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
Robert Z. Orlowski, Ph.D., M.D.Director, Myeloma Section
Professor, Departments of Lymphoma/Myeloma & Experimental TherapeuticsPrincipal Investigator, M. D. Anderson SPORE in Multiple Myeloma
Chair, Southwest Oncology Group Myeloma Committee
Chemotherapy vs. Transplant
• Not all randomized studies, however, have shown a benefit
• TTP 46 mos. with len vs. 27 mos. for placebo• 35 deaths on len arm vs. 53 on placebo arm
Early vs. Salvage Transplant
Fermand, JP et al. Blood 92: 3131, 1998.
Successful PBSC
collection(N = 185)
Early HDT1 Induction VAMP x 3-4 cycles
Preparatory lomustine, VP-16, cyclophosphamide, melphalan at 140
mg/m2 + TBIThen auto-PBSCT
(n = 91)
Late HDT1
Monthly VMCPFor 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)
Consort Chart
Fermand, JP et al. Blood 92: 3131, 1998.
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%
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
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.
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.
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.
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”
E4A03 Study Design
REGISTRATION
Lenalidomide25 mg po days 1-21
+ High dose Dex40 mg days 1-4, 9-12, 17-20
x 4 cyclesCR/PR/Stable
Less thanPR
SCT possibleas early
as 4 months
Thal/dexx 4 cycles
Lenalidomide25 mg po days 1-21
+ Low dose Dex40 mg days 1, 8, 15, 22
x 4 cycles
445 patients
Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
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%
87%
75%
With Longer Follow-up
Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
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 4No SCT
Off after 4+ SCT
Continued past4 cycles
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
Landmark Analysis
431 patients alive at 4 cycles
Off therapy at 4 cycles
n=183
Primary therapy beyond 4 cycles
n=248
no transplantN=93
(median age 68)
Transplant n=90
(median age 57)
Ldn=140
(median age 66)
LDn=108
(median age 65)
Outcomes in Younger Patients (<65)
Progression Free Survival Overall Survival
Outcomes in Older Patients (≥70)
Progression Free Survival Overall Survival
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
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)