Running head:
Consensus on maintenance therapy in myeloma
IMWG consensus on maintenance therapy in multiple
Myeloma
Heinz Ludwig1, Brian G.M. Durie2, Philip McCarthy3, Antonio Palumbo4, S. Vincent
Rajkumar5; Andrew Spencer6, Pieter Sonneveld7; Jesus San Miguel8, Gareth
Morgan9, Thierry Facon10, Keith Stewart11, Maria-Victoria Mateos12, Meral Beksac13;
Anders Waage14, Cyrille Hulin15, Henk Lokhorst16, Pierre Wijermans17, Axel Hinke18,
Michele Cavo19, Michel Attal20
Affiliations:
1Wilhelminenspital Hospital, Vienna, Austria; 2Cedars Sinai Samuel Oschin Cancer
Center, Los Angeles, California, USA; 3Roswell Park Cancer Center, Buffalo, New
York, USA; 4University of Torino, Torino, Italy; 5Mayo Clinic, Rochester, Minnesota,
USA; 6The Alfred Hospital, Melbourne, Australia; 7Erasmus MC, Rotterdam,
Netherlands; 8University of Salamanca, Salamanca, Spain; 9Royals Marsden
Hospital, Sutton, United Kingdom; 10Hopital C. Huriez, Lille, France; 11Mayo Clinic,
Scottsdale, Arizona, USA; 12University Hospital of Salamanca, Salamanca, Spain;
13Ankara University School of Medicine, Ankara, Turkey; 14St. Olavs Hospital/NTNU,
Trondheim, Norway; 15Intergroupe Francophone du Myelome, Nancy, France;
16University Hospital Utrecht, Utrecht, Netherlands; 17Haga Hospital, The Hague,
Netherlands; Axel Hinke18; 19University of Bologna, Bologna, Italy; 20University
Hospital, Toulouse, France
Key Words:

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IMWG consensus on maintenance therapy in multiple myeloma
Multiple Myeloma, Maintenance, Thalidomide, Lenalidomide, Bortezomib
Word Count:
Abstract: 249
Text: 6181
Number of Tables: 5
Number of Figures: 1
Number of References: 48
Correspondence:
Prof. Heinz Ludwig, MD
Department of Medicine I, Center of Oncology and Hematology
Wilhelminenspital
Montleartstrasse. 37, 1160 Vienna, Austria
Phone: +43 1 49150 2101, Fax: +43 1 49150 2109
E-mail: heinz.ludwig@wienkav.at
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IMWG consensus on maintenance therapy in multiple myeloma
Abstract
Maintaining results of successful induction therapy is an important goal in multiple
myeloma. Here, members of the International Myeloma Working Group review the
relevant data. Thalidomide maintenance therapy after ASCT improved the quality of
response and increased PFS significantly in all 6 studies and OS in 3 of them. In
elderly patients, 2 trials showed a significant prolongation of PFS, but no
improvement in OS. Meta-analysis of all evaluable above mentioned studies revealed
a significant risk reduction for PFS/EFS (HR: 0.66, CI: 0.60-0.73) and death (HR:
0.74, CI: 0.63-0.88). The role of thalidomide maintenance after MPT is not well
established. Two trials with lenalidomide maintenance treatment after ASCT and one
study after conventional MPR induction therapy showed a significant risk reduction
for PFS (HR: 0.45, CI: 0.37-0.54) and an increase in OS in one of the transplant
trials. Bortezomib-thalidomide maintenance treatment revealed increased PFS over
control and bortezomib-thalidomide proved superior over bortezomib-prednisone in
one study each. One trial revealed significantly increased OS with a bortezomib-
based induction and bortezomib maintenance therapy compared to thalidomide-
based induction and maintenance treatment. In conclusion, maintenance treatment
with thalidomide and lenalidomide after ASCT and after conventional treatment
prolongs PFS, and in several settings OS. Bortezomib maintenance is also a feasible
option. Maintenance treatment may be associated with significant side effects and
none of the drugs evaluated is approved for maintenance therapy so far. Treatment
decisions in individual patients must balance potential benefits and risks carefully, as
a widely agreed upon standard is not established.
