Multiple Myeloma Therapy Doublet, Triplet, and beyond October 2013 The IV. International Eurasian Congress of Hematology Rafat Abonour, M.D.

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1 Multiple Myeloma Therapy Doublet, Triplet, and beyond October 2013 The IV. International Eurasian Congress of Hematology Rafat Abonour, M.D.

2 Multiple Myeloma Facts Second most prevalent hematologic neoplasm, but only 1% of all cancer cases Nearly 101,000 new cases diagnosed yearly around the world Median age at diagnosis is 70 years Survival is increasing but cure has not been realized Based on SEER data the 5 survival of those diagnosed was only 37.1%

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4 MM Therapy Over the Last 60 Years ACTH 1950 Prednisone 1957 Carfilzomib 2012 Bortezomib 2002 Thalidomide Merphalan 1957 Melphalan 1962 Autologous transplantation 1983 Bisphosphonates Lenalidomide 2006 Pomalidomide 2013

5 OS Based on Time of Diagnosis Kumar SK, et al. Blood. 2008;111:

6 The New Paradigm Induction: Rapid cytoreduction to alleviate symptoms related to myeloma Safe and allow for successful mobilization of autologous stem cells Intensification: High dose melphalan to increase the rate of Very good partial response (VGPR) and complete remission (CR) Consolidation/Maintenance: Provide further control of myeloma and improve progression free survival and eventually overall survival

7 Induction Regimens Two new classes of drugs are being used in the management of multiple myeloma patients: Proteasome inhibitors Immune modulatory drugs. The choice of initial induction therapy can be influenced by the underlying medical conditions of the patients and their prognostic features.

8 ECOG E4A03: Lenalidomide + Low- or High-Dose Dexamethasone Newly Diagnosed Multiple Myeloma N = 445 Lenalidomide High-Dose Dexamethasone 1:1 (RD) Lenalidomide Low-Dose Dexamethasone (Rd) CR PR < PR Thal Dex Primary Endpoint Response at 4 months SCT or Continue Off Study 1:1 CR PR SD Lenalidomide: 25 mg daily, days 1-21 of a 28-day cycle High-Dose Dex: 40 mg, d1-4, 9-12, (total 480 mg) Low-Dose Dex: 40 mg, d1, 8, 15, 22 (total 160 mg) Rajkumar SV, et al. Lancet Oncology 2009

9 ECOG E4A03: Lenalidomide + Low- or High-Dose Dexamethasone Response Lenalidomide High-Dose Dex N = 223 Lenalidomide Low-Dose Dex N = 222 PR within 4 cycles 79% 68% VGPR within 4 cycles 42% 24% < Toxicity Any grade > 3 non-heme toxicity 53% 31% < Early deaths (< 4 months) 5% 0.5% P Rajkumar SV, et al. Lancet Oncology 2009

10 Lenalidomide + Low- or High-Dose Dex ECOG E4A03: Overall Survival Lenalidomide High-Dose Dex N = 223 Lenalidomide Low-Dose Dex N = 222 P 1-year OS 85% 95% year OS 78% 88% year OS 74% 75% NS Rajkumar SV, et al. Lancet Oncology 2009

11 ECOG E4A03: Landmark Analysis 431 Patients Alive at 4 Cycles Off 4 Cycles N = 183 Primary Therapy Beyond 4 Cycles N = 248 No Transplant N = 93 (Median Age 68) Transplant N = 90 (Median Age 57) Rd N = 140 (Median Age 66) RD N = 108 (Median Age 65) Median Follow Up: 36 Months

12 ECOG E4A03: Overall Survival Patients Surviving (%) Patients Surviving (%) SCT After 4 Therapy Cycles 3-yr OS: 92% P = NS P = NS Time (months) Rd Continued Primary Therapy (Beyond 4 Cycles) RD 3-yr OS: 79% P = NS Time (months) Unplanned analysis, includes unbalanced arms

13 IMIDs Combination RD CRD CyBorD n >ncr (%) P<0.001 VGPR (%) P=0.003 PFS (years) (%) P= years OS (%) P=0.23 BJH Volume 156, Issue 3, pages , February 2012

14 Bortezomib based regimen prior to Auto Transplant Author Induction Regimen Harousseau et al VD Post transplant Therapy 1 or 2 (lenalidomide maintenance in some) Cavo et al VTD 2 + VTD consolidation + dex maintenance Sonneveld et al PAD 1 or 2 + Vmaintenance Rosinol et al VTD 1 + VT maintenance

15 Bortezomib based regimen prior to Auto Transplant Author VGPR CR/nCR Median PFS Harousseau 68% 39% 36 mos Cavo 89% 71% NYR 68% (3-yr) Sonneveld 76% 49% 35 mos Rosinol N/A 46% 56.2 mos

16 Regimen N with ASCT Post-Induction Response Rates >PR VDD 20 93% VRD 31 94% RVDD 24 96%* VTD 48 96% VTDC % CyBorD 83 97% CVDD 30 89%/100 (stand/ high risk) RVD + vorinostat % CRd 7 100%** CTD 39 91%*

17 THE VRD Phase 2 study of 64 patients All patients achieving at least a partial response after a median of 10 cycles 74% of patients with VGPR and 37% with CR The estimated PFS with or without ASCT at 18 months was 75% Richardson. Blood 2009;114(22):

18 The CyBorD n Intent to treat 33 Post 4 cycles 28 Post transpant 23 CR/nCR 39% 46% 70% VGPR 61% 71% 74% ORR 88% Reeder. Leukemia 2009;23(7):

19 The VDCR Quadriplet Randomized study comparing 2 three drugs regimen versus four drugs regimen Modifications was made to the VDCR to increase cyclophosphamide from 2 days a month to three days a month Kumar. Blood May 10, 2012 vol. 119 no

