wedSijjiw :Sw 'uoioel) UoiIB[B JeINJLIIUBA Y3| 43N] 'wes8oy :83 'Bnup Alorejnpowounuwiwi i 'dnous Supjopn BWORAN [euolRUIdIU| :DMIAIT 'dnoun ABojodu dAneladoo) uidises :npo7 'WdIsAS SnoAIdU |ea3ud :SND 'a4n|iej peay aA13sa8u0d :H) 'OAIlsod 103dadaa uasijue JuBWIYD +yYY) 'Yeud ssedAq Aiae Aieuouod :ogy) 'usdijue uojjeaniew ||92-9 (YINDY uonpuny w33sAs uedio alenbapy - sAep 00T < uoneljuejdsueny Jo 3|qi8yau1 1Hs snoBojoiny - Apoqnue |euoja0UOW GED-1IUE UR 0 JueJsajolul Jo pue Aloloead |eqo|D ;UGB dwoJpuAs SINOd - | 'Al pue |d ue 01 Aloloeljay - MC_UUU_Q sjuawleal NEO_0>E|_HCN aiay fiNuENMN&Q 1[6= AOmOU [BUJIDIUI JO [ESOINW DAJIIE {UOIHPUOD [BUBL BAIDY - | JO SaUj| snojaad €2 paAIaday - a3q 10U JjIM pup Ya4 Y1 3y/8Ws'z) N (Ayzedoaessy aieund ¢-0josmeIs 5023 - | Aq pano.iddp jou som asop 96T = (12101} N pliw 1dooxo) aseas|p |ellsyHda |eaulod Juasin) - DM 01 Sujpiodae by/bw g paipnis ay | 1DS d1oua8ojje paA@day - | ewo@Aw a|diynw Aloloelssl Apnis 8nup |euonesiisoaul Jo 'Sp10J3)SOJIHO3 Jo pasde|as pawauo) - syoom | Jajuddnnw '|1sge| | (82952SE0LDN) asop-ysiy o1wsisAs 'saidesayy YINOg Sholnald - 98e JosieaA T 2 - 33Jy3 AJaAs /8w g -uado '|| aseyd | ;. Z-ININVIHA gewejuejag ¢-0josniels oOod3 - Adesay) ewojpAw -ljue JuII3J JSOW JO syluow uonedxo g udisag Apnmis (LON) femL BLI2HJY) UOISN|IX] BLIDNJD UOISN|IU| juauieas ) S]USIUO) JO 9|ge] 03 uIN1ay ewo|aAl a|diy|n\ - 1oday |euld 06 98ed TZ0C 'M3IA3Y d1WOU0D] pue [ed1ul|) JO} SINNISUIQ (ooT) L6 UN UN (9°28) s8 UN (t'v8) 80T (5'18) vt (258} 09 {ooT) ¥ (%) u 'Aroyoerjas-ajduL (oot) L6 (oot) LT uN (oot) L6 (oot) 29/29 | lo0OT)8CT Joot)szt | ,oor)ser | L0OT)S8eT (%) u 'pasodxa-ajdiL ~ } _ _ €€=N ~ ) _ 5 (a8uey) ueipay (tz-€)L (tr-€) v (6-T) € (81-€)9 "e7-5) £ (91-€) 9 (€T-€) s (9T-€)9 (¢T-v) 6 SuaWBoY JOjid 40 JOGUINN (69%) ('0b) (v'16) (0'05) Jeap Jod uaw)Soy UN N uN UN 6°9%) 09 L0b) e ¥'1S) 9 0°0S) Z JuBWIEBI] T< } i i ) i i ] m (eev) ey (89¢) 12 N (Tve) eg/8 (rot) 12 (8'vT) 8 (1) 21 (osa)t aSe3s aseasiq Ss| UN UN dN (s'8v) €g/9T (8'05) 9 (6'19) 8¢ {(9'8v) vE (osz) € uapung Jown] ysiy (%) u i uN i sls"sp) ] . . . Ay 'uonejndog (ezv) v N (£€2) €2 - (T'sg) sy (v'iv) ¥T {9'82) 02 (oSt a10u80343 YBIH o "_u__._ (v°Z) uonajdapoydwAi o UN N (TsL) e ,mm . (sz8) Tt (0'£8) L¥ (t-£8) 19 {ooT) ¥ 0} Joud Adesayy Sui8pLig paniaday ('z2) (8'62) (veT) (z'22) (T6€) (9'62) (9'87) (0) asessid LT2) T 8'6C) LT P'ET) €T L2 €€/6 1'6€) 0S 9'6¢2) 9T 9'8Y) vE 0)0 Asejnpowesixg UN (T've) 9t UN (6't6) LS | (£'69)€€/cT | (7's8) 60T (e'€8) S¥ (£'58) 09 (oot1) ¥ (%) u " uoissaidx3 yINDE Jowny (o0t uN (0'6-0T) 0'F (z8tT €e=N '(09 | (0'81-0T) (01T (08T (0zt (23uey) sieap MOI) S -9'1) 6°S -0'T)0'S 09 -0'T) 09 -07) 0L -0'9) 0'0T uelpal 'sisouse|q dduls dwill (s9t) 9t ydelg , UN UN UN UN UN N N N (%) u 'a2ey (zvL)ee aUYM (9729) 18 (£v9) 1T {9°69) v€ (8'85) £S5 | (9'€9) €€/1C (r'65) 9L (0"€9) ¥£ (e¥S) 8€ {(oot) ¥ {%) u 'sjey (0£-09 (0eL (0ze (08¢ (08¢ (08¢ (09 (069 : 98uey) sieaj ueipa =) HOI) 059 -0'SE)T'SS | -0°£T)0VS | -O'EV) 019 (¥N) 0'T9 -0"€€) 0'19 -0'€¥) 079 | -0°€E)0'T9 | -0°6%)O'¥S ( u) A UEIPON "23Y L6 [T LS L6 w29 8t1 ¥s oL v N (8%/3w 5'2) 3/siPd 3/si2d 3/siPd 3/sid 3i/snd 3/siPd qeweuelsn L4V L+¥v) L+¥v) llesdn0 lleJaA0 L+¥VD 1L+4v) L+¥v) suy sOTXTZ'0 00T X 6°0 JOTXTZL'0 40TX 0S¥ s0TX 00€ sOTX0ST ns3uelr ol 'uifliny ue,ix ol ) S el -WIVIHa | 'SusyzBuey) | ,,Zz-AN3DI1 | -3ANLILAYD | " 6sTOV"8U) worEINAHEN 1B N@NlflZwmvw-_ gewejuejeg |22-ey1D |192-9p| UOUdAIRIU| qewejuejag pue '[23-e31) '|93-ap| :sAIsUIBPRIRY) duldseq 'Z'€d d|qel S]USIUO) JO 9|ge] 03 uIN1ay ewo|aAl a|diy|n\ - 1oday |euld 16 98ed TZ0C 'M3IA3Y d1WOU0D] pUe [ed1ul|) JO} SINNISUIQ (,1'87) 6°6€ ured '0£3-070 4N UN uN 4N 4N (7 £t 4N dN 4N Snsnes 21403 (vve) v (e'gg) 8T (6z€) €T (0sz) € 12 (%) u '12s €6 (Tiv) 8 (sL1) 0T (£'68) L8 | (0'L6) €€/C€ sno3ojoiny (8'€6) 0TT (£'06) 6¥ {(£'s6) L9 {ooT) ¥ 1 paniasay dN UN UN (0°66) 96 %mfim \mmv +(00T) 8¢T +(00T) ¥S +(00T) 0L +00T) ¥ o a:vfirmwflcflwfl.flfl"d 5/a (Te) e 4N uN 4N 4N dN UN qewixnjes) (ooT) L6 UN (o'zz)zo/sy | (T's8) 60T (€'€8) S (T'28) 19 (osz) e qewnwnieieq (%) u (9'98) ¥8 (seg) T8 | (8'8L) €€/9¢ uN UN HN UN aplwopjjewod 'saidesayl (£'68) L8 uN uN UN (£72L) €gfve UN UN N UN aplwopijeud dolid 03 (6'79) €9 (679)€9 | (9°£5) €g/6T N Y N Y quwozjiey Aiopreyoy (€9L) vt UN (909) €€/02 UN uN UN UN qiwozayog (te)e (6s) 1 dN uN qewixmes) (00T) L6 UN UN (0°06) z9/95 qewnwnieseq (%) u (8'T6) 68 (69) T (9e) (6°€6) €€/1€ aplwopijewod 'pan@Iay 4N 4N 4N UN 4N (oot) L6 (8'85) 0T {6'€P) ST (oot) €€/€€ aplwopijeua saidesayy (€92) vz (811)¢C (81T)T (6°06) ££/0¢€ qiwozjye) Jond (6°L6) S6 (rz8) vT ('89) 6€ (oot) €g/¢€ qiwozayog (ooT) L6 UN uN (0'66) 96 UN (8'e6) 0TT (9°26) 05 (€'v6) 99 (ooT) ¥ (%) u 'Aloroeljai-qy 8EAD-IUY w UN 4N (ezh) v (z'81) £€/9 (8'97) €€ (8¥1)8 (eve) vT (o0sa)t (%) u 'Adoroelyai-eruad U (T L UN (s'e8) 18 | (8'8L) €€/9¢ (zo9) LL UN UN 4N (%) u 'pasodxa-ejuad L6 (T LS L6 .09 8¢T S oL v N (33/3w €°2) 3i/fs1190 3i/s112 3/s1190 3i/s1199 3i/s119 3i/s1190 qeweaueog L+4vD L+v) 1+4vD llesano llesd3n0 L+4vD L+uvD L+4vD suy sOTXTL0 s0T X S°0 sOTXTL0 o0TX 0S5t s0TX 00€ oOTXO0ST ns3uelr 'uifin ue,l -E_\"_fimzo .mcm;.mmw_m;u NwN.n:,__.wE._ -mo:..H_fiEe.u s'esTOV-8UI o PAALIEN IeHL 26C-ONIDT gewejuejg 193-e)D |93-3pI uonudaAIU| SJUSIUO)) JO 9|qE] 0} UIN}dY 76 98ed ewo|aAl a|diy|n\ - 1oday |euld TTOT 'M3IASY J1WOU0DT pue [BJIUI[D 10§ INMISUIQ uone|ndod syl UIYHM JudWIeRAI] |[33-2P| PAAIDISL 0} siudned €€ 1541y 9y syuasaudal €€ Jo N 'uonendod TOY-GYD PRIEDIL SUI1IUD DY) SIUISAIADI 79 JO N s uona|dapoydwA| aioyaq pue sisaiaydeyns| Jaye paSIuIWpY K |0d0304d Apn)s uo paseq apew uoidwnssy # (9TvT)1 10 (FTiv (d/T)19p :So1Mjewaouqge Suimo)|o} 3y3 Jo douasaud syl Aq paulyaq § Adeuay} Jo auj| Ju3231 1sow Sulanp 9Seasip dAIssaI80.ud + uolines yum paiaadiajul 9q pinoys pue paziusip ale eyeq 4 +VINDE %05< Se paulaq « aJieuuoiisanb ajq Jo Aljenp :DTO 'UonelARp paepuels (S 'Juejdsuesy [|92 wia)s ;1S 'PaModal 10U YN Jaquinu [B10] N 'Jaquinu :u 'weaSijjiw 3w 'weldopn) 8y 'panuiluodsip :/q '493ue) JO JUSWIeaL] pue Ydieasay Joj uoneziuesio ueadoung :D1HO7 'sniels duewopad dnoin ASojoouQ aalesadoo) uiRlse] :Sd HOIT 'DAaisod 103dad3a uaBijue JUBWIYD (YYD 'udBilue uoleinlew |93-9 (YINDY S$109)49 apIs 01 anp Adeiayy jo sul| 1se| 3/Q 'sisouBelp 1e a8e 'ySiom WYSISH :sa11s1I810eIRYD BUIlaSEq SUIMO|[0) BY] 40} paodal Jou eleq (8'sT) 6 (1°9) €€/¢ (e e (L€l ot (0)o z : A00T) 26 - - - : ; (%) u +00T) £6 400T) LT (viv) Lz (97€9) €€/12 (T°es) 89 {£€s) 6T (evs) 8¢ (osa)t 1 'sd 5033 (89¢g) 12 «0)0 (€0€) €€/01 (s¥¥) LS (9 zh) €2 (evv) TE (osz) € 0 (e'sT)0Z8 19943 apIs 0ZAN-OTD + uN uN dN uN uN ATve) ves swoldwAs aseasig J1403 (,9702) £'09 100/Yy3eaH |eqo|D ] ] Sujuonpung (as) (,1'52) 769 |eaisAyd 103G UBIAI L6 1 LS L6 .09 871 ¥s 0/ ¥ N (33/3w €°2) 3i/fs1190 3i/s112 3/s1190 3i/s1199 3i/s119 3i/s1190 qewelueiog 1+4vD 1L+YY) L+4vD llesan0 llesan0 L+4vD 1L+uv) 1L+4v) suy s0TXTL 0 0T XS0 s0TXTL 0 J0TX 0St s0TX 00€ 40TXO0ST ns3uelr ac 'uiliny ue,Ix ozt . - e Je el -WINIVIHa | 'SusyzBueyd | ,Z-aN3DIT | -3aNLILHVD | © 6sT0V-8YD ot NAHEN IeHL 2s¢-ANIDI gewejuejg 193-e)D |93-3pI uonudAIU| S]U3IUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld €6 98ed TZ0C 'M3IA3Y J1WOU0D] pUe [ed1Ul|) JO) SINNISUIQ [€v€ 'S 8T] [9'T¥ 'S 9T] [0°9€ '@"¥T] [9°08 '9°0] . ! u 'Auane8au- (018) Lefog uN uN {(0'92) €€ {(0'82) 6ST "ove) sL1 "(0's2) sT [10%s6] £(56) u "Aantsedou-auin UN UN UN (6°2€) UN J[€67) UN Ap'22) ¥N {0P2) UN | (%) u 'SYyluoW ZT 18 Sdd N N N J[Tsv) UN (€°09) YN JP'9€) UN J[{0v2) uN (%) u 'syo 6 1@ S4d enmang N N N J(£79G8) UN (€°69) YN J(£°8Y) UN NORZAR[Y (%) u "syo 9 1e S4d 201 + 4N 4N 4N [(02L) ¥N .(6°08) ¥N (T°69) ¥N J(9°08) N | (%)u'SYIUON €18 Sdd | uoissaiSold e o N (ozt et o (€Tt o fror) o et e (12%56) SyuoW (6TT1'6°'5)88 | (TCT'C'L)6 07) S (91T '9'5) 8'8 'g8) -1 (6g'z¥)8s | AN'DT)8T 'uopEING URIPO UN UN UN (0'82) UN (%) u 'syluo 2T e SO UN N UN AT¥8) UN (%) u 'syluo 6 1© SO UN HN UN ,(0°06) YN N N N (%) u 'syiuoy 918 SO |BAIAINS - . eIDAQ UN UN UN (T'S6) ¥N (%) u 'syauol € 1e SO I - ) (AN (aN "o. i (12%56) sywuoN (AN 'z6T) T'VE ''62) Ve 'g"0T) AN (IN 'z'8T) ¥'6T 'uopeing ueIpaN N N N (T'12) LT (£91)6 (£'s2) 81 (0)o (%) u "ud (s'v9) ot (6'8L) 0F (6'8¢€) £ (5'6T) 5S¢ (6's2) T (evT) 0T (ost)t (%) u "dd3n (£'8€) ¥ (8'9¢€) 1 (6'8€) £ (8'z€) v (6'8€) TC (9'82) 0T {ost)t (%) u Y/ uds UN . [T'18 '8°59] ' . "g'st) Lv (5'68) v€ dN (0°0S) 6 "vL) 16 (5'18) vv (9'89) 8¥ (00s8) ¢ [1D%S6] (%) u 'Y40 (£€T (8'v1 (9'6€ (11 1T (0Tt JaN (10%S6) syauoiN asuodsay 'L'L) €01 '€'9) 0°0T '6T) L'ET '06) £°OT '€0T) €'TT 'v's) 6'6 '8'¢) UN 'uopesnd uelpaiA ) v (98uey) syauo '191109 UN UN N (8'TT-0T)8C UN UN UN 10 4D 03 BWLL UEIPOIN (o8uey) €€=N . . ¢ d {0'E-50) T UN UN (8'8-50) T UN UN UN SYIUOIAl 'Osuodsay [eniu] 0} awl) uelpaAl SYIUOW £'¥T SYIUOW €'€T dn-mojjo4 uelpain +C9 8¢ 8T 871 ¥s oL ¥ (pa1ean-se) N /s 3/si /sid /s 3/siPd llesd2n0 L+4v) 1L+4vd llesan0 1+4vD L+¥v) L+dvd swuy 40TX 0Str s0TX 0ST J0TX 0Str s0TX 00E 90TX0ST h@.flO.@lmflU HH.QHN-)--Z._NV_ lenlL [92-3p] :saw02nQ Adedyy3 '€'€d a|qel SJUDIUO) JO 9|qe] 0} UIN1ayY ewo|aA a|di|ny - Hoday jeuld 6 28ed TTOC 'M3IA9Y dlWOU0I] pue |edjul|) JO} 91NUISUIQ uoissai8o.d aseasip 19} palealldl 919M SJudlled H uojiejndod syl ulyHMm JuBWIED.] |92-Bp| PAAIDIAU 0] Sludlled £€ 1541 9yl syuasaudad €€ Jo N 'uone|ndod TOY-gYD paileaJl aJ1us syl sluasaudal g9 JO N # 191199 40 Jsuodsas 319[dwod yum sjuanled ul passasse AjAie3au-qyin § sjuaned ajgenjeas + uojInes yum pailaadialul aq pjhoys pue paziisip ale eleq 4 N |lews 018N , asuodsaJ |ennied poo3 AIaA :HdS8A 'Jouia paepue)s 135 'Osuodsal a1a|dwod Juaduldls 1Y)s '@suodsal |eided :4d '|eainns 93.-uoissaiBouid :S4d '91ed asuodsal ||eIaA0 1YY 'PaHOdaI 10U YN 'O]qRwIlSS J0U 1IN Jaquinu [Bl0] N '4quinu :u '9seasip |enpisal [ewiuiw :QYIA 'weaSo 8y '@suodsau 913|dwoa 1Y) 'DAsod Joidadas uadiiue ouBwWIYd +YYyD) '4031dadal uadipue duBWIYI (YYD '|BAISIU| 92UBPLUOI %56 1D %S6 N N HN (6'T2) 82 UN N UN (%) u qusuneasnsay (085) 79/9¢ UN UN (€9)8 UN UN UN (%) u 'uoissaiBo.q aseasiq (00z) 01/2 (rrog) TT/v (%) u 'syauo ZT W a|qea39p N N N N UN - (0Ls) gz/eT (z65) 6¥/6C (%) u 'syauoN 9 1y S|199 L-YVD (3s) sAea N N N (UN) 1T (UN) 1T (UN) 1T (UN) vT 'uojsuedxg |90 14y yead uepain Bi/s1190 3i/s1199 B/s1190 Bj/s1190 3i/s1190 lleJ9n0 L+4YD L+¥vD lle4aA0 L+4YD L+4YD L+4VD suy J0TX 0St J0TX 0ST J0TX 0St s0TX 00€ 90TXO0ST hwflcfllmflu .__.__.e.__ms__z._mv_ |euL S]U3IUO) JO 9|gE] 0} uImay 56 98ed ewo|aA a|di|ny - Hoday jeuld TZ0T 'M3IASY IWIOUODT PUE [BJ1UI]D 0} SINHISUIQ z's9C-UNIDAT mw.mwNun_ N35I11 HN «{"89) §6€ (8°16) 495 (%) u 'Ayanedau-qun V/N v/N (%99) YN (%) u 'syluow 8T Iy (0°£s) 6/s {T°09) YN (9°9£) YN (%) u 'syuow gT I J[9'sz) ¥N [€99) YN J[{€°08) YN (%) u 'syluow 6 1y [eAIAInS 9314 J{r'€8) uN J[T18)UN J{S°£8) ¥N (%) u 'syiuow 9 1y -uoissaJSo.g ,(0°56) ¥N p'98) ¥N ,{0"86) YN (%) u 'syluow € 1y ] e g} g (1D%s6) {(dN) o8t (0'TE '9°6) 66T payoeau 10N SUIUOI 'UORIEING URIPOIN V/N V/N (6°08) UN (%) u 'syuow 8T Iy {(€'Z8) UN J[€8L) ¥N (5'88) UN (%) u 'syuow ZT Iy [T°68) YN [S'T8) ¥N UN (%) u 'syruow 6 1y {1°68) N L(r'z6) ¥N +{8°€6) N (%) u 'syauow 9 1y [EAIAINS [[BI3A0 [T°68) YN [8'26) UN dN (%) u 'syiuow € 1y '- i (1D%5s6) xPayoeal JoN (IN 'v9z) T'9€ +P3YIeal JoN SUIUOI 'UOJIRING UBIPOIN dN (s01T)9 (€) e {%) u °ud (6'S)T (s'e)e (vT) ¥1 (%) u "4d8n (r'z8) vT (2t ey (0)o {%) u v UN UN (6'52} vt (%) u '¥ds [0'66 '0'79] (2'88) ST [0's6 '0°oc] (6'L6) 56 [19%56] /(%) u '4¥0 dsuodsay (£'£8) 0S8 (1D%5s6) N (un) L2 {PIUIELION SUYJuo|lAl 'uonelnq uelpaiN . cean) (e e (28uey) syjuo 'asuodsay (dUN) o't (s'e-v0)0oT (£'01-60) 1 ERIU] 03 BULL UBIPAI SYIUOIN 92 SYIUOA ST SYluoW 8T dn mojjo4 ueipan L1 LS L6 (pa1ean-se) N /51192 1L +4VD ,0TXL'0 1/51193 L +4VD ,0TXS 0 llesan0 swy ns8ueir 'uiliny '8uayzsue uel fruriny 4 W X ozt T-3ANLILYY) leMl [92-e3]1) :s3w023nQ Adedy3 v ed a|qel SJUdIUO) JO 9|qE] 0} uinldy 96 98ed ewo|aA a|di|ny - Hoday jeuld TZ0T 'M3IASY IWIOUODT PUE [BJ1UI]D 0} SINHISUIQ 431139 J0 asuodsal [ejued Yum siusned 44 aw dn mojjo} Yauow-ZT 1 sjudied sjqenjeas Suowe passasse ANAIRSOU-QHIN # asuodsal 919]dwod yum spualied ul passasse AHARSSU-QYIN § awl dn moj||0} Yluow-8'g uolned yum pajaidialul q pinoys pue paziysip ale ejeq 4 |EAIDIUI DIUDPHUOD %/ S6 4 asuodsal |eied pooS AJaA :HdS8A 1o piepuels 135 'Osuodsal 919|dwod Juaduins YHs 'Osuodsal [eiued yd '|eaaIns 931)-uo1ss9480.d :S4d 'O1eJ dSuUOdSal [|BISA0 (YHO 'poHOdal 10U YN 'D|qeWIISI 10U (3N 'S]qE|IBAR JOU :y//N 'Jaquinu |B10] :N 'JSqWNU U '9seas|p [enpisal ewiuiw YN 'weado 18y 'Dsuodsas 31a|dwod 1Y) 'Sanisod 101da31 uaBijue JuBWIYD (+YY) 101da3aa udSinue JUBWIYD YYD '|eAIDIUl BIUIPLIUOD %SE6 (1D %S6 SYIUOW ZT PUE 9 1B 3](e1931ap S[[92 1-HVD '@suodsad 319|dwiod 03 3wl Uelp3IAl :S9W023n0 Adedlysa Suimo||o) syl 4o} paliodal Jou eleq (£v9) 1T «{0"9€) +40G/8T HN (%) u 'uoissaSoud aseasiq (c6-6) (o8uey) N N 556/ €1 sAe( 'uoisuedx3 ||9) 1-4V) Yead uelpan /51193 1L +4VD J0TXL'0 31/51195 L +UVD 0TXS 0 l[esan0 swy ns3uelr 'uiliny '8usayz8ue uel iruriny 4 P X ozstprT-3ANLILYY) ledl z2's9C~ANI9AT ww.mwNun_ N3I5I11 S]U3IUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld /6 98ed TZ0T 'M3IASY IWIOUODT PUE [EdJUI]D) 0} SINHISUIQ aw dn-moj|o} Yluow-€°g uornes yum pajasdialul aq pjnoys pue paziusip aJe ejeq 4 [EAIIUI BIUDPLUOD %/ G6 asuodsau |eiled poo8 A1aA 1YdSA 'Joad piepuels 13§ '@suodsal 919|dwod JUaBuLs (YOS 'osuodsau jered jyd '|BAIAINS 93.4)-U01sSa480.d 1S4d 'O1ed asuodsal [|BJaA0 YHO 'PaOodal J0U YN 'O]gewWIsa J0U (3N 'S|ge|leAe Jou /N 'Jaquinu |B301 :N 43qWinu :u '3SEISIP [BNPISAJ [BWUIW QYA 'welsjjiw :Sw 'weiSon| :8y 'asuodsal 339|dwod 1Y) '1ed4] 0} UOIUDLU| ] || '|BAIDIUI DIUDPIIUOD %56 1D %S6 Ayane8au-qyiN 'asuodsal |_I}UI 0] W} UBIPSW 'SYIUOW ZT PUB g 1B 9|qe1ddlap S|92 1-4v) 'Osuodsal 919|dwod 03 awi) ueipafy :sawodano Adediyd Suimo||o) sy} 1o pajodal jou eleq 8709) 65 (%) u "uoissaiSoug aseasiq %ETT (%) u 'syiuo ZT IV %LT (%) u 'sy3uoN 6 I %ZE (%) u 'syyuoiN 9 1v |BAIAINS 93.4-uoissdi80.d %L Ty (%) u 'syIuoN € I (9€9T)8'C (12%56) SYluoIAl 'uoneinq uejpaiy (6'95) 6v/8¢ (%) u 'syauo ZT IV J[0°€9) 99/L€ (%) u 'syruo 6 IV J[9zL) 99/8v (%) u 'syjuoN 9 v [EAIAINS |[BJIAQ [zes) LL/e9 (%) u 'syauoy € 3y (poyoeas J0u '6°6) L'ET (1D%S6) SYIUO 'uoneinq uelpsiy (reT) €T (%) u 'dd (eTT)TT (%) u "4dSn (zs)s (%) u 'WD asuodsay (ta)e (%) u "¥ds Joev '1zl f(oze) e [1D%s6] '(%) u 'Y40 (payoead jou '2'¥) 0°'TT (1D29%S6) SUIUOIAl 'uoijelnQ uejpa SYIUO €T dn mojjo4 uelpain L6 (L) N /8w T SuLy ezC-WINY3IYA leL qewejuejag :sawodnQ Adediy3 *s'€a 3|qel S]U3IUO) JO 9|gE] 0} uImay 86 98ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOU0DT pUE [BJIUI[D 10§ 3IMISUIQ uolined yum palasdialul aq pjnoys pue paznid|p sJe eyeq 4 $J012B4 Sl 1noYUMm sjuaiied snsiaa yum siuaned ussmisq Jopip Ajpuediyiusis 10U pid 4 '9suodsal [eiued poo8 AJaA :4d8A 'osuodsal [ejed (Y4d '|eAlAIns 93.)