2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TRANSPLANTATION FOR MYELOMA
Alternately for less aggressive disease, many experts in
the field advocate the use of a two-drug regimen of either
bortezomib and dexamethasone or lenalidomide and dexamethasone
depending on the patients’ comorbidities. The
lenalidomide plus low-dose dexamethasone approach has
good tolerability and 2-year OS data in both young and
elderly patients. 7 Although the point at which patients
should receive transplant on this induction regimen remains
controversial, it is clear that prolonged exposure to lenalidomide
may impair stem cell yields. Therefore, if a transplant
is planned, transplant physicians recommend that stem cell
collection should occur before the six months of lenalidomide
exposure. 8
Who Should Undergo a Transplant?
Age Limits for Transplantation?
Myeloma is a disease of elderly patients with a median of
72 years at presentation. Therefore, if arbitrary age cutoffs
are used, a large portion of patients with myeloma would be
ineligible for a transplant. In earlier eras, autologous transplantation
was generally reserved for patients younger than
60 or 65 years. The original IFM trial—which served as the
platform for high-dose therapy in multiple myeloma—enrolled
patients 65 years and younger. However, since that
time, there have been several trials suggesting that age is
not a prognostic variable to transplant outcome in myeloma,
but rather it is disease-related indices. A group from M. D.
Anderson Cancer Center published their experience with 84
patients with the median age 72. All patients met the
standard organ function criteria for transplant and received
melphalan doses between 140 mg/m 2 and 200 mg/m 2 .
Nonrelapse-related mortality was 3%, and 5-year OS was
67%. 9 A larger registry-based study comparing patients
older than 60 years and younger than 60 years showed no
difference in transplant-related mortality or PFS between
older and younger patients. Though the median age in the
older than age 60 group was still on the younger side at 63
years. 10
Specific issues about elderly patients to consider begin
with the choice of induction therapy for a patient that one
KEY POINTS
● The use of novel agents as induction therapy for
myeloma can improve post-transplant progressionfree
survival.
● Studies are ongoing to determine the optimal timing
of transplantation after an effective induction strategy
(i.e., early compared with delayed transplant).
● Patients with high-risk myeloma—especially those
with 17p deletion—remain a challenge and may be a
subgroup for whom allogeneic transplantation should
be considered.
● Post-transplant strategies to reduce relapse, such as
consolidation or immunotherapy, are being studied.
● Age should not be considered a barrier to transplantation,
but appropriate assessment of the older patient
should include geriatric assessments and
traditional functional testing.
would consider “transplant eligible.” As previously mentioned,
melphalan-based regimens are to be avoided because
of potential stem cell toxicity. High-dose dexamethasone is
also particularly difficult for the older patient because of
toxicity. In addition, increasing age has been correlated
inversely with CD34 counts. 11 Therefore, stem cell collection
should be considered early in the disease course, and the use
of agents such as plerixafor may be necessary.
Before transplant, Karnofsky performance status is the
most traditional evaluation in addition to organ function
testing. However, in the older patient, performance status as
the only marker of functional status may be inadequate. The
concept of frailty is important to consider. For example, the
very fit older person who exercises and is fully independent
has different needs than the mildly frail individual who may
need help for household tasks. Frailty in and of itself is a
predictor of outcome in elderly patients. 12 The geriatric
assessment tool may be helpful as part of pretransplant
assessment. Although it has not yet been validated in the
transplant setting, it has been a predictor of chemotherapy
toxicity with conventional chemotherapy. This tool, in addition
to comorbidities, encompasses cognition, psychologic
status, social functioning and support, and nutritional status.
13 Optimal assessment of all these factors could help
predict the older patient who may pass all the functional
testing but may have the potential for significant debility
with the transplant. In addition, it may help with needs
assessment for post-transplant care.
Patients at High Risk
Risk stratification is an important part of the initial
assessment of a myeloma patient and obviously influences
the choices of induction therapy, but what role should it play
in the transplant paradigm? Generally, risk stratification
encompasses International Staging System (ISS) staging,
cytogenetics, and fluorescence in situ hybridization (FISH)
analysis and possibly gene expression profiling (GEP). The
early transplant studies did not differentiate between patients
at standard risk and those at high risk. Also, although
later trials did attempt to stratify patients and as the
definition of “high-risk” disease evolves, the applicability of
those older trials is limited. Recent trials tend to define
“high risk” as t(4,14), t(14,16), deletion 13, or deletion 17p. A
retrospective study reviewed approximately 500 patients
who received bortezomib plus dexamethasone before highdose
melphalan compared with a group treated with vincristine,
doxorubicin, dexamethasone (VAD) induction before
high-dose melphalan. 14 The use of bortezomib could abrogate
some of the high-risk prognosis conferred by t(4,14).
Event-free survival (EFS) was 28 months for patients
treated with bortezomib compared with 16 months for the
VAD group (p � 0.001). However, this still remained a poor
prognostic factor compared with patients without t(4,14). In
contrast, no improvement in either EFS or OS was seen for
patients with 17p deletion treated with the bortezomibbased
induction. However, in the HOVON-65 GMMG-HD4
trial, bortezomib-based treatment before and after stem cell
transplant markedly improved DFS and OS in patients with
17p deletion compared with those treated with VAD induction
and thalidomide maintenance. 15
GEP has also been studied as a prognostic indicator in the
era of novel agents plus high-dose therapy as part of the
Arkansas Total Therapy 3 protocol. 16 For patients with
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