1. Treatment of Transplant Ineligible/Elderly MM Patients Ruben Niesvizky Department of Medicine, Division of Hematology/Oncology, Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA Myelomacenter.org run9001@med.cornell.edu

2. Disclosures Speaker’s bureau: Celgene, Millennium, Onyx

3. Case 65 year-old Hispanic male –Presents to emergency room with chest pain, fatigue; found with: Creatinine: 5.0 Hemoglobin: 8.9 Multiple lytic lesions Total urine protein: 20 gm/24 hr UPEP: 19.4 gms kappa light chain SPEP: 0.1 monoclonal peak β 2 M: 15.0 BM: 50% plasma cells

4. Case Discussion As you discuss with him his disease and his prognosis, he is concerned that his age precludes him from aggressive therapy. You advise him: 1.He is a “young person with lots of experience,” and his age should not preclude him from receiving aggressive therapy with the intent of changing the natural history of his disease 2.Patients over the age of 65 should not be considered for aggressive therapies

5. Nearly half of multiple myeloma patients are considered elderly Current distinction of elderly based on transplant eligibility (European and North American trials) Patients under 65 years of age, 35% Older patients from 65 to 75 years of age, 28% Elderly patients over 75, 37% The Elderly Patient The median age at diagnosis is 70 years. Elderly Older 37% 28% 35% Palumbo A, et al. Hematology Am Soc Hematol Educ Program. 2009:566-577.; Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5 Version 2.0. Lyon: IARC Press; 2004.; Ries LAG, et al. National Cancer Institute. SEER Cancer Statistics Review. Source: SEER 13. Accessed August 24, 2010 at: http://seer.cancer.gov/faststats

6. < 65 years>65 years Myeloma: 5-year Relative Survival Rates 42.9% 25.2 % SEER 1995-2001

7. Novel Agent Limitations in the Aging Population Median OS<65 60 m Median OS>65 32 m Kumar et al. Blood 2007

8.  What is the goal of treatment (does CR matter)?  What is the best induction treatment?  Is it possible to individualize the treatment?  Can novel drugs improve outcome Treatment of Elderly MM Patients Leading Questions Treatment of Elderly MM Patients Leading Questions

9.  What is the goal of treatment (does CR matter)?  What is the best induction treatment?  Is it possible to individualize the treatment?  Can novel drugs improve outcome Treatment of Elderly MM Patients Leading Questions Treatment of Elderly MM Patients Leading Questions

10. Median not available, OS calculated from 2yr (San Miguel), 3yr (Palumbo) and 5yr (Zervas) estimates 5 of 13 studies failed to show association: primarily due to the confounding effect of a therapy that generates high CR and is simultaneously too toxic Two polarizing impact of a therapy on survival (higher CR leading to longer survival vs higher toxicity leading to shorter survival) confounds analysis Mean = 3.6% ΔCR/nCROSΔOS +10%35m+12.6m +10%50m+18m Medline/OVID search from 1980 – Mar 2008 13 studies (4396 patients) meeting the criteria: randomized comparative trials in newly diagnoses MM reporting CR or CR/nCR and survival (either median survival or survival rate) Percent improvement in survival for each percent increase in the CR/nCR rate was calculated for each study CR in Non-Transplant Setting van de Velde et al. Haematologica 2007

11. Hematologic CR Correlates with Long-term PFS and OS in Elderly Patients Treated with Novel Agents Gay et al. Blood 2011; 117(11):3025-31 PFS OS P<0.001 CR VGPR PR CR VGPR PR Probability Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175) First-line treatment MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254) Significant benefit also seen when analysis is restricted to patients >75 years old

12. 6050403020100 100 80 60 40 20 0 Months P =0.001 PFS Immunophenotypic CR 90% at 3y “Stringent CR”38% at 3y Conventional CR57% at 3y PR (≥70% reduction) 28% at 3y Paiva et al; J Clin Oncol. 2011;29(12):1627-33. The Better the Quality of the Response the Longer the Survival (Immunophenotypic CR): GEM2005>65y