-uolssaldoud :S4d 'asuodsal [|eddA0 SO '91e1 dsuodsal ||eJdA0 (YYO '1aquinu |B1O] 1N 'Iaquinu :u 'Bsuodsal Jo uolelnp :YOq 'Osuodsal 919|dwod 1Y) '|eAIDIUL SOUIPLIUOD %56 (D %S6 dd 'Hd3A Isyluow T 1e SO 'SO uelipaw 'syuow 9 3e Sid Jo Anjigeqoud 'syiuow 92 YyOQ 0 Aujiqeqouad :3uimol|oy 3y 1oy paniodal Jou eyep dnoisgns [eeT 'TE]l [zt '6] HN [TTT 'T€l [28 '8Tl [€TT '61 [6TT '8V] [9'TT '5G] [6'0T 'T°6] [1D%S6] syruo ot 9'8 6'8 6 S/ 8 8'8 6L 'Sdd uelpaiy [¥'11 '6°€l 71T 's'p] uN [€TT '06l [€0T '6°T] [€TT 'T°9] [AN 'g79] [v'1T '06l [€TT 'vs] [1D%s6] syauon 0Tt 60T S0t 69 0T L0T 60T 6 '400 uelpa [6'sS 'T"¥T] [oov '81l | [evv'see] | [Teh '88Tl [vog '21l [8'T¥ '9'8T] lovy 'orL1] | [S€v '€'sel [z'8€ 'T'€T] [1D%s6] {lose) £ TTE) V1T {veg) 8¢ {o0g) 8T {loot) ¢ lo'6Z) 6T ote) vt love) 8¢ ove)zt '(%) u 4D [00T '6'94] [s'e6 g0zl | 122 °T9s] | [6'92 "9'TS] [zos'sse]l | Jvt8'zss] | [rzs 'vss] | [9°64 'T29] L[T1°28 'v'ssl [1D%s6] '{0'06) 8T 'v'v8) 8¢ {9°£9) 95 {{0'59) 6€ {o's) OT otL) 9v (069) T€ {lo'tL) 08 (0'0z) s€ '(%) u '4yo 0z St €8 09 12 59 St 1t 0s (po1ean-se) N dn SUYIUO €'TT -MO|[04 UBIPBIAl JeIA sy Adesayy siedA oL 2 siedh g9 2 siedh g9 > J9d uawiSoy mm_".._mmmwflm ..o:Eo-_E:mm_ nauasolfy SuiSpug e o__m«MMMh N 10 SSI 1 YSiH y3IH panjaroy linp x3 sdnoi3qns sdnoup ady Asid Yy3iH sezeTiCNIINIE)Y et |92-ap] :ejeq Adediy3 dnoa8qns *9°gQ djqel SJUdIUO) JO 9|qE] 0} uinldy 66 28ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUODT pUE [BJIUI[D 10§ 3IMISUIQ asuodsaJ |ejued poo3d AJsA :Hd8A 'osuodsal |eied :4d '|eAlAIns 88.)-uojssaudoud :Sdd '@suodsal ||eJ2A0 SO 'D1ed asuodsal ||BI9A0 (HYYO 'paniodad Jou (YN 'D[gewilss Jou (N '4agquinu [B1o} :N 'dagquinu U 'aseas|p Aej|npawelixa :qIAI '@suodsal Jo uolieinp :yOQ '@suodsad 318]dwod 1Y) 'uaBijue uoileinlew [|193-9 (YINDG '|BAI2IU] 9IUIPLUOI %S6 (D %S6 syjuow 18 SO 'SO uelpaw 'S4d ueipsw 'YOQ uelpsw 'syjuow g je S4d Jo Ajljigeqodd '92 YOQ Jo ANjigeqo.d :S3wo23Ino uimo||o) 3Yy3 Joj paliodal Jou eiep uwohmgmw (€9)T (L9)T (Tt (zra) e (%) u 'ud (0s2) ¥ (00z) € (982) ¥ (zzd) e (%) u '4d3n (0)o (£9)T (ev1) 2 (TTo)T (%) u 4> [£z6 '9'L¥] {(0'SL) TT (Tee'evv] {(e€L) 11 [oot "8°9£] '(00T) ¥T [£66 '8'TS] *(6°88) 8 [1D %56] '(%) u '4d0 9T ST VT 6 (po1eda3-se) N SYWON €°TT dn-mojjo4 ueipay uapang Jown] YsiH _ Ysiy 213duadolr) ydiH i Adesay] 8ui8plg panjaaoy dseas)g Asejjnpawenyx3 6sTOV-aYD lenl 11 |93-9p| :ejeq Asedyy3 dnoadgns /€@ d|qel S]U9IUO) JO 9|gE] 0} uIMay 00T @3ed ewo|aA a|di|ny - Hoday |euld TZ0T 'M3IASY JJWOUODT PUE [BJIUI]D 0} SINHISUIQ uojnes yum paiaudialul aq pjhoys pue paziisip ale eleq , asuodsaJ |eiyed poo8 AIaA :HdDA '@suodsal |eied :4d '|eAIAINS 98.)-uolssaldoud :Sdd '@suodsal ||BJ2A0 SO 'D1ed asuodsal ||BI9A0 (YO 'pauIodad Jou (YN 'Djgewilss Jou 3N '4agquinu [e1o} iN 'dagquinu :u 'aseas|p Ale||npawexa :qIAI '@suodsal jo uojiednp :yOQ '@suodsad 319|dwod 1Y) 'uaSinue uoileinlew [|33-9 (YINDG '|BAIDIU] BIUBPLUOI %56 (D %S6 Z-dN31937 Jo T-3anLILyVD Joy elep dnoidgns 'syjuowl g 1e S4d Jo Alljiqeqoud '92 HOd 40 Aljiqeqo.d :S3woa1no Suimojjo) Y3 Joj pauodal jou eyep dnoiggns (sous ns3ueir 'uiliny 'SBuayz8uey)) mw.mwNnn_ [EDE]] |\ (6'z6) UN UN UN (%) u 'syauo ZT 1€ SO [Ter'gelsL [3N '0's€] payoeas 10N [UN]l 6°€T payoeal 10N [12%56] syuo 'SO ueipaiN [ro9'L1Tl e [AN '6'6T] T'8T [¥UN]T'8 [AN-9] 1T [1D%S6] syiuoN 'sdd ueipaiy dN [UN] T°62 4N 4N [1D%56] sUIUO "YOQ uelpan UN 4N «(9TT) ¢ (8¥T) ¥ (%) u 'ud 4N 4N «(9TT) T (Le)t (%) u '4d3a dN 4N +{0°09) 0T (0'€9) LT (%) u '4D dN uN [uN] '(v'e8) vT [uN] «(s'T8) TT [1D %56] '(%) u '4¥0 ST t L1 £6/1¢ (poreani-se) N syiuow Qg syjuow g QD-E-O__O"_ UeIpaiA PaAalydy Jo0N panalyay ana %02 sdnosSqns asuodsay 919|dwo) ysiy YSiH uoissaldx3 yno9g ueiX lenL [22-e31) :ejeq Adediy3 dnoadqns 'g €@ a|qel S]U3IUO) JO 9|gE] 0} uImay 10T @3ed ewo|aA a|di|ny - Hoday jeuld TZ0T 'M3IASY IWIOUODT PUE [EdJUI]D) 0} SINHISUIQ (£78S-0°TT :ID %S6) %E TE :92USPIFUOI Ul JIWIIPEIL SB PIAIDIAI Sem dn-moj||0} JO SYIuowWw €T 18 YHO § (0°91-L'€T 1D %56) % PE : 93UDPIIUOI Ul IWSPEIE. SB PaAIaIaJ sem dn-moj|o) JO SyIuow €T 1e YHO + W €27 T/ulW/w 09>-0€2 4D Se pauyap juawliedwi [eUBl 3JRIBPOW 'W £/ T/UlW/IW 06>-09F Y49 Se pauyap Juawiedw! [euss piIA 4 |EAIIUI 32UPYUOD %G /6 « asuodsal |eiled poo3 AJaA :YdDA '@suodsau [eiued 2dd '|ealadns 9944-uoissaldoud :S4d 'Dsuodsal [|B1an0 SO '91ed suodsad [|BIAA0 (YO 'PaHO0dal J0U YN '4SqUINU [B10] :N 'JOQUNU tU UIU|IjjIW W 'DINUIW uIw 'patenbs siajaw ;W 'a1el uonesy|y Jeinidawold :y4o 'asuodsal Jo uoieinp :YOQ 'Osuodsal 239]dwW0d 1Y) '1eaJ]1 03 UOIUDIU| 11 || '|BAIDIUI BIUIPLIUOD %G6 1D %S6 Hd 4D :sawod1no Suimo||o} Y3 Joj pauodal Jou eiep dnoidqns . (1D %561 % 'SO Yiuow UN UN (19 'cel sv UN UN -ZT Jo Aujiqeqold [TeT 'el [12%s6] syuon UN 4N v'6 4N 4N 'SO uelpaN . . . [12%56] % 'Sid 4N UN [sv '9Tl O€ [ev 'LTl 0€E [os 'o] s€ IO 40 AIIgegOLd [payoeau ] [o€ 'T2] . p . [19%s6] syuon ON '0" e form] T e ier] e el o HN UN azhm: 2z [zegolte | [9e'TTlTe | [£Ss'STl6C 'S4d URIPOW . . . [19%S6] % 'syuoN UN dN [££ '02l S (68 'v¥] €L [€8 'TE] €9 92 Y04 Aujiqeqoud [payoeau [payoeau [payoeau syjuo P3yoealioN | paydealioN 1N 'v'T] 10N '0] 1oN ''] __wxmm_ oW . . d404a uelpain payoeal 10N T€T 01T UN UN (0z) e (0'0z) 01 (0'21)8 (%) u "4d3n mflm..vm *Hm.m.v - =y . e . fonn . f g - d=y . fms . (e H _ 761] 12l _owm VNB ?fi 09 MWE Hmfimm mvm: Hmfimq wm: Lw [47 v:z Lw 9y vmm: *:M £ vmmz A _wxmm qe (o (e '(g {o "o o '(%) u '5'25) 9 "9'TE) bZ LT 9'EP) LT £€'€E) 8 €TE) ST 0'L2) 1T 0°0€) ST 0'veE) 9T %) U 'Yo 9T 9L €1 6€ ¥z 8y |44 0s Ly (L) N SYIUOIN €79 SYWUON €79 SYIUOWN 6 SYIUO 6 SYWON #°ZT dn-mojjo4 ueipaiy sieah sanauasoln) saidesayr saidesayr oe| M sieal djelapo 1 e Him S | g1>0159 1519PON PIIA ASIY Y31 Lz 9-€ sdnoi3gng Aduyi3 / adey ady Jlusuwjedw) jeuay sy YSiH saidesay] 10ud sevenC-ININVIHA |eul gewejue|ag :ejeq Adediyg dnoaSqgns '6'€q 9|qel S]USIUO) JO 9|ge] 03 uIn1ay ewo|aA 3|diynA - 1oday |euld 70T 98ed 120 'M3InaY J1wouod3 pue [edlul|) Joj INUISU|Q UN N N UN (zor)9 (s'vE) 8¢ uonesonIad UN N N N (zee) et (s'vv) 6¥ aduey) oN N UN UN UN uN (9'28) vE (6'07) €7 | fwawsnoidwy | Buiuopduny e Hrot e . (1D%S6) °lod Hz oom.mm ) '€ 6T-) Hy omm.M S-) | +6 H%Hfi 8-) UN UN 21035 UBBIN vy '19 wouj a3uey) (61T) L (s°sv) 0s uonesola1ag (6'9T) OT (svE) 8¢ a8uey) oN uN uN (€Tl Ty (007)zz | fwawonoidw) | Suwonduny | gy ) e (1D%s6) amyudod | -pToO +He L 7 | Hy €T €) 21035 UBBN 31803 99 80 19 woyy a8uey) UN UN UN UN N N (a'8) s (ss€) 6€ uonesoualad UN UN UN UN N UN (zee) et (zge) 1€ adueyd oN (TT2) ¥ (8'sT) € (922)8 (e'8Z) €T N (T'eL) ve (€'65) S€ (¥'9€) oF fiuawanosdw | Suuonduny (1D%S6) I1ed1sAyd 1ESsES) 169e9) | +(£8'8C) | 1(6'6°50) He'LT'6L) Hoz'ev) i . . . 4N 4N i i 2102S Ues\l 10 €0 0€ 15 €T T 1 wouy a3ueyy 61 61 6T 17 o€ Ly 65 011 N (69T) OT (Tvv) 6v uopeioulad (81T)T (v'vT) o1 aduey) oN UN UN SVA U3 (€'18) 8% (r'TY) op Juswanosdw| 65 111 N (s8)S (T'vv) 67 uoneloua3dg (€28) zz (r'18) 25 a3uey) oN Xapul HN UN 15 (z'¥s) Te (1'62) €€ uswaAodw| -as-o3 65 111 N ST AP9M 6TAPM | ET¥PIM L9M v8TAea | 00T Aeg 6 YO T Aeg dn-mojjo4 (£6=N) 3 /3w 5 (89=N) l1eJ2n0 (8ZT=N) lleJoA0 {N) sy szvzC-WINVING ZT-3aN1ILHYD L leyy (LLl) qewejuejeq (pa1easi-se) [93-e3 1) (pajeauy-se) |92-ap| UoIUBAIR| qewejuejeg '|92-e}1) '|92-ap| :Saw0nQ pauoday Juaned "0T'€d d|qel SJUdIUO) JO S|gEeL 0} UIN1dY ewo|aA 3|diynA - 1oday |euld €0T 98ed 120 'M3InaY J1wouod3 pue [edlul|) Joj INUISU|Q 4N UN (Lov) vT (z81)0z | tuswsnoidw eJUWIOSUY| (el e (s'sT) LT uoneIoLIIaq N dN (9vL) vy (169) 92 aSuey) oN eayaeiq (oza) et (s'sT) LT fiuswanoidw) (ts)e (e'2€) v uopelolalad N N (€9¢) sv (s¥S) 09 adueyd oN uonednsuo) (98T)TT (z8)e6 fluswanosdw| (zot)o (¥'95) 29 uoneJouaaq : Suniwop dN UN ('¥9) 8¢ (eL8) TH asSueyy oN Jeasnen (r'se) st (r9) L $1uswanoadw) UN N UN UN N UN (zot)o (812) ve uolIeIoR}3] N UN N UN UN N (8'80) LT (9°ev) 8p asuey) oN (8'sT) € (Tt ¥ (o'te)6 (7"0€) ¥1T UN (T'TL)gg (0'T9) 9¢ (s'pE) 8 fluswanosdu ureq {11 's'97) HzvT6v) | H0'9 vyT) | HSEDET) | H(E°0-'9LT-) | +(UN9IT) | 4(€8T-'TOE) | 4(9°SOET) | sum_w_wwm_..u._m Ic 67 vy Ly '6'8- 6'8- 8'€Z- L8 wouy a8uey) dN UN UN UN UN UN (T9)e (r'op) TS uopelola1ad N UN UN N N UN (880) /T (8'8¢7) ¢e asuey) oN (9'T€) 9 (91€) 9 (r'iv) 2t (£s¥)Te HN (T'79) uUN (1°99) 6€ (s'sz) 8z fuswanosdu an3ney HovT 'oL M.fi.fiv H8T99T) | HSZTTL) | H0T-vor) | HISTe) | f(ULr-'T62) | +lyTrse) | sum_w_mww.u._m gt a°0- €L 6€ 6 S T- 8¢ L'L wouy sBueyy (611) £ (T°6€) v uoneJouaq Suiuonpung 4N dN (t'e) ot (zse) a8uey) oN e10s (0°19) 9¢ (Lze) st fiuswanoidw) (e02) Tt (o ob) vv uoneJoualaq ¥N UN (882) LT (6°0€) vE a3uey) oN Sujuopouny |euonowy (8'08) o€ (1'62) € fiuswanosdw| szidIM | 6TWPM | ETIIM L99M v8TAea | 00T Aeg 6 YIUOW T Aeg dn-mojjoq (£6=N) 3/3w o'z (89=N) l1e42A0 (82T=N) lIe49A0 (N) suuy szveC-WINVIYA 2z1-3aNLILYYD zBININIeY leny (LLI) qeweluejog {poieasy-se) [93-e31) (po1easy-se) |92-ap| uoljuUdAIRU| S]USIUO) JO 9|ge] 03 uIn1ay ewo|aA 3|diynA - 1oday |euld 0T 98ed 120 'M3InaY J1wouod3 pue [edlul|) Joj INUISU|Q UN UN (8'62) LT (6TT) €T fluswanosdwy | a8ew| Apog UN UN HN HN (8'sT) 6 (0'e€) 9¢ uonelola1ag sannadsiad dN N N N HN (ov2) v1 (972€) TP aduey) oN aamny (0)o (0o)o (o)o (o)o (+9°65) ¥€ (v'e62) 2€ fluswoanoidu HN N UN UN UN N o)y (zoo)te uoneioualad 0ZAN uN N N N uN uN (T°6v) 8T (1799) 2z asuey) oN U.M_Wm (€€€) 9 (82L27)S (987) 8 (828 LT UN uN (6°€v) ST (8'€T)ST | $uswanosdw | SwordwAs (1D%S6) asedsid Hs'L'se) +(5'8 UN) Hssze) | H8eTs) e evt) | HLTve) . - o - 4N 4N imy - 2103G UesAl 00 1T 80 Sz 0002 YTT g wiouy a3ueyy 8T 8T 8T Sb UN Ly LS 60T N UN N UN N UN N (zor)9 (602) €T uoneioualad UN N UN UN UN N (z'6v) 6T (z'8s) ¥9 adueyd oN UN uN uN uN dN (T18) ¥T (2 ov) v (6702) €2 fuswoanoisdw) | 100 / YyeeH . . . . . , (12%56) #9019 Hgz1Ter) Hsy6'8) | L8e00T) | F9Ls) Heoz'ge) | +LL-'ST) e - e . 4N 4N . e 21035 UesAl Ly £T e vo ¥'StT 1S 18 wioxy 38ueys (esT) 6 (z'8T)0C uoneIoLD1ad somnd ; ; 1nayna UN UN (8'£9) ot (81L) 6L a8uey) oN epueu (69T) 0T (oom) TT fluowsnodwi| (zot)9 (6'08) 95 uoneioualad <o : : 1 N UN (e'69) s€ (LTy) Ly aduey) oN aaaddy (s0g) 8T (o)L $1uawanosdw) (6'8) s (z8)6 uopeloualaq UN UN (£79) L€ (ooz) 22 aduey) oN eaudsAg (8'87) LT (8'12) T $iuawanoadw) (zor)9 (s°sT) LT uoneson1ad (z'6¥) 62 (r'99) €2 asuey) oN ST PPIM 6T dooM i €T yooM LM ¥8T Aeg _ 00T Aeq 6 YIUON T Aeq dn-mojjo4 (£6=N) 33 /3w 5°¢ (89=N) llesar0 (8Z1=N) Ilesan0 {N) sy mN.¢NN|_2_>_<W~_Q NN.HlmQ:._._._.E<U ._"Nm_\,_s_hmv_ jeuL (LLI) qeweluejog {poieasy-se) [93-e31) (po1easy-se) |92-ap| UOIUIAIDU| SluLju0) JO 3|qe] O} uinlay G0T @8ed ewo|aA 3|diynA - 1oday |euld TZOT 'M3IASY J1WOU0dT pue [ed1Ul[D 40§ 3IMNISUIQ an311ej Jo uled ul uojnpad e 3ed1pul sadueyd aanesaN # syulod-gz1< Jo a8ueyd § sjulod oT< Jo a8uey) ¢ uopines yum pailasdialul aq pinoys pue paziusip ale eleq 4 50'0>d Judswaroidwi Juediusis Aj|ea13s1els 9|eas 8ojeue |BnsIA :SYA '@41eUU0lISanb OED 9417 Jo ANjEND :0£D-DTD '941 Jo Anjenb 70D 'xapu| 9Se3SIQ 90BHNS JEBINIO :|ASO 'PaH0dal Jou YN '4aquinu |10} :N 'Jaquinu :u 'aljeuuoiisanb ajnpopy ewoRAN :0ZAW 'weasijjiw :Sw 'wesSojy :8) 'sjpA9)| § suolsuawWip § |oDo4ng 115-aS-D3 '493ue) JO JUBWILAI] PUB Ydleasay Jo} uoneziuedio ueadouny :J1HOT '1891 0 UOIIUSLU| 1] || '|BAIDIUI DIUBPLUOI %56 11D %S6 Z-aN3D31 'TOY-gy) :S|iesd Suimoj|o} 943 o) paxodad Jou sawodino papodal Jusned YN a3uey) oN 1g-15s0d Ajl19A3g (o'zL) gg 1slom woly ujewog jJuswanosduwi| Sujuopduny o §(5'6v) o N U ey | PR | 1050 (12%56) FI uN 9402§ UedAl '19 woJj a8uey) uN 26 uN uN N (8'67) LT (otT) Tt uoljeiola1aq (6'v9) L€ (6795) 79 asuey) oN N N (€s)€ (TZe)SE | pwdwdnoudw] | o500 gpic s e HOBL | e LS0- 19 woJj a8uey) (02) v (9sT) LT uoneJouadq (z€9) 9t (szL) 6L a3uey) oN SZdM | 6TWPM | ETIIM | L¥am v8TAea | 00T Aeg 6 YIWOW T Aeg dn-mojjo4 (£6=N) 3/3w o'z (89=N) l1e42A0 (82T=N) lIe49A0 (N) swuy LY Jeny mN._uNNl_Z INV3IHAa zz1-3AN1ILEYD (LLI) qeweluejog {poieasy-se) [93-e31) (po1easy-se) |92-ap| UOIUIAIDU| S]USIUO) JO 9|gE] 0} uImay ewo|aA a|di|niy - Hoday |euld 90T 98ed TZ0C 'M3IA3Y d1WOU0D] pUe [ed1Ul[) JO) SINNISUIQ (€'69) €V UN UN (£:L¥) 19 (00s) L2 (T°£v) €€ (ose)t T apeio (0'9z) v (T'z6) S€ (e1T) 2L (9'€8) LOT (€'96) ¢S (£'sL) €S (00s) € llesan0 . ; ; (%) u 's¥d €e=N'(ze-T) s UN UN (€9-T) S (e9-T) ¢ (8z-2) ¥ (£-€) s (8uey) sAeq 'uopieing uejpalAl €E=N(ST-T) T UN N (zT-1) 1 (oT-T) T (zt-T) ¢ (zT-2) L (98uey) sAeqg '19suQ uejpaiN (oot) 9 (91)C lemelpyuM Judlled (0°8s) 9¢ "N (08T) €2 uN uoissaSo0id aseasiq (%) u (oot)9 (0zg) v yieaq 'uopenunuodsig (0'6L) 61 +(9'15) 99 llesan0 (0) 9€/0 (80T ainjie4 Sulnyeynue (0)9g/0 (Tev lemelpyuM Judlled (%) u (0)9g/0 (80T JUDA] 3SIaAPY "uawyea.] o3 Joud (e8) 9g/¢ tN (801 N uoissai3o.d aseasiq uonenuiuoIsig (0) 9€/0 (9T) ¢ yreag Apms (€'8) 9g/€ (re)zt l1e4dn0 (e8uey) {0€-9) "N (%) sAeq 'Aeis jo ua ued UN dN 4N @ "Aess jo thBua) uean u 'suonezijendsoH (8'£1) LOT/6T sNII UN (sQ) L (o) v (ev) € (0)o Y10 UN (0z)6 (ve)v (T2)s (0)o sav , 4N %) u 'Aujerion N (T'12) LT (0€1) £ (£'s2) 81 (00s) ¢ uojssasdoud aseasiq (oo1) 9 (r've) vv (8'22) ST (9'8€) LT (00s) ¢ lle1aAQ UN UN (%) u "savs pajejai-Juaweas) (L96) €g/te UN (z'66) LCT UN v/€ speis / / (%) u s3y Auy (ooT) €€/€€ (oot) 821 lle19n0 179 8€ 8T 871 ¥s oL ¥ (pa1ean-se) N /s /s119 3/s119 /sl 3/s19d llesan0 1L+dvd L+¥v) llesdn0 1L+4vd L+4v) L3V sy s0TX OSY s0TX 0ST 40TX OSP 40TX 00€ s0TX0ST 1965 FOV-8YHD sz1r'orBINNEY lenl [92-ap] :saw023InQ Alajes "IT°€d d|qel S]USIUO) JO 9|gE] 0} uImay ewo|aA a|di|niy - Hoday |euld 0T 93ed TZ0C 'M3IA3Y J1WOU0D] pUE [ed1Ul[D JO) SINNISUIQ (T'9) €€/t (612) 8T N N UN € apeinz (%) u 'suoidaju| (v'zy) ee/vt (8'89) 88 (voz) 8¢ (T°29) LV (o'sz) € lle1aA0 (0°£s) s (€72s) L9 4N 4N UN € 9peJnz (%) u (ovz) o (€'€9) 18 (8'%9) s€ (€v9) s¥ (00T) ¥ TEIETYS) 'euadojhdoquiosy) (0'£5) s¢ (z09) 2L N N UN € apeunz UN (%) u 'ejwauy (0'9z) tv (s°69) 68 (0°€9) ve (6'2L) 18 (ooT) ¥ llesaA0 (0'68) sS (T68) V1T N N UN € apeunz (%) u 'ejuadosinanN (0'z6) LS {r'16) LT1T (v've6) 1S (ev6) 99 (o0T1) ¥ ([e13A0 UN N UN uN UN € opeunz (%) u 'ejuadolr) UN (0°L6) vTT (t°86) €5 (£s6) £9 (oot) ¥ llesaA0 (0o (0o (0)o (0o {(0)o (o)o (0o)o S apean (o1) 1 UN N (0)o (0)o (0)o (0)o ¥ opesn (o1)1 (es)t (0o (Te) v {(95) € (ro)t (0)o € apeun (1'68) 52 4N dN (ss) ¢ (99) € (L8) v (0)o Zdpesp (%) UN N (ve) 1 (€6)s (oot) £ (0o T apeio u 'AypixojoinaN (sev) L2 {(9-zs) oz (8'22)S {(ogtT) £C (roz) 1T (Te1) 21 (o)o lleJan0 N dN UN (9z-T) € (zz-1) S (9z-2) € V/N (a8uey) sAeq 'uoneanq ueipaiy UN HN N {ot-T) T (s-T) 2 (0T-1T) € V/N (93uey) sAeq 4asup uelpsiN UN (o'8T) €2 (6'52) 1 (621) 6 (0o 9s0Q 13 (%) u 's¥> N UN (eve) vv (Lov) 2z (0'0€) 12 (os?)t ssoq T Joj qewnzjjol (zTT) €€/2L (€72S) £9 (£'99) 9€ (8'2v) o€ (0se) T llesano palinbay N HN UN «(2'59) o€ dN dN N 72 01 T @peJn wouj uoissas3oid (0o (0o (0o (80)1 (0)o ot (0)o S apesn (0o (0o (0)o (80)1 (0o 1T (0)o ¥ apesn (59) v (62)€ (0o (6'€) s (ev) € (60)¢ (0)o € apelp UN N (s0g) 6€ (Lov) e (6ct) ot (ose) 1 Z apeio /5119 /51190 3/s1190 3y/s119 /51120 llesan0 L+4VD 1L+¥v) l[es9n0 L+4VD 1+4vD L+¥vD suy J0TX 0S¥ s0TX 0ST ,0TX 0SP ,0TX 00€ J0TX0ST 19'6sP07-8YUD serotcWINJE)Y leML S]USIUO) JO 9|gE] 0} uImay 80T @3ed ewo|aA a|di|niy - Hoday |euld TZ0T 'M3IASY JWIOUODT PUE [BDIUI]) 0} SINHISUIQ JUDAD 2180]0JN3U INOYUM JO YlIM SY) 01 3anp § eAIINR)Y Joj dn-mOj[04 JO SYIuoWw pz 01 dn # paieaJial aJam oym spuaied T sapnjoul uoneindod ay3 UIYUM JUBWIERI] [32-2p| PRAIRIRJ 0 Sjudlied €€ 1sJlj Y sjuasasdal €€ Jo N 'uonejndod TOp-gY4D paleaJl 2J13us ay3 syuasaldal 29 JO N ¢ SYD Z< apelo SuiAey se paziJo8aled syualied . "JUIAD 3SIDAPE SNOLI3S :JYS 'parodal Jou (YN 'a|qedljdde Jou 1y/N "4aquinu |10} N 'J]aguinu :u 'weadijiw :Sw 'weaSo| 18y 'Uun a1ed BAISUSIUI :ND)| 'DWOIPUAS asealal aupolAd Sy '@Ailsod Jo3dadal uaSijue JLAWIYD H+YY) 'JUSAS 9SI3APE (1Y SJUDAD |B3UJIOD 'SISOWOJY] '@INn|ie) [Buad 'AUS0ISIA JadAy 'e|wiao|eaIadAy 'aseasip auoq 'Adealy)s Jo doe| pue Jy 01 aNpP UOIBNUIIUO0ISIP 'sTy palejaJ-luswieall 's1ys Auy :sawo021no Alajes 8uimo||o) ayl Joy paliodal 10U eleq 3i/s1190 3i/s119 3i/s1190 3i/s119 3 /s1199 llesano L+4vD L+vD llesano L+4v) 1+4vD L+4vd swuy o0TX 0S¥ sOTX 0ST s0TX 0S5t 00TX 00E oOTXO0ST hw.mmflcfilmflu uN.._"._".c.__Gs__)_hmv_ ledl SJUDIUO) JO 9|qe] 0} UIN1ayY ewo|aA a|di|ny - Hoday jeuld 60T a3ed TZ0C 'M3IA3Y J1WOU0] pUe [ed1Ul]) JO) SINNISUIQ (g's€) 9 (o) v (T'€) € € 9peJo i (T'se)oe (zeg) 8¢ Z9peso (8'85) OT - : (rev) Lz {s'0S) 617 1 apeio (ooT) LT (s'68) TS (8'v6) 26 llesan0 (%) u 'sHd ] ) (28uey) UN (ts€)6 (L6/T) ¥ sheq 'uOPEING USIPOW ] ] (o8uey) UN (61-T)6 (e1-1) L sheq 425uQ UBIPOW UN UN Adediy3 jo yoeq UN uN sy UN UN UN uoIssaid0.d aseasiq (%) . . u 'uojlenuuodsiq (8'62) LT (rvT) vT yieag dN (7'vT) T lles3A0 (0o 24njieq Sulnjaejnuep (v'v) €TT/S [emepyIM Judled (%) u : uoissaidoud aseasiqg 'Juauneail o3 Joud HN dN (8'T)ETT/C 1 1 . (08) eTT/6 yreaq Apms (zvT) €ETT/9T lle43n0 (81)1 UN PY10 (se)e (€6)6 sy , dN (%) u 'Ajeron (9%2) ¥1 (zs)s uoissasBoud aseasiq (8'62) LT {r'vT) ¥T lle4an0 UN UN (%) u 's3vs pajejai-juawieal) uN «(6'19) LE UN (%) u 's3vs Auy dN dN (%) u 'Iv pairejai-juswieas) (oot) £5 (oot) L6 (%) u '3v Auy L1 LS L6 (parean-se) N 3 /s1190 L +4VD ;0TXL'0 /51192 L +4VD ;0TXS0 By /s1199 L +4VD ;0TXTL'0 suy ns3uelr 'uiliny '8uayzduey) ue,Ix - el 2'se'er-ONIDTT 99'970-ANIDTT 0zl"3ANLILNYI IetiL [92-e}1) :sawo02nQ A1ayes "ZT'€a 3|qel S1U9U0) JO 3|qe] O} uiniay 01T @3ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUDDT pUE [eJIUI[D 10§ BIMNISUIQ awil dn Moj|0) YIuow-g UeIpalA | Sqv €< 3pelo , JOLI3 pJepuels 135 'SJUDAS SIDAPE SNOLIBS :JyS 'patiodal jou YN 'Blge|ieAr 10U [y/N 'Jaquinu [e301 :N "4aquinu :u 'welSojy 18y 'wolpuAs asesjaJ aup03AI :SHD '@AINsod Jo3da3a) UISIIUR JLISWIYI H+YYD 'JUSAS 3SISAPE (7Y elwd2jeasadAy 'Ausodsia 1adAy 'aunjie) [eual 'siIsoquiodyl 'aseasip auoq 'suonezijeldsoH :sawo2ino Alajes Suimo|joy ay3 oy parodal jou ejeq (9°6T) 6T € 9pein 2 . 4N 4N - (%) u 'suondayu| (££S) 95 lleJaA0 uN (gzelet (8'65) 85 g9peln 2 (%) u (T'67) 8T (reL) LL llesan0 'eluadoifroquiosyy (s£1T)OT (0'89) 99 € 9peinz UN (%) u 'erwduy (8'62) LT (r'T8) 6L llesano uN N (8'v6) 6 € 9peinz (%) u 'eluadosinan dN N (6's6) €6 llesdn0 * opelnc (8'85) oT UN UN € 9peunz (%) u 'eadorky (r'z8) vt UN UN lle4an0 (on)t G apeJn (o}o i ¥ speto (€6)6 € apelo (0)o (%) u "Ayd1x0304N0N Z 9peun (8T)T {eot) 0T T apeso (81)T {(9'02) 02 lle4aA0 ) . ) (%) (6'25) 6 Hosy) 9z (1°69) £9 u 'qewnzyo03 paanbay T2 011 3pess HN HN HN wouJ} uoissaiSoid (69)T (0)o (o)t G apeJn (0)o (0)o (o)t ¥ apeso /51193 1L +4VD J0TXL'0 31/51195 L +4VD 0TXS 0 /1193 1L +4VD J0TXTLO sy ns3uejr 'uifiny '8uayz3uey) ue,Ix - eu 2'soer€-ANIDIT 99's979€-ANIDTT 0zl"3ANLILUYI IBHL S]UaIUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUDDT pUE [eJIUI[D 10§ BIMNISUIQ (Tza)te g€opein z (625) o€ T (%) u 'eluadorfooquioayl (T'T2) 0z € opeinz v €t lledano (%) u 'eluisuy (€6)6 € apeinz et) en llesano (%) u 'euadonnan e e € 9pesnz H{LeT) €1 [ledano (%) u 'epwsojeasadAy 10)o (%) u 'Ausoasia JadAH HtT)T (%) u 'aunpie4 jeuay 1(TT)T (%) u 'suondayu) (0)o (%) u "Audixoj04nap (0)o (%) u 'sud )T Adeayg jo e (ze) e SJUdA] [EBUI0) (s6)6 s3v +{8°09) 65 uoissaiSoud aseasia (%) u 'uonenuguodsiq oze) 1€ yieaq H89L)eL lledano Hre) € 1#Y10 (ze) e s3y +(€'92) ST uoIssa480.d aseasiqg (%) u "Ayjerom 1{9'zE) 1€ [[e43A0 (oTT)TT (%) u 's3vs parejas-juswieas) (T'2p) o (%) u 's3vs Auy (v'88) ¥8 (%) u 's3v pajejai-Juawieas] (6°L6) €6 (%) u 'av Auy <6 (uonendod A1ajes) N 3 /3w gz qewejuejdg SwIy szsr1C-WNYIHA |euL qewejuejag :sawodnQ Alajes "€T°€d 3|qel S1U9U0) JO 3|qe] O} uin3ay ¢T1 @8ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUDDT pUE [BJIUI[D 10§ BIMNISUIQ ejuadolAd 'sisoquioly] 'aseasip auog 'suopiezijeldsoH $awo01no Alajes SuImo||o) ay3 4o} paliodal Jou eleq (0)o (%) u "dn-mojjo4 1se7 JO Se paIaA0IdY 10N (2As Buppas-1an9q T=N (zz-22) 0'te (58uey) sAeq ',uoinjosay 01 Swj] UelpaAl ay3 uj asiom 10 00Z/0¢ (tz-12)0°1e (a8uey) sAeq 1asuQ 01 awi| uejpaiy J0 VAD4) VADS ul sd8uey) ToT (%) u 'llesano Injdujueay Ajjeojuid (9L1) LT/ (%) u 'dn-moj|o} 15€] JO SE P3IdA0I3J 10N (9Aa Sujeas-1omaq ¥T=N(¥9-£) §'TC (98uey) sAeq ',uonnjosay 03 dwi] uelpaN ay3 uj 8sI0M 10 05/02 (zv1-02) 099 (98uey) sAeq '4asuQ 03 swiy] ueipay 40 YAD4) YAD4 ul saduey) (6°21) LT (%) u 'lesano Inj3uiuesy Ajjeasuid (L) v¥/vE §({2%) u '©2udLINIIQ 15414 WOI) PAIDA0IDY (£zT-8) O0'€E (9Suey) sheq 'uoneing ueipa (€TZ-02) O'tv9 (28uey) sheq 19suQ 03 swi] ueipaiN (TT)T ¥ apeto VADg Ul sasueys (s62) 8¢ € apeJp (8'sT) ST Z 9peip e e 1 apeun (£'€s) TS (%) u 'lesano (0o (%) u "sso7 uoIsSIA JusuRWIRd (£vT) ¥T (%) u 'aA3 Mg (e'52) v (%) u 'uoIsIp paan|g §(2'92) 09/9t (%) u "@3ud.1uN2DQ 15114 WL} ,PBISA0IDY (0'85£-0°'8) 598 (%) uz= (o8uey) sAeq 'uoneinqg uelpay apess (s33W) Ayredoressy (0'eb1-0'6T) O°'LE (a8uey) sheq "asuQ o0} awi] uelpaN (Tt ¥ ape.p (€'sv) ¥ € 9pead (8'91) 9T Z9pesn (%) u '(s93n) Ayredoresa) (r'8) 8 1 9pesp (91£) 89 llesano /8w 'z qeweiuejeg SuIY ezerrC-WINVIYA leuy S]UaIUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld €TT 93ed TTOC 'M3IAJY dlWOU0I] pue |edjul|) JO} 91NUISUIQ JUSAD 3SJIAPE SNOIBS (TS 'Pajodad Jou (YN '4aquinu [B10} :N "Jaquinu U 'DWOoIpuAs 9sea[aJ auPolAd :SYD Z-aN3D937 'T-IaNLILYYD 'sdnoadqns ysid YySiy ejalNIe) :8uimo)|o) 8Y) Joj 3|geieAe jou ejep Alajes dnoudgns 'ejwaue 'ejusdolAroquolyy 'uolsiA paaan|q '@Aa Aip 'Ayredolelay 'sJusAa asiaApe snolias Aue 'SJUaAd BsiaApe Auy :sawod1no Suimol|o) a3 Joy paiodal Jou elep dnoa3qns 4N uN 4N (09T (68) ¥ €2 9peJn (%) 4N 4N 4N (0'0g) 9 (rve) Tt llesan0 u 'Aipxo0r0inaN UN UN 4N (oot} e (ryv)e g2 9pelo , : : : : (%) u 's¥d (osz)ezt (06L) 1T (0zs)6 (0oT) 0Z (6'88) O lle4a80 91 1 1T 0¢ St N SYIUON €°TT SYIUO €°TT dn-mojjo4 uejpaiy uaping Jown] ysiH _ Adesay] Suj8prg sieah g9 2 sieah g/ < _ sieah g9 2 sdnoJ3qns ys1y YSiH sjuaned Aop|a sjuaned Auapja ss1OV-8HD z=BINIALIE) lenL |32-9p] :eleq Arojes dnoadqns pT €Q d|qel dn-moj|0} 1S€| JO SB PRIAA0IAI oym sjudned ul i 91eas (VA)) Aunoe jensia pue Ayjedolelay ayy 19d SJUSAD g2 dpedo J0) eleq § s8uipuly wexa ou/s8uipul) wexa aAs T apelo Auy awil dn moj|o) yluow-¢€°9g 4 UOIIRUI [BIIA 4 "10119 pJepue)s 135 'SJUBAD 9SIDAPE SNOLIBS :3yS 'paliodal Jou (YN 'S]qe|ieAe Jou iy/N '4aquinu [B10] N 'Jaquinu :u 'wedijjiw 8w 'sadueyd |eljpayuds a)1|-1sA20.01N SO 'wesSo 18y 'Dwoupuis asea|al auP0IAI 1Y) 'DAINsod Jo1dadal uadiue JLIBWIYD +YYD 'ANINde |ensIA Pa19aa10d 153q (YADE 'JUSAS aSIaApe 7y S1U9U0) JO 3|qe] O} uin3ay ¥1T 98ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUODT pUE [eJIUI[D 10§ 3IMISUIQ W €27 T/ulW/Tw 09>-0£2 Y49 Se pauyap juawliedwi [eUdl 31RIBPOW 'W £/ T/Ul/IW 06>-092 Y49 Se paulap Juswiedw! [eudl PN 4 SJUDAD OSJaApe SNOLIFS :$3YS 'A1I2IX0104N3U | N 'pPaLIod 10U YN 'I9qUINU [B101 IN "JOqUINU U "JS|Ij[IW W '@INUIW :ujW 'paJenbs sI1919W :,W 'S1eJ uonell|l Jejniswo|s :y4o uoISIA paJun|q £2 aped8 'aAs Aup g2 apeud 'AJDIX0101N3U 'SWOIPUAS 9SBI|3] U 0IAD 'SJUDAD IsIaApe Auy :Suimo)jo} 3y o4 paodal Jou ejep dnoiBgng (o'sz) 9 (8'8T)6 UN (o'Tg) 9t (o'tT) S €2 apeun -- (z62) L (T'22) €T (r'v2) o1 UN UN llesan0 ' (osz) 9 (8'8T)6 UN (oog) ot (o21) 8 €2 apetn ejuadojfroquioyl (0's?) 9 {6z 11 (sT¥) LT UN UN lle1an0 (LT) ¥ {8'02) 01 (s'6T) 8 UN UN lle1an0 UoISIA padinig ()T (881)6 (zer)s UN HN llelan0 aka Mg (€€g) 8 {ost)zt UN (oz2) vt (ogg) 91 €2 apetn Ayredojesay (sz9) st (8'89) €€ (5'85s) vz N UN llesan0 (o0s) Tt (e€e)ot (€9t} 6T UN (%) u 's3vs Auy SYIUON 6 SYIUOA 6 SYWON 1'ZT dn-mojjo4 ueipay ve 8P TP 0S LY N sonauadoir) 91eJapo) 1 y saidess saidesd - 1eJ9pOA PN std YBIH idesay) £ 2 idesay) 9-¢ sdnoaSqns sludwedw) jeuay ysiY YSIH s9jdesay] Jopd scpeC-ININVIHA ledL gewejuejag :ejeq Ayojes dnosdqns *ST'€d d|qel S]UaIUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld GTT a8ed TZOT 'M3IASY J1WOU0I] PUE [eJ1Ul[D 1O} 3INUISUIQ S3wo21no Alsjes Joj pauodal Jou ejeq z000=d 100°0>d o e ) . {290 '§T0) S£°0 {450 'b20) 95°0 N (98°0 'ST0) 9€°0 {12%56) ¥H 'SO '0>d (£5'0 '€2°0) LE'O . .jo @ i 1000°0>d '(69'0 '€€'0) 817'0 (9z:0'22°0) s¥°0 {129%56) HH 'S4d sawo2nQ (€£°0 '2v'0) SS°O o o o . Aaeayy3 UN UN 10000>d (T2 VO TP (12%56) HY 'Ud3A 100°0>d . £ . . . VQ f . [ . " . £ . . & (6¥°9T 'v6°2) 969 (v6°8 267) TT°S T000°0>d '(€€ 'L'T) ¥'T *HH (ET'TT 's€T) 2T's (12%S6) HO "HHO UN (oer)zs | (0'w8) 801 (oo1) £6 (0'¥8) 80T (%) u 'Asopesges-adul (Te)e UN qewixnjes| {oot) L6 uN qewnwnjeleq (%) u uN uN (8'16) 68 4N aplwopljlewiod | 'panidlay (oot) L6 dN apiwopieust | seidesayl (€9L) L N quuoz|ye) 1o0l4d (6'L6) S6 UN qiuozaliog (0°0€) LS (zse) sy (€zv) v (zSE) Sy | (%) u 'sopduaBodhy ysp-ysiy | SUHSsed ] ] ] (o8uey) paniaday (4N) s (91-€) 9 (tz-€) L (91-€) 9 suawi3aY Jold UEIPSIN uN (t)8 (botT) 12 (eev) v (boT) T2 (%) u 'g a3e3s sS| i } i (%) dN {(1'6€) 05 () ee (165) 05 u 'aseasiq AJe|[npawex dN (r'6s) 9L {(9'zs) 1% (r'e6s) 9z (%) u 'ajey ¥9 19 59 (82-€€) 19 SJEdA ueIpaN 98y €€ 7ot €11 [3A9] Apnis £€T syjuoly 'dn mojjo4 ueipa (€€=S53) 3%/s1122 _ _ (£6=N) _ 1 +4VD 40TX0SY (£9=553) |122-2p| :u.wflu, .MM_N%_ /3w sz hfl_w'.hw_w_ suuy [92-9p| Z-WINY3IHd HLOWIAYIN "SA BN IALIE) +PHOM Z-IWINVIYA "SA BIAIIAIIR) s|el) |eay BIAIMR) "SA BIAIINIEY : #w020Z HSY yeys »020Z OISV Yreuueser £,0202 YH3 01910-zon81poy aainos |93-9p] :sesAjeuy Alepuodas "9T €d d|qel S1U9U0) JO 3|qe] O} uin3ay 91T @3ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUODT puE [eJIUI[D 10§ 3IMISUIQ (8'ov) v s3vs Auy (%) u N (€'88) 16 s3V pajejaJ Juawieal] 'Sawo021n0 (T°86) TOT s3v Auy Aiayes (089) 2z (%) u 'syjuow g 3e SO (4N) 9'C dN (12%56) syow 'sid ueipaiy sawo02NQ0 (9'22) 62/8 (%) N/U (12%S6) ¥y '4d8a Aeay3 (v'1¥) 62/2T (%) N/u (1D%S6) HO 'YO L N (%) u 'Ao1oeiyal 31d1L (881)9 qewixnies] (696) TE qewnwnjeleq (s'28) 82 N apiwopijewod (%) u 'paniaday (9°06) 62 apiwopijeua] saidesay) Joud (1°8L) ST quuiozjie) (8€6) OE qiwozayiog aulaseg (612) L (zLT)8e (%) u "so118ua801A) Ysu-ySiH (tT-€)9 (tz-€) L (93uey) suawiSay Jo1d uelpsN 4N (8'6€) TV (%) u 'g a8ess sS| dN (vo) Tz (%) u 'aseasiq Atejnpawesyxy (r"6S) 6T (s0s) zs (%) u 'alen (88-6¥) 969 (0's8-0'6€) 0°S9 sJeaA ueipow '98y (8'€1-5°0) £'S N syuoAl "dn mojjo4 uepaiy fimuz,o_w_:\_mm_"_:"wh. uese (€0T=N) $1/3ws'Z qewejuejag suLy PlHOM |eaY Z-IWINV3IYQ pue T-WINV3IYQ p3jood sjen1 +0Z0T VH3 1e8euys 00202 VH3 [9pnJL 321n0s gewejuejag :sashjeuy Auepuodas */1°€d d|qel (soms [ed1uld wouy eiep [9as)-1uaned '(Ay-eWINLEY) Apnis 9A1109ds043a4 '|euoijuaaIduIuou) ety ANjiqi8iD einn4e)y Sunaasw sjusiled plaom [edy , asuodsal |eiued poo8 AIaA :yd8a 'SJUaAD Ssianpe SNOLIDS VS 'O11B1 JSH 1YY '|eAIAINS 934)-uolssaJdoud :S4d '91eJ asuodsal [|BIDA0 1YY 'Ol3e1 SPPO YO 'pajodal Jou (YN 4aquinu |B1o) :N "4aquinu :u 'welsijjiw :Bw 'wesBoyy :8y 'o1rea paezey :YH 'azis ajdwes aA1109YS ST 'OA1lsod Jo1dadas usBiue JLIBWIYD H+Y YD JUDAS 9SIDAPE (] '|eAIDIU] DIUIPLUOD %S6 (D %S6 S]UaIUO) JO 9|gE] 0} uImay LTT @3ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUDDT pUE [BJIUI[D 10§ BIMNISUIQ asuodsaJ |ejued poo3d AJ3A :HdOA 'SIUBAD ISIBAPE SNOLIDS 11VS 'Ol1e] YSH 