20 Patient disposition. Kumar S et al. Blood 2012;119: by American Society of Hematology

21 The VDCR VDC VDR VDCR VDCR-mod Number > VGPR 58% 51% 41% 53% CR 25% 24% 22% 47% 1-year PFS 86% 83% 93% 100%

22 Kaplan-Meier analyses of treatment outcomes. Kumar S et al. Blood 2012;119: by American Society of Hematology

23 The VTDC: 4 not much better than 3 VTD VTDC Post Induction (%) ORR CR CR+nCR Post Transplant (%) CR+nCR Negative MDR Ludwig H et al. JCO 2013;31:

24 The VTDC: 4 more toxic VTD VTDC Overall survival 80% 80% Grade 3-4 Toxicity 47% 57% SAE 22% 41%

25 Change in Global Health status over time. Ludwig H et al. JCO 2013;31: by American Society of Clinical Oncology

26 vtd versus VD VD vtd Post Induction (%) CR CR+VGPR Post Transplant (%) CR CR+VGPR 58 74

27 Progression-free survival. Moreau P et al. Blood 2011;118: by American Society of Hematology

28 Total Therapy Three Induction: 2 cycles VTD-PACE Transplant: Mel 200 x 2 Consolidation: 2 cycles VTD-PACE Maintnenance: Year one: VTD Year 2-3 TD 330 patients in phase 2. Barlogie BJH, 138, 16-85, 2007

29 Total Therapy Three At 24 months: 83% ncr sustained at 2 years in 88%. 2-year EFS 84% and OS 86%. Treatment related mortality was 5% Thrombo-embolic events 27% PN was 12% Barlogie BJH, 138, 16-85, 2007

30 Stringent complete response (scr) in patients with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) AJ Jakubowiak, 1 K Griffith, 2 D Dytfeld, 3 DH Vesole, 4 S Jagannath, 5 T Anderson, 2 B Nordgren, 2 K Detweiler-Short, 2 D Lebovic, 2 K Stockerl-Goldstein, 6 T Jobkar, 2 S Wear, 7 A Al-Zoubi, 2 A Ahmed, 2 M Mietzel, 2 D Couriel, 2 M Kaminski, 2 M Hussein, 8 H Yeganegi, 9 R Vij 6 1 University of Chicago, Chicago, IL; 2 University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; 3 Poznan University of Medical Sciences, Poznan, Poland; 4 John Theurer Cancer Center, Hackensack, NJ; 5 Mount Sinai Medical Center, New York, NY; 6 Washington University School of Medicine, St. Louis, MO; 7 Multiple Myeloma Research Consortium, Norwalk, CT; 8 Celgene, Inc, Summit, NJ; 9 Onyx Pharmaceuticals, South San Francisco, CA

31 Treatment Schema Transplanteligible and - -ineligible patients CRd Induction CRd Cycles 1 4 CRd Cycles 5 8 Transplant-eligible PR ASCT Stem cell collection CRd Maintenance CRd Cycles 9 24 Lenalidomide (off protocol) LEN Cycles 25+ Until disease progression or unacceptable toxicity Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with ncr Cycles 1 8 CFZ Days 1 2, 8 9, at assigned doses 1 LEN 25 mg Days 1 21 DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5 8 Cycles 9 24 CFZ on Days 1 2 and only CFZ, LEN, DEX at last best tolerated doses After Cycle 4, pts could undergo stem cell collection and then continue CRd with the option to proceed to ASCT 1. Jakubowiak AJ, et al. Blood. 2011;118: abstract

32 Patient Characteristics Characteristics (N=53) Median age, years (range) 59 (35 81) 65 years, n (%) 23 (43) Male, n (%) 39 (74) ISS stage II/III, n (%) 32 (60) Durie-Salmon stage II/III, n (%) 46 (87) Unfavorable cytogenetics*, n (%) 17/51 (33) del 13 /hypodiploidy t(4;14) t(14;16) del 17p 10/50 5/49 0/48 7/48 (20) (10) (0) (15) * 1 or more of the abnormalities listed; available for 51 of 53 patients del 13 by metaphase only 32

33 Response (%) Responses after Extended Treatment 100 ncr scr Overall n=53 Median 12 cycles (range 1 25) 4+ Cycles n=49 Median 13 cycles (range 4 25) 8+ Cycles n=36 Median 16 cycles (range 8 25) 33

34 Are We Closed to the R-CHOP Regimen? Only 40-60% achieved true CR even with total therapy III. R-Chop results in improved EFS/OS only in large cell lymphoma. Multiple Myeloma is extremely heterogeneous even more than lymphoma. Lack of complete response does not mean inferior outcome in myeloma.

35 Is Complete Response the Goal? Barologie failed to show that CR in standard risk patients fared better than those with lesser response. Even in the high risk group the benefit was marginal. CR may be a prognostic factor as may select for biologically better subset. Comparing CR to no CR group may not account for early death that can be as high as 8% making land mark analysis inherently bias.

36 Why single drug may not eradicate MM? B Cell PAX 5 Activated B Cell CD30 Plasmalymphocyte ERAD lo CD 20 CD 27 PA X5l o XBP1s- ERAD lo CD 20 CD 27 PA X5l o XBP1s- ERAD mo IL6R y CD 27 y y y CD 38 XBP1s+ ERAD h i IL6R Plasmablast CD 138 y y y y y y CD 38 XBP1s+ ERAD hi IL6R y y Plasma Cell y CD 138

37 So what to do? Multiple myeloma is extremely heterogeneous disease. Better classification to predict the biology of the disease is needed. Combination therapy is promising with early results showing unprecedented responses. Including newer classes of drug may help overcome resistance.