13. PFS Sequential Approach NDMM Patients PAD, bortezomib-pegylated doxorubicin-dexamethasone; MEL100, Melphalan100 mg/m 2 ; Len-Pdn, lenalidomide-prednisone; Len, lenalidomide; PFS, progression-free survival; OS, overall survival; CR, complete response; VGPR, very good partial response; PR, partial response; NDMM, newly diagnosed multiple myeloma Transplant MEL100 two courses Median follow-up 66 months Median age 70 years OS according response months Induction PAD four 21-day courses Consolidation Len-Pdn four 28-day courses Maintenance Len until progression 0.00 0.25 0.50 0.75 1.00 20406080100 CR VGPR PR 12 Gay F, et al. Gr. Emat. Milan 19 November 2012 PFS according response VGPR

14. Important Aim of Treatment: Achievement of high-quality, sustained CR balanced with acceptable toxicity CR Should Be an Important Objective in Elderly MM Patients

15.  What is the goal of treatment (does CR matter)?  What is the best induction treatment?  Is it possible to individualize the treatment?  Can novel drugs improve outcome Treatment of Elderly MM Patients Leading Questions Treatment of Elderly MM Patients Leading Questions

16. THALIDOMIDE

17. MPT vs. MP : Efficacy in Newly Diagnosed Elderly Myeloma Patients  3 trials (IFM99 1, IFM01 2, HOVON 3 )………. > RR, PFS & OS  2 trial (GIMEMA 4, TURKISH 5 )………………. > RR, PFS  1 trial (Nordic 6 )…………………………….. > RR RR : 59% vs. 37 % (>22%) CR : 10% vs. 2,5% (>8 %) PFS : 20,4 vs. 15 m ( 6 m)………… HR 0,67 OS : 39,3 vs. 32,7 m(>6 m)…………HR 0,83 Thal maintenance in Italian, Nordic, Hovon 1.Facon et al. Lancet 2007;370:1209–1218; 2. Hulin et al. JCO 2009; 27(22):3664-70 ; 3. Wijermans JCO 2010; 28: 3160-6; 4. Palumbo et al. Blood 2008; 112: 3107–3114; 5. Beksac M et al. Eur J Haematol 2010; 86:16-22; 6. Waage et al Blood 2010;116(9):1405-12; Fayers PM et al. Blood 2011; 118(5): 1239-47

18. MPT vs. MP : Toxicity Palumbo A. Haematologica 2012; Epub ahead on August 8 *Appropriate thromboprophylaxis is required ** p of significant value MPTMP Grade 3-4 hematologic Aes 32%29% Grade 3-4 non-hematologic Aes40%**18% -Infection13%**9% -Peripheral Neuropathy15%**3% -Deep Venous Thrombosis6%**2% -Toxicity-related discontinuations35%**5%

19. Other Thalidomide-based Combinations in Front-line Study ResultsReference Phase 3 Thal/dex vs MP In patients > 75 years, OS longer with MP (41 vs 20m) In patients <75 years, similar OS Higher mortality during 1st y with thal/dex vs MP (28 vs 16, p=0.02) Ludwig et al. Blood,2009 ; 113:3435- 43 Phase 3 CTDa vs MP Morgan et al. Blood 2011; 118(5): 1231- 8 CTDaMP ≥ PR 64%33% CR 13%3% OS 33m31m Thal/Dex * MP ≥ PR 73%42% TTP 21m29m OS 41m49m Thal: 200 mg daily; Dex: 40 mg days 1-4; 9-12

20. LENALIDOMIDE

21. Secondary Comparison MPR-R vs. MPR Addition of MPR arm per EMEA advice MP M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 PBO: days 1-21 Primary Comparison MPR-R vs. MP MPR M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 Placebo Lenalidomide(R) +/- MP: MPR-R vs. MPR vs. MP Phase III Study Scheme N=459 patients > 65years M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo. MPR-R M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1 -21 RANDOMISATION Double-Blind Treatment Phase Disease progression Lenalidomide Continued Tx Lenalidomide (25 mg/day) +/- dexamethason e Open-Label Extension/ Follow-Up Phase Stratified by age (≤ 75 vs. > 75 years) and stage (ISS 1,2 vs. 3) 10 mg/day, days 1-21 Cycles (28-day) 1-9 Cycles 10+