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IMWG consensus on maintenance therapy in multiple myeloma
Introduction
Maintaining the response of first-line therapy is an important objective in multiple
myeloma, where even the most intensive therapy followed by autologous stem cell
transplantation (ASCT) is usually unable to extend progression-free survival (PFS) to
beyond 36 months, with the majority of patients eventually experiencing relapsing
disease. Hence, it is understandable that every novel treatment that has been
introduced into myeloma therapy also has been tested for its capacity to maintain the
benefits of first-line therapy in order to prolong remission--a period usually devoid of
symptoms of the disease and of toxicities of therapy--and importantly, to extend
overall survival (OS). The first attempts to accomplish this had already been
undertaken with the use of conventional chemotherapy shortly after its effectiveness
in MM had been demonstrated (1-3). Because results of these initial and of later
studies (4-10) remained unsatisfactory, efforts to improve the outcome of
maintenance concepts are ongoing. Here we review the recent results obtained with
novel drugs for maintenance treatment and provide recommendations for clinical use.
Methodology and Statistics
Members of the International Myeloma Working Group met twice during the IMF
summits on the occasion of the EHA meetings in 2010 and 2011 to review and
discuss the evidence for maintenance treatment with novel agents and to formulate
recommendations for clinical practice. All relevant data published in the literature or
presented at meetings of the American Society of Oncology, American Society of
Hematology, European Society of Heamatology, and the International Myeloma
Workshop were considered.
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IMWG consensus on maintenance therapy in multiple myeloma
For meta-analysis, randomized controlled trials (RCTs) of patients receiving
thalidomide, thalidomide combination, or lenalidomide maintenance therapy were
included. Extraction of summary statistics from the published data was performed
according to standard methods for survival-type endpoints, with hazard ratios and
their confidence intervals as preferred sources for estimation, and logrank p
values/event counts as second choice (11). Standard techniques for meta-analysis
(12) were used to calculate the pooled estimates, as incorporated in the software
packages METASUB V. 1.1 (idv, Gauting, Germany) and Review Manager V. 4.2
(Nordic Cochran Centre, Copenhagen). Both fixed (primarily) and random effects
model methodology were applied. All reported p-values result from two-sided
versions of the respective tests.
Chemotherapy, Interferon and Glucocorticosteroids
The first trials designed to prolong the duration of the maintenance phase and OS
simply continued chemotherapy after successful induction treatment with MP (1-3).
This led to a significant prolongation of the duration of remission but not to superior
survival, and thus was not pursued further.
Interferon was shown to exert anti-myeloma activity as a single agent in 1979 (13),
and subsequent trials employed interferon for induction and for maintenance therapy.
Individual trials revealed variable results, with significant prolongation of maintenance
duration and also of survival in some, and negative outcomes in other studies. Two
meta-analyses, one on individual patient data (4) and the other using published data
(5), revealed a significant but limited improvement in both maintenance duration and
survival of about 6 months. Due to toxicity and the inability to select those patients
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IMWG consensus on maintenance therapy in multiple myeloma
likely to benefit from and tolerate interferon, this concept has, with few exceptions,
generally been abandoned.
Glucocorticosteroids have significant activity in myeloma as single agents (6) and
induce additive or synergistic activity in combination with other drugs (7). Berenson
(8) showed a significant increase in remission duration and in survival with 50 mg
prednisone every other day compared to 10 mg every other day, but in another study
with single-agent dexamethasone (40 mg d 1-4, q 28 days) no benefit was observed
(9). A comparison of dexamethasone with interferon maintenance treatment showed
similar remission durations, but more relapsing patients could be re-induced with
melphalan-dexamethasone
after
interferon
maintenance
therapy
than
with
dexamethasone (10). Taken together, the available evidence is insufficient for
recommending corticosteroid maintenance therapy.
Thalidomide
Three (14, 15, and 23) of the six trials with thalidomide maintenance treatment after
ASCT (14-23) used thalidomide only as maintenance treatment. In two studies
thalidomide was administered both during induction and maintenance phase (18, 22),
while in the MRC Myeloma IX study (16), approximately half of the patients
randomized to thalidomide maintenance treatment had thalidomide during induction
therapy (Table 1).
In the IFM study, patients were randomized after double ASCT to thalidomide plus
pamidronate, to pamidronate alone, or to control (14). A significant improvement in
the quality of response was observed in the thalidomide-containing arm, with more
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IMWG consensus on maintenance therapy in multiple myeloma
patients achieving VGPR or CR compared to the two other groups (67% vs. 55% vs.
