1. Induction Therapies in Transplant Eligible Patients Tomer M. Mark Department of Medicine, Division of Hematology / Oncology Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA

2. Disclosures CompanyRole(s): CelgeneSpeakers Bureau, Research Funding, Advisory Board MillenniumSpeakers Bureau, Advisory Board OnyxSpeakers Bureau, Research Funding

3. Treatment Paradigm for MM Induction Transplant eligible? Comorbidities? Lifestyle / Social Factors? How long to treat? Transplant Delayed vs. upfront? One or two? Maintenance Necessary? Which agent(s)?

4. What induction therapy should be used? What is More Important? – Predicted response to induction – Patient factors Comorbidities Age Degree of symptoms due to MM

5. EFS p =.0007 p = 7 x 10 -5 IFM99 Double ASCTIFM90 CR + VGPR: 440 022446688 0 25 50 75 100 ≥ 90% (n = 51) ≥ 50% (n = 81) < 50% (n = 46) 02501,5007501,0001,2505001,7502,0002,250 0.00 Survival Distribution Function (%) 1.00 0.75 0.50 0.25 PR: 290 OS CR + VGPR: 440 0 2501,5007501,0001,2505001,7502,0002,250 0.00 Survival Distribution Function (%) 1.00 0.75 0.50 0.25 PR: 290 Deeper Responses are Better: Impact of CR + VGPR on Outcome EFS = event-free survival. Moreau et al, 2008; Attal et al, 1996, 2006. p = 7 x 10 -5

6. Impact of CR From PETHEMA Group Martinez-Lopez et al, 2011.

7. Importance of Immunophenotypic Remission Paiva, B. et al. J Clin Oncol; 29:1627-1633 2011

8. Does Consolidation With ASCT Improve Outcomes?

9. Significance of Depth of Response Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

10. Significance of Continued Response to HDT “ Upgraders ” do better Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008 Improvement for PR to nCR or CR post transplant increases OS

11. Impact of Response To Induction Therapy Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

12. Initial Response to Induction Conventional Chemotherapy does not Impact Transplant benefit Singhal et al, 2002. Survival post C-VAMP induction ASCT had no correlation with C-VAMP response. Kumar et al, 2004. 50 patients with primary refractory MM (mostly VAD) compared to 100 with chemosensitive disease pre-ASCT. 20% vs. 35% CR post transplant ( P = 0.06). 1-year PFS 70% vs. 83% ( P=0.65). Alexanian et al, 1995. MM resistant to VAD or high-dose dex quadrupled OS compared to matched controls.

13. Initial Response to Induction Chemotherapy does not Impact Transplant benefit Important factors on MV analysis: PCLI >1, CR, abnormal cytogenetics, serum M-protein, circulating PC at harvest. Kumar et al. Bone Marrow Transplantation. 2004. 34: 161-167.

14. Initial Response to Induction Chemotherapy does not Impact Transplant benefit Is this still true in the era of novel agents?

15. Impact of Response Failure To Induction with IMiDs N = 286 PFS from Day 0 of transplantation Plateau (232), Refractory (29), Relapse (25) Thal/Dex (189), Len/Dex (97) Medians: 22.1 m (plateau), 15.1 (refractory), 12.0 (relapse) on induction therapy Gertz, M. A. et al. Blood 2010;115:2348-2353

16. Impact of Response Failure To Induction with IMiDs Overall survival from Day 0 of transplant Med OS 73.5 (plateau), 32.7 (refractory), 23.8m (relapse on tx) Gertz, M. A. et al. Blood 2010;115:2348-2353

17. Factors that impact transplant success with IMiD induction VariableUnivariable PMultivariable P Plateau vs. relapse- refractory < 0.0010.04 Albumin0.58 Sex0.78 B2 Microglobulin0.0160.30 Bone marrow plasma cells<0.0010.33 Age0.92 Abnormal Cytogenetics<0.0010.02 CTX mobilization0.0360.30 Labeling Index<0.001 Gertz, M. A. et al. Blood 2010;115:2348-2353

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

19. The Ideal Induction Regimen Deep response Quick response (?) – May not be necessary for asymptomatic MM Tolerable CyBorD vs. VRD vs. BiRD CRD – molecular remissions

20. More is not always better: VTD vs. CVTD Ludwig H et al. JCO 2013;31:247-255

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

22. CyBORD 3 N=35 BCD + BDT 4 N=65 BiRD 1 N=72 VRD 2 N=65 CR 392838.926 nCR NA1813.918 VGPR 223020.830 PR 27NA16.725 MR 1NA5.6NA Refractory 1NA00 Overall 8810090.3100 1.Niesvizky et al Blood, 111, 1101-1109; 2008. 2.Richardson et al. ASH 2008, Abstract 92 6176 73 74 3. Reeder et al, Leukemia 2009, 23:1337-41 4. Bensinger et al. ASH 2008, Abstract 94 Popular Induction Regimens

23. Responses Deepen With Length of Therapy CR/VGPR PR Number of responders 20 40 60 80 100 MM-009/MM-010 Phase III 46% of CR/VGPR achievers started with a PR and achieved a CR/VGPR with further treatment cycles Mayo Phase II BiRd Phase II C1C2C3C4C5C6C7C8C9C11C13C15C17C19C21C23C25

24. Richardson, P. G. et al. Blood 2007;110:3557-3560 Responses continue to deepen as more therapy is given Long term APEX data

25. CyBORD 3 N=35 BCD + BDT 4 N=65 BiRD 1 N=72 VRD 2 N=65 CRD 5 N = 53 CRD 6 N = 45 CCyTd7 N = 64 CR 392838.92642519 nCR NA1813.9182016NA VGPR 223020.830192157 PR 27NA16.72517924 MR 1NA5.6NA0 ≥VGPR 61767374818863 Overall 8810090.310098 91 1.Niesvizky et al Blood, 111, 1101-1109; 2008. 2.Richardson et al. ASH 2008, Abstract 92 3. Reeder et al, Leukemia 2009, 23:1337-41 4. Bensinger et al. ASH 2008, Abstract 94 Popular Induction Regimens vs. Carfil Combos 5. Jakubowiak et al Blood 120, 1801-1809; 2012 6.Korde et al ASH 2013, Abstract 538. 7.Mikhael et al ASK 2013, Abstract 3179

26. MRD with Carilfzomib Induction Combination Jakubowiak: 23/26 patients in nCR/CR were MRD negative – Patients with sCR and MRD negative: 3 yr OS 100%, PFS 89% Korde/Landgren: 27/27 pts in nCR/CR were MRD negative – Overall 18-month PFS: 91% Paiva, B. et al. J Clin Oncol; 29:1627-1633 2011

27. What is More Important? – Choice of Agent for Induction 3 drugs in combination appear effective Carfilzomib may enhance initial response rates, yet: – We don’t know whether the use of transplant abrogates initial differences in response – We don’t know long-term use consequences – We don’t know implications for subsequent therapies (ie PFS2) – Response attained in Induction MRD will likely trump all What induction therapy should be used?

28. Conclusions Combinations of novel agents lead to deeper responses pre-transplant Deeper responses pre-transplant tend to translate to better responses post transplant – ASCT is supplementary to induction, not a substitute. – ASCT is a tool to achieve high CR and prolonged PFS Lack of difference in OS is a reflection on efficacy of salvage tx. Lack of difference in responses over time indicate that many good induction therapies exist and the choice should be tailored to the patient. Further study of MRD is needed to correlate initial responses with utility or predicted benefit of stem cell transplant.