1. Timing of Transplant for Multiple Myeloma Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Professor, Departments of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator, M. D. Anderson SPORE in Multiple Myeloma Chair, Southwest Oncology Group Myeloma Committee

2. Chemotherapy vs. Transplant Not all randomized studies, however, have shown a benefit San-Miguel, JF & Mateos, M-V. Hematology 2009, ASH Education Book.

3. Autologous SCT vs. CCT Progression- free survival is improved by autologous stem-cell transplantation vs. conventional chemotherapy Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.

4. Overall Survival Impact Survival benefit is less impressive in this meta- analysis Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.

5. Single or Double ASCT ? Double autologous stem cell transplantation provides advantages over single transplantation Attal, M et al. N Engl J Med. 349: 2495, 2003.

6. Subgroup Benefits Benefits were especially notable in patients who did not achieve a CR or VGPR after their first autologous stem cell transplant Attal, M et al. N Engl J Med. 349: 2495, 2003.

7. Consolidation Therapy Post-transplant consolidation with 4 cycles of VTD CR 15%  49% Molecular CR 3%  18% Tumor burden reduced 4.14 logs Ladetto, M et al. J Clin Oncol. 28: 2077, 2010.

8. Lenalidomide Maintenance : CALGB 100104 McCarthy, P et al. N Engl J Med. 366:1770, 2012. TTP 46 mos. with len vs. 27 mos. for placebo 35 deaths on len arm vs. 53 on placebo arm

9. Early vs. Salvage Transplant Fermand, JP et al. Blood 92: 3131, 1998. Successful PBSC collection (N = 185) Early HDT 1 Induction VAMP x 3-4 cycles Preparatory lomustine, VP-16, cyclophosphamide, melphalan at 140 mg/m 2 + TBI Then auto-PBSCT (n = 91) Late HDT 1 Monthly VMCP For patients ≥PR continue to plateau Transplant as per above if progression, resistance after 6 cycles, or in relapse (n = 94) Untreated, symptomatic patients < 56 (N = 202)

10. Consort Chart Fermand, JP et al. Blood 92: 3131, 1998.

11. Overall Survival Fermand, JP et al. Blood 92: 3131, 1998. No difference in overall survival at median follow-up of 58 months 80% 78% 73% 71% 66% 61%

12. Quality of Life Fermand, JP et al. Blood 92: 3131, 1998. Longer time without symptoms, treatment, and treatment toxicity (TwiSTT) –27.8 months for early HDT, vs. 22.3 months for salvage HDT

13. Data After Longer Follow-up Comparable OS (A; 47.8 vs. 47.6 mos.) and EFS (B; 25.3 vs. 18.7 mos.) with median follow-up of 120 months Fermand, J-P et al. J Clin Oncol. 23: 9227, 2005.

14. Improved Quality of Life Maintained longer time without symptoms, treatment, and treatment toxicity (TwiSTT) Fermand, J-P et al. J Clin Oncol. 23: 9227, 2005.

15. Early Harvest and Late Transplant Stem cells collected within 6 mos. of diagnosis Received VAD Transplant at progression –Median 38 mos. Gertz, MA et al. Bone Marrow Transplant. 23: 221, 1999.

16. Concluded Late Transplant Feasible Median survival 58.5 months Gertz, MA et al. Bone Marrow Transplant. 23: 221, 1999. “Underlying biology of the disease has a greater impact on survival than the timing of transplant”

17. E4A03 Study Design REGISTRATIONREGISTRATION Lenalidomide 25 mg po days 1-21 + High dose Dex 40 mg days 1-4, 9-12, 17-20 x 4 cycles CR/PR/ Stable Less than PR SCT possible as early as 4 months Thal/dex x 4 cycles Lenalidomide 25 mg po days 1-21 + Low dose Dex 40 mg days 1, 8, 15, 22 x 4 cycles 445 patients Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

18. RD vs. Rd Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010. More is not necessarily better in the novel agent era Stopped early; recommendation of IDMC; median follow-up of 12.5 months 96% 87% 75%

19. With Longer Follow-up Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

20. Landmark Analysis Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010. 90 patients went off LD or Ld after 4 cycles for SCT OS 92% at 3 years 248 patients continued on therapy past the initial 4 cycles 79% 3-year overall survival PFS at 3 years 46% for RD vs. 50% for Rd Off after 4 No SCT Off after 4 + SCT Continued past 4 cycles

