2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Trial
Author and Year
Table 2. Bortezomib Maintenance Studies after ASCT and Conventional Chemotherapy
n
age Maintenance Dose Comparator
will respond to increased doses of lenalidomide (25 mg) and
the addition of dexamethasone at the time of myeloma
progression. Longer follow-up is currently needed to assess
that issue.
Can Maintenance Therapy with IMiDs Also Prolong
Duration of Response in Elderly Patients or Those
Ineligible for HDT?
Fewer data are available concerning maintenance therapy
with IMiDS in elderly patients and in the nontransplant
setting.
Thalidomide. Three melphalan, prednisone, and thalidomide
(MPT) trials were reported that included thalidomide
maintenance (MPT�T). 18-20 The MPT�T schedule was compared
to melphalan and prednisone (MP) with placebo and
thus it may be difficult to determine the value of maintenance
therapy per se as the studies were designed to
evaluate the entire treatment program. Median PFS was
improved in MPT�T arm in 2 of the 3 trials but there was
no OS advantage with long-term thalidomide use. The MRC
Myeloma IX maintenance study, was properly designed to
evaluate the influence of thalidomide maintenance in the
nonintensive pathway. 13 Results indicated that thalidomide
had only a marginal effect in improving PFS in nonintensively
treated patients (median PFS 11 months vs. 9
months, p � 0.014). Furthermore, it suggests that it may be
related to thalidomide exposure at some point during the
treatment course rather than directly attributable to its use
in maintenance.
Lenalidomide. Prolonged treatment with lenalidomide
has shown a clear benefit in elderly patients, making it a
good choice for long-term maintenance. Several trials are
examining this role with the most mature data emerging
from the International study MM015. 21
In this large, phase III trial, a total of 459 patients older
Duration of
Maintenance PFS/EFS OS
Bortezomib Trials
Post ASCT Bor� Bor� Bor� Bor�
HOVON 65/HD4 800 Bortezomib Thal 50 2 yr 48%* 42%* 78%* 71%*
Sonneveld et al 2010 � 65y 1.3 mg/m2/2 wk (3-yr PFS) (3-yr OS)
PETHEMA/GEM 266 Bortezomib Thalidomide 100 mg/d 3 yr 78%* 63/49%* N/A
Rosinol et al 2011 � 65y 1.3 mg/m2/3 mo Or (2-yr PFS) No difference
Post Chemotherapy
�
Thalidomide 100 mg/d
IFN
GIMEMA 511 VMPT VMP Until
NR* 27 mo* 89% 87%
Palumbo et al 2010 � 65 y �VT
Bortezomib 1.3 mg/m2,
d1,15/4 wk
Thalidomide 50 mg/d
�observation progression
(3-yr OS)
GEM2005MAS65 260 VMP or VTP VMP or VTP 3 yr VT 39 mo* VT NR
Mateos et al 2011 � 65 y �VT �VP VP 32 mo* VP 60 mo
Bortezomib 1.3 mg/m2
d 1, 4, 8, 11/3 mo
Bortezomib 1.3 mg/m2
Thalidomide 50 mg/d d 1, 4, 8, 11/3 mo
Prednisone 50 mg
alternate day
(median, mo) (median, mo)
Abbreviations: PFS, progression-free survival; EFS, event-free survival; OS, overall survival; y, years; mo, months; N/A, not available.
* Statistically significant.
518
ATTAL AND ROUSSEL
than or equal to age 65 with newly diagnosed multiple
myeloma (MM) were enrolled. Induction consisted of nine
28-day cycles of melphalan 0.18 mg/kg (d1–4), prednisone
2 mg/kg (d1–4), and lenalidomide 10 mg (d1–21) (MPR) or
MP. After induction, patients receiving MPR-R received
lenalidomide 10 mg (d1–21) maintenance until progression;
patients receiving MPR and MP received placebo. The MPR
regimen resulted in significantly higher response rates
(MPR-R: 77%, MPR: 68%, MP: 50%, p � 0.001). Sixty percent
of responses were achieved within 3 months following
induction treatment initiation. Further improvements in the
quality of response occurred with continued treatment, particularly
during the first year, with a few patients achieving
further tumor reduction thereafter. A landmark analysis
showed that the addition of lenalidomide maintenance to
MPR decreased the risk of progression by 68% (p � 0.001)
and significantly prolonged the median PFS (MPR-R 31
months vs. MPR 15 months (p � 0.001) and MP 12 months
(p � 0.001), respectively). In addition, a subgroup landmark
analysis showed that the benefit of MPR-R over MPR was
maintained regardless of Internatinal Staging System (ISS)
stage (ISS I and II vs. III), response (� VGPR vs. PR) and
age (65–75 vs. �75 years old). With a median follow-up of
41 months, the estimated 4-year OS was similar between the
3 groups (58% to 59%).
Maintenance Therapy with Proteasome Inhibitors
Data concerning maintenance with bortezomib are less
mature. Several randomized studies by European and
American study groups are ongoing. The IV formulation
makes bortezomib a less attractive option for long-term
treatment. However, SC administration and the future
availability of oral forms of proteasome inhibitors will certainly
boost potential maintenance trials with these agents
(Table 2).