NcXHF

MOREAU AND TOUZEAU
other effıcacy endpoints, including response rate, TTP, time
to treatment failure, time to second-line antimyeloma therapy,
and duration of response (DOR). Rd also was generally
better tolerated than MPT. 30
The current standard regimens MPT and VMP are based
on melphalan and are administered for a fıxed duration (9 to
12 cycles). 4 The alkylator-free doublet regimen Rd, delivered
as a continuous therapy, has demonstrated superiority over
MPT, 30 and continuous Rd will likely become a new standard
of care for transplant-ineligible patients with NDMM. This
represents a dual paradigm change in a disease in which alkylating
agents and fıxed-duration therapy have been standard
for decades. We anticipate that the two most important
front-line therapeutic options in 2015 and 2016 probably will
comprise either VMP or Rd.
RELAPSED MULTIPLE MYELOMA AFTER ASCT
Four general approaches to the management of symptomatic
disease relapse following initial ASCT may be considered: (1)
reinduction followed by salvage ASCT, (2) reinduction followed
by alloSCT, (3) reinduction with continuation of conventional
chemotherapy using rational combinations of
novel therapies for relapsed/refractory disease, and (4) participation
in clinical trials to evaluate any of the fırst three
possibilities. Currently, only limited comparative data are
available to support one approach over another. 31
REINDUCTION FOLLOWED BY SALVAGE ASCT
No guidelines on the optimal salvage regimen exist. The
choice of the reinduction regimen typically depends on patients’
responses to the initial induction therapy; comorbidities,
such as persistent peripheral neuropathy (PN) related to
prior bortezomib; burden of disease; or patients whose disease
relapsed on maintenance lenalidomide and/or bortezomib. 31-32
Triplet reinduction regimens commonly are used. In case of
prolonged TFI following front-line ASCT, it is reasonable to
consider using the same combination regimen that was used
as the initial induction therapy, such as VCD, VTD, or RVD.
Patients who will benefıt most from salvage ASCT are those
with chemotherapy-sensitive disease at relapse and those
with a long duration of response to the initial ASCT. 31-33 On
average, the PFS benefıt following a salvage transplant is approximately
one-half that of the PFS after the fırst transplant.
Salvage ASCT may not be recommended if the time to relapse
following the fırst ASCT is less than 18 to 24 months. 31-33
Whether salvage ASCT yields better outcomes than salvage
chemotherapy is not conclusively known. Retrospective and
uncontrolled data have suggested a possible trend toward improved
survival with salvage transplant versus salvage combination
chemotherapy. 31 A recent multicenter randomized
phase III study compared salvage ASCT to cyclophosphamide
single-agent administered for 12 weeks. 34 Patients
were eligible if their disease had progressed or relapsed at
least 18 months after the initial ASCT. All patients received reinduction
with the PAD (bortezomib, doxorubicinm dexamethasone)
regimen and were randomly assigned to either
ASCT or cyclophosphamide. Although the median time to progression
was substantialy longer for patients undergoing ASCT
(19 vs. 11 months), the OS did not differ between the two arms.
Many experts considered the cyclophosphamide arm of this
trial to be suboptimal. Since salvage regimens that are more effective
than single-agent cyclophosphamide are now available,
additional prospective randomized trials comparing novel triplet
combination therapies to salvage ASCT are needed.
REINDUCTION FOLLOWED BY SALVAGE ALLOASCT
Reduced-intensity conditioning alloSCT in the salvage setting
sometimes is considered an appropriate option for younger patients
with good performance status and high-risk features, including
adverse cytogenetics, a high-risk gene expression
profıle, high LDH, or plasma cell leukemia. No prospective randomized
studies comparing salvage alloSCT to salvage ASCT
are available. Some retrospective analyses comparing these two
approaches have been reported; they show a higher nonrelapse
mortality rate with alloSCT, and PFS/OS rates in salvage
ASCT. 31 A limited number of studies with few patients have
evaluated salvage alloSCT versus no alloSCT. These studies have
shown improved PFS for patients undergoing salvage alloSCT
but without an OS benefıt. 31 As the number of effective regimens
for relapsed MM continues to increase, the use of salvage
alloSCT should be restricted to clinical trials. 13,31
SALVAGE CHEMOTHERAPY AND CLINICAL TRIALS
Numerous options exist for relapsed disease and the number of
effective and available agents and combinations is increasing
rapidly (Table 1). Only one trial has prospectively compared
two- versus three-drug combinations in patients whose disease
relapsed following front-line ASCT. Garderet et al demonstrated
that the triplet combination of VTD was associated with
a higher response rate, a longer time to progression (18.3 vs. 13.6
months), and a trend toward improved OS. However, VTD also
was associated with a higher incidence of grade 3/4 toxicities as
compared to thalidomide/dexamethasone. 35
Two other recent prospective phase III trials have confırmed
that triplet combinations are superior to doublets. However,
these studies enrolled not only young, but also older patients. All
had received one to three prior lines of treatment, and only a
part of the patients were treated with front-line ASCT. In the
PANORAMA-1 study, which compared VD-placebo versus
VD plus the HDAC inhibitor panobinostat, 58% of the patients
were younger than age 65, 56% had received a previous ASCT,
and 51% were treated at the time of their fırst disease relapse. 36
Overall, the median PFS was substantially longer in the panobinostat
group than in the placebo group (12 vs. 8 months; hazard
ratio [HR] 0.63). This benefıt was observed across the subgroups
of patients younger than age 65 (HR 0.59), those who were
treated for their fırst disease relapse (HR 0.66), and those previously
treated with ASCT (HR 0.64). Of note, this triplet combi-
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