MULTIPLE MYELOMA TRANSPLANT: ROBERT ORLOWSKI
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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
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Chemotherapy vs. Transplant
• Not all randomized studies, however, have shown a benefit
San-Miguel, JF & Mateos, M-V. Hematology 2009, ASH Education Book.
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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.
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Overall Survival Impact
• Survival benefit is less impressive in this meta-analysis
Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.
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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.
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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.
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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.
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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
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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)
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Consort Chart
Fermand, JP et al. Blood 92: 3131, 1998.
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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%
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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
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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.
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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.
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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.
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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”
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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.
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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%
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With Longer Follow-up
Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
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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
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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
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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)
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Outcomes in Younger Patients (<65)
Progression Free Survival Overall Survival
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Outcomes in Older Patients (≥70)
Progression Free Survival Overall Survival
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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
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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)
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IFM/DFCI 2009 Study
RVDx3
RVD x 2
RVD x 5
Lenalidomide 18 mos
Melphalan 200mg/m2 + ASCT
Induction
Consolidation
Maintenance
CY (3 g/m2) MOBILIZATION
Goal: 5 x 106 cells/kg
RVDx3
CY (3 g/m2) MOBILIZATION
Goal: 5 x 106 cells/kg
Randomize
Collection
Lenalidomide 18 mos SCT at relapse
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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.
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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.
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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.
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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.
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Role of CR in Total Therapy 3
Barlogie, B et al. Br J Haematol. 138: 176, 2007.
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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
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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 2m, SCr, ISS stage
Wang, M et al. Bone Marrow Transpl. 45: 498, 2010.
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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.
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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
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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