57%, P=0.03). Furthermore, an increased event-free survival (EFS) (3-year EFS:
52% vs. 37% vs. 36%, P<0.009) as well as improved OS (4-year OS: 87% vs. 74%
vs. 77%, P<0.04), could be shown, but the benefits of thalidomide maintenance
therapy were seen only in patients with less than VGPR after double ASCT, and only
in those without del13 and high ß-2 microglobulin. Survival after relapse did not vary
between the three study arms (P=0.7). Thirty-nine percent of patients stopped
thalidomide maintenance therapy due to intolerance, mainly because of peripheral
neuropathy (PNP). After long-term follow-up of patients with cytogenetics available
(thereby excluding 90 patients) (18), the initially observed survival benefit was not
maintained, with an estimated 5-year OS rate of 74% in the thalidomide-pamidronate
arm and 70% in both control groups (P=0.53).
In the Australian trial (15), patients were randomized after single ASCT to either
thalidomide maintenance treatment in combination with alternate-day prednisolone or
to prednisolone alone. Treatment with thalidomide was planned for 12 months, but
alternate-day prednisolone could be continued in both arms until progression. Fifty-
eight percent of the patients initially randomized to thalidomide remained on
maintenance therapy. The thalidomide-containing treatment resulted in a higher rate
of VGPR (65% vs. 44%, P=0.001), increased PFS (3-year PFS estimate 42% vs.
23%, P<0.001) and increased OS (3-year OS estimate: 86% vs. 75%, P=0.004). OS
after relapse did not differ between the two groups (P=0.237). Thirty percent of
patients stopped thalidomide maintenance therapy due to intolerance, mainly due to
PNP, with 10% experiencing grade 3-4 PNP. Nine percent discontinued treatment
because of progressive disease (PD).
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IMWG consensus on maintenance therapy in multiple myeloma
The MRC myeloma IX study (16) consists of 2 trials, one in younger and the other in
older patients (17). In the transplant study, patients were randomized to CVAD or
CTD before ASCT and thereafter to thalidomide maintenance or to control.
Thalidomide increased the rate of CR after ASCT by 17%, and increased PFS, but
not OS. Patients with del17p had significantly shorter survival with thalidomide
therapy. Survival after relapse was significantly shorter in thalidomide-treated
patients but not in those who were rescued with novel agents (18).
Bart Barlogie compared thalidomide in combination with total therapy II (TT II) and
post-transplant chemotherapy to the same chemotherapy without thalidomide (19-
21). Maintenance thalidomide was given until PD or intolerance. After a median
follow-up of 40 months, both significantly higher CR rate (62% vs. 43%, P=0.001)
and EFS at 4 years (65% vs. 44%, P=0.01) were noted, while for OS no difference
was observed. After relapse, survival was significantly shorter in patients pre-
exposed to thalidomide (1.1 vs. 2.7 years, P=0.001) (19). A re-analysis after a
median follow-up of 6 years revealed a survival estimate of 57% in the experimental
arm and of 44% (P=0.09) in the control arm (20). EFS was superior in the
thalidomide arm, with a median of 6.0 years versus 4.1 years (P=0.001). Patients
with metaphase-defined cytogenetic risk factors had significantly longer survival (OS
at 5-years (56% vs. 43%, P=0.02). The cumulative frequency of CR was significantly
higher in the thalidomide group, regardless of cytogenetic status. Segregation of
survival curves became evident 2-3 years after the start of therapy in patients with
cytogenetic abnormalities, and after 7 years in those without, Survival after relapse
was significantly longer in control patients without cytogenetic abnormalities (5-year
OS estimate: 25% vs. 6%, P=0.04), but was similar between both treated and
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IMWG consensus on maintenance therapy in multiple myeloma
untreated patients with cytogenetic risk factors (5-year OS estimate: 29% vs. 33%,
P=0.99). A further re-analysis after an additional 38 months of follow-up, for a total
follow-up of 87 months, finally showed OS to be significantly extended in the
thalidomide arm (P=0.04), despite discontinuation of thalidomide for toxicity and other
reasons in nearly 80% within 2 years (21).
In the HOVON-50 study (22), patients were randomized to either TAD followed by
single or double ASCT and maintenance therapy with low-dose thalidomide (50
mg/day), or to VAD followed by single or double ASCT and maintenance treatment
with interferon alpha. Maintenance treatment was given until progression. Patients
randomized to thalidomide maintenance achieved a significantly higher VGPR rate
(66% vs. 54%, P=0.005), longer EFS (34 vs. 22 months, P<0.001) and a tendency
for improved OS (median: 73 vs. 60 months, P=0.77). Survival after relapse, was
significantly shorter in patients exposed to thalidomide induction and maintenance
treatment (median: 20 vs. 31 months, P=0.009). Fifty percent of patients developed
PNP, and 58% had dose reductions or discontinued thalidomide.