22. Response & PFS: MPR-R vs. MP vs. MPR %RR (%CR): 77(10) vs. 50(3) vs. 68(3) Palumbo et al. N Engl J Med 2012; 366: 1759-69 Median PFS MPR-R 31 months MPR 14 months MP 13 months Median follow-up 30 months HR 0.49 P <.0000001 Time (months) 0510152025303540 0 25 50 75 100 HR 0.40 P =.153

23. OS: MPR-R vs. MPR vs. MP Median follow-up 30 months Palumbo et al. N Engl J Med 2012; 366: 1759-69

24. MPR-R (N = 150) MPR (N = 152) MP (N = 153) Hematological, % G3 G4 Neutropenia 67 35 64 32 29 8 Thrombocytopenia 35 11 38 14 12 4 Non-hematological, % Infections 9 1 13 2 7 - DVT 1 - 4 - 1 - SPM, n1294 - AML52- - MDS231 - Non-hematologic SPM543 DVT, deep vein thrombosis; SMP: Second primary malignancy; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome AEs During Induction: MPR-R vs. MP vs. MPR Palumbo et al. N Engl J Med 2012; 366: 1759-69

25. BORTEZOMIB

26. VMP Cycles 1–4 Bortezomib 1.3 mg/m 2 IV, d 1,4,8,11,22,25,29,32 Melphalan 9 mg/m 2 IV, and prednisone 60 mg/m 2 IV, d 1–4 Cycles 5–9 Bortezomib 1.3 mg/m 2 IV, d 1,8,22,29 Melphalan 9 mg/m 2 IV and prednisone 60 mg/m 2 IV, d 1–4 MP Cycles 1–9 Melphalan 9 mg/m 2 IV and prednisone 60 mg/m 2 IV, d 1–4 RANDOMIZERANDOMIZE 9 x 6-week cycles (54 weeks) in both arms Stratification: β 2 -microglobulin, albumin, region  Primary end point: TTP  Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy, OS, PFS, QoL (PRO) VISTA: Bortezomib (V) as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone Patients: Symptomatic multiple myeloma/end organ damage with measurable disease –≥ 65 years or < 65 years and not transplant-eligible; KPS ≥ 60%

27. Bortezomib+MP (VMP) vs. MP: Efficacy Data (682 patients) San Miguel et al. N Engl J Med 2008;359:906–917; Updated by Mateos et al JCO 2010 ORR: VMP 71%, MP 35%, CR: VMP 30%, MP 4% 036912 Time (months) 1518212427 0 20 40 60 80 100 VMP MP Patients without event (%) Time (months) 0481216202428323640 0 20 40 60 80 100 VMP MP Patients without event (%) Time to progressionOverall survival 52% reduced risk of progression on VMP~36% reduced risk of death on VMP Median follow-up 36.7 months 3-year OS: VMP: 69% MP: 54%, P=0.0008 VMP: 24.0 months MP: 16.6 months, P<0.000001

28. OS (ITT) 31% reduced risk of death with VMP Median OS benefit: 13.3 months 5-year OS rates: 46.0% vs 34.4% 100 90 80 70 60 50 40 30 20 10 0 Patients alive (%) 06121824303642485460667278 Time (months) Number of patients at risk: 33830126224021619616815313311261243 34430028827024623221619917615878341 GroupNEventMedianHR (95% CI)P-value MP338211 43.1 VMP344176 56.4 0.695 (0.567, 0.852)0.0004 San Miguel et al. ASH 2011; abstract 476

29. Grade 3/4 Adverse Events VMP (n=340)MP (n=337) Gr 3Gr 4Gr 3Gr 4 Neutropenia, %30102315 Thrombocytopenia, %20171614 GI, %1915<1 Peripheral Sensory Neuropathy, %13<100 Pneumonia, %5241 Herpes Zoster, %3020 Hematological SPM*, n(%)3(1%) Non-hematological SPM*, n(%)16(5%)10(3%) San Miguel et al. ASH 2011; abstract 476 1Howlader N, et al. SEER Cancer Statistics Review, 1975-2008. http://seer.cancer.gov/csr/1975_2008/browse_csr.php?section=2&page=sect_02_table.07.html