1YY '|BAIAINS 93.41-U0]sSa480.d 1S4 '@1eJ asuodsal [|eJaA0 (HYO 'Ol1ed SpPo YO 'pawiodad 10U YN '"4aquinu [B103 :N "Jagquinu :u 'welSjjiw 8w 'weSojry :8) 'Olied pJezey :YH 'azis ajdwes aAI139443 :$ST '@A1sod J01daal USSIIUR JLIBWIYD YYD 'IUSAS 8SIaApE Ty (0o €opein 2 4N aA3 Aug (ztT) et lle43n0 (6'€) v g€9pesn 2 4N UOISIA pasin|g {r'eT) 0T llesan0 (8'sz) 1€/8 (z12) 82 g€3pein 2 Ayyedojesay (s'v9) TE/0T (0'99) 89 lle43n0 (0eT) €T/€ (s£1) 81 g€apeinz eluadojhd (v'o€) €T/L (e€) ¥ lle13n0 -oquioayL (r'81) 6T €2 apeun dN ejwauy (T9n) Lz [Ie13A0 (60T s3yS paiejai-jusawiea.] jeyed (ozT) €1 s3yS paiejoi-juswiesl] (ze=N) /3w '€ pue 57 qewejuejag (E0T=N) /BuS°Z Gewerueig suiv PIMOM [e3Y C-IWINVY3IHQ Pue T-WINVY3HAQ pa|ood sjeul 90¢0¢ YH3 1edeuys g90€0C YH3 [9PNJL 921Nn0$ S1U9U0) JO 3|qe] O} uin3ay 81T @3ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUDDT pUE [BJIUI[D 10§ BIMNISUIQ JoyqIyui aseajold :|d "daquinu |e103 :N 'Apogiiue [euojaouow :gyolA 'ewojaAw ajdiinw (Al 'Snup Alolejnpowounwiw] Al 85=N (d3>@) uneds pue 'apisodols 'apiweydsoydojAd 'auoseylowexap Jo/pue (dg) duosiupaud/aurisnwepuaq Jo S[oAI JUO 1SeI| 1B PIAIDIDY Apnis 1oyod W Aloloeuyal-ejusd/pend 9AadsoJlal '493uad-3|3uls 42020T YHwWisp|oD TS9¢=N {avo 8€ad SpJ402J2J Yy3jeay 21uoi3da9|s -ljue ue pue 'qiAl| SUo '|4 Suo 1ses| 1e Suipn|aul) Adeayl Jo saul| € 1SeI| 18 PaAISdRY y}eaH uoJileld 'susaned sisouSelp WIA JudW)edJ) pIoM-|eay 20202 _IYa 9seasIp aAIssa180.d Jo 3UdPIAG YUM pue uawigaJ Juswieal) SululeIu0I-gyYOoIN 8EAD B YUM SH99M 1SeD| 18 10} Juswiead | S/Z=N (uolreuiquwod ul Jo sUoje pPaJISIUIWpPE.) qewixnies! Jo qewnwnielep 0} Aloloelsay INIAl 9An2e Jo sisouSelq Apnis Loyod aAndadsoliay (HLOWWVYIN sansuaeIRY) JUdIRd udisag Apmis/jeny suawi8ay aie) jensn :udisaqg Apnis "8T°£d d|qel suawibay ain) [onsn S]U3IUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld 61T @3ed TZ0C 'M3IA3Y J1WOU0D] pUe [ed1Ul|) JO) SINNISUIQ (oot) 1€ (oot) L2 (z°L6) vvre (oot) 0L (9°86) 9v'T (z'86) 0Lt aplwopijeud] () u HN HN (oot) TSC (T'26)891se911e | (7€) 8ET 1se|1R | (T'E6) 9ST ISES| 1R | qewnwnleleq 'pasodx3 (TvL) €T (s18) TT (T'62) €L (00T) O£ (0)o (v'se)oL (%) u 'Aoyresyai-ejuad (8's7) 8 (S'81) S UN (0)o N UN (%) u 'Aorsesya.-pend UN UN (9°9v) £1T (oot) 0L (€°Lv) 0L (T°£5) £ST (%) u 'pasodxa-eyudd (sT-1)8 (sT-¥) 9 (9 'e :WoI) ¥ (9T1-2) S (t1-1) ¥ (91-T) ¥ .m_aE_u.H.L__Mww_::m_voE (€°06) 82 (s'18) T «(298) TPT (T°29) Lv (€°0L) voT (0zL) 861 (%) u '1S sno3ojoine pan1aday V/N Z apely snjeis N . dN 1 9peso aJuew0M9d (res) veT 0 opeis 5023 (T'91) S (6's7) L (L'vT) 29 (9°81) €1 (8'T€) Lv (1'62) 08 € a3e1s (%) u 'asers (Lge) Tt (€€€) 6 (s€z) 65 (eve) vz (ozz)ov (s0g) 8 Z 98e1s 252351 S| (0627) 6 (8vT) v (s°6T) 617 (eve) L1 (0zz) op (192) 69 1 98ers dN UN UN (v)s et (08) 2z (%) u 'yuonduny jeuay uN UN (LvT) 29 (£s€) sz (vr8e) v (T6z) 08 (%) u 'sanauadorh) ysiy YSiH (zetT)sy | (TEe-TT) LY '08z A_N_Mw - (rv1-970) LS (r61-v0) ¥ (r'6T-¥0) ¥ .m_mocmmuw_uuum"__w MM_.H:@_BE . ) (rit)8 (Tg)et (0'8) ¢ B3y10 (el (o)o (ozt) o€ - - - (62)¢ (Lot (Td9 djuedsiH (%) u (L'6) € (8vT) v (T°sT) 8¢ (981) €1 (8'¢1) 6T (va1) av yoelg 'Mp1uyia/eoey (T8) L2 (zs8) €t (6'89) €£T (T°29) Lv (r'8L)9tt (s'€L) zoz auym (v8v) ST (rvv) Tt (zvs) oet (£°ss) 68 (v°Ls) s8 (€ss) zst (%) u 'sjlen (€£-8€) 09 (s8-8€) 19 :.mwm..Mw o) (0"9.-0°<€) 5°8S (0°s8-0"€2) 0°09 (0'06-0°£2) 0°59 (98uey) siea) uelpa 'a@8y 4N (8'01-£'C :¥DI) 0°9 (ecr-6'T) 90T syuom d.w.mnwflw 1 UeIPOW 1€ Vi 152 oL 8vT SLz N d3)a d9 Aoydeajaua-ajdial Aioydeajal-ejuad -h""uu\mh_fi"._. [[ELYe] suly 20207 YHwspjoo (20202 BIY3N (HLOWNVIN Apmis/jenL suawiSay ale) [ens :sdlsUAIRIRY) BUIjaseq "6T €A d|qel S]UaIUO) JO 9|gE] 0} uImay 0CT @3ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUDDT pUE [BJIUI[D 10§ BIMNISUIQ 1p/8wg < dujuieas) ¢ paydads Jou 105 Jo adA] uejdsuely (122 wals :1DS 'pariodal Jou [YN 'O|qe|ieAe JoU (/N 'Jaquinu [B10] N 'Jaquinu :u 'wesdijjiw :Sw '98uel sjiuenbuiaiul YOI 'dnoug A8oj0duQ aAllesad00) LIISe] (50D 'JaN|P3P p 'une|dsid pue 'apisodola 'apiweydsoydooAd 'Duoseylawexap :d3)q 'duosiupaid/aunsnwepusd :dg 1YB1om 819K :sansuRdRIRYD SulPseq uimo||o) 9yl uo papodal jou eleq UN UN (002) ¥1 (Tv)o (r8) e aplwopljeyl UN UN (evT) OT (s'sT) €2 (veT) ve qlwozex| 4N 4N UN 4N 4N qewnznio|3 (oot) 1€ (oot) L2 "N (£s6) L9 (9°8€) LS (€Lv) O€T qiwoz|iye) (%) u (oot) 1€ (oot) L2 (986) 69 (885) L8 (T'59) 64T aplwopljewod 'Moyeyay (oot) 1€ (oot) L2 (T°26) 89 (ezL) Lot (¥'89) 88T qiwozayog (oot) 1€ (oot) L2 (9'86) 69 (TeL) LTT (£9L) 112 aplwopjjeua] (TvL) €T (s'T8) TC (T°L6) 89 (zes) 8€T (T°e6) 952 qewnuwnjeleq UN 4N 4N (6'z€) €T (9°L1) 92 (002} 5S apjwopljeyL UN UN 4N (vt e (TotT) vz (6'€T) 8€ qiwozex| 4N 4N (9°6) T 4N 4N 4N qewnznjo|3 (oot) 1€ (oot) L2 (8°£8) svT (T°L6) 89 (v'1s) s8 (8'¥9) 84T qlwozjiyie) (oot) 1€ (oot) L2 (6'89) €41 (9'86) 69 (s'19) T6 (£'89) 68T aplwopijewod (oot) 1€ (oot) L2 (0°06) 92T (9°86) 69 (9°86) 91 (9°86) TLT qiuozapuog Aoydeayau d32d dd Aiopeyas-aidiag Aloyreusal-ejusd -penp/aidiL llesan0 suuy 020202 YHWISp|oD 2020Z _BIY3W (HLOWWYW Apms/jeny S]UaIUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld TCT 98ed TZ0C 'M3IA3Y d1WOU0] pUe [ed1ul]) JO) SINNISUIQ (8'8) 6¥2/2C (%) u '4dSn UN 4N 11101 Joe YO (02) 6¥2/S (%) u 'ud/uds (e°s2) £8/tt 1€101 (s°12) 8ST/¥E 12101 (T12) 6T/Y QlAll + qewnzniofj 4N 4N (9°9€) Tv/ST Q! + qewnwnleseq (ozv) 61/6 lojejhyjje + qiwioz|yie) +T101 (%) U 'HHO (v'ze) 89/te paseq-qiwozjijied (0€) €9/6T (62) L6T/LS (o'T€) 6172/8L llesano 4N 4N (59°0 "€0°0 :10%S6) ¥T°0=HO so139ua803A) Ysiy-ysiH UN UN (9'9%) 6¥72/9TT llesan0 [6T=N]{9'¥1-6'T) €8 dlNI + qewnznlo|3 [T¥=N] {(9'91-5'8) 9°¢CT Q!WI + qewnuwnieleq 1T101 [6T=N] {5'61-6'S) £CT JojejAyje + quuiozjyed UN UN [89=N] !(¥'21-5"6) 6°0T paseq-qiwozjijie) (1D%S6) (o'0T 'T'8) TE'6 101 3uanbasqns T < paAl9lay SYJUOA 'SO UelpaiN [zz=N]'1€0°0=d (4N) L€ »uoiduny [eusy pasredw [08=N] '#520°0=d (4N)'9°S $2139ua803A) ySIY-YSiH (8L's°€)9S (1t Te (66CL)98 llesan0 [6T=N](T¥-T'T)9C Q!NI + qewnznlo|3 [T¥=N] {(€'9-8°2) SV Q!WI + qewnwnieleq . N uN [61=N]'(£'6-97T) L'S JojejAxje + qiuiozjyed (4H 10 1D%S6) [89=N] '(¥000=d '090 HH) T'¥ paseq-qiwoz|ie) SYIUOIAl 'Sid uelpaiN (ov 82 ve 11017 3uanbasqng T 2 paA1aIay UN llesano (€zr-6'T) 90T (28uey) syjuow 'dn-mojjo4 uelpa oL 8vT SL2 N Alopeuyaa-ejuad | Aoesgal-penp/ajduL [[[IELYe) suy (HIOWWVIN ledlL | suawiSay aie) [ens( :sawo02nQ Adedyy3 '0z'€a 3|qel SJUDIUO) JO 9|qEe] 0} UIN1aY ewo|aA a|di|ny - Hoday jeuld 71 98ed TTOC 'M3IA9Y dlWOU0I] pue |edjul|) JO} 91NUISUIQ *)SIJ pJepuels SnsIaA Aojoeuyaa gyoN 8€QD Suiwodaq 1aye Adesays jo aull {(€101) P4yl 4o '(z1O1) puodas '(T101) 1s414 | 'Ip/8wg < duiuieas) , 'asuodsau |eijed poo8 Aiaa :yd8a 'osuodsas 915|dwod JusaBuials 1Y)s 'asuodsal [ended Yd '|eAlans 33.)-uoissasdoad :S4d '|EAIAINS [|BISAO (SO 'D1R1 9SU0dSDI |[BIDAO :YHO 'Ol1k) SPPO YO 'pauodal Jou YN 'Jaquinu |elol iN 'Jaquinu iu 'Apoqiiue |euojpouow :gyoN '(Alordelyal AvOoIN 8£aD Sulwodaq Jaye) Adesay) jo aul| 107 'Snip Alolejnpowounwiwg (Al 'Oled piezey :YH 'Osuodsal 313]dwod YD '|BAISIU] 93UBPLUOD %56 1D %S6 (suawn8au 19]du1] 'uawndau 19|qnoq 'Adeiayiouoiy 'paseqg-apiwopiiey ] 'paseq-qiwozex| 'paseq-apIWopIeud] 'paseq-qIuozanog 'paseq-apiwoplewod) paaiadal 1 01 :sawodino Adesya Suimol|o) ay) 1o} papodal jou eleq (605) 6 (99¢) 6v (67¢2) LS (%) u 'syuauneau) paseq-qewnwnieleq UN UN (9'2) 6T (%) u 'syuawieal) paseq-qewnzniol3 hioreyay avon (eT) 8 (tze) ev (€£2) 89 (%) u quauneal paseq-qiuiozjiied wmmw.w ""omh_a,"_""m N YN (o1-1)Z (s8ueJ) u 'pans@dai 107 velpa Sujnad9y swusned €9 vET 6V N (978€) LT (£s2) 8¢ (082) LL (%) u 'aseas|q anissai3o.d (s°02) 6v2/1S (%) u 'ud Aropeysi-ejuad | Alopeyas-penp/ajdiL llesdn0 swy (HIOWWVIN leny S]UaIUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld €71 98ed TZ0C 'M3IA3Y d1WOU0] pUe [ed1ul]) JO) SINNISUIQ (€82) €L1/6¥ aplwopijewod yum uN HN HN (697) Svi/6€ quiozgEs wawneanay () v (62) v (872) ¢ udwiSay 19jduL (tve) et (T°6€) ¥S (6°€€) S8 UN uawiday 19|qnoq (T°8¥) 9¢ (0zv) 85 (0rev) €21 Adesayjouoy (8'v1)8 (8'€t) 6T (02) s UN paseq-qewnuwnieleq W) v W)t (8v) Tt N paseq-apiuopijeyL (%) U 'paAIadaY (€6) S (1°81) ¢ (8'8) 2¢ 4N paseq-qiwozex| Adesayl uN (0€T) L (8'€T) 6T (5°ST) 6€ (cea) Ls paseq-apiwopijeua] Jo saur (oen) L (8ct)6T (€9T) TH (357} 9 paseq-qewnznio|3 (zza (vee)ee (L8T) LY (T'ce) €8 paseq-qjwozauog (£91)6 (897) L€ (€0g) 9L (06€) 86 paseq-apiwopljewod (zzo) ot (T81) Sz (eze) 18 (Tyv) 1T paseq-qiwozjiied N N N (8T)z -o_n_hfiwwflwflvnv"w_m_uw"m'wvw"""w"_ 101 u 'Aoydesjas-apdiiL vs BET 15¢ 15¢ Sulwodag 4oy Juswleal)] SulAPIDY N N N N .u:prmhw.me_N_ m."a""fl. uelpsiN UN UN 4N 4N HN UN (%) u 'aseas|q anissaidoud (062} 6 (TT1) € (%) u'ud aun (ze)t (8vT) v dN (%) u "4dSn uanbasqng (ze) T (0)o:¥d (%) u 'ud/uds 15414 J9yje YHO (ssE) TT (652) L 4N 4N dN 4N (%) u '4y0 (8'1-¥v)T9 (os1-€0) 28 uN uN UN (9°€T '2'8) O'TT (12%56) SYIUO 'SO uelpaINI (8'e-ST) LT (OT-TT) VT UN 4N dN (to'ce)sy (12956) sUIuoW 'sid uelpsN dN (8'0T-£"Z :HDI) 09 (98ury) syruo 'dn-mojjo4 ueipal 1€ [T ¥S 8€T 152 152 N dia dd +E101 +C101 +T101 llesano swy 0z020T YyHwispjoo z020T B1YaN Apms Il suawiSay aJe) jensn :sawo02nO Arediy3 *TZ'€d a|qel ewo|aA a|di|ny - Hoday |euld TTOT 'M3IASY J1WOUDDT puE [eJIUI|D 10§ BIMISUIQ SJUDlUO0) JO 3|qe] 01 UIN}ay ¥¢T 98eq aseasip aAIssalfoid :qd 'paniodal 10U (YN "4aquinu [e101 :N 'Jaquinu :u 'Snip Aloreinpowounwiwil :QIAI| 'Oonel piezey iy H 'unejdsid pue 'spisodols 'apiweydsoydo)dAd 'suoseyiawexap :d3)d 'duosiupaid/aunsnwepusy idg '|eAISIUl SIUSPYUOI %S6 D %S6 "wie 0z0z edys Aue Jo 'swue Aojoelyal-eluad Jo Alojoelyal-penb/sidinl HLOWINVIN 104 paniodal jou elep Alajes (Te)t (zet sisdas (ze)t (et awoJpuAs sisA1 Jown) 4N (e'c€)6 UN { apeln ejuadoljfroquioayl (tot) s UN $J9A9y dluadosinaN eluadosinan dN (s8T) S ¥ apeun N {¥6°0 '¥'0) ¥9°0 suawi3ay aINI + qewnwneleq (1D%S6) ¥H (s8'0 'zv'0) 09°0 suawiSoy paseq-quiozjyie) | 'Yieaq 1o ad Jo ysiy N (ezvr-6'T) 90T (98uey) sywon 'dn-mojjo4 uelpanl T€ LT SLT N d3ida dg llesdro suy 9z020T Ylwispjon (H1OWAVIN Apnis/jenL suawSay aie) [ensq :sawodnQ Ayajes "zz €d 3|qel *A1o10eI)3) ssed-adL] Sujwodaq 1aye Adesayl Jo aull (€1017) P41y 4o (z101) puodas '(T10O17) 15414 e Buialpoal sjuaied jo dnoi8gns,, asuodsai |eied poos Auan :yd8a 'osuodsal 319]dwod Juadunls :yDs 'asuodsau jeiued :yd '|eainins 3a.)-uoissaudoud :S4d '|BAIAINS [|BIBAO SO 'D1ed asuodsal [|_ISA0 tHYO 'paHodal Jou YN '42quinu [elo) :N '4aquinu :u 'Adesayy jo aul| 1101 'une|dsio pue 'apisodols 'apiweydsoydo)dAd 'auoseyiswexap :d30q 'esuodsal 919|dwod 1YyD 'duosiupald/aulisnwepuaq dg '|eAIalul 9IUIPLUOD %56 (D %S6 (s'€T) TST/PE qewnuwnjeleq dN apilwopiieyl UN qlwozex| ; (%) (s'22) vve/ss aplwopljeua N/u 'uswiSey (Tv)ve/t qewnznjo|3 panj22ay (6°1€) 92¢/TL qlwozanog Ajsnoinaug dida dg +E101 +2101 +T101 llesan0 suuy 020202 YHwspjoD z020Z BJY3IW Apms SJUDIUO) JO 9|qe] 0} UIN1ayY ewo|aA a|di|ny - Hoday jeuld GZT 98ed TZ0C 'M3IA3Y J1WOU0D] pUe [ed1Ul|) JO) SINNISUIQ (68) s (6'92) L6 UN lles9n0 (%) u "Ayiedoinan (81T)T (9g) €1 (00)o ¥/€ apeso (%) u '@an3pey (0z) 11 {r'62) 90T (o'st) 6 l[esan0 (s) e (9'0)¢ (eeT) 8 b/€ opeio (%) u "suondayul (6LT) 0T (0€z) €8 (0°99) 6€ llesano - - opel (81)T UN (€8)s /€ apein (%) u 'eiwaoASiadAy (set) L uN (o0z) 2T l[esan0 - opel UN UN (€'8) s v/€ apeio (%) u 'enuadoydwAT uN HN (oot) 9 l[esan0 (9€)z (T'61) 69 (€8)s /€ apelo (%) (s°2€) 1T (0'T€) 2T1 (0'sT) 6 lle43A0 u 'ejuadoitroquiosyy (cot)9 (r'6) vE (oot) 9 ¥/€ apeso (%) u 'elwauy (9'69) 6€ (s'82) €01 (o'sz) st lles9n0 (9°6T) TT (za 18 (e€T) 8 ¥/€ apei (%) u 'eluadoainanN (£5€) 0T (£ze) 81T (e vT llesan0 (v1) 8 {9'9T) 09 (8T)TT (%) u 's3v 03 anp uopenupuodsid (T v uN (€8)s v (9€)¢ UN (e€T) 8 uojssasdoud aseasiq (%) u 'Ayjjerion (ser) e (Tv) et (1) €T llesan0 UN {(s'9v) 891 (€5) 2€ (%) u 'savs +(897) ST (ovL) £92 (£95) ¥€ (%) u 's3v £2 spein «(9'82) vv (€°86) SS€ (£96) 85 (%) u 'sav dN HN (89) ¥ (%) u 'Aiopesgai-3jgnoq UN UN (8-2) € (98uey) uelpalN 'sardesay) 101id (£-89 :HOI) TL (t6-8€) 99 (18-£¥) 69 (98uey) ueipay @8y 95 19¢ 09 N 'uoneindod A1ajes SYuoW 8T SYIUOW €€ SYIUOA T'6 WNWIUIN dn-mojjo4 ueipai\l xadg + A) +4e) X3Q + ud + ex| X9Q + wod + 0|3 udwieal] o0sT0Z uaydung TIWI-INTYIAIINOL 1c£-ININDOT3 Apnis/lent 4suawiSay aJe) [ensn [eUORIPPY :Saw02InQ Alases "€zZ°€d djqel SJU2IUO) JO 9|qEe] 0} UIN1aY ewo|aA a|di|ny - Hoday |euld 9¢T 98ed TTOC 'M3IAJY dlWOU0I] pue |edjul|) JO} 91NUISUIQ 'suswi8al aied |ensn JO SSOUDAINIDYS 9Y) JUdSaIdal 0] pa1Ia|as saIPNIS dAI123dS0119. 