The NCIC CTG trial (23) randomized patients to either thalidomide 200 mg daily and
alternate-day prednisone (50 mg) or control. After a median follow-up of 4 years the
survival rate was 68% for the maintenance group and 60% for the control group
(P=0.21). PFS was significantly longer for patients randomized to maintenance
therapy (28 vs. 17 months, P<0.0001, HR 0.56, 95% CI 0.43 - 0.73). The 4-year PFS
rate was 32% for thalidomide/prednisone and 14% for the observation only group.
Quality of life was inferior in patients on maintenance therapy in most domains, with
the exception of appetite and sleep, which were better with thalidomide/prednisone
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IMWG consensus on maintenance therapy in multiple myeloma
therapy. There were more non-hematologic toxicities (Grade 3: 92%, Grade 4 16%)
and a higher VTE rate (7%) in the thalidomide/prednisone group than in the
observation group (Grade 3: 49%, Grade 4: 7%, VTE: 0).
A recently presented meta-analysis of 5 of the 6 transplant studies revealed a
significant improvement in PFS (HR 0.64, 95%CI 0.55-0.75, p<0.001) and OS (HR
0.73, 95%CI 0.60-0.89, p=0.002) with thalidomide maintenance therapy (24). Grade
3/4 neuropathy (reported in two trials) was worse with thalidomide (RR 6.97, 95%CI
1.44-33.78, p=0.02), and grade 3/4 thromboembolic complications (reported in 4
studies) were more common (RR 2.01, 95%CI 0.96-4.23, p=0.07) in the thalidomide
arms; for other toxicities no relevant difference was noted.
In both trials exploring thalidomide maintenance treatment after conventional therapy
(16, 25), approximately 50% of patients had already been exposed to thalidomide-
containing induction regimens. In the CEMSG trial patients were randomized to
thalidomide pus interferon or to interferon maintenance therapy. The thalidomide-
containing combination induced a significant increase in PFS (27.7 vs. 13.2 months,
P=0.0068), but OS was similar between the two groups (52.6 vs. 51.4 months,
P=0.81) and did not differ between patients aged 75 years or more and younger
patients (P=0.39). PFS and OS tended to be shorter in patients with adverse
cytogenetic (FISH) findings compared to the standard-risk group, but differences
were not significant (P=0.084 and P=0.082, respectively). Survival after disease
progression tended to be shorter in patients exposed to thalidomide-interferon
maintenance therapy (P=0.056). Patients receiving thalidomide-interferon had more
neuropathy (69% vs. 38%, P=0.0015), constipation (44% vs. 19%, P=0.0004), skin
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toxicity (33% vs. 11%, P=0.0041) and elevated creatinine (13% vs. 5%, P=0.026). In
the myeloma IX study of the MRC, a similar increase in PFS with no difference in OS
and shorter survival after relapse in patients receiving thalidomide maintenance
treatment has been observed. Survival after relapse was influenced by the selection
of salvage therapy, and was improved when novel drugs were administered, a finding
which was noted in younger patients as well (17).
Our meta-analysis of the published results revealed a significant reduction of the risk
for progression (HR: 0.66, 95%CI: 0.60 ­ 0.73) and for death (HR: 0.74, 95% CI: 0.63
­ 0.87) (figure 1A and 1B) with thalidomide maintenance therapy. Outcome did not
differ between trials that used thalidomide during maintenance phase only and those
that used thalidomide both for induction and maintenance treatment.
Six randomized trials have compared MPT with MP in elderly patients (26-32), and in
4 of them thalidomide was given after MPT as maintenance (26, 30-32).There was
significant heterogeneity in the design of these studies, with differences in the dose,
schedule, and duration of MPT therapy (table 2). A borderline significant
improvement in OS with MPT followed by thalidomide maintenance therapy was
noted in the HOVON trial (30) (40 vs. 31 months, P=0.05), while in the three other
studies with thalidomide maintenance therapy after MPT, no difference in OS (47.6
vs. 45 months; P=0.79 (26), 29 vs. 32 months, P=0.16 (30), and 26 vs. 28 months,
P=0.0655 (31), respectively) was observed.
