Treatment of newly diagnosed transplantation candidate patients

Treatment of newly diagnosed transplantation
candidate patients
Currently, treatment of young patients usually includes 3-6 cycles of
induction therapy, intensification with ASCT, and the possibility of
consolidation and maintenance therapy.
Induction
With VAD (vincristine, doxorubicin, and dexamethasone) or T-Dex
(thalidomide– dexamethasone) combinations, only 2/3 of patients
achieve a partial response (PR) and 10% achieve CR. In contrast,
after induction with bortezomib (Bz)-based triplet combinations with
either alkylators or IMiDs [bortezomib-cyclophosphamide-dexameth-
asone (Bz-Cyclo-Dex), bortezomib-thalidomide-dexamethasone
(BzTDex), or bortezomib-lenalidomide-dexamethasone (BzLenDex)],
90% of patients respond with 30% CR.22 These schemes are also
associated with longer PFS than with VAD or T-Dex.26 New protea-
some inhibitors such as carfilzomib and ixazomib are being investi-
gated in combination with Len-Dex; both schemes show high prelimi-
nary activity: immunophenotypic responses with the former while the
second is very attractive due to its oral formulation.
ASCT
Prospective randomized trials of high-dose therapy (usually mel-
phalan 200 mg/m2) followed by ASCT compared with chemo-
therapy showed a significant improvement in CR and PFS and have
provided evidence for 10-year survivorship in at least a subset of
patients.27 In the setting of novel agents, ASCT also enhances the
response rates obtained with these new induction regimens, suggest-
ing that induction with novel agents and ASCT are complementary
rather than alternative treatment approaches. Moreover, this strategy
favors the upfront exposure to all active antimyeloma agents
(proteasome inhibitors, IMiDs, corticosteroids, and high-dose mel-
phalan) to minimize the risk of subclonal escape. Nevertheless,
some investigators argue that this approach is challenged by the
optimal results obtained from “long-term” treatment with novel combi-
nations [eg, carfilzomib-lenalidomide-dexamethasone (CRd)]. Three
randomized trials comparing early and late ASCT are under way
(IFM/DFCI, EMN MM-RV-441, and GIMEMA MM-RV-209), and
the third one has already shown an improvement in PFS, but not yet in
OS, for early ASCT.28 Until these results become more mature, we
propose that ASCT should remain the standard of care for young MM
patients. Attempts to improve the efficacy of high-dose therapy are also
being investigated, including the addition of bortezomib to melphalan
200 or busulphan-melphalan. Tandem ASCT is less widely used
because a similar benefit is obtained with consolidation therapy (eg,
BzTDex). In contrast, a second transplantation at relapse may be used if
the response to the first transplantation has lasted for more than 2-3
years. In addition, recent results have suggested that tandem ASCT
may be of benefit in patients with high-risk cytogenetics.18
Consolidation and maintenance
Consolidation consists of 2-3 courses of combination therapy
(generally a triplet similar to induction) with the aim of reducing
residual disease after ASCT, whereas maintenance involves a
prolonged treatment (until progression or at least 1-2 years) that
aims to control the residual tumor clone. The Italian group has
demonstrated the value of BzTDex consolidation both in terms of
improving the CR rate, including molecular responses, and prolong-
ing PFS.29 With respect to maintenance therapy, 6 randomized trials
have explored the value of thalidomide. Although, all 6 studies
showed prolonged PFS (by a median of 6 months), only 3 of them
showed a similar improvement in OS.30 The situation is clearly
different for lenalidomide, for which 3 trials found a marked
prolongation in PFS (median 18 months), one of which also noted a
beneficial effect on OS.31,32 Although lenalidomide maintenance is
associated with increased incidence of second primary malignan-
cies, this risk is outweighed by the survival benefit. Bortezomib has
also been tested as a single agent or in combination with thalido-
mide, giving positive results for PFS in both trials and for OS in one
of them.33 Overall, these studies indicate that maintenance signifi-
cantly prolongs PFS and probably OS, although the duration of
maintenance remains to be determined. We need to establish the
benefit of treatment until progression over a fixed period (eg, 2
years), because continuous treatment could theoretically favor the
emergence of more resistant clones, would reduce the possibility of
retreatment after a treatment-free interval, and might be associated
with unnecessary costs and toxicity. In addition, we need to
establish the benefit in specific cohorts such as CR and high-risk
patients. MRD techniques may help to monitor treatment efficacy,
particularly during consolidation and maintenance therapy, so that
undertreatment and overtreatment can be prevented.
Allogeneic SCT
Allogeneic SCT is a potentially curative therapeutic approach in
MM. However, it is associated with a high transplantation-related
mortality (up to 30%) and high morbidity, mainly due to chronic
GVHD. Six randomized trials have compared double ASCT with
ASCT followed by allogeneic-reduced-intensity conditioning regi-
mens; only in 2 of them did the allogeneic approach prove to be
superior, so we do not recommend this treatment in newly diag-
nosed patients.34 However, the role of allogeneic SCT should be
reexamined in the era of novel drugs using “integrated programs” in
the context of clinical trials designed for high-risk patients.