9911 9Y] Ul ejep A1ajes Juamiynsul sy} Juswad|ddns 03 Juesaw MIIAI J13BWIISAS SY) 03 Aj|euldIXS PIIII|S SJudwWeal) pasn Ajuowwo)d Jo sjel) aaRdadsold aanejuasasday | *S]UDAS 9SJOAPE 3130|01BWDH , SJUDAD DSIIAPE SNOLISS 1y3S 'Spiwopljewod :wod 'paxodal Jou (YN 'Jaquinu |B1o) N '4aquinu :u 'Oplwopijeud)| :uaq 'qiwozex :ex| '98uel J|13Jenbialu] (YD| 'qewnznio|d 0|3 'auoseyiawexap :xaq '@piweydsoydodAd :AD 'qiwoz|ijied 11e) 'SJUDAI ISIDAPE STy (0o (s2)6 N v/€ apeio _ xaqg + A) +.4e) X9(Q + ud7 + ex| XaQg + wod + 0|3 judwieal) 0eVT0Z usysuug szTININ-ANITVIARINOL 1¢€-LININDO13 Apmis/jeuy S]U9IUO) JO 9|gE] 0} uIMay ewo|aA a|di|ny - Hoday |euld LTT 98eq TTOT 'MIA3Y d1WOU0d3 pue [ed1ul|D 10} 9INHISU|Q SIUBAD 3SISAPY - 9SBasIp d|qeinsealy - auaga) QYN 'SO "Sdd 1 4o 0 Smeis I3 - 'd0Q '@suodsal juawiea) 1sej o3 Aloelal 'Apognue (elnne)) 013wl 'U - 8€QD-11ue ue pue 'QllAl| 'Id PaAIRIRY - 6¥T=N ewoRAW ajdninn :Asepuodas uswi8au (sl192 1 +4vD 40T :JUSW([OIU3 [ENIOY Alo)oeijoy pue Yoea JoJ JuaWIea1] JO S3[OAI SAIINIASUOI X 0S¥ - 0ST :98uel pasde|ay yum s1afqns ¥202 '1 40 - € 3se3] 1 yum sjuswieasl WA Joud €2 - asop) |92-3p| - [eUL [ediuld i ul TZ124q9 Jo Apnis JaqWIaAON Aewpd suojisnpuj 1UOJJUBAIRIU| aseyd 'wJy 3|8uis A1a)es pue Adeany3 *219 ain|ie} Leay aAsaduod Al 40 [ sse2 jo Aioasiy 'sapueusijew puo23s 'SUOIIPUOI PIgJOW-03 eIIUSIS - uonduny moJdlew auoq 'aireday '|euas ayenbapeu| - 9seasIp SND umouy| - :suoisnjox3 (asop [syauopy 09] ainsodxa eJep pue 'il 'Id shoiasud papuawwodal) yum WIN Aloldeagal/pasdelal Jo sisouselq - |93-9p|- YUd "UdBA '4D 'HYO - (v ved) :(g ved) :Aepuodas snojaa.d Jo qIAll pue |d e 01 ,Aloloelyal aseyd uoisuedxy -3|qnop,, 29 40 'QINI '8 Id Buipnpul L9=N 6¢6859C0ION (sanua1xo1 Sumwi Adesay} jo saui| JoLid JuaIayIp € Ised| je (S1192 L +¥vD 90T :JUSWI[0JUS [eN1Y asop Suipnpui) Yyum A Aloloeuyal Jo pasdelad jo sisouseld - | x ogy - OST :98ued auagdP) SJUDAD 3sJanpe aseas|p a|qeJnsesy - asop) |93-9p| - |ell el | €202 '0€ JO @3uapu| - T Jo Jo snieis Hodg - (v 1ed) aseyd | oaseyd 'paziwopuel ewoRAW o|dnInn J9qWAAON :Arewnid isuoisnpu| uonejessy asog -uoN 'ded-om) ul TZT299 Jo Apnis uopajdwo) pajewns3 sawolno uonjendod juaiied SWLIY JuswWIeds | ugisag Apnmis Josuods |euy / 3L [92-9p] :sa1pms Suio3uQ "T'vqQ d|qel saipms 3ulo3uQ 'va S]U3IUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld 8¢T 98ed TTOC 'M3IA9Y dlWOU0I] pue |edjul|) JO} 91NUISUIQ 1DS J1suaso||e snoialld - [sibaf z2 | sisoplojAwe juediu8is Ajjeaiuld 'awoupuAs SINJOd 'elwaujngojSosoew [s10aA s,WoJIsuU3pjem 'elwayng| |93 ewseld aAldY - 53] 0ZAW-DTO BUWIO[RAW Y1IM JUSWSA|OAU] -)1403 "15-as-03 SN 'ASojoyied SN 1ueAdas Jo AI0ISIH - dnoun J0001N3 sisaJaydeyna| o} Jouud sAep '0€2-D10-21403 - | T Adesayy ewojaAw-nue JwaisAs 'Adesayy [s103A 2] uoijelped 'Aia8uns Jofew 'sisasaydewse|d SIUBAD 3SIBAPY - 's8np |euolle8iisanu] 8ulalsy - $70T09E05N AW 'uolssalSoud 'suoisndx3 013Wn 'sO auag|a) 'S4d 'asuodsal sjuswjieaJl Jolid 01 anp SaIUIIX0] 01 8w '4od - |esi8ojoleway-uou aulaseq Jo T dpeln - (z-eINaEY) HHO '¢ Hoyo) - TS sn1e1s ood3 - I8T =N | ewoAN ajdiniAl sty YD T Hoyoy - uawigas Juawieady Joud T yum JUSWIoIud -ySiH yum spafgns ui :Alepuodas | 1afqns (z WoYo)) 'suswiSas Juawiealy Joud paiewnsy | pue ewodA adiInN £2 YyUM s1afgns NN Aloldeayau/pasdelal (s1120 L +4vD 40T Alo)enoy pue ) iz Hoyo) - (T Woyo)) :sauawadinbau olydads-Hoyod - | x oS - 0ST :98uel jer] [edwul) | pasdejay yum syalgng 9¢0¢ 44O T Woyo) - a5eas|p s|qelnsesiy - 9s0p) |92-9p| - Il 9seyd 1oyod u] TZTZqq jo Apnis '€T AN :Alewnid :suoisnpuj {UOIUBAIBIY| -NIA 'way 3j8uis | Ajajes pue Adediy3z uy 10s onsjodojewsy a1vuado)je jo AIOISIH - [syauow $z3] uonounj uedio arenbapeu| - BIWNJ| 92 ewse|d Jo AJ01SIY 4O IAIPDY - 0ZAW-OTO A3ojoyied SND 1ueAs|al jo aduasaid -31403 "15-as-03 10 BLWOJ9AW YHM JUSWIAJOAUL SND UMOU) - dnouo [opoJn] isuoisnjox3 8V/T9EE0ION '0€2-0T0-01403 - uonadwo) -- sawolInp uonejndod juaned SWIY Juswijeau usisaqg Apnis Josuods el / 9L S]U3IUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday |euld 6¢T 93ed TTOT 'MIA3Y d1WOU0d3 pue [edlul|D 10} 9INHISU|Q Adesay) ewojaAw [s1024 § 01 dn] iU UoaNpu! 4o s3(242 € 5 PaN1@23l seH - 09 = N JUSWI0IUS | (p-eNINIE) (WINGN) SJUDAD ISIDAPY - T>4josneis Hod3 - paiewinsy ewodA adninN [s1DaA N Isl-y8iy sey 323lqns - | (s]130 L +¥VD 40T pasouseig AjmaN Yysiy Z 01 dn] Aixol 95e3s|Ip d|geJnseaw sey 33[qng - X 008-0ST :98uel el YSiH yum syfgqns Scoc Suipwi-asoq - INW onewoidwiAs jo sisoudelp MaN - asop) |92-9p| - [e3l) T aseyd | ul TZTZAd Jo Avjes ayy 'ST Alenuer :Arewing suoisnpu| IUOIUdAIRU| 'dnouo 98uis 9jenjeag o1 Apnis y uolleziwopuel 01 Joud syPam g1 1)S snoSojoiny - siaylo ay1 Jo auo aAI1933J Aew 1nq ujeSe 11 aA1923 Jouued udwidal JudIDI-ISOW Se sudswidal 8CTTS9EO0ION Jojeiedwod Y3 Jo SuUo Yim paleall 103lqns - *219 'sisoplojAwe ausgisy 'awoupuAs SINJOd 'elwaulngojSosoew S, WwI0J1Suapjem 'elwayna| |22 ewseld (E-INIALEY) (WINYY) [s10af gz] | @AI1dE JO Jo Aloasly 'saloueusijew jo AJoisIH - ewooAW a|dIyNIA 0ZAW-OTO N A1032.1035-UON - Aioyoelyay pue -21403 "15-as-03 :suoisnpx3 pasdejay yum spalqns dnoun j0p04N3 xag/wod/oj3 - ul suawSay paepuers '0€2-0T0-D1H03 - juawiealy Joud xaq/ie) - SNSIIA 121299 SJUDA 9SI9APY - | T< 0149119Q JO asuodsal [ewiuiw pPaAsIydy - xaqg/uai/ex|- jo Apnas A1ajes pue asuodsal 01 awl uswiSaJ Juswieal) ise| 0} AJojoeljay - xaq/iog/eieq - Areany3 (e-eNINIE)) "40a '¥ 'i sajoAd xa@/wod/eseq- T8€=N (WINYY) ewoPAN "dY0 'leAlnns 3AIINJ3SUOD Z< 10} JuaLWidal Sululejuod suswi3ay pJepuels :JUSWI[oJUD adiyny Asoyoeipay 934)-1USA2 'SO - | -QIIN| Ue pue '|d B 'BJep YUM Juswieal) Jold - parewnsy pue pasdejay yum :Alepuodas | suawi8al WA Joud < 10U INQ 72 PAAIDIRY - (SI199 1L +¥v) 40T $393[qns uj] suawi3ay T Jo Q0 jo sneis 503 - X 0S1-0ST 98uel el piepuejs snsiap §202 '9 Sdd- 9seas|p s|qelnses - asop) [92-3p] - [e21u1]) 11| seyd 121294 j0 Apmis JOqWIBAON :Aewid :suojsnpuj :uoRuUaAIA| 'paziwopuey A1ajes pue Aoeaiy3 uonadwo) -- Sawo2nN0 uonejndod juaned SWY Juswieal] usisaqg Apnis Josuods el / 9L SJUDIUO) JO 9|qEe] 0} UIN1aY ewo|aA a|di|ny - Hoday jeuld O€T d3ed TTOC 'M3IA9Y dlWOU0I] pue |edjul[) JO} 91NUISUIQ (S21pN1s [RUOIIBAIDSCO pUE S|eLI} [BIIUl]D YOG SPN|oul 9)S UO palsi| SIIPNIS 131 ON) A0S S[ELL[EDIUID MMM :324n0s "asuodsau eiued poosd Aiaa 'Hd8A quejdsueu |92 wials :1DS '@piwopljewod :wod 'sadueyd upys pue 'udlold ewojpAw 'Ayledouridopus 'Ajedawouedio 'Ayredoinauijod :SINTOd 'douqiyul aseaj04d :|d '|BAIAINS 331)-U01$SIS0.d :S4d '|BAIAINS [|BIDAO SO 'O1R1 3Suodsal [|BIDAO tYYO 49quinu |B10] N '3SEISIP [enpIsal [ewjuiw QYN 'ewodAw 3jdijjnw ININ 'Oplwopijeud] :ud 'qiwozex| :ex| '8nip Alojeinpowounwuwi :giN| 'qewnzniold :0]3 'dnoun ASojoduQ aairesadoo) uiaise] :npI7 'Osuodsau Jo uoizeinp :HOQ 'auoseylawexap :xaq 'qewnuwnielep ieseq '@suodsad 939]dwod 1Y) 'WIISAS SNOAIBU |BIIUII :SND 'QIUIOZ|IJIED 1B 'ILIO0ZBYI0] [10g 'JUIAS SSIDAPE 1Y Adugppyapounwwi Asewud jo AosiH - sjuessasddnsounwiwig 31UOJY2 SPadU {SUOIHPUOD Areuownd Jo oeipued sey 133[gng - uoisuayadAy Aleuow|nd a1aAas 10 31LIBPOIN - Adeaayi onnoquouyi-inue ogiapun j0uued 1§ snjoqwa Aleuow|nd/siIsoquouiy) Adesayy uiaA daap SuidojaAap s ysiH - oueudulew ASojoyied sND juesiusis Ajjeatund - olawj] - Adesayy SO 'S4d uonoanpul o sapAs € 03 dn ueyy Jaylo "dOd 'HHO YD - AN JO sjuawileal) Aue paaladad algns - I6V96IV0ON [sipak W Al1032103s-UON - 6Z] :Aepuodss suoisnjax3 auag|a) uona|duiod SawodIn0 uonje|ndod 1uaiied Sy JuUdwWleds | udisaqg Apnis Josuods el / 9L pajewns3 S]USIUO) JO 9[ge] 03 UIN1ay ewo|aA 3|diynA - 1oday |euld TET 28ed TZ0T 'M3IA9Y JlWoU0d] pue [ed1Ul[D 10} 9INUISUIQ [sip3A 73] sisa1ayde alojaq 571 4uswidojanag S)y9OM ZT ulyum 19s snoSojolne sisasayde % YpIeasay uassuer 15-0S-03 '0ZAW-010 940J2q syluow g ulyum 1Js d1uado|ly - pue 0€3-DT0 1403 - VINDg 031 pa3adiel (t Q4N 'SO 'S4d Adesayy '1a3ie} Aue je Adesayy |-HVD Joud - -3aNLILYYD) ewosAN '40OQq '491aq 40 Yd8A - suojsnjox3 ajdini Asordelsay SJuadAs Jo pasdejay yum ISIOAPY ¢ 9Seyd - oseasip 0>_mm0.hm0hfl JO 9JUIPIAT - mu.-._flfi_u_tflfl uj A<_>_Ufly :Asepuodas Id pue @iiN| 03 Aloloeasal 3|gnop 9ZI =N uasiuy uoneinie Jo '(Apoquue gead-nue ue pue 'QiN| :JUSW|OIUS | |]93-9 IsuteSy paivaad HHO 'g 3seyd - '|d Buipnjoul) saidesay) Joud €2 paAISdBY - pa1ewnsy Adesayl (1-¥vd) 119D SIUdAD T 10 Qjosnieils H0d3 - 1 10)d223Yy uadnuy [44074 9SI9APY :qT 9Séyd - aseas|p a|qe.nsea|N - | (YN :9s0Q) [92-B)1D - | [ew] |edjuld Z-qT JBWIY) B '8ZSH8T89 'og |udy :Aiewinng suoisnpu| IuoiUdAIAU| | 3seyd 'way 28uis -fNrjJo Apmis v JUSWAA|OAU] SND d11ewoldwAs Jo saseiselaw SN JO S9SEISIP SUNLIWIOINE BAIIDY - JUBWI||OJUD JO SYIUOW 9 UlYyHM QHAD Joy uoiiesipaw juessaiddnsounwwi) alinbai uo QHAD d1uoIYd Jo 91nde 3A3ae) DS d1ausdoje Jo AoISIH - uswidas Adesayiowayp Jo sisataydeyna| 1O SY99M 7 UIYHM Pl0J3)S0|1I0) JaYyjoue MoJdJew auoq ul 40 1uajeAInba Jo suosiupaud Aep/3w g ueyy 6S9060E0ON s|192 ewoAw a|diynyy - Jo1e2438 Adelayl p104a1SOdILI02 JIWRISAS - wnJas :suoisnpx3 '0J Yiajolg ur uiqojdounwiw puasaq SujfueN jueusaqe ul saduey) - saulopind 00T =N [syiuouw 9¢] :Azepuodag 92110e4d |B2IUID NDDN Ul BLUBIID asdejay - JuawWo1us | (z-aNIDI1) ewoRAN (quuozapiog Suipnpul (83/51192 L +4VD pa1ewnisy aidpinAlL (4/y) SJUDAS 3SISAPE 'suswi8au sond €2) WIN Alooeljoy - 90T X 6-G°0 :98uel Aloyoelyoy/pasdejay 120T '1€ pa3ejaljuswieal) - WIN @A1108 Jo sisougelp pauLijuod OMINI - asop) |92-eyy1) - [elL (el 11/ Suneas) 12qwiadaqg [qiuow 1] :Asewnad isuoisnpuy IUOUAAIRU | 9Seyd wily 9j8uIs ul S|I9) INSEF-UVYI1 [93-e31) :s31pms Sulo3uQ 'Z'va d|qel S]USIUO) JO 9[ge] 03 UIN1ay ewo|aA 3|diynA - 1oday |euld TET 98eq TT0T 'M3IAY 1WOU0D] pue |ed1ul|D 10} 2INHISU|Q watie; SEIEETPOON Aue oy Adeiayl | Yy Yum Judwiedl) Joud - 'suoisnpIx3 371 4uawdojanag B YdJeasay uassuer Adesoyy Jopd ou 'pasoudelp Aiman :3 Loyo) - (2 [sinaf zz] Adeuayy |emui sa2A2g-1 Jo Aioisiy xaQq/ua7/i0g/eleq -3ANLILYYD) ewoRAN Yum WIA pasoudelp AimaN :q Hoyo) - | + [90-B}1d :3 Woyod - aidiyny yum SJUDAD 3SIBAPY - Adesayy (syuedpiied awos 00T =N | siuedpiued ui (yND4G) 40Q '4ad pa1daJip-yINDg pue Apogiue |euojpouoLu Ajuo) apiwopijeua) :JUSWI]|0IUS uasSiuy uoneiniep '191194 10 YdSA 'YYO -| 8EAD-IUE 'QIAI '|d YUM paleal] D) Woyod - | +[32-elf1d :q Moyod - Pa3ewilsy | 193-9 suiedy pajdaag :Auepuodas | asdejau Alea 'Adesayi yo aul suQ :g Hoyod - |82-B3|12 1) Joyo) - Adesay) (1-4v)d) 119D Adesayy [83-e319 :g Hoyo) - [elIL [eD1UI) T 1 401da33y uasnuy 20t [ipaf T2] QU - Joud jo saul| €-T paAladay iy Yoyo) - [92-B312 iy 1oYyo) - | aseyd 'wue d3uls dLRWIY) e 'BZSHRZR9 'sc Ainr :Arewinid suoisnpu| IUoIUdAIRU| 'dnoup 9|8uis -fNf Jo Apmis v pouad Jnoysem juapIynsul 'Adesayy Jowniijue soud - TTVESE0N sapueusijew SAISBAUI |AJN-UOU 10} paleal) Jo pasoulelq - 103 Yp3301g sisaJayde 0] Jold syaam puasai Suifuen 2T 10S snodojoiny !N Jo} DS d1auaso|ly - VIND4 0} palasiel Adesays (T-NV4ILEYD) Aue 1981e3 Aue je Adesay) 1-4v) Joud - ewoyRAW adiynn [s403A z2] 'suoisnIx3 AJo1oeuay 10 pasde|dy yum syuedpdinied SIUDAD S8SI9ARY - 9seasip w>_mmwhmo.hn_ JO JUIPINT - asauyd ui A<_>_Uflv Q4N 'SO 'S4d (ANl pue |d B paA1adal fauj| 09 uasnuy uoneinie 4OQ "49119q Jo Yd8A - yoes Joj Juswieadl Jo 9242 a19|dwod 1) = N :TUSW([0JUS | [92-g suleSy pajauig nENVEOUOm juawuleasy NN JO saul| LO_LQ €S POAIDIDY - % >QN._O_._._. :.-zsv 1?2 T 40 0 jo snieis pod3 - -1 Joydadsay uadnuy 20T 'o€ 4o - aseasip d|qeinseaN -| (YN :9soq) [92-e}D - el [eatuid |1 | auswIy) e 's||a 1-¥YD 19qWIBAON :Aewinig isuoisnpuy IUOUAAIAU] | 3Seyd 'wly 9j8uIS | INBEG-YVYI1Jo ApniS Y WA JO JUSWISA|OAUI [ea8uUlUaW Jo SND jo Alo3sly Joud/aAlloe umouy - L0Z8VSEOLIN ewo|aA 3|diynA - 1oday |euld TZOT 'MSIASY J1WOU0dT pue [ed1Ul[D 40§ 3IMISUIQ S]USIUO) JO 9[ge] 03 UIN1ay €€T a8ed (sa1pn1s |EUOIIBAIDSUO PUB S|BL] [BIIU][2 Y10g BPN|IU] BUS U0 Palsl| S3IPNI1S :JLON) A0S S|el L |BIIUI[D MMM :824N0S asuodsau |eied poo8 A1aa :ydDA 'Quejdsuedy [|99 wid)s ]IS 'asuodsal 91a]dwod JuaBulils 1Y)Ss 'Opiwopijewod :wod '1o0Nqiyul asealoud :|d '|eAlIAINS 93JJ-uo|ssa.80ud :S4d '|BAIAINS ||RIBAO (SO 'D1BJ 3SUOdSal ||BIDAO IHYO "YIOMIBN Jadue) aAIsuayaldwo) [euolieN :NDJN 4aguinu |e101 :N '@seas|p |enpisad Jewiuiw gy Nl 'weld)|iw :Bw 'ewopAw 3jdinw (NN 'Opiwopijeud] :ud1 'dnoun Sunjoan BWORAW [euoieuIdIU| :DMIAI 'Snip Alojenpowounwiw QAL '9seasIp 150y snsiaa Yeud :gHAD 'dnoun ASojoouQ aailesadoo) uialse] :00)3 'Osuodsau Jo uoneinp :YOJ 'DUOSeYIDWEXSP X3 'qewnwnielep :eieq 'suodsau 9191dwo3 1Y) 'WIISAS SNOAIDU [BIIUDI (SN 'D1BJ HJBUIQ [BIIUIID 1YED '401dDIau udsiue JuBWIYD YYD 'qIWozalog (Jog 'Usgjjue uojlelnlew ||93-q YIADEG sAep [ urlyum Adesayl Snip Asojejnpowounww| 'shep T ulyum Adesays Alouqiyul awosealold Jo Adeiayy d1x0103A) 'shep T Ulylum Juswieasy Apoqiiue [BUO[DOUON - Adesayy Jaouedjue snojaaud wouy Aydixol Sulo8up - VIND4G 8uina8iey Adesay)l snoinald - 1081e] Aue 1e pajoauip Adessy) |99-1 YYD J0ld - LTBT8TVOLION I11 'quawdojanag @ Y24easay uassuer ewodA a|dnnA Alojoeayoy -9plwopljeua pue pasde|ay yum syuedpdpied uj (pd@) suoseylowexaq pue apjwopijewod 007 =N 'qewnwnjele( 10 :suoisnpx3 ;JUSW]oIUs | (pAd) Suoseyawexaq [sipad g 01 dn] Xxag/wod/eleq- parewnsy pue qiuozayuog el193140 aseyd Bujusauos xag/wod/iog - 'apiwopijewod SJUDAS 9SIDAPY - 8upaaw sanjea AJojeloqe| [eJJUID BABH -| :suawiSoy pJepuels [euL snsiap '(VINDE) QYN 'SO "4Is/dD Ydo - aplwopijeus| 0} Alojoelay - (el € aseyd uasSiuy uoneinien :Asepuodas 9s5eas|p aAlssasdoud Jo aduspIag - (83/s1199 L +4vD "luswudissy [192-9 1suiely Adesay) Jo saul| Jold €-T PaAISdeY -| 90T 4 SZ°0 J0 asop I9l|eied parauag AdesayL 9¢0¢ Sdd - 9SESSIp 3|qeinsesajN - 1981e1) [92-eY1D - 'paziwopuey | 1-4VD e '8ZSY8Z89-INI 'T |udy :Arewinid suoisnpuy| {UOIIUBAIRIY| :[EUCIIUBAIDIU| Sunedwo) Apnis v ewoRAw s|dijnw JO JUdWBAjoAUI [e38ulUBW JO SND) JO AIOISIH - sAep /7 ulyum (3wp/g) suosiupald - (Ayredounau jesayduaad Jo eppasdoje 1do2x3) ssa| 40 T apeso Adixol Sulo8up - S]USIUO) JO 9[ge] 03 UIN1ay ewo|aA 3|diynA - 1oday |euld vET @8ed TZ0T 'M3IA3Y J1WOU0D] pue |ed1ul|D) JO} INUISUID S]UDAD 9SiaApe sjuedinied T9E6VSTOION SNOLIAS 'SJUBAD DSIDAPY - juaned o1 ys11 dAISSIIXI 3sod jou 1shwi g uly - :Aepuodas 'Awo3o91e49y [epiyadns Sulodiapun | - gewelueaq aulpIYwsoxe[o sisouse|p sadueyd + A3oj01Ad SZ = N :JusW||oJud sajysuedRIRYD |eljaynda ay1-1sA2043jW pue geweluelag uojssasduwi| pajewnsy | unopoje qewejuelag s18ojoyied jeuiouqy - YUM JUDIIBIL) POAIDIDI SBY/SDAIRIDI 8ujo8iapun yum pajeal) uojyisodwos wnypyyda oym NN Alordelyaa/pasdelas yum siusiled - sjyuedidilied |el] el € | sueddied ul saSuey) 0zZ0¢ '0§ [eau.0d jewiouqy - J3p|o Jo siedh 8T a8y - T Wiy -| aseyq 'paziwopuey |eldyady jeauso) JaquiaAoN :Aewnd suoisnjau| IUOIUAAIRU| -uoN '|a|jeJed Jo uoneziiaypeley) '219 s3joueus|jew Jaylo 'aseas|p Alel|iq/JaA]| a|qeisun 'Bupas|q |euJtajui/[esoanuu aAlloe 'UoiIpuod |euald dAIde 'aseasip |eljayuda [eaulod Juaun) - 190§ o1oua8ojje sold - Suiusaids JO 3w} e ejwayn3| |92 ewse|d aailoe 'SINI0d dA1noe 'sisopiojAwe djewoldwAs - sAep $T uiyum 8nip jeuoilesiisanu] 'sp10131$ 3sop ySiy yum juawiessy 'Adesay) ewojdAw-1jue ojwalsAs - §7952SE09N suoisn|dx3 qewellElsg aulYHWISOXE|D uoljouny waisAs uedio arenbapy - pazijiydoA| SuoId3}u| /8w p'g g Wiy - (2 WAV3¥Q) 2Al10E OU 1@ JUswljjolua >U_'._u.m 0] LO_LQ gewejlue|aq >"u°£_u.