30. Progress in the Treatment of Elderly Patients with MM Novel agents SHOULD be included: Evidence based: bortezomib, lenalidomide > thalidomide Generating promising data: lenalidomide, bortezomib, carfilzomib

31.  What is the goal of treatment (does CR matter)?  What is the best induction treatment?  Is it possible to individualize the treatment?  Can novel drugs improve outcome Treatment of Elderly MM Patients Leading Questions Treatment of Elderly MM Patients Leading Questions

32. 8% if fully independent 14% if dependent in IADL 27% if dependent in ADL  40% if institutionalized 2-Year Mortality Rate for Persons Age 70 Years and Older Reuben. Am J Med. 1992;93:663.

33. Comorbidity is a Key Factor in Survival Charlson et al. J Chronic Dis. 1987;40:373. Age-Comorbidity Score N Actual 10-Year Survival (%) 0-136997-99 213687 310979 44247 52934

34. Functional Assessment

35. UPFRONT Protocol Induction: 21-day cycles Maintenance: 35-day cycles Cycles 1–4 Cycles 5–8 Vc: 1.6 mg/m 2, days 1,8,15,22 Rest period: days 23–35 VcD Vc: 1.3 mg/m 2, days 1,4,8,11 D: 20 mg, days 1,2,4,5,8,9,11,12 VcTD Vc: 1.3 mg/m 2, days 1,4,8,11 T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5,8,9,11,12 VcMP Vc: 1.3 mg/m 2, days 1,4,8,11 M: 9 mg/m 2, days 1,2,3,4 of every other cycle P: 60 mg/m 2, days 1,2,3,4 of every other cycle RANDOMIZE 1:1:1 Vc: 1.3 mg/m 2, days 1,4,8,11 D: 20 mg, days 1,2,4,5 Vc: 1.3 mg/m 2, days 1,4,8,11 T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5 Cycles 9–13 POSTER presentation ASH: 2013

36. VcD (N=100) VcTD (N=100) VcMP (N=100) Median age, years (range)73.5 (39–91)73.0 (38–88)72.0 (42–86) ≥75 years, %484034 ≥80 years, %201713 Male, %584557 Race, % White787372 Black91917 Other11810 Not reported201 IgG / IgA / Light chain, %59 / 28 / 1358 / 28 / 1463 / 21 / 14 KPS 50–60 / 70–80 / 90–100, %9 / 42 / 489 / 38 / 5313 / 47 / 40 ISS stage I / II / III, %15 / 55 / 2936 / 33 / 3126 / 43 / 31 Charlson co-morbidity index 0 / 1 / ≥2, % 51 / 25 / 2455 / 30 / 1562 / 24 / 14 Serum creatinine >1.5 x ULN, % 1613 Median  2 -microglobulin, mg/L 4.53.43.7 Patient Demographics and Baseline Disease Characteristics

37.  Median follow up was 13.4 months for the entire study population  Median PFS was 13.8, 18.4, and 17.3 months for the VcD, VcTD and VcMP arms, respectively  None of the pair-wise comparisons are statistically significant PFS (ITT population N=502) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0246810121416182022242628303234 VD:168144123957968503425201715972––– VTD:16713411784715945322317131264–2–– VMP:1671451251028169573932211611631––– Time (Months) Proportion of patients VcTD (N=168, 29% PFS events) VcD (N=167, 40% PFS events) VcMP (N=167, 36% PFS events) Patients remaining, n

38. Patient-reported QoL (mean global health status score by treatment arm)  In all three treatment arms, there was a trend for decreasing QoL during induction, followed by an improvement/stabilization in QoL during maintenance  There was a trend for poorer QoL in the VTD vs. VD and VMP arms UPFRONT QoL poster (Niesvizky et al., ASH 2011, abstract 1864) 58 56 54 52 50 48 46 44 42 40 Score BaselineCycle 3 Day 1 Cycle 5 Day 1 Cycle 7 Day 1 Cycle 9 Day 1 Cycle 11 Day 1 Cycle 13 Day 1 Timepoint VDVTDVMP InductionMaintenance

