1. Debate: What is the best induction therapy for transplant-eligible patients? Sequential therapy. 1 Tomer M. Mark Department of Medicine, Division of Hematology / Oncology Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA Lymphoma & Myeloma 2013

2. Disclosures 2 Research Funding: Celgene Inc.; Onyx Inc. Speakers Bureau: Celgene Corp; Millenium Inc.; Onyx Inc. Membership on an entity's advisory committees: Celgene Corp., Millenium Inc. Off-label usage of bortezomib, lenalidomide, and carfilzomib are discussed.

3. How do we best treat a chronic malignancy? Cure versus control: improved survival is the goal Regimen tolerability Regimen cost Do we burn bridges by using combination therapy? Do patients benefit more from deeper response or longer duration of therapy? 3

4. Stewart et al, 2009. Not for debate: combination therapy gives deeper responses

5. What do we “know” ? Therapy has become better Survival now approaches a decade Although growing, therapy options are limited Myeloma is not curable More chemo is more toxic than less chemo Deeper response to therapy does not always translate into longer survival –We need to look at long-term follow up to see this. 5

6. How do you maximize a limited arsenal? 6 Lenalidomide Bortezomib Corticosteroids Alkylators Carfilzomib Thalidomide

7. Goals of induction: quick reversal of symptoms & obtain disease control to lead to extended survival 7 InductionConsolidationMaintenanceRelapseSalvage PFS OS Dx Death

8. Possible Treatment Scenarios: a) combination therapy adds to OS; salvage is just as effective 8 Combination Induction +/- ASCT MaintenanceSalvage 1Salvage 2Salvage 3 Sequential Induction +/- ASCT MaintenanceSalvage 1Salvage 2Salvage 3 PFS OS Dx Death

9. Possible Treatment Scenarios: b) combination therapy prolongs PFS but not OS due to less efficacious salvage 9 Combination Induction +/- ASCT MaintenanceSalvage 123 Sequential Induction +/- ASCT MaintenanceSalvage 1Salvage 2Salvage 3 PFS OS Dx Death

10. Which scenario fits the MM model better? Tumor Volume → Time → Ineffective treatment High-Dose Therapy Alkylators Dexamethasone Goal of newer therapy options Ultimate goal: Cure Limit of detection

11. Natural History of MM: Asymptomatic 20 50 100 Refractory Relapse MGUS* or Smoldering Myeloma Active Myeloma Plateau Remission Symptomatic Relapse Therapy ~60,000 ~20,000 New cases in U.S. 2 ~11,000 Annual deaths in U.S. 2 Prevalence in the U.S. M Protein (g/l) *Monoclonal gammopathy of uncertain significance Therapy

12. Response is not everything… In TT-2, OS not increased in thal arm, but CR frequency was higher 1 –SUS-CR at 3 yrs predicted increased OS –Achievement, then LOSS of CR predicted worse OS. –Loss of CR correlates with negative prognostic factors (high ISS, IgA) Benefit of CR may be limited to high-GEP risk group. 2 Pts with MGUS or SMM may not benefit from getting to CR. 3 12 1.Barlogie B. et al. Cancer. 2008.113;2:355-359 2.Haessler J. et al. Clin Cancer Res. 2007.13:7073-7079 3.Pineda-Roman M. et al. Br J Haematol. 2007.136:393-399.

13. Update of IFM 2005/01: Bortezomib/Dexamethasone (VD) vs. VAD Induction in Newly Diagnosed MM VAD: Vincristine 0.4 mg/m 2 + doxorubicin 9 mg/m 2 Days 1–4 continuous infusion; Dexamethasone 40 mg Days 1–4 (Cycles 1–4) and Days 9–12, 17–20 (Cycles 1–2) VD: Bortezomib 1.3 mg/m 2 Days 1, 4, 8, 11; Dexamethasone 40 mg Days 1–4 (Cycles 1–4) and Days 9–12 (Cycles 1–2) DCEP: Dexamethasone 40 mg Days 1–2; Cyclophosphamide 15 mg/m 2, etoposide 400 mg/m 2, and cisplatin 10 mg/m 2 Days 1–4 continuous infusion Untreated MM patients ≤ 65 years N = 482 VAD 28-day/cycle VD 21-day/cycle DCEP Two 28-day cycles Melphalan 200 mg/m 2 + ASCT a 4 cycles VD 21-day/cycle a Second ASCT or reduced-intensity conditioning allogeneic transplantation if < VGPR. DCEP = dexamethasone, cyclophosphamide, etoposide, cisplatin; IFM = Intergroupe Francophone du Myelome. Harousseau JL et al. J Clin Oncol. 2010. 28;30:4621-4629.

