Timing of Transplant for
Multiple Myeloma
Robert Z. Orlowski, Ph.D., M.D.
Director, Myeloma Section
Professor, Departments...
Chemotherapy vs. Transplant
• Not all randomized studies, however, have
shown a benefit
San-Miguel, JF & Mateos, M-V. Hema...
Autologous SCT vs. CCT
• Progression-
free survival is
improved by
autologous
stem-cell
transplantation
vs. conventional
c...
Overall Survival Impact
• Survival
benefit is less
impressive in
this meta-
analysis
Koreth, J et al. Biol Blood Marrow Tr...
Single or Double ASCT ?
• Double autologous
stem cell
transplantation
provides
advantages over
single
transplantation
Atta...
Subgroup Benefits
• Benefits were
especially notable in
patients who did not
achieve a CR or
VGPR after their
first autolo...
Consolidation Therapy
• Post-transplant
consolidation with 4 cycles
of VTD
• CR 15%  49%
• Molecular CR 3%  18%
• Tumor ...
Lenalidomide Maintenance : CALGB 100104
McCarthy, P et al. N Engl J Med. 366:1770, 2012.
• TTP 46 mos. with len vs. 27 mos...
Early vs. Salvage Transplant
Fermand, JP et al. Blood 92: 3131, 1998.
Successful
PBSC
collection
(N = 185)
Early HDT1
Indu...
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 mo...
Quality of Life
Fermand, JP et al. Blood 92: 3131, 1998.
• Longer time without
symptoms, treatment,
and treatment toxicity...
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 ...
Improved Quality of Life
• Maintained longer time without symptoms,
treatment, and treatment toxicity (TwiSTT)
Fermand, J-...
Early Harvest and Late Transplant
• Stem cells collected within 6 mos. of
diagnosis
• Received VAD
• Transplant at
progres...
Concluded Late Transplant Feasible
• Median survival 58.5 months
Gertz, MA et al. Bone Marrow Transplant. 23: 221, 1999.
•...
E4A03 Study Design
R
E
G
I
S
T
R
A
T
I
O
N
Lenalidomide
25 mg po days 1-21
+ High dose Dex
40 mg days 1-4, 9-12, 17-20
x 4...
RD vs. Rd
Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
• More is
not
necessarily
better in
the novel
agent era
Stopped ...
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
•...
2010 ASH Abstract 38
Outcome with Lenalidomide Plus Dexamethasone
Followed by Early Autologous Stem Cell
Transplantation I...
Landmark Analysis
431 patients alive
at 4 cycles
Off therapy
at 4 cycles
n=183
Primary therapy
beyond 4 cycles
n=248
no tr...
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 pr...
Outcomes
Kumar, SK et al. Cancer 118: 1585, 2012.
• Four year overall survival was identical in
the two groups (73%)
• TD ...
IFM/DFCI 2009 Study
RVDx3
RVD x 2
RVD x 5
Lenalidomide 18 mos
Melphalan 200mg/m2
+
ASCT
Induction
Consolidation
Maintenanc...
Is Achieving CR the Key ?
• GEM2000 trial
– 1,075 pts enrolled
– 632 response-
assessable
• Uniform induction
– VBMCP foll...
Value of CR Post-transplant
• After induction,
patients went on to
single or tandem
high dose
chemotherapy with
autologous...
Value of CR in IFM Studies
• IFM 99-02 and
99-04 trials
– VAD, then
tandem ASCT
• Best post-ASCT
data available for
802 pt...
Value of CR in Asia
• Korean Multiple Myeloma
Working Party study of 197
chemosensitive patients who
received a single SCT...
Role of CR in Total Therapy 3
Barlogie, B et al. Br J Haematol. 138: 176, 2007.
Achieving and Maintaining CR
Barlogie, B et al. Cancer 113:
355, 2008.
• Sustaining CR within
a 3-year landmark
from treat...
M. D. Anderson Data
• Retrospective analysis of 758 patients with
newly-diagnosed myeloma
• Received dex-based induction -...
SCT in CR
• High dose
therapy did not
improve
outcomes for
patients already
in CR
Wang, M et al. Bone Marrow Transpl. 45:
...
Other Considerations
• Access to novel agents
– SCT may best achieve cytoreduction/CR if
novel agent access is limited
• C...
Conclusions
• Randomized trials are needed in the novel agent
era comparing the effectiveness of early vs.
delayed transpl...
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MULTIPLE MYELOMA TRANSPLANT: ROBERT ORLOWSKI

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MULTIPLE MYELOMA TRANSPLANT: ROBERT ORLOWSKI

  1. 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. 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. 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. 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. 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. 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. 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. 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. 9. 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 + TBI Then auto-PBSCT (n = 91) 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) Untreated, symptomatic patients < 56 (N = 202)
  10. 10. Consort Chart Fermand, JP et al. Blood 92: 3131, 1998.
  11. 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. 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. 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. 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. 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. 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. 17. E4A03 Study Design R E G I S T R A T I O N 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. 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% 87% 75%
  19. 19. With Longer Follow-up Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
  20. 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. 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. 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. 23. Outcomes in Younger Patients (<65) Progression Free Survival Overall Survival
  24. 24. Outcomes in Older Patients ( 70)≥ Progression Free Survival Overall Survival
  25. 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. 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. 27. 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
  28. 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. 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. 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. 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. 32. Role of CR in Total Therapy 3 Barlogie, B et al. Br J Haematol. 138: 176, 2007.
  33. 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. 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 β2m, SCr, ISS stage Wang, M et al. Bone Marrow Transpl. 45: 498, 2010.
  35. 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. 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. 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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