=< gEAd-NuUY sAep 00T 1 Ajuo 1DS snogojoine jo A1oisIH - uszoy ue yum juawieal) [syaam gy 01dn] aseasip a|qednses|y - | 84/8w '€ ig Wiy - 10144 pajied dAeH Oym Id pue il 8uipnjour Adesayl jo sauy SyOIM TZZ=N ewoRAN a|diInn SO 'S4d 'd0Qq '¥4d - Joud gz pajiey sey 'a|qi8ijsul-jue|dsueny CEITWNEYE) :JUSW([0JUS [EN1DY yum sjuedpiied :Aepuodas Jo 19s snodojoine suodiapun sey gewejuelaq ul 9T6ZS8DISD {INN pawuyuod Ajjesi8o|o1Ad/A||eoi80l0IsIH - udzoJ4} el JO sasoq om] jo 0202 '0¢ HHO - 7-0josmeis o0l - | /8w gz T wiy- | [ediul) || aseyd wiy | Alajes pue Adesry3 ayy 19qWIanoON :Arewiud isuoisnpu| SUOIIUBAIRIU| -om] 'paziwopuey | 3lediasaau] 03 Apms y gewejuejag :saipnis SuioSuQ *¢'vq diqel S]USIUO) JO 9[ge] 03 UIN1ay ewo|aA 3|diynA - 1oday |euld GET a8ed TZ0T 'M3IA3Y J1WOU0D3 pue |ed1ul|D) JO} INUISUID aseasip Alel|iq JO "J9A]| B|qEeISUN 'UOIIIPUOI [BUDI BAIDY - aWoUpuAs SINI0d 'sisoplojAwe opjewoldwAs - sAep 7/ ulyym sisasaydewse|d 'shep T uiyum s8nap jeuoriesiysanu) 10 Adeiay) ewopAw-1jue J1wdlsAs - juejdsueny ||92 wid)s d1ud8ojje Joud - isuoisnpIx3 Ayiedounau EZ8LLAVOION |esayduiad g apeun 'T apeln s aq 1snw sa1I2Ix0] paje|al-juswiealy Joud |y - auIpIyIWSOXED [syuow 6T 01 dn] suojldun walsAs uedio ajenbapy - 9seasIp 9|qeinsea|y - (WWyY) si919wesed Ansiwayd Joyqiyul swoseajoud pue ewoeAW 21diInIn pue ASojojewaH - | Snip AJojejnpowounww Ue 0} Aloloelyay - S=N Aioyresyey/pasdejay aunssaud poojq juBUIEal} BLIORAW JUSWI([0IUS [eNY yum syuedpised J1j035eIp pUe J1j01SAS - -1jue Jo saul| Joud g Isea| je pajie] - syoam € Alana ul AJAIDY eatul)d :Aiepuodas 9|qIsea) pawaap jou juejdsuedy || gewelue[aq 7T = N :Juswjjoiua pue AadiuaSounwiw| wa3s/iuejdsuer) [|92 WS suosiapun sey - /8w g - paTewnsy 'sypBuUpjoleWLIEYd S91101X0] Suwi|-asoq - sisouseip s)y99m € AJana 'Ayqessjol SJUDAD 9SJIAPE NN pawiiuod Ajjedi8o]olAd/|es180]0asIH - gewelue[aq [eL] [edud T 'Aajes a1edisany| TZOZ | SNOLISS 'S]UBAS BSIaAPY - Z-0Josmes ood3 - 8)/8w gz - | aseyd 'dnoun oj8uis 0} uljopojein '1€ Ainr :Aewnd suoisnjau| uoppuaAIu| 'pazjwopuel-uoN | qeweluejaq jo Apnis v 9Aa Apnis -uou 3y} Ul ssaupul|q [eSa] Jusuewldd - [s)3am g 01 dn] SIN3AN DAY - suolpRulI dA3 - suo|s9| Bunjeay punom paAe|ap Jo dsi SS9IX] - geweluejaq |eljayuda |eaulod Japiosip + Awoldaiesay pue 'swoldwAs [eauiod au1e1ydAsd Jo [eaipaw 9jgelsun/snouss - |enyaadng 's8402S YAD4 |ewiouqy - suojsnjox3 Buro8isopun SJUdIUO) JO S[gEeL 0} UIN}dY ewo|aA 3|diynA - 1oday |euld 9€T @8ed TZ0T 'M3IA3Y J1WOU0D] pue |ed1ul|D) JO} INUISUID [3/2A2 App-1Z 1noybnouyl] uoiouny walsAs uesio alenbapy - aneday SUOI3I34UI dlesapow aulpyuwsoxe|o gewejue|aq 40O |eAIDUI 3AI}2E OU 1§ JuUaW||oJuad Apnis 03 Jold yum sjueddiued - Buisop ayrsanodny - | sAep 00T JI Ajuo 1DS snoBojoine jo AloisIH - syoam g A1aAa (€T WINVY3NQ) SW|1-Uo|1eJIu3dU0I 9seasip s|qeJnsealN - gewelue|aq uoidung ameday ewse|d 10} ONY - Id pue il 8uipnjour Adesayl jo saul /8w Ob = N :JuswoIud pasiedw) pue [ewJoN uol1eJ1uUaduUod Joud zz pajie} sey 's|qi8ijpul-juejdsues) G'Z -uoiuny parewnsy yum syuedpinied ewse|d asopaid - Jo 1DS snodojoine auo8iapun sey J11eday |ewdou ewoPA ajdiInn uol1eJ1UadU0d 'NN pawulyuod AjjesidojoiAd/AjjedldojosiH - | yum sjuedioied - [elaL [edtuD ul (9T6LS8ISH) vzoz ewse|d paAIasSqo XeAl - Z-0Josmeis pod3 - (r | 9seyd '|9|jeded unopojeN '9 Aey :Alewnd suoisnppu| | Med) uoluaAiIalu| 'paziwopuey-uoN | qewejuejaq jo Apnis y 219 '9seasip J1Wd3SAS PaJ|0JIUOIUN JO DI3A3S 'Suipas|q |eUJ]UL JO [BSOONW BAIIDE 'DSeasIp [e1]9Yy1da |eauI0d 'UOIIPUO)I [BUSI DAILDY 10§ 219uago||y Sujuaauos jo swn 12 elWwNI| |92 ewse|d sAnoe 'Swolpuls SW3I0d 2A1de 'sisoplojAwe sijewoidwAs asop [sipaf z'z 03dn] | 35414 Jo shep 7 uiyum sisalsydewseld 'sAep Z6782850ON T ulyum Adeiayy Jowni-jjue JjwalsAs - uolleujwexa suoisnpxa auIPIYNWSOXED Jejnao pue |eaisAyd 'DH3 'sugis |eyA [ewiouqy - 7 @peso Ayiedounau jesayduiad g xag/wod sjusweas sio1owesed epadoje 1dadxa 'T apeto S Sa13IIIX0} Jold - + qewejuelag - ewojoAN Uy auun 'Aisiwayd |eauld Joud xag/iog T = N :JUSW|[OJUS | J10ldd pajled dAeH OYMm 'ASojojeway Jewiouqy - | sAep 00T < jue|dsuedy ||92 wa3s snodojolny - + qewejuejdg - paTewnsy ewojaAW ajdijny SIUSAD SSI9APY - 9SeosIp 9|qednsed|N - 1z ved >._°u.uw._m0¢\v0mnm_0~_ [tz Aoq@] ¢-0josmeis Hod3 - UL [ea1Ul) | yum spdfgns asaueder €20C 'St sa110IX03 Suiwi-esoq - Jap|o Jo siedh g 98y - Adesayjouow | 9seyd 'uolye|easa u] Apn)s uojjejessy Alenigo4 :Alewnud :suoisnpu| | qewejuejag i Med | -3soq 'dnoun sj8uis asoq '|oqej-uadp uy Apnis Japun aseasip ueyl Jayio sapueus|eN - S]USIUO) JO 9[ge] 03 UIN1ay ewo|aA 3|diynA - 1oday |euld LET 28ed TZ0T 'M3IA9Y JlWoU0d] pue [ed1Ul[D 10} 9INUISUIQ sAep 7/ ulyum sisasaydewse|d 'shep T uiyum s8nup jeuonnediysanu) Jo Adeiayy ewopAw-1jue J1walsAs - juejdsueny |92 wd)s d1uddojje JoUd - isuoisnpIx3 Ayiedounau 0TZZ9TVOION |esaydiiad z apeun 'T spesn s aq Ishw sai3|dixo} paje|al-Juswieauy Joud ||y - BuIpIYNWSOXE[D suojpuny wajsAs uedio slenbapy - 9Se3SIp 9|qeINSeIN - (WWHY) Joyiquyur swoseaoud pue ewopAW ajdiniy [syauow g5 01dn] | Snip Aloienpowounwiwi ue 03 Alopenay - (esop Aiopeyay/pasdejay juswiea.] ewodAw Mo|) xaq/wod - 08€=N yum sjuedpiied SIUBAD ISJIAPY - -lue Jo sauj| Jopd g 1ses)| 3e pajle] - :10jesedwo) JuswjoIua uj {(xag/wod) 40Q '¥8D 'HYO 'SO - 9|qiseay pawasp 1ou Jue|dsuely |32 parewnsy auoseylawexaq :Aiepuodasg wals/iue|dsuesy [|93 wWa)s suosiapun seq - s)yaam € AlaAa 9sop-mo1 snid INIAI pawIuod Ajjedi8o]01Ad/|edi8oloasIH - gewejuelaq el [eau) | aplwopiewod snsiap ¥20Z '12 [syruow gz 01 dnj S4d - 2-0 o smeys ood3 - MfBw gz- £ 95eYd '|9||eded | unopojein qewejuelog Jaquidnon :Arewiud isuoisnpu| IUOUBAIDU| 'paziwiopuey jua8y aj8uis jo Apnis SIEdA 7 1SBI) 1€ 10J 9|qels Aj|edipaw ssajun s)yooM € AJoAd S9JouBUSIjEW JUSIINDOUOD 1O SNOIADI] - qeweluejaq Z 9pean o031 dn /3w Ayredounau jesayduad Jo eppadoje 1daoxa 6T 40 85/3w Judwieal) snoindad wouy ANdixol apeln gz - §°C :uojpuny Joud sy2am g paniadal onedsy s1aAss Joyqiyui apndadAjod Sunuodsueuy uolue YuM sjuaned - s1uedio Buonys Jo 8nup euopesSiisaau| - )z 12S218uadoje Jold - | 1eq) uouaAIBIU| [sipaf e|Wau|ngo|SoJde(A WS0JISUSPIEM ¥ 02 dn] syusAa asianpe 'awoJpuAs SINJOd dA13oe 'sisoplojAwe syoaMm ¢ AJans SNOLIAS 'SIUBAD BSIaAPY - | d1rewoldwAs 'ejwayna| |32 ewseld aAIdY - gewelue[aq :Asepuodas 'suoisnIx3 /3w S'C :uauwliedwl 08986€V0.LON S]USIUO) JO 9[ge] 03 UIN1ay ewo|aA 3|diynA - 1oday |euld 8€T a8ed TZ0T 'M3IA3Y J1WOU0D] pue |ed1ul|D) JO} INUISUID 6T Jo 3%/3w G :(sisAjeipoway uo) @ys3 Yum sjuained - sJedA g 1sea| 1k 4oy} d|gels Aj|eoipaw ssajun syoom € AJand S9[2UBUS||EW JUBIINDOUOD JO SNOIADId - gewejue|aq Z 9peJap 03 dn 8y/3w Ayredounau jesayduad Jo epadoje 1daoxa 6T 10 Syy/3w Juswieau) snoiaaad wouy ALDIX0] speln z2 - ' :(sishjep Jopd syaam g paAiadal JoNqiyu| uo J0U) QY¥S3 apndadAjod Buiodsuely uojue dluedio YIIM sjuaned - 8uouis 'qewejuelaq 'Snap jeuoie8iisonu| - (e [sipaA 135 01eusB0|je JOUd -| ieq) uonuanIaiu| ¥ 01 dnj s1uaAa asianpe elwauj|ngojSoJdelA WaoIISu3plepm SNOLIDS 'SIUBAD BSIIAPY - '3WOUIpUAS SINTOd AR 'SisoplojAwe syoaMm € AJaAa :Aepuodas | onewoldwAs 'ejwa)na) |99 ewse|d aAIY - qewejue|aq suoisn|dx3 /3w SVZS6EVOION (531242 Abp-TZ £ 01 dn] S 'uswuiedw uoiouny walsAs uesio alenbapy - |eual aJanas auIpIYUWSOXe|D gewejue|aq JO |BAIDIUI SuoI123}u| YHM sjuajled - Sujsop ayyJano Iny - 9AI}2E OU g JuBW||oJua Apnis 03 Jold Syoam ¢ Alana (2T WINV3uQ) uol1eJ1Uu3dU0D sAep 00T J! Ajuo 12s snogojoine Jo AJolsiH - gewejuejaq uonduNd [euay ewse|d asop-aid - aseas|p s|qednsesN - 85/8w pasiedw] jo aa18aq uoisnjul Id pue il 8uipnjoul Adesayl jo sau| §°Z :uojpuny Suiliep pue jewsoN JO pusd 1e geweluedq Joud gz pajiey sey 'a|qi8ijpul-Jue|dsuer) |euads pasiedwi 9€ = N :JUsW|oIud yum sjuedpjied uoljesuaduUo) - 10 | DS snodojoine suodiapun sey pjiw/jewaou parewnsy ewo|dAp a|dinin UOI1eJ1UIIUOD 'WIN pawuyuod Ajjesigojoiho/Aj|eaiBojolsiH - yum syuaned - ul (9T6LS8ISD) Sz02 ewse|d panIasqo "Xep - Z-0J0smei1s nod3 - (T | ewdl [edwup | 9seyd unopojeN '1 Yyouey :Aewnd isuoisnpu| | Med) UolUdBAIDU| 'poziwopuey-uoN | qeweluejdaq jo Apnisy Apnis J3pun aseas|p ueys Jay3o sapueudien aseasip Alel|iq 10 "J9Al| 9|qeISUNn 'UoINIPUOI [BUSI DAITDY ejwayng| |92 ewseld 'awolpuls SINI0d 'sisoplojAwe dijewoldwAs SJUdIUO) JO 9[gEeL 0} UIN}dY ewo|aA 3|diynA - 1oday |euld 6ET 98ed TZ0T 'M3IA9Y JlWoU0d] pue [ed1Ul[D 10} 9INMISUIQ (sa1pnis |eUOIBAIDSUO pUEB S|BLI [EDIUID YIOG DPN|dU] BHS UO PaIsl| SAIPNIS 131 ON) ACT S|ELIL[EJIUID MMM :32Jn0S lue|dsuedy ||92 wiBls i 1DS 'a1e4 919|dwod Juaduils (YIS 'asuodsal [elnled :Hd 'apiwopijewod :wod 'sadueyd upjs pue 'uidlod ewojaAw 'Ayledouridopua 'Ajedawouedio 'Ayredoinsuijod ISINTOd 'Jonqiyul aseajoud :|d |BAIAINS 9345-U0ISSd4804d :S4d '|BAIAINS ||BIDAO SO 'D1RJ 3suodsal [|BISAO (YYO '19quinu |e1o] :N 'OSeasIp |enpisad Jewiuiw (QYIN 'weddjjw :Sw 'ewojsAw ajdijnw AN 'ewixew :xew 'wesdo|iy :8Y 'Snup AJolenpowounwiwi :qIAI| '@seasip |euaJ adels-pua :qys] 'dnouo ABojoouQ aAnesadoo) wialse] :00D7 'wesdoipiedoyds :n)7 '@suodsal Jo uollednp :HYOQ 'SAUDIX03 Sulwi| Ssop :17q 'Duoseylswexap :xag '@suodsad 919|dwod YD 'W1SAS SNOAIBU |RIIUDD (SN 'D1.J Jauq [edjul|d :ygD '401dadau uadijue duBWIYI YYD 'AlNDY [BNSIA PR123410) 1599 (WADE '9AIND 3y}l Japun eale DNy [syruow 9g 01dn] qewejue|ag Adesayiouow 03 Jejiwis Ajjeajwayd sSnup 03 Asesouhsolpi qewejuejag - SJUDAD 9SJ9ApE Jo uonpead AliaiisuassadAy pakejaq - :J01esedwo) SNOLIS 'SJUDAS 3SIIAPY - SHPIM 7 UIYHM Juswiealy Juase andY SO "H0a 's4d [euofie8iisaAul Jopd 'syjuow € ulyum 00Z9ZIV0ION "4Ds '4D "Ud3A "d "4ad - Adesay | ¥y) Joud "ue|dsuedy ojuagolje qewijiesoq :Asepuodos Joud 's)am z uiyum Adessyloiped Joud - + qewejuejag BuIYUWSOXE[D aseas|p [eljayyda [eauso) - :p Apn1sqng - HYO - suoisnpx3 1e1s90e80.IN (s WINVIHA) (ININHY) si1a1oweled + qewelue|dg ewolaAN ajdiniA ge| sisAjeunn 9SeasIp 3|qeinsea|y - :€ Apnasgns - Y9 =N Asoyesyay/pasdelay pue 'Ansiwayp [eduld T-0 sn1eIs DOd3 - 6096SEENSD :JuswjoIua yum syuediied 'ABojojewsay ui saduey) - juaw(joJud 03 Jorid sAep 00T< + qewejue|ag parewnsy uj sjusuneas] su8is jue|dsuedy |92 wals shoSojoine jo AIOISIH - 1z Apnisqng - 13sued-niuy [eUA Ul Ajljewsouqy - (Apognue 866V TENSD [eld L [eatud 11/ YuMm uonjeuiquio) SIUBAR 3SI9APY - | |euojdouOcW 8EAD-1IUE '|d 'Al Sulpn)dul) + qewejuelsd aseyd 'Quawusissy | ui pue Adesayjouol se 8707 'vt $313191x03 SulNwi|-asoq - sjuswieaJ} ewolaAw-3ue Jo sauj| Joud £ - :T Apnasgns - |ennuanbag | unopojen qeweluelag Alenuga4 :Aewud suoisnpuy IUOUAAIRU| 'paziwopuey Jo Apnis wuojield syo9m € AJana gewejuelaq 35/3w D5. Previous Systematic Reviews and Technology Assessments We identified two ongoing health technology assessments, one of belantamab and one of ide-cel by the National Institute for Health and Care Excellence (NICE) summarized below. We also identified one systematic review and meta-analysis of BCMA CAR-T therapies and one systematic review that aimed to put the ide-cel and cilta-cel clinical trials into an appropriate comparative context. NICE Technology Assessments Belantamab mafodotin for treating relapsed or refractory multiple myeloma after 3 therapies [ID2701] NICE is currently conducting an appraisal of the clinical and cost effectiveness of belantamab in relapsed and refractory multiple myeloma patients who have received three prior therapies. The expected publication date is to be confirmed. Idecabtagene vicleucel for treating relapsed and refractory multiple myeloma in people who have received at least 3 prior therapies [ID1442] NICE is currently conducting an appraisal of the clinical and cost effectiveness of ide-cel in relapsed and refractory multiple myeloma patients who have received at least three prior therapies. Comparators in the final scope include pomalidomide-dexamethasone and panobinostat- bortezomib-dexamethasone combinations, reflecting a difference in preferred treatment in England as compared to the U.S. The expected publication date is to be confirmed. Previous Systematic Reviews Roex G, Timmers M, Wouters K, et al. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma. J Hematol Oncol. 