2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Stem Cell Transplantation for Multiple
Myeloma: Who, When, and What Type?
Overview: Early randomized trials of high-dose chemotherapy
with autologous stem cell rescue showed improved
progression-free survival (PFS) over conventional chemotherapy.
However, in the era of novel agents for myeloma in
conjunction with the evolution of hematopoietic stem cell
transplantation, many new questions arise. First, how can
novel agents be incorporated into the transplant paradigm?
Given the efficacy of new induction regimens, should transplant
be delayed until relapse? Also, in the era of individualized
medicine, chronologic age alone should not drive
decisions regarding transplantation. Therefore, the feasibility
and role of transplantation in older patients with myeloma is
THE CONCEPT of dose-intensive chemotherapy to treat
a malignant disease is a paradigm that has been
explored for over a quarter century. A group from The Royal
Marsden Hospital 1 demonstrated that increased doses of
melphalan could induce responses in nine patients with
myeloma; however, this was at the cost of significant hematologic
toxicity with a median of 46 days of neutropenia. In
later trials with the use of autologous hematopoietic peripheral
blood stem cell support, this approach became safer.
Ultimately, a randomized trial by the Intergroupe Francophone
du Myelome (IFM) demonstrated the superiority of
high-dose chemotherapy in terms of both OS and diseasefree
survival over conventional chemotherapy. 2
The IFM trial is now more than a decade old, and in this
era of novel agents, many new questions remain unanswered.
For example, the original IFM trial included patients
65 years and younger. In this modern era, should
there be an age limit for myeloma transplant? Also, what is
the optimal induction regimen, and how many cycles of
therapy should be administered (i.e., when do you transplant
a patient)? Lastly, what is the best way to incorporate
novel agents into the post-transplant setting?
When to Transplant
It is common knowledge that the use of melphalancontaining
induction regimens should be avoided in patients
who could potentially undergo autologous transplantation. 3
In contrast, there is little consensus on the optimal nonmelphalan-containing
induction regimen. The summary by
S. Vincent Rajkumar, MD, will discuss in depth the choice of
an optimal induction regimen. In regard to the optimal
number of cycles before transplant, there remains no consensus.
There are numerous phase I and II clinical trials of
two-, three-, and even four-drug induction regimens. All
incorporate at least one novel agent and traditionally still
include a steroid backbone, although with an intent to be
more steroid-sparing by using lower doses of steroids. The
lenalidomide, bortezomib, and dexamethasone (RVD) regimen
was initially used in a phase I trial in the relapsed
setting and demonstrated good tolerability and high response
rates. 3 In the upfront setting, response rates are
extremely high (100%), as is depth of response (complete
remission [CR]/near CR [nCR] 40%). 4 In that initial trial,
patients had the option to proceed to transplant after four
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By Amrita Krishnan, MD
being studied. The controversy of transplant type (i.e., autologous
compared with reduced intensity allogeneic transplant)
remains unresolved. Several large international trials have
demonstrated conflicting results in regard to an overall survival
(OS) benefit with the allogeneic approach. The role of
allogeneic transplant remains under study especially in the
high-risk population, which has high relapse rates with traditional
autologous approaches. Future directions to reduce
relapse include post-transplantation consolidation and maintenance
therapy with either approved agents or new agents
and immunotherapy, either vaccine based or natural killer (NK)
and T-cell based.
cycles, and the response rate was reported after four cycles.
However, the investigators report 75% of patients had a
further upgrade of responses at six or eight cycles. It is
unknown whether this would ultimately affect posttransplant
PFS.
A new three-drug regimen that may soon gain traction is
the combination of the new proteasome inhibitor carfilzomib,
lenalidomide, and dexamethasone (CRD). 5 Preliminary
results showed very high response rates (100% �
partial response [PR]) in phase I and II trials, as well as the
highest depth of response seen outside a transplant setting
(79% CR/nCR). Twenty-four of 49 patients in this trial had
stem cells collected. However, too few patients have gone on
to transplant to be able to assess the effect of this induction
on post-transplant survival either with early or delayed
transplant.
Indirectly, one can extrapolate from phase III trials that
improved responses before transplant can mean further
improvements post-transplant, at least in terms of PFS.
There have been several large phase III trials in Europe
comparing traditional regimens to newer three-drug regimens
incorporating novel agents. For example, Cavo et al
compared bortezomib, thalidomide, and dexamethasone
(VTD) with thalidomide and dexamethasone (TD). 6 Both
arms received three courses of induction before transplant,
followed by two cycles of consolidation with VTD or TD. Not
surprisingly, the CR/nCR rate pretransplant was higher in
the VTD arm (31% vs. 11%; p � 0.0001 for TD). Posttransplant
this translated into an improved PFS at three
years (69% vs. 37%) but not an OS benefit. Though it
remains unknown whether this was due to induction or
consolidation or both.
In the MRCIX trial of CTD versus CVAD, the post-SCT
CR rate was 50% versus 37% in the CVAD arm. PFS was
greater in patients who received a CR post-transplant.
Further statistical modeling suggested that with longer
follow up this translated into a small PFS benefit.
From the City of Hope Cancer Center, Duarte, CA.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests Amrita Krishnan, MD, 1500 E. Duarte Road, Duarte, CA,
91010; email: akrishnan@coh.org.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10