39. Once-weekly Administration of Bortezomib as a Strategy to Improve Tolerability Study details Grade ¾ GI toxicity Grade 3/4 peripheral neuropathy Discontinuation due to AE VISTA: VMP 1-3 Bortezomib twice-weekly 20%14%34% (GIMEMA) 4 Bortezomib once-weekly -5%17% (PETHEMA/GEM) 5 Bortezomib once-weekly 7% 12% † † Discontinuations due to SAEs 1. San Miguel et al. NEJM 2008;359:906 2. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix 3. Mateos et al. J Clin Oncol 2010;28:2259-66 4. Palumbo et al. JCO 2010; 28:5101-09 5. Mateos et al. Lancet Oncol 2010;11:934-41

40. Study details CR+PRCRPFS3 yrs-OS VISTA: VMP 1-3 Bortezomib twice-weekly 71%30%TTP:24 m68% Modified VISTA 4 (GIMEMA) Bortezomib once-weekly VMPT  VT VMP 90% 81% 42% 24% 37 m 27 m 85% 80% Modified VISTA 5 (PETHEMA) Bortezomib once-weekly VMP vs VTP  VT vs VP 80% 23%  42% 31 m70% Once-weekly Administration of Bortezomib as a Strategy to Maintain/Improve the Ffficacy 1. San Miguel et al. NEJM 2008;359:906 2. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix 3. Mateos et al. J Clin Oncol 2010;28:2259-66 4. Palumbo et al. J Clin Oncol 2010;28:5101-9 5. Mateos et al. Lancet Oncol 2010;11:934-41

41. Once-weekly Administration of Bortezomib as a Strategy to Improve Tolerability Study details Planned bortezomib dose Delivered bortezomib dose VISTA: VMP 1 Bortezomib twice-weekly 67.6 mg/m 2 38.5 mg/m 2 Modified VISTA 2 Bortezomib once-weekly (GIMEMA) 46.8 mg/m 2 39.4 mg/m 2 Modified VISTA 3 Bortezomib once-weekly (PETHEMA/GEM) 36.4 mg/m 2 32.9 mg/m 2 Mateos et al. IMW 2011: abstract 175

42. Bortezomib IV versus SC 222 relapsed and/or refractory MM patients. Bz is given at conventional dose and scheme Moreau et al. Lancet Oncology 2011; 12(5): 431-40 Arnulf B et al. Haematologica 2012: Epub ahead of print Bortezomib IV (n=73)Bortezomib SC (n=145) Primary endpoint: response after 4/8cycles (single agent bortezomib or +/-dex)) ORR42%/52% CR8%/12%6%/10% TTP9·4 m10·4 m Bortezomib IVBortezomib SC All gradesGrade ≥3All gradesGrade ≥3 Periph Neurop53%16%38%6% P=0·04 and 0·03 No diferences in pharmakokinetics studies

43.  What is the goal of treatment (does CR matter)?  What is the best induction treatment?  Is it possible to individualize the treatment?  Can novel drugs improve outcome Treatment of Elderly MM Patients Leading Questions Treatment of Elderly MM Patients Leading Questions

44. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma Jakubowiak, et al Blood, 2013 CR 42% >VGPR 62%

52. ECOG 00602641 ECOG 00602641 Palumbo 0109319 Fun Neo San Palumbo 0109319 Fun Neo San Celgene 0109319 Celgene 0109319 SWOG 0109319 SWOG 0109319 Baz 617591 OncoTx 317811 OncoTx 317811 UPFRONT 507416 UPFRONT 507416 Evolution 507442 Evolution 507442 Boccadoro 1063179 Boccadoro 1063179

53. Collaborators Tomer Mark MD Morton Coleman, MD Roger Pearse, MD Adriana Rossi, MD David Jayabalan Karen Pekle Arthur Perry Susan Matthew, PhD Scott Ely, MD/MPH Selina Chen-Kiang, PhD Monica Guzman, PhD Linda Tangenstam Kathleen Pogonowski Yasphal Agrawal, PhD Paul Christos Stanley Goldsmith MD Maureen Lane PhD Paul Christos Myelomacenter.org