2020;13(1):164. This systematic review and meta-analysis assess the safety and clinical efficacy of BCMA-targeted CAR-T-cell therapies in patients with multiple myeloma. Including a total of 27 clinical studies pertaining to 23 different BCMA CAR-T-cell therapies, it is the most comprehensive review to date. One study for each of the two most advanced therapies (ide-cel and cilta-cel) were identified. For all BCMA CAR-T patients evaluable for clinical response, high response rates were achieved. Response rates for high dose ide-cel and cilta-cel were comparable (ORR 82% and 88%, respectively). The median PFS among evaluable patients treated with high-dose ide-cel was 12.1 months (95% Cl 8.8, 12.3) and 19.9 months for patients treated with cilta-cel (95% Cl 9.6, 31.0). Although high response rates were achieved across BCMA CAR-T studies, toxicity was also high. 80.3% patients evaluable for safety experienced CRS with 14.1% experiencing CRS of grade 23. High dose ide-cel and cilta-cel had higher than average rates of CRS overall (96.3% and 89.5%, ©lnstitute for Clinical and Economic Review, 2021 Page 140 Final Report - Multiple Myeloma Return to Table of Contents respectively) but lower rates of grade 23 CRS (7.0% and 5.6%, respectively). Rates of neurotoxicity differed considerably between studies. The population included in the ide-cel study was generally older and more heavily pretreated, possibly contributing to its higher neurotoxicity rate. Overall, BCMA CAR-T-cell therapies prove to have high response rates, but equally as high toxicity. Despite toxicities, this meta-analysis provides robust evidence that BCMA CAR-T therapies are considered highly efficacious even in heavily pretreated MM patients. Shah N, Sussman M, Crivera C, et al. Comparative effectiveness research for CAR-T therapies in multiple myeloma: appropriate comparisons require careful considerations of data sources and patient populations. Clin Drug Investig. Published online February 18, 2021. https://doi.org/10.1007/s40261-021-01012-x This systematic literature review sought to evaluate the most appropriate data sources and populations for comparison to the novel CAR-T therapies ide-cel and cilta-cel, specifically their single-arm KarMMa and CARTITUDE-1 trials. Investigators reviewed clinical trials of regimens preferred by the National Comprehensive Cancer Network (NCCN) for previously treated multiple myeloma and assessed them for comparability to the CAR-T trials' patient populations. None of the clinical trials identified were conducted in patient with triple class exposed (TCE) or triple class refractory (TCR) multiple myeloma exclusively and thus were not suitable for comparison. Additionally, investigators systematically reviewed real-world studies of patients with TCE and/or TCR multiple myeloma. Five real-world studies were included, with two exclusively focusing on the TCR patient population. Based on currently available data, real world studies with matching TCE and/or TCR patient populations make the most appropriate comparators for the single-arm trials of ide-cel and cilta-cel. Of note, the two real world studies identified by this systematic review, Gandhi 20197 and Mehra 2020%, were included to define the comparator population in this report. ©lnstitute for Clinical and Economic Review, 2021 Page 141 Final Report - Multiple Myeloma Return to Table of Contents E. Long-Term Cost-Effectiveness: Supplemental Information El. Detailed Methods Table E.1.1 Impact Inventory Type of Impact Included in This Analysis from [...] Notes on Sources Sector (Add additional domains, as Perspective? ,('f quantlflfed), relevant) Health Care | Societal Likely Mag|.1|tude & Impact (if not) Sector Formal Health Care Sector Health Longevity effects X X Outcomes Health-related quality of life X X effects Adverse events X X Medical Costs | Paid by third-party payers X X Paid by patients out-of-pocket O O Future related medical costs X X Future unrelated medical costs O O Informal Health Care Sector Health- Patient time costs NA O Related Costs | Unpaid caregiver-time costs NA O Transportation costs NA X Non-Health Care Sector Productivity Labor market earnings lost NA X Cost of unpaid lost productivity NA X due to illness Cost of uncompensated household | NA O production Consumption | Future consumption unrelated to NA O health Social services | Cost of social services as part of NA O intervention Legal/Criminal | Number of crimes related to NA O Justice intervention Cost of crimes related to NA O intervention Education Impact of intervention on NA O educational achievement of population OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 142 Return to Table of Contents Housing Cost of home improvements, NA O remediation Environment | Production of toxic waste pollution | NA O by intervention Other Other impacts (if relevant) NA O NA: not applicable Adapted from Sanders et al" Target Population The model focused on an intention-to-treat analysis, with a hypothetical cohort of patients in two different populations: 1) triple- or quad-refractory with 3+ prior lines of treatment being treated with ide-cel or cilta-cel, and 2) triple-, quad-, penta-refractory with 4+ prior lines of treatment being treated with belantamab. Cohort characteristics for each treatment group are described in E.1.2 and E.1.3. Table E.1.2, Baseline Population Characteristics: Triple- or Quad-Refractory MM (3+ prior lines of treatment) Triple-Class Refractory Idecabtagene vicleucel | Ciltacabtagene autoleucel Triple and Quad- MM Refractory Comparator Median Age 61 61 60 Percent Male 59% 59% 57% Refractory Status, % Anti-CD38 Ab-refractory: | Triple-refractory: 88% Anti-CD38 Ab-refractory: 94% 100% Triple-refractory: 84% Median Prior Lines of 6 6 4 Treatment Source Munshi et al, 2020%° Madduri et al, 20204 Gandhi et al, 20197 Table E.1.3. Baseline Population Characteristics: Triple-, Quad-, or Penta- Refractory MM (4+ prior lines of treatment) Penta-Refractory MM Belantamab Triple/Quad/Penta-Refractory Therapies Median Age 65 59 Percent Male 53% 56% Refractory Status, % Anti-CD38 Ab-refractory: 100% in | Anti-CD38 Ab-refractory: 100% 2.5 mg/kg dose Median Prior Lines of Treatment 7 5 Source Lonial et al, 20204 Gandhi et al, 20197 OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 143 Return to Table of Contents Comparators The primary comparator for each type of therapy is listed below. Because of differences in population indications, interventions were not compared to each other. Given the numerous available therapies used by clinicians at various lines of therapy, a market basket approach was used to compare to each intervention based on refractory status using the MAMMOTH study." The market basket composition was approximated by both broad-therapy and specific-therapy estimations. For belantamab, we used a weighted average of MAMMOTH subcohorts so that the proportion of penta vs triple/quad refractory patients from the MAMMOTH comparator cohort matched that in the DREAMM-2 study. MAMMOTH results for these cohorts were used to inform comparator PFS and OS in the model. Specific regimens that are commonly employed in the relevant populations were also identified for the purpose of estimating market basket costs. For the triple- or quad-refractory population, the comparator market basket included {(comparator for ide-cel and cilta-cel, sub-population within belantamab also compared using this market basket): e Carfilzomib + cyclophosphamide + dexamethasone (KCd) e Pomalidomide + cyclophosphamide + dexamethasone (PCd) e Carfilzomib + pomalidomide + dexamethasone (KPd) e Elotuzumab + pomalidomide + dexamethasone (EPd) e Ixazomib, lenalidomide, and dexamethasone (IRd) Comparator market basket for the penta-refractory population {used in weighted average comparator basket along with triple/quad for belantamab): e Carfilzomib + cyclophosphamide + dexamethasone (KCd) e Pomalidomide + cyclophosphamide + dexamethasone (PCd) e Ixazomib, pomalidomide, and dexamethasone (IPd) e Elotuzumab + pomalidomide + dexamethasone (EPd) e Ixazomib, lenalidomide, and dexamethasone (IRd) e Bendamustine, prednisone, dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) Within each progressed state, we also applied a proportion of patients on palliative chemotherapy consistent with current evidence. Tables E.2.2 and E.2.3 provide dosing, administration schedules, and costs for each market basket of comparators. E2. Model Inputs Model inputs were estimated from the clinical review, published literature, and information from expert stakeholders. The inputs that informed the model are described below. The base case ©lnstitute for Clinical and Economic Review, 2021 Page 144 Final Report - Multiple Myeloma Return to Table of Contents analysis took a health care system perspective and focused on direct medical care costs only. Outcomes were estimated over a lifetime time horizon using a monthly cycle to capture the potential impacts of short-term and ongoing morbidity and mortality. Costs and outcomes were discounted at 3% per year. Treatment Regimen Inputs Treatment regimens for the interventions are described in Tables E2.1. The market basket of therapy regimens for three or more lines of therapy and four or more lines of therapy are described in tables E2.2 and E2.3. Table E.2.1. Treatment Regimen Recommended Dosage Squibb/bluebird bio Category/Therapy Idecabtagene vicleucel | Ciltacabtagene autoleucel Belantamab Brand Name Abecma TBD Blenrep Manufacturer Bristol Myers Janssen/Legend Biotech GlaxoSmithKline Route of Administration Single infusion Single infusion Infusion once every 3 weeks Dosing 150-450 x 10sCAR+ T 0.75 x 10s (range: 0.5-1.0 | 2.5 mg/kg of body cells x108) CAR+ T cells/kg weight Use of Lymphocyte Fludarabine (30 mg per | Cyclophosphamide (300 N/A Depleting Chemotherapy | square meter of body mg per square meter per surface per day) and day) on days -5, -4, -3 cyclophosphamide (300 mg per square meter per day) on days -5, -4, -3 ©lnstitute for Clinical and Economic Review, 2021 Page 145 Final Report - Multiple Myeloma Return to Table of Contents S1U9U0) JO 3|qe] O} uiniay 9T aded ewo|aA a|di|ny - Hoday jeuld TZ0T 'M3IASY JJWIOUODT PUE [Bd1UI]D) 0} SINHISUIQ o6t'62$ 1507 |e10] 98euane paySiom %96 (sa2Ad 7 saye poyjdde) Alsuaiu| asop a8esane paiySia (sopAd 7 4oy paljdde) T€STS JuswWaBeuew 1502 JUSAS 3SJaApe 98eJane paySiIom OET'ES $1S02 UOIIBISIUIWPE S3EIAE PAIYSIaM TT'ST'8T Aep/3woy 8t auoseylawexaq 12T Aep/swge 8T apiwopijeua ST'8'T Aep/3wy 8¢ quuiozex| 16€°C¢S %071 auoseylawexaq 'Opiwopijeua 'qiuozex| C2'ST'S'T Al Swg+eso Swgg 8¢ auoseylawexaq 121 Aep/3wy 8T apiwopijewod 2T pue''sT '8 'T /8w ot 8¢ qewnznio|3 9/99€$ %6T auoseyldwexaq 'apiwopijewod 'qewnznio|j TT'sT'8'T 8w oz 8¢ suoseylawexaq T¢-T Aep/3wy 8¢ Splwopljewod (21-2S9pPM)IT ''ST'6'8 'T 'T (T3PA) 9T 'ST '68 T 'T Zw/8w /g 'zw/Swog 87 qiwoz|ie) TLV'0ES %81 auoseylawexaq 'Oplwopijewod 'qiwozjiie) 8T-ST pue $-T Aep/3wor 8¢ auoseylawexaq T'sT'8'T Aep/3wo0g 8T apiweydsoydojiy 12T Aep/3wy 8¢ splwopljewod £80°/1S b4 auoseyawexaq 'apiweydsoydo|ar) 'Opiwopiewod 9T puUBST '68 'T 'T 8w ot 8t auoseylawexaq ST'8'T Tw/3woog 8T apiweydsoydopA) (sa2A2 Buiulewal) 9T 'ST '2 'T (TapA) 9T 'ST 682 'T Tuwi/3w og 8¢ qiwoz|iued 9/9°CCS %81 auoseylawexaq 'opiweydsoydo]dA) 'qiuoz|iyie) 1509 uoneuiquo) ysej uo 3Py suoped o sheq "ulwpy asoq T 9PA) oAy /sheq uoneuiquo) Adesayl 13d uoipodoad 150D |elo] pue a8esoq papuswwoddy (Juswieasy jo saul| Joud +g) 19)segq 1aj4eA Jojesedwo) WIN Alojaesjay-penD Jo -ajduil "z'Z'3 9|qel S]U3IUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld LYT 98ed TTOC 'M3IA9Y dlWOU0I] pue |edjul[) JO} 91NUISUIQ v'eETT w/3woyp 8¢ apisodol] VETT Tw/3wQoy 8¢ apiweydsoydopA) YETT Aep/3wor 8T auoseylawexaq AN auosiupald w/8woe 8¢ sunsnwepuag unoidsy pup 'apisodoya 'apiwpydsoydosfo L06°6S %6¢ 'auospylawinxap 'auosiupaid 'aunsnwopuag TTST'T Aep/3wor 8T auoseylawexaq T¢-T Aep/3wsg 8¢ aplwopijeua ST'8'T Aep/3wy 8¢ qiwozex| £6€'CCS %01 auoseylawexaq 'apiwop]jeua 'qiuozex| 2TST'8'T Al Bwg+|elo 3wgg 8¢ auoseylawexaq 121 Aep/8uwy 8¢ aplwop|jewod 7T puR''sST'8 'T /8w o1 :14 qewnznio|3 9/9'9€$ %ET auoseylowexaq 'apjwopijewod 'qewnznio|j TT'ST'T Aep/3wor 8T auoseylawexaq 121 Aep/3wy 8¢ aplwop|jewod ST'8'T Aep/3wy 8¢ qiuozex| €TELTS %6 duoseylawexaq 'Opiwopjewod 'qiuozex| 8T-ST pue t-T Aep/3worp 8T auoseylawexaq T'sTe T Aep/3wo0g 8¢ aplweydsoydopA) 11 Aep/3wy 8¢ aplwopijewod auoseylawexaq €80°LTS %LT 'apiweydsoydo|ah) 'apiwopijewod 9T PuUe ST 6 '8 '2"1 8w oz 8T auoseylowexaq ST'S'T Tw/8woog T4 apiweydsoydopdAy (sa2A2 Buujewal) 9T 'ST '2 'T (T 9PA) 9T 'ST 68T 'T zw/38w 0g 8¢ qiwoz|iye) 9Sv TS %CC auoseylawexaq 'opiweydsoydo)dA) 'quuiozjiyie) 1503 uoneuIquwo) aphd 12d Yde3 uo sjusped sAeq "ulwpy asoq T 3PA)Y apAy/sheq uopeuiquo) Adesayy Jo uonuodoad 150 |e10) pue 98esoQg papusawwioday {jusawjieasy jo saujj Joud +p) 19y seg 1)Je Jojesedwo) AN Alordelyay -ejuad Jo '~-penp '-ajduil "€'Z'3 9|qel S1U9U0) JO 3|qe] O} uin3ay 87T a8ed ewo|aA a|di|ny - Hoday jeuld TZ0T 'M3IASY JJWIOUODT PUE [Bd1UI]D) 0} SINHISUIQ 166229 1507 |e10] 98eane paySiom (sapho %96 7 191e paijdde) Alsuaiu; asop a8esane palySiam (s912A2 7 10y paidde) Juswadeuew 6STTS 1500 JUSAD 9SIIAPE d8eIDAR PAIYSIaM TOETS $1502 UOI1EJ]SIUIWpPE. SFEIDAE PAIYSIaM YETT w/3wot 8¢ unne|dsp Detailed Description of Curve Digitization and Survival Extrapolation Kaplan-Meier curves from the evidence were digitized using the algorithm by Guyot and colleagues to impute patient-level time-to-event data.'® Base-case survival was derived from parametric fits to each intervention's available PFS and OS Kaplan-Meier curves.!%1443 Table E.2.4 delineates the evidence that was used to calculate transition probabilities. The comparator OS evidence was derived from the MAMMOTH study using triple- and quad-refractory curves (for comparison to CAR-Ts) and a weighted average of triple-/quad-refractory and penta-refractory curves (for comparison to belantamab )." Given we did not have available PFS curves for the comparator populations (i.e., triple-, quad-, or penta-refractory in Gandhi et al.), we assumed similar distribution parameters as other curves in triple-, quad-, or penta-refractory MM and adjusted to fit a PFS to OS relationship as observed in meta-analyses. 37,38 The model curves considered included distributional forms Weibull, exponential, log-normal, log- logistic, and Gompertz. The base-case distributional form was selected separately for each curve based on the best model fit using the Akaike information criterion (AIC) values, visual comparison, and clinical plausibility. Transition probabilities were then calculated for each time period in the model (monthly cycles). In some cases, we used piecewise modeling techniques to fit survival distributional forms at different time points after examining hazard functions.