2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TRANSPLANTATION FOR MYELOMA
compared with transplant delayed until first relapse, although
early transplant improved quality of life scores. 23
However, this was in the era predating novel agents. The
novel agents clearly have improved tolerability and efficacy
over the historic conventional agents. On the converse side,
it is also unknown whether we can effectively use high-dose
melphalan to salvage patients who relapse after initial
induction with the novel agents. Therefore, are patients
missing the optimal window to benefit from high-dose therapy
if they delay transplant?
The Mayo Clinic studied 290 patients with newly diagnosed
myeloma treated with an IMiD-based induction regimen.
Patients who underwent stem cell harvest and
transplant within 12 months of diagnosis were considered
early transplant, and those who underwent these procedures
more than 12 months after diagnosis were considered
delayed transplant. The overall response to transplant was
the same in the early and delayed transplant groups. The
time to progression after transplant also was not significantly
different between the early and delayed transplant
groups (20 months vs. 16 months). However, the retrospective
nature of the trial precludes accurate assessment of why
some patients opted for early rather than delayed transplant.
In addition, the patients in the delayed transplant
group primarily had transplant at first relapse, so it is
unknown whether comparable results for deferred transplant
would be seen after multiple relapses.
The current US-French Intergroup trial would be the most
relevant trial in the era of novel agents to answer the early
or delayed transplant question. However, it too cannot
address the question of the comparability of transplant after
multiple relapses. In this trial, patients with newly diagnosed
myeloma will receive one cycle of RVD and then be
randomly selected to receive either additional RVD followed
by stem cell apheresis and autologous transplant or further
RVD and stem cell collection and no transplant until relapse
(Fig. 2). This large trial will also look at important
surrogate and prognostic features, such as cytogenetics and
GEP.
What Is the Optimal Post-transplant Therapy?
Despite the increased response rates seen with autologous
transplant after induction therapy using novel agents, most
Fig. 2. Abbreviations: ASCT, autologous stem cell transplant; MEL,
melphalan; RVD, lenalidomide, bortezomib, and dexamethasone.
Fig. 3. Abbreviations: MM, multiple myeloma; SCT, stem cell transplantation;
RVD, lenalidomide, bortezomib, and dexamethasone;
ASCT, autologous stem cell transplant.
patients will ultimately relapse. Options to reduce or delay
post-transplant relapse include consolidation therapy and/or
maintenance therapy. This article will focus on consolidation
therapy.
Consolidation Therapy
This approach is akin to the leukemia therapy (i.e.,
further intensive chemotherapy after initial induction therapy).
However, in contrast to leukemia consolidation, there
is no standard in myeloma in regard to either the agents or
the number of cycles administered. Before the approval of
novel agents, one “consolidative approach” was in fact a
second transplant as part of a tandem transplant in patients
who failed to achieve a very good partial remission (VGPR)
or better. The Arkansas Total Therapy 3 approach uses
tandem transplant but with novel agents as consolidation:
VTD PACE; bortezomib, thalidomide, dexamethasone, cisplatin,
adriamycin, cyclophosphamide, and etoposide as induction
and post-tandem transplant. 24
Novel agents used as consolidation may serve to both
improve depth of response and prolong responses. A proof of
principle was the work by Ladetto et al, who treated 39
patients in a VGPR postsingle autologous transplant. These
selected patients had a detectable quantifiable molecular
marker based on immunoglobulin heavy chain rearrangement
that could be followed. They were treated with four
courses of VTD, and the molecular markers were followed by
polymerase chain reaction (PCR) using tumor clone specific
primers. CR increased from 15% post-transplant to 49%
post-VTD, and even more striking was the increase in
molecular remissions from 3% to 18%. 25 In addition, patients
who had a quantitative depletion in tumor burden
above the median as measured by PCR had an improved
PFS.
The Nordic study group used a different post-transplant
consolidative strategy in a randomized phase III trial. In one
arm, patients received bortezomib in the traditional schedule
for three cycles followed by weekly dosing for four cycles,
and the observation arm had no therapy. The treatment arm
had a higher response rate and PFS but no benefit in OS. 26
The ongoing BMT CTN 0702 STAMINA trial may be illuminating
regarding the benefit of consolidation. In this threearmed
trial, all patients will receive a single autologous
transplant, one arm will receive a subsequent second transplant,
one arm will receive RVD for four cycles, and one arm
505