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
Chemotherapy vs. Transplant
• Not all randomized studies, however, have
shown a benefit
San-Miguel, JF & Mateos, M-V. Hematology 2009, ASH Education Book.
Autologous SCT vs. CCT
• Progressionfree survival is
improved by
autologous
stem-cell
transplantation
vs. conventional
chemotherapy
Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.
Overall Survival Impact
• Survival
benefit is less
impressive in
this metaanalysis
Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.
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.
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.
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.
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.
Early vs. Salvage Transplant
Untreated,
symptomatic
patients < 56
(N = 202)
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)
Fermand, JP et al. Blood 92: 3131, 1998.
Consort Chart
Fermand, JP et al. Blood 92: 3131, 1998.
Overall Survival
80%
73%
66%
78%
71%
61%
• No difference
in overall
survival at
median
follow-up of
58 months
Fermand, JP et al. Blood 92: 3131, 1998.
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.
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
• “Underlying
biology of the
disease has a
greater impact
on survival
than the timing
of transplant”
Gertz, MA et al. Bone Marrow Transplant. 23: 221, 1999.
E4A03 Study Design
Lenalidomide
R
E
G
I
S
T
R
A
T
I
O
N
25 mg po days 1-21
+ High dose Dex
40 mg days 1-4, 9-12, 17-20
x 4 cycles
CR/PR/
Stable
SCT possible
as early
as 4 months
Less than
PR
Thal/dex
x 4 cycles
445 patients
Lenalidomide
25 mg po days 1-21
+ Low dose Dex
40 mg days 1, 8, 15, 22
x 4 cycles
Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
RD vs. Rd
96%
87%
Stopped early;
recommendation
of IDMC;
median follow-up
of 12.5 months
87%
• More is
not
necessarily
75%
better in
the novel
agent era
Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
With Longer Follow-up
Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
Off after 4
No SCT
Landmark Analysis
• 90 patients went off LD or Ld
after 4 cycles for SCT
• OS 92% at 3 years
Off after 4
+ SCT
• 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
Continued past
4 cycles
Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.
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
no transplant
N=93
(median age 68)
Transplant
n=90
(median age 57)
Primary therapy
beyond 4 cycles
n=248
Ld
n=140
(median age 66)
LD
n=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
• 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.
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.
IFM/DFCI 2009 Study
Randomize
RVDx3
Induction
RVDx3
Collection
CY (3 g/m2) MOBILIZATION
Goal: 5 x 106 cells/kg
Melphalan 200mg/m2 +
ASCT
Consolidation
RVD x 5
RVD x 2
Maintenance
Lenalidomide 18 mos
CY (3 g/m2) MOBILIZATION
Goal: 5 x 106 cells/kg
Lenalidomide 18 mos
SCT at relapse
Is Achieving CR the Key ?
• GEM2000 trial
– 1,075 pts enrolled
– 632 responseassessable
• Uniform induction
– VBMCP followed by
VBAD
Lahuerta, JJ et al. J Clin Oncol. 26: 5775, 2008.
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.
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.
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.
Role of CR in Total Therapy 3
Barlogie, B et al. Br J Haematol. 138: 176, 2007.
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.
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.
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.
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
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