*® Table E.2.4 presents sources for each curve. Table E.2.4. Sources of Kaplan-Meier Curves to Calculate Transition Probabilities Triple- Survival Idecabtagene Ciltacabtagene and Quad- Penta-Refractory Estimate vicleucel autoleucel Refractory Belantamab {Comparator (Comparator to Belantamab)* to CAR-Ts)* Progression- | Phase CARTITUDE-1 PFS curve fit Updated PFS curve fit to free Il KarMMa results to DREAMM-2 PFS | proportional survival proportional | curve relationship relationship reported in previous reported in meta-analyses previous meta- analyses Overall Phase CARTITUDE-1 MAMMOTH Updated MAMMOTH penta- survival Il KarMMa results triple/quad- DREAMM-2 OS refractory refractory curve Sources Munshi et al, Madduri et al, Gandhietal, | Lonial etal. Gandhi et al, 2019' 202111 20201415 20197 2021 * Comparator to belantamab weights outcomes from both populations exposed to three or more lines of therapy and populations exposed to four or more lines of therapy OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 149 Return to Table of Contents S]U3IUO) JO 9|gE] 0} uImay ewo|aA a|di|ny - Hoday jeuld 0ST @8ed TTOC 'M3IA9Y dlWOU0I] pue |edjul[) JO} 91NUISUIQ {|lewJou Alojoeljal ,6T0T -801) |ealnang %6¢€ penb/3|dul et aJnsl4 | '|13 Iypueo 0eT ET'C | S9tv [|e49A0 g:€10T 'Ie 19 Xl|84 ,6T0C s9sAjeue-e1ow snoiadud | '|e 19 lypueo (Jlewsou-807) uj pajodau diysuopieal VAN TA R E] |EAIAING D244 | J03esedwio) Aloyoel oy %0T | |euoniodoad 01 1) 9AINI S4d sojnodowiq 00T T V/N uoissat8oud -penp Jo -3jduiL Jo1oweded djeds (linqom) syjuow 0} Juawisn(pe yum aaind »1020T '18 |eAlAINS 8T 1 %6°08 PUB %68 | Sdd Se adeys awes pawnssy 12 UNppe | 99°6F 19T | 98T¢C [IELYe) syuow ZT 18 Sdd pue aAlje 9 uo (Iingqiam) paseq pajeiqijed 2404249y} +1020T '|e |eAIAING 9244 %LL 'paydeal Jou Sid uelpain 19 LUNppeiN | ¥T'6C 19T | 9'81¢ uoissaigo.d 192-e3|1D {(|lewJou A4 -801) |eainang %8L V/N | '[e3d1ysuniy €6°0 Ve | L'v0C [|edaAQ (jlewsou-307) 111¢0¢ [EAIAINS 994 %0V V/N | 'e iysuniy | 00T 1€C | 6'S8T uoissaigo.d [32-9pI Stzuot S3J0N 22inosg c¥la | T3S v :o_Mflmno_"_uw_Q ZT e % pPaj2poiN /3less | fadeys awo3No |[SPOIAl [eUl{ 10} Si3j3Weled 3]eas pue 'adeys '}4 3AIND [BAIAINS "G 2 ] 3|qel '(S4d HLOWINVIN 'SO [99-BY{1D "2'1) UMOYS 10U OS|e dJe S3ullll} DAIND JoY10 Wwody suonndwnsse uo paseq suoliejodelixy "SUOIIRIDPISUOD BIUDPIIUOD Ul JlWdpede 01 @Np UMOYS 10U dJe suofjejodesixa qewejue|aq Suimoys saundi4 "f''3 03 T'y'3 s24nBi4 Ul SSAIND |AY pajewixoidde 03 suoiejodelixa aAlleUI) e pinoad DN "9AIND Yoea Joj salMjiqeqold uolsues) Juapuadap-awi} 93esauad 03 pash 21am sid3dwedled djeas pue adeys 3yl "(DIv) uoldIID UoK_WIOUI B)IBYY PUB UOI}d3dSul [BNSIA UO paseq [2pow 3yl 0} Uasoyd Suoiinguasip [euly ay siuasald §'z'3 a|qel S1U9U0) JO 3|qe] O} uiniay 16T @8ed ewo|aA a|di|ny - Hoday jeuld TTOT 'M3IASY J1WOUODT pUE [BJIUI[D 10§ 3IMISUIQ AdeJay) jo sauj| aiow Jo noj 01 pasodxa suonendod pue Adesayy Jo sauj| aJow Jo 334y} 03 pasodxa suolle|ndod Yyioq Wwouj Sawodano siydiam qeweluelaq o3 Jolesedw o), (linqiam) (6T0C [BAIAINS %IT | Aopeusi-euadersundly | 'lelsiypued | 19, €9'T | 0'6CE |leJ3A0 (610 sasAjeue-elow snojaald | 'e 19 Iypuen (jlewsou-807) u| pauodas diysuonejad | /10T '|8 19 |EAIAINS 9244 Jojesedwo) %G'T | |euolnodoad 03 11§ 9AIND S4d sojnodowig 1.0 0T Vv/N uoissaldoud Aioydeijoy-ejuad {lewuou T¢0c -8017) |eniaIng %S '[e 18 [eluoT] 961 0T | ¥98¢ [leJ2AQ (T£'8 = 1915wWeJed) (lewJou-807) uonnquisip |elluauodxa 0} T20C |eAIAINS 9914 9%/T | Buiyoums syjuow g je jouy| '|e 13 |eluo] €0°T G60| 8TVE uolssatgoud sgewelue|og SYIUoO (esoud S9I0N 92Jno0g d|ess | adeys o]\ uonnquisiq) €T 18 % P3|9poN awonnQ Progression Free Survival Figure E.2.1. Progression-Free Survival Extrapolations for Ide-Cel 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Progression-Free Survival 0.2 0.1 Weibull (AIC: 184.2) Lognormal (AIC: 185.9) Log-Logistic (AIC: 186.3) Exponential (AIC: 187.3) Gompertz (AIC: 182.9) ===-KarMMa (Approximate) 0 5 10 15 20 25 30 35 Model Cycle (Months) 40 45 50 55 Figure E.2.2. Progression-Free Survival Extrapolations for Cilta-Cel 1 0.9 0.8 0.7 0.6 0.5 0.4 Progression-Free Survival 0.3 0.2 01 0 5 10 15 20 25 30 35 40 Model Cycle (Months) ©Institute for Clinical and Economic Review, 2021 45 50 55 60 60 Weibull (AIC:218.6) Lognormal (AIC: 218.8) Log-Logistic (AIC: 218.6) Exponential (AIC: 221.9) Gompertz (AIC: 219.8) ===-CARTITUDE-1 (Approximate) Overall Survival Figure E.2.3. Overall Survival Extrapolations for MAMMOTH Triple- or Quad-Refractory Cohort* 1 0.9 0.8 Weibull (AIC: 443.7) 0.7 - 06 Lognormal (AIC: 426.5) > E 0.5 @ 04 Log-Logistic (AIC: 430.6) "o . g & 03 Exponential (AIC: 442.5) 0.2 ===-MAMMOTH Triple/Quad 0.1 (Approximate) 0 0 5 10 15 20 25 30 35 40 45 50 55 60 Model Cycle (Months) *Gompertz not shown due to poor fit of observed data from MAMMOTH Figure E.2.4. Overall Survival Extrapolations for Ide-Cel 1 0.9 0.8 0.7 o6 Weibull (AIC: 205.5) g o \ \ Lognormal (AIC: 204.7) &a Log-Logistic (AIC: 205 3) ?_': 0.4 Exponential (AIC: 212.8) 303 Gompertz (AIC: 207.8) 0.2 ====KarMMa (Approximate) 0.1 0 0 5 10 15 20 25 30 35 40 45 50 55 60 Model Cycle (Months) Health State Utilities The most current and best available evidence on health utilities comes from the KarMMa study, with elicitation of utilities using the European Quality of Life-5 dimensions 5 levels (EQ-5D-5L) health state classification instrument.*? The analysis elicited utilities from the US, UK, and Canadian populations across different time points including baseline, pre-progression, and post-progression. ©lnstitute for Clinical and Economic Review, 2021 Page 153 Final Report - Multiple Myeloma We applied the baseline utility value to the progressed state, the highest utility value elicited for the progression-free off therapy state, and the first month pre-progression overall utility for the progression-free on therapy state. Given feedback from RRMM patients, we applied a separate utility to the progression-free off therapy state for both ide-cel and cilta-cel to reflect the benefits of being off therapies for a disease that commonly continues patients on therapies until death. See table E.2.6 for health state utilities applied in the model. Adverse event disutilities were applied for two cycles in the model (i.e., two months) as evidence suggested most adverse events were resolved within 1-3 cycles with additional dose adjustments. Consistent with previous health technology assessments,"""8 a utility score of 0 was applied for grade 3 or higher cytokine release syndrome for a duration. Table E.2.7 details the disutility estimates applied for adverse event disutilities. Table E.2.6. Utility Values for Health States Parameter Three or More Lines of Therapy Progression-free on Therapy and Responding 0.78 Progression-free off Therapy and Responding 0.82 Progressed Disease/not Responding 0.71 to Treatment Source Delforge et al, 2020* Adverse Events The model included any grade 3/4 adverse events that occur in 5% of patients in any of the treatments and comparators. Given the potentially significant impact of cytokine release syndrome on health care resource utilization and quality of life, we included all grades 1-4 for these adverse events and adjusted costs and quality of life estimates accordingly. The costs and disutility of adverse events were applied to the first two cycles for each intervention and comparator. After cycle 2 of the model, we applied a dose adjustment factor, assuming adverse events would be resolved with lower dosing of each therapy. Table E.2.7 includes the proportions of patients with adverse events applied in the model. ©lnstitute for Clinical and Economic Review, 2021 Page 154 Final Report - Multiple Myeloma Table E.2.7. Included Adverse Events Parameter Idecabtagene vicleucel ° Ciltacabtagene autoleucel 4 Belantamab % Proportion with 41% 49% N/A grade 1 CRS Proportion with 23% 39% N/A grade 2 CRS Proportion with 2% 3% N/A grade 3 CRS Proportion with 1% 1% N/A grade 4 CRS Proportion with 12% NR N/A CRS and NE <=2 Proportion with 3% NR N/A CRS>= 3 and NE <=2 Proportion with 3% NR N/A CRS<=2 and NE=>3 Anemia See above categories 68% 20% Neutropenia 95% 9.5% Thrombocytopenia 60% 20% Lymphopenia 49% 16.8% Leukopenia 61% Keratopathy N/A 27% Hypercalcemia NR 7.4% Hypophosphatemia NR 5.3% NR: Not reported Adverse event disutilities or utilities are described in Table E.2.8. Adverse event disutilities were applied for two cycles in the model (i.e., two months). Consistent with previous health technology assessments,"">'8 a utility score of 0 were applied for grade 3 or higher cytokine release syndrome for 8 days in the first cycle. ©Ilnstitute for Clinical and Economic Review, 2021 Page 155 Final Report - Multiple Myeloma Table E.2.8. Adverse Event Disutilities Adverse Event Parameter Disutility Source Anemia -0.31 Brown et al. 2013 7° Neutropenia -0.15 Brown et al. 2013 7° Thrombocytopenia -0.31 Brown et al. 2013 7° Lymphopenia -0.07 NICE TA 510 % Cytokine release syndrome 0.00* Hettle et al. 2017 77 Keratopathy -0.05 Sullivan 2006 {ICD-9 369) & Hypercalcemia -0.04 Sullivan 2006 {ICD-9 289) 8 Hypophosphatemia -0.04 Sullivan 2006 (ICD-9 289) & *This value corresponds to a utility, not a disutility. Economic Inputs Cost Inputs All costs used in the model were updated to 2020 dollars. Drug Acquisition Costs For CAR-T therapies, the base-case findings use the list price for ide-cel. There is not a price yet for cilta-cel; therefore, we assume the same price as a placeholder. For belantamab we used WAC pricing for the base-case findings. Comparator therapy prices were a function of one or more therapies on the market, inclusive of discounts, rebates (15% discount for comparator oral therapies based on FSS pricing schedule), patient assistance programs, and concessions to wholesalers and distributors. Patients that discontinued the CAR-T treatment before receiving the CAR-T infusion were not charged the CAR-T costs. Costs for subsequent therapies, including a proportion on palliative care, were assigned to the progressed state for 4 cycles using the appropriate comparator therapies for each population. The progressed state costs were consistent across treatment comparisons. Infusion therapies were subject to ASP + 6% pricing. OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 156 Table E.2.9. Drug Costs Intervention (Dosage) WAC/List Price per Unit Net Price per Unit or Source or per Time Period* per Time Period Idecabtagene vicleucel $419,500 N/A Market analyst estimates®? Ciltacabtagene autoleucel Assumed same as ide- N/A Assumption cel Belantamab $8,277 per 100mg Micromedex package Solutions*> Comparator therapies See Table E.2.3 and See Table E.2.3 and Multiple Table E.2.4 Table E.2.4 *WAC as of March 25, 2021 Administration and Monitoring Costs Tables E.2.10 through E2.12 detail administration and monitoring utilization and costs applied in the model. Table E.2.10 includes pre-infusion regimens and unit prices for CAR-T therapies. Table E.2.11 includes administration and monitoring utilization applied at different stages of the model. We used recent evidence in heavily pre-treated patients with multiple myeloma to inform average utilization inputs per cycle.8 We then applied unit prices from Table E.2.12 to each utilization parameter estimate. For hospital admissions we applied a fee-for-service approach. Table E.2.10. Pre-Infusion Regimens for CAR-T Therapies Final Report - Multiple Myeloma Treatment Regimen Unit Price Source Cyclophosphamide | 300 mg/mg(2) on days -5, -4, -3 $33 Fludarabine 30 mg/m{2) on days -5, -4, -3 $50 Munshi et al, Cytarabine 500 mg/m(2) for 2 days a week, 2 weeks total $1 2020 Methotrexate 1000 mg/m(2) for 1 day a week, 2 weeks total $2 ©lnstitute for Clinical and Economic Review, 2021 Page 157 Table E.2.11. Administration and Monitoring Utilization Neurotoxicity adverse events Neurotoxicity adverse events Other AE- related costs Model Stage Idec.abtagene Ciltacabtagene Belantamab Comparator Marl.(et Basket vicleucel autoleucel of Therapies Leukapheresis o Leukapheresis Ophthalmic ¢ |V administration costs ¢ CRS-related o CRS-related examinations at | ¢ Other AE-related costs Prior to and during treatment treatment baseline and therapy Inpatient days e |npatient days prior to each administration (2inIcu) (2inicu) dose Complete blood count testing Liver function testing Complete blood count testing Liver function testing Complete blood count testing Liver function testing Complete blood | ¢ Complete blood Treatment- e Treatment-specific count testing count testing specific outpatient visits per cycle Liver function o Liver function outpatient visits | ¢ Complete blood count Post-therapy testing testing per cycle testing each outpatient monitoring; Complete blood visit progression-free count testing ¢ Liver function testing 8 each outpatient visit Liver function testing 4 cycles of e 4 cycles of 4 cycles of ¢ 4 cycles of subsequent subsequent subsequent subsequent treatment administration treatment treatment treatment with market basket administration administration administration | ¢ Complete blood count X 83 with market with market with market testing Progressed disease ) . . basket basket basket ¢ Liver function testing OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 158 Table E.2.12. Other Administration and Monitoring Unit Prices Value Source Cost per hospital day* $3,190 HCUP Statistical Brief #1253 Cost per day in ICU $5,563 Dasta, 2005 % Office visit $74 Physicians' Fee and Coding Guide (HCPCS code 99213)%€ Leukapheresis (CAR-T only) $1,323 Physicians' Fee and Coding Guide HCPCS code 3651156 Intravenous treatment $140 Physicians' Fee and Coding Guide (HCPCS administration (first hour) code 96413)%¢ Intravenous treatment $29 Physicians' Fee and Coding Guide (HCPCS administration (each additional code 96415)% hour) Visual acuity test $31 Physicians' Fee and Coding Guide (HCPCS code 99173)%6 Complete blood count test $44 Physicians' Fee and Coding Guide (HCPCS code 85027)%€ Slit lamp exam $110 Physicians' Fee and Coding Guide (HCPCS code 92285)%6 Liver function test $62 Physicians' Fee and Coding Guide (HCPCS code 80076)%¢ *Inflated to 2020 USD Adverse Event Costs The unit cost of adverse events applied to patients experiencing these events are shown in Table E.2.13. Adverse event costs were applied for the first two cycles of the model. Specific to CAR-T therapies, we relied on recent evidence that combined CRS and neurotoxicity events in different categories.?® OInstitute for Clinical and Economic Review, 2021 Final Report - Multiple Myeloma Page 159 Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Table E.2.13. Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs Adverse Event Unit Costs