NcXHF

SEQUENCING MYELOMA TREATMENTS
imens, 4,6,9 the 2015 recommendation is the use of a threedrug
regimen based on bortezomib/dexamethasone, with
the third agent cyclophosphamide, adriamycin, thalidomide,
or lenalidomide. 4,10
Novel agents also have been included in the post-ASCT setting.
Their incorporation into consolidation therapy 11 has
resulted in the achievement of deep molecular- or flow cytometry–defıned
complete responses, with some patients remaining
alive and free of disease, with a minimal residual
disease (MRD) negativity, which are vital prerequisites for
extended disease-free survival. 12 These unprecedented
results were only possible previously with allogeneic transplantation
(alloSCT), the routine use of which is not recommended
outside clinical trials in MM because of excessive
transplant-related mortality. 13 Recent data also show that
maintenance following HDT may dramatically increase
progression-free survival (PFS) by almost 2 years. 14 The implementation
of an optimal strategy, consisting of novel
agent-based induction, HDT, and the use of novel agents in
consolidation and maintenance, may result in a 5-year survival
rate of 80%, which is unprecedented. Moreover, a subset
of patients who present with good prognostic features at the
time of diagnosis might be considered cured. 15-16 However,
the strategy of optimized induction, HDT, and ASCT followed
by PI- and/or IMiD-based consolidation and maintenance
is currently restricted to clinical trials.
The high effıcacy of novel agents has resulted in questioning
of the role of up-front ASCT. A number of studies have
been initiated to investigate these agents up front without
ASCT. In a nonrandomized phase II trial of RVD (lenalidomide,
bortezomib, dexamethasone) in the up-front setting, no difference
in outcome was seen for patients undergoing HDT or
not. 17 Impressive results, including high rates of MRD-negative
responses, also have been reported for the combination of carfılzomib/lenalidomide
and low-dose dexamethasone (KRd) without
up-front ASCT in another phase II study. 18 Based on these
results, some physicians are considering that delaying ASCT to
the time of the fırst disease relapse could be an attractive option.
In 2015, only limited data from randomized studies are available
to address the issue of early versus late ASCT. However, preliminary
results favor early ASCT plus novel agents over novel
agents alone. The fırst prospective study comparing conventional
chemotherapy plus novel agents to tandem ASCT in
newly diagnosed MM patients is being conducted by the Italian
myeloma group and was recently reported by Palumbo et al. 19
Patients received lenalidomide/dexamethasone (Rd) induction
and then were randomly assigned to melphalan/prednisone/lenalidomide
(MPR) or tandem ASCT. Both PFS and OS were
substantially longer with high-dose melphalan plus ASCT than
with MPR (median PFS, 43.0 vs. 22.4 months; and 4-year OS,
81.6 vs. 65.3%). Two other ongoing trials, one conducted by the
European Myeloma Network (EMN02 study, NCT01208766)
and another by the IFM in conjunction with a U.S. consortium
(IFM/DFCI 2009 study, NCT01208662) are investigating the
same question and have enrolled 1,500 and 1,000 patients, respectively.
Although variability in consolidation and maintenance
strategies may affect PFS when comparing early versus
late transplant approaches, these two studies will solve many issues
regarding the role of systematic front-line ASCT in the
treatment of young patients eligible for HDT. Results, however,
are not expected before the end of 2015.
FRONT-LINE TREATMENT OF PATIENTS NOT
ELIGIBLE FOR ASCT
Since the introduction of thalidomide, bortezomib, and lenalidomide,
the median OS in older newly diagnosed multiple
myeloma (NDMM) patients has increased from approximately
30 to 60 months. 5,20 Several regimens that include one
or two of these novel agents have been explored. The combination
of melphalan/prednisone/thalidomide (MPT) is a
standard option for NDMM patients who are not candidates
for ASCT. 4,10,21-22 The addition of thalidomide to melphalan/
prednisone (MP) was shown to delay disease progression in
several randomized trials and to improve OS in some patients.
4,21 A meta-analysis of published data from six randomized
trials confırmed an improvement in PFS and OS
with MPT compared to MP. 22 The reported median PFS and
OS with MPT were 20.3 and 39.3 months, respectively.
The combination of bortezomib/melphalan/prednisone
(VMP) is another well-established standard of care. This regimen
initially consisted of 2 times a week intravenous administration
of bortezomib, based on the phase III VISTA trial, 23
which showed that VMP was superior to MP across all effıcacy
endpoints, including response rate, CR rate, median
time to progression (TTP, 24 vs. 16.6 months) and OS. Based
on clinical data published in 2010, bortezomib use evolved
from 2 times a week to 1 time a week, 24 and from 2012, the
subcutaneous route of administration has found increasing
use over the intravenous route based on data demonstrating
improved tolerability for this mode of administration. 25 The
fınal analysis of the VISTA trial after a median follow-up of
60 months confırmed the superiority of VMP versus MP in
terms of median time to second-line antimyeloma therapy
(31 vs. 20.5 months) and median OS (56 vs. 43 months). 26
Bortezomib/dexamethasone (VD) and bortezomib/thalidomide/dexamethasone
(VTD) have yielded similar results in
the up-front setting in nontransplant eligible patients. 27
Lenalidomide mainly has been used in combination with
MP (MPR), 28 or with low-dose dexamethasone (Rd). 29,30 For
the MPR regimen, tolerability was found to be reduced in
patients over age 75, and the combination also has been associated
with an increased incidence of second primary hematologic
malignancies. 28 In the recent phase III FIRST
study, which included 1,623 transplant-ineligible patients,
the continuous Rd regimen administered until disease progression,
intolerance, or for a fıxed duration of 18 cycles (72
weeks; Rd18) was compared to MPT administered for 12 cycles
(72 weeks). Continuous Rd substantially extended PFS
and OS compared to MPT. With a median follow-up of 37
months, the median PFS was 25.5 months for Rd, compared
to 20.7 months for Rd18 and 21.2 months for MPT. The
4-year estimated OS was 59% for Rd, 56% for Rd18, and 51%
for MPT. In addition, Rd was superior to MPT across all
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