A meta-analysis of all six trials, which includes data from 1685 individual patients
(33), revealed a significantly longer PFS (20.3 vs. 14.9 months, HR: 0.69, CI 0.56 -
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IMWG consensus on maintenance therapy in multiple myeloma
0.81, p<0.001), OS (39.3 vs. 32.7 months, HR: 0.83 (95% CI 0.73­0.94, p=0.004),
and better one-year response rates (PR: 59% on MPT vs. 37% on MP) for the MPT
group. The average benefit of MPT over MP amounted to a gain of 6.6 months in
survival, equivalent to 20% of total survival expectancy. The two studies that showed
a clear survival benefit (28, 29) had no maintenance therapy at all. A meta-analysis
of published data (34) confirmed the improvement in response rate and in PFS with
MPT with or without thalidomide maintenance therapy, but hazard ratio for OS did not
reach statistical significance (HR: 0.80, 95% CI: 0.63-1.02, P=0.07). The analysis
revealed a significantly higher incidence of high-grade peripheral neuropathy and
deep venous thrombosis in the MPT-treated patients (odds ratio: 6.6 and 2.4,
respectively).
Lenalidomide
The CALGB 100104 study randomized 460 patients after ASCT to lenalidomide
maintenance therapy or to placebo (35). The induction regimen before ASCT was not
specified and patients were stratified according to previous thalidomide or
lenalidomide exposure during induction therapy and to ß-2 microglobulin levels. After
a median follow-up of 28 months from ASCT, time to progression was 48 months in
the lenalidomide maintenance, and 30.9 months in the placebo group (HR: 0.39, 95%
CI, 0.27 - 0.56, P<0.0001). Lenalidomide maintenance treatment was equally
effective in patients with high or low ß-2 microglobulin levels, and in those previously
exposed to thalidomide or lenalidomide therapy. Overall survival was significantly
increased with lenalidomide maintenance therapy despite a cross over to
lenalidomide by some of the placebo patients after unblinding the study in January
2010. Twenty-three deaths were observed in the treatment and 39 in the control arm
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IMWG consensus on maintenance therapy in multiple myeloma
(P=0.018). Patients receiving lenalidomide maintenance therapy had significant more
episodes of neutropenia (P<0.0001), anemia (P=0.0639), and thrombocytopenia
(P=0.035), significantly more grade 3-5 non-hematologic adverse events (P=0.0048)
including more infections (P<0.0001), but there was no difference in the frequency of
fatigue, neuropathy, rash, and thromboembolism. Twelve percent of patients on
lenalidomide and 1% on placebo came off therapy due to AEs and 20% (29) of
patients on lenalidomide and 7% (14) on placebo came off therapy for other reasons.
At the time of reporting (IMW, May 2011), 29 second malignancies, 7 prior to
randomization, 18 in the lenalidomide maintenance and 4 in the control group, had
been observed. Event-free survival (EFS) analysis where events were progression,
second cancers and deaths demonstrated median EFS of 43 months in the
lenalidomide arm and 31 months in the placebo arm.
In the IFM lenalidomide maintenance trial, 614 subjects who had single or double
ASCT were treated with 2 cycles of lenalidomide consolidation therapy, and were
thereafter randomized to lenalidomide maintenance therapy or placebo (36). After a
median follow-up of 24 months following randomization to maintenance, an
independent data monitoring committee recommended stopping and unblinding the
trial because of an increased incidence of second primary malignancies in the
lenalidomide maintenance arm. Consolidation therapy with lenalidomide resulted in
an upgrade of the quality of response, with CR increasing from 14% to 20%
(P<0.001) and VGPR from 58% to 67% (P<0.001), respectively. Improved
response correlated with longer PFS. Best response during maintenance therapy
was slightly, but not significantly higher in patients maintained with lenalidomide (CR
rate: 25% vs. 22%, P=0.4, VGPR rate 77% vs. 70%, P=0.08). PFS was significantly
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IMWG consensus on maintenance therapy in multiple myeloma
longer in patients randomized to lenalidomide maintenance therapy (41 vs. 24
months, HR: 0.5, P<10-9); the benefit in terms of longer PFS was noted in all
subgroups, independent of the quality of response at randomization, type of induction
regimen, ß-2 microglobulin, del13, and t (4; 14), but overall survival was still shorter
in the t (4; 14) population compared to patients without this risk factor. In patients
with del17p, no benefit of lenalidomide was noted. For patients progressing during
placebo, cross-over to lenalidomide maintenance treatment was not allowed. OS at 5
years post diagnosis was similar in the lenalidomide and control groups (79% vs.
