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 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. 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
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. 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. 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 Survival Overall Survival

24. Outcomes in Older Patients ( 70)≥
Progression Free Survival Overall 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/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. 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 β2m, 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