21. 2010 ASH Abstract 38 Outcome with Lenalidomide Plus Dexamethasone Followed by Early Autologous Stem Cell Transplantation In the ECOG E4A03 Randomized Clinical Trial David Samuel diCapua Siegel, Susanna Jacobus, S. Vincent Rajkumar, Rafat Abonour, Natalie Scott Callander, Michael S Katz, Rafael Fonseca, David H. Vesole, and On behalf of the Eastern Cooperative Oncology Group

22. Landmark Analysis 431 patients alive at 4 cycles Off therapy at 4 cycles n=183 Primary therapy beyond 4 cycles n=248 no transplant N=93 (median age 68) Transplant n=90 (median age 57) Ld n=140 (median age 66) LD n=108 (median age 65)

23. Outcomes in Younger Patients (<65) Progression Free SurvivalOverall Survival

24. Outcomes in Older Patients (≥70) Progression Free SurvivalOverall Survival

25. Case Control Study Kumar, SK et al. Cancer 118: 1585, 2012. 290 patients treated with an IMiD-based induction regimen prior to transplant 123 got TD, 167 got LD Late transplant: occurred after 12 months 42 had gotten SCT; median 44.5 mos. Early transplant: within 2 months of harvest, 12 months of diagnosis Median 5.3 mos. to SCT

26. Outcomes Kumar, SK et al. Cancer 118: 1585, 2012. Four year overall survival was identical in the two groups (73%) TD 68% vs. 64% LD 82% vs. 86% Time to progression after transplant similar 20 mos. (early) vs. 16 mos. (late)

27. IFM/DFCI 2009 Study RVDx3 RVD x 2 RVD x 5 Lenalidomide 18 mos Melphalan 200mg/m 2 + ASCT Induction Consolidation Maintenance CY (3 g/m 2 ) MOBILIZATION Goal: 5 x 10 6 cells/kg RVDx3 CY (3 g/m 2 ) MOBILIZATION Goal: 5 x 10 6 cells/kg Randomize Collection Lenalidomide 18 mos SCT at relapse

28. Is Achieving CR the Key ? GEM2000 trial –1,075 pts enrolled –632 response- assessable Uniform induction –VBMCP followed by VBAD Lahuerta, JJ et al. J Clin Oncol. 26: 5775, 2008.

29. Value of CR Post-transplant After induction, patients went on to single or tandem high dose chemotherapy with autologous stem cell rescue Lahuerta, JJ et al. J Clin Oncol. 26: 5775, 2008.

30. Value of CR in IFM Studies IFM 99-02 and 99-04 trials –VAD, then tandem ASCT Best post-ASCT data available for 802 pts Harousseau, J-L et al. J Clin Oncol. 27: 5720, 2009.

31. Value of CR in Asia Korean Multiple Myeloma Working Party study of 197 chemosensitive patients who received a single SCT CR prior to transplant (upper panel) and after transplant (lower panel) predicted a better outcome Kim, JS et al. Biol Blood Marrow Transplant. 15: 463, 2009.

32. Role of CR in Total Therapy 3 Barlogie, B et al. Br J Haematol. 138: 176, 2007.

33. Achieving and Maintaining CR Barlogie, B et al. Cancer 113: 355, 2008. Sustaining CR within a 3-year landmark from treatment initiation was associated with a highly superior survival (P <0.0001) Achieving and losing CR worse than no CR

34. M. D. Anderson Data Retrospective analysis of 758 patients with newly-diagnosed myeloma Received dex-based induction -/+ high-dose therapy (+ in 395) within 1 year Groups were comparable in  2 m, SCr, ISS stage Wang, M et al. Bone Marrow Transpl. 45: 498, 2010.

35. SCT in CR High dose therapy did not improve outcomes for patients already in CR Wang, M et al. Bone Marrow Transpl. 45: 498, 2010.

36. Other Considerations Access to novel agents –SCT may best achieve cytoreduction/CR if novel agent access is limited Cost of chemotherapy vs. transplant –SCT is a cost-effective way to achieve rapid cytoreduction vs. long-term novel drugs –Allows novel agents to be reserved for the time of relapse, thereby saving healthcare resources

37. Conclusions Randomized trials are needed in the novel agent era comparing the effectiveness of early vs. delayed transplant Available (albeit limited) data do not suggest that patient outcomes are compromised by reserving transplant until first relapse Possibility remains that relapse after novel agent induction/consolidation/maintenance may be less sensitive to melphalan-based approaches