73%, P=0.8) (36). The median interval between time of progression and death was
relatively short (11 vs. 13 months). Patients on lenalidomide maintenance therapy
had an increased incidence of secondary malignancies (26 vs. 6 cases). Common
toxicities were relatively low: treatment was discontinued due to toxicity in 21% of
patients on lenalidomide and in 15% on placebo.
The MM-015 three-arm trial randomized elderly patients to 9 cycles of MPR followed
by lenalidomide maintenance treatment (MPR-R) until PD or intolerance, or to 9
cycles of MPR, or MP without maintenance therapy (38). The MPR regimen resulted
in significantly higher response rates (MPR-R: 77%, MPR: 68%, MP: 50%, P<0.001)
with roughly three times as many CRs in the maintenance arm compared to MP only
(MPR-R: 16%, MPR: 10%, MP: 4%, P<0.001). Sixty percent of responses were
achieved within 3 months, but improvements in the quality of response occurred with
continued treatment, particularly during the first year, with few patients achieving
further tumor reduction thereafter. After a median follow-up of 21 months, PFS and
time to next treatment were significantly longer with lenalidomide maintenance
treatment (31 vs. 14 vs. 13 months for MPR-R, MPR, and MP, respectively; MPR-R
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vs. MP, HR: 0.398, P<0.00001 and median not reached vs. 66.3 weeks, HR 0.34,
95% CI [0.28, 0.56], log rank P<0.001, respectively). OS rate at 2 years was similar
between the 3 groups (75%-82%). A landmark analysis at the beginning of cycle 10
showed similar increase in PFS with MPR-R in patients aged 75 years (HR: 0.39,
P=0.12), but as tolerance in this age group was poor, a significant PFS improvement
in the entire group of elderly patients (>75 years) was not observed (HR: 1.04, CI:
0.52 - 2.1). Grade 3 and 4 neutropenia and thrombocytopenia were significantly more
frequent in the MPR arm, and prophylactic G-CSF was administered to 49% of
patients in the MPR-R group compared to 29% of patients in the MP arm; platelet
transfusions were administered to 6% and 5% of patients, respectively. Overall 20%
of patients in the MPR-R, 16% in the MPR, and 8% in the MP group discontinued
therapy due to adverse events. A subsequent analysis revealed an increased rate of
secondary malignancies in the MPR-R and MPR compared to the MP group (12
(8.0%), 9 (5.9%), and 4 (2.6%) patients respectively).
Our meta-analysis of the published results of the 3 lenalidomide maintenance
studies, which included a total of 1380 patients, revealed a 65% risk reduction for
PFS for patients on lenalidomide maintenance therapy (Figure 1C) (HR: 0.45, CI:
0.37, 0.54, P<0.00001).
Bortezomib
The Spanish PETHEMA trial randomized 260 patients aged 65 years or older to
either VMP or to VTP for induction treatment (39) (Table 4). The induction therapy
consisted of one 6-week cycle with biweekly bortezomib followed by five 5-week
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cycles with weekly bortezomib to reduce toxic side effects. Twenty percent of
patients on VMP and 28% on VTP achieved a CR. After a median follow-up of 32
months from first randomization, the median PFS for all patients was 31 months, and
OS at 3-years was 70% with no significant differences between the VMP and VTP
groups in PFS (HR: 1.2, 95%CI: 0.9 - 1.7, P=0.1) and OS (HR: 1.2, 0.7 - 1.9, p=0.1).
VMP treatment was associated with more neutropenia (P=0.008), thrombopenia
(P<0.0001), and infections (P=0.01), and VTP with more cardiotoxicity (P=0.001).
After induction, 178 patients were randomized to either VT or VP maintenance
therapy. Bortezomib maintenance was administered every three months using the
conventional days 1, 4, 8, 11 schedule. The VT group received thalidomide at a dose
of 50 mg/day and the VP cohort received prednisone at a dose of 50 mg/m2 every
other day. Both treatments were given for up to 3 years. VT and VP maintenance
treatment improved the quality of response with the CR (IF-) rate rising from 24% to
44% in patients on the former and to 39% in patients on the latter therapy. After a
median follow-up of 22 months from second randomization, PFS from this time point
was 32 months for patients receiving VT and 24 months for those treated with VP
(HR: 1.4, 95%CI 0.8 - 2.1, P=0.1). The non-significant benefit of VT maintenance
therapy was independent of the type of induction therapy (HR: 1.6, 95%CI: 0.8 - 2.2).
OS did not differ between the two groups (HR: 1.2, 95%CI: 0.6 - 2.4). During
maintenance treatment, no grade 3 or higher hematological toxicities were noted,
and grade 3 PNP was seen in 2% of patients in the VP and 7% in the VT group (39).