14. VD vs. VAD as Induction Therapy: Efficacy Harousseau JL et al. J Clin Oncol. 2010. 28;30:4621-4629.

15. CRs and PFS does not translate into OS! Median PFS: 29.7m VAD vs. 36m BD Median OS: NR. At 32m: 81% VAD vs. 83% BD alive Harousseau JL et al. J Clin Oncol. 2010. 28;30:4621-4629.

16. VTD vs. Thalidomide/Dexamethasone (TD) → Double ASCT in Newly Diagnosed MM Cavo M. et al. Lancet. 2010. 476: 2075-2085  Primary end point: CR/nCR after 3 cycles of induction ≤ 65 years N = 474 RANDOMIZERANDOMIZE Bort: 1.3 mg/m 2 Days 1, 4, 8, 11 Thal: 200 mg Days 1–63 Dex: 320 mg/cycle Thal: 200 mg Days 1–63 Dex: 320 mg/cycle PBSC collection cyclophosphamide Transplantation Mel200 x 2 Bort: 1.3 mg/m 2 Days 1, 8, 15, 22 Thal: 100 mg/day, Days 1–70 Dex: 320 mg/cycle Thal: 100 mg/day, Days 1–70 Dex: 320 mg/cycle VTDCONSOLIDATION TD 3 x 21-day cycles 2 x 35-day cycles

17. VTD vs. TD Induction → ASCT: Efficacy Cavo M. et al. Lancet. 2010. 476: 2075-2085

18. Thal-Dex vs. MP in elderly NDMM TD vs. MP in 268 pts ≥ 65 with NDMM Thal 200 daily, dex 40mg days 1-4 & 15-18 (odd cycles only) of 28-day cycles. Mel 0.25mg/kg and prednisolone 2mg/kg on days 1-4 of a 28-42 day cycle. 18 Ludwig H et al. Blood 2009;113:3435-3442

19. TD vs. MP 19 Ludwig H et al. Blood 2009;113:3435-3442

20. VTD vs. CVTD in NDMM 20 RANDOMIZERANDOMIZE Bort: 1.3 mg/m2 Days 1, 4, 8, 11 Thal: 100 mg Days 1–21 Dex: 40 mg Days 1-4, 9-12 Bort: 1.3 mg/m2 Days 1, 4, 8, 11 Thal: 100 mg Days 1–21 Dex: 40 mg Days 1-4, 9-12 CTX: 400mg/m2 IV on Days 1,8 PBSC collection Transplantation Mel200 x 1 or 2 VTD CVTD 4 x 21-day cycles Pts not eligible for ASCT or in CR post-induction received 4 more cycles, with Dex 20. Ludwig H et al. JCO 2013;31:247-255

21. VTD vs. CVTD 21 Ludwig H et al. JCO 2013;31:247-255

22. Ld vs. CRD vs. CyBorD: retrospective comparison of 3 phase 2 studies 22 RD N=34 CRD N=53 CyBorD N = 65 P- value CR+nCR351541< 0.0001 VGPR123226.0003 ORR948590.33 PFS3.2 yrs2.3 yrs2.7 yrs.11 OS – 3 yrs887988.23 Grade 4 Toxicity 6258.02 PN211559<0.0001 Khan M. et al. Br J of Haematol. 2011. 156:326-333.

23. No phase 3 studies for 2 vs. 3-drug lenalidomide combinations We are left to compare phase 2 + retrospective data 23

24. Phase 2: 2 vs. 3 drug regimens CyBORD 3 N=33 BiRD 1 N=72 VRD 2 N=66 Rd 4 N = 72 CR 3945.82913.9 nCR NA 11NA VGPR 2227.82719.4 PR 2716.73345.8 MR 15.6NA Refractory 1002.8 ORR 8890.310079.1 PFS NR48.3m75% at 18m 27.5m OS NR89.7 at 3yr97 at 18m 73 at 3yrs 1.Niesvizky et al. Blood. 2008. 111;3:1101-1109. 2.Richardson et al. Blood. 2010. 116;5:679-686. 61 73 74 3. Reeder et al. Leukemia. 2009. 23:1337-41 4. Gay et al. Am J Jematol. 2010. 85;9:669-669. 33.3

25. Possible Treatment Scenarios: b) combination therapy prolongs PFS but not OS due to less efficacious salvage 25 Combination Induction +/- ASCT MaintenanceSalvage 123 Sequential Induction +/- ASCT MaintenanceSalvage 1Salvage 2Salvage 3 PFS OS Dx Death

26. Conclusions 26 Combination Tx Sequential Tx Options Remain for Salvage Equivalent OS Longer treatment duration Higher tolerabilityLonger PFS Quicker Response Deeper Response There is no clear evidence that combination therapy improves OS compared to a sequential approach. There IS clear evidence that combination therapy is more toxic.

27. Thank you 27