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Timing of Transplant for Multiple Myeloma

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.

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Timing of Transplant for Multiple Myeloma

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

  9. Early vs. Salvage Transplant Early HDT1 Induction VAMP x 3-4 cycles Preparatory lomustine, VP-16, cyclophosphamide, melphalan at 140 mg/m2 + TBI Then auto-PBSCT (n = 91) Untreated, symptomatic patients < 56 (N = 202) Successful PBSC collection (N = 185) Late HDT1 Monthly VMCP For patients ≥PR continue to plateau Transplant as per above if progression, resistance after 6 cycles, or in relapse (n = 94) Fermand, JP et al. Blood 92: 3131, 1998.

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

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

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

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

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

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

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

  20. Landmark Analysis Off after 4 No SCT • 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 + SCT Continued past 4 cycles Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

  21. 2010 ASH Abstract 38Outcome with Lenalidomide Plus Dexamethasone Followed by Early Autologous Stem Cell Transplantation In the ECOG E4A03 Randomized Clinical TrialDavid 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. 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) Landmark Analysis

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

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

  25. Case Control Study • 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 Kumar, SK et al. Cancer 118: 1585, 2012.

  26. Outcomes • 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) Kumar, SK et al. Cancer 118: 1585, 2012.

  27. IFM/DFCI 2009 Study Randomize RVDx3 Induction RVDx3 CY (3 g/m2) MOBILIZATION Goal: 5 x 106 cells/kg CY (3 g/m2) MOBILIZATION Goal: 5 x 106 cells/kg Collection Melphalan 200mg/m2 + ASCT Consolidation RVD x 5 Maintenance RVD x 2 Lenalidomide 18 mos SCT at relapse Lenalidomide 18 mos

  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 • 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 Barlogie, B et al. Cancer 113: 355, 2008.

  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 b2m, 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

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