A GIMEMA (40) study randomized 511 patients to either nine 6-week cycles of VMPT
induction therapy followed by VT maintenance or to nine 6-week cycles of VMP
induction treatment. After inclusion of 139 patients, the biweekly administration of
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bortezomib was reduced to a once-weekly schedule to enhance tolerance of
bortezomib, and both the VMPT and the VMP schedules were changed to nine 5-
week cycles. Patients on VMPT followed by VT maintenance achieved a higher rate
of CR and VGPR (38% vs. 24%, P<0.001, and 59% vs. 50%, P=0.03 respectively)
and had both a significantly higher rate of PFS at 3-years (56% vs. 41%, P=0.008)
and a longer time to next treatment (72% vs. 60%, P=0.007). The OS rate at 3-years,
however, was similar in both groups (89% vs. 87%, P=0.77). Patients in the
extensive treatment arm experienced more grade 3 and 4 neutropenia (38% vs. 28%,
P=0.02), thromboembolic events (5% vs. 2%, P=0.08), and cardiologic side effects
(10% vs. 5%, P=0.04).
The joint HOVON/GMMG trial randomized 613 patients to bortezomib-doxorubicin-
dexamethasone (PAD) or VAD induction therapy followed by single or double ASCT
(41). Patients started on PAD received bortezomib maintenance (1.3 mg/m2,
biweekly for 2 years) and those randomized to VAD were treated with thalidomide
maintenance therapy (50 mg, daily for 2 years). After a median follow-up of 40
months, nCR/CR rate was 38% in the VAD/ASCT/thalidomide arm and 50% in the
PAD/ASCT/bortezomib arm; the respective rates for VGPR were 61% and 75%.
PFS and OS were significantly longer in the PAD/ASCT/bortezomib-treated patients
(HR: 0.81, P=0.047, and HR: 0.74, P=0.048, respectively), with PFS and OS rates at
36 months of 48% and 78% in the VAD/ASCT/thalidomide group and of 42% and
71% in the PAD/ASCT/bortezomib/group, respectively. 67% of patients in the
VAD/ASCT/thalidomide arm and 57% in the PAD/ASCT/bortezomib arm started
maintenance therapy. 64% of those on thalidomide maintenance discontinued
maintenance therapy because of PD (31%), toxicity (31%) and other reasons (2%).
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IMWG consensus on maintenance therapy in multiple myeloma
In the bortezomib arm, 47% discontinued maintenance because of PD (29%), toxicity
(9%), or other reasons (9%). In essence, the PAD/ASCT/bortezomib protocol was in
all study objectives superior to the VAD/ASCT/thalidomide regimen, including
patients with renal impairment (42) and with adverse FISH-determined cytogenetics
(t [4; 14], amplification of 1q21, and del 17p) (43).
Discussion
After the demonstration of the limited benefits of interferon (4, 5) and corticosteroids
(6-10) as maintenance therapy, thalidomide became the next logical candidate for
clinical evaluation. The absence of severe hematotoxicity and its availability as an
oral drug are favorable prerequisites for long-term use, but these advantages are
partly abrogated by its specific toxicity profile, in particular neurotoxicity. Thalidomide
as maintenance treatment has mainly been studied in young patients after ASCT. In
three trials (16, 18, 22) thalidomide therapy was started during induction phase in at
least 50% of patients, while in the other three studies (14, 15, 23) thalidomide was
used after ASCT during the maintenance phase only. In all studies a moderate
improvement in the quality of response and a significant increase in PFS or EFS
were noted, while OS was only significantly increased in two individual trials without
thalidomide-containing induction therapy (14, 15). When the five trials with sufficient
available data were analyzed, a gain in PFS or EFS as well as in OS was noted for
thalidomide maintenance therapy after ASCT (24).
An interesting phenomenon of different outcomes at different periods of trial maturity
was noted in the total therapy II and the IFM studies. In the former study, OS was not
different after 42 months of follow up, became superior in patients with metaphase-
18

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IMWG consensus on maintenance therapy in multiple myeloma
defined adverse cytogenetics after 70 months, and was significantly longer in the
total group of patients after 87 months of follow-up. In the IFM study an analysis of
88% of patients initially enrolled revealed an inverse pattern, with a significant
advantage seen at first analysis that was lost at later follow-up (21) The pattern of
increasing benefit in the TTII trial indicates the favorable impact of thalidomide
maintenance primarily in good-risk patients, because an effect in high-risk patients
should have become evident much earlier. The conversion of survival curves after
long follow-up in the IFM trial does not support this explanation, and may reflect the
significant influence of salvage therapy in good-risk patients on overall survival.
Both thalidomide maintenance trials in elderly patients (16, 25) included roughly 50%
of patients that had already been exposed to thalidomide-containing regimens in the
induction phase. PFS was significantly increased with thalidomide, while for OS no
difference was noted. Similar to the results obtained in younger patients, survival
after relapse was significantly shorter in elderly patients randomized to thalidomide
maintenance therapy. When all data of thalidomide maintenance trials published or
presented at meetings were meta-analyzed, a significant reduction in the risk for
disease progression and for death was observed (figure 3).
In the 4 trials comparing MP with MPT plus thalidomide maintenance treatment, a
borderline increase in OS was noted in 1 study only (30), while in the two trials
without thalidomide maintenance therapy (26, 27) OS was significantly improved,
showing no or minor effect of thalidomide maintenance therapy after MPT. When all
six trials were meta-analyzed employing individual patient data (32) or results of
published studies (33), a significant improvement in both PFS and OS was noted.
19

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IMWG consensus on maintenance therapy in multiple myeloma
The improvement in quality of response with thalidomide maintenance reported in
most trials (14, 15, 16, 18, and 22) supports a consolidation in addition to a
maintenance effect of thalidomide. Patients with unfavorable cytogenetics defined by
FISH did not benefit from thalidomide maintenance in the IFM and the MRC IX
studies, and patients with del17p may even experience worse outcome as suggested
by data from the MRC study (17). These observations and evidence from other
studies suggest that patients without FISH-defined cytogenetic risk factors are more
likely to benefit from thalidomide maintenance treatment while those with a FISH-
defined high-risk profile likely should not be offered this form of maintenance therapy.
In Arkansas, genetic risk is defined both by metaphase cytogenetics and more
recently by gene expression profiling (44). Patients defined this way are only party
comparable to FISH-defined high-risk patients, which may explain the greater benefit
of thalidomide in the Arkansas high-risk group.
The optimal dose of thalidomide should be the minimal effective dose that is
associated with superior tolerance and least toxicity. Since its introduction, the doses
of thalidomide have continuously been decreased from the initial 400 mg/day (18) to
as little as 50 mg/day in the HOVON-50 study (22). As the results have been similar
in most trials, a dose of 50 to 100 mg/day may be recommended as the starting
dose.
The median duration of thalidomide treatment varied between 13.2 months in elderly
patients (25), 15 months in the IFM trial (14), and almost 24 months in the HOVON
study (22), which used the lowest dose of thalidomide and in which 47% of patients
20

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IMWG consensus on maintenance therapy in multiple myeloma
were still on therapy at that time point. Recommending a specific length of
thalidomide therapy is difficult, but in a multivariate analysis, no impact of treatment
duration was noted (20). Limiting the duration of thalidomide exposure should reduce
the risk of severe side effects, particularly of polyneuropathy which is the most
relevant toxicity (14, 15). Other side effects are constipation, fatigue, mood
disturbances, and, particularly in elderly patients, arrhythmias, bradycardia and
thromboembolic complications
Lenalidomide is an attractive drug for maintenance therapy. It inhibits proliferation of
myeloma cell lines even in those with high-risk cytogenetic abnormalities such as t
(4; 14), t (14; 16), del17p, del13, and hypodiploidy (45), and was found to be
particularly active in patients with high IRF4 expression (46). Dexamethasone
enhances the anti-myeloma effect of lenalidomide (47), but antagonizes the
immunostimulatory effects in a dose-dependent manner (45). Hence, single-agent
lenalidomide seems to be the logical choice for maintenance treatment when tumor
load has already been reduced significantly and control of the residual tumor cells by
active immune surveillance is the clinically relevant priority. A pilot phase II study
showing the feasibility and efficacy of lenalidomide consolidation and maintenance
therapy laid the basis for further clinical testing (48). The significant increase in PFS
with reduction of the relative risk of relapse by 65% is unprecedented. Importantly,
lenalidomide maintenance treatment is similarly active in patients with different risk
profiles and even in those with unfavorable cytogenetics (36), but while better than
control, it is does not fully overcome the poorer prognosis conferred by certain
cytogenetic risk factors such as t(4;14). Lenalidomide maintenance therapy is
effective both in patients subjected to high-dose therapy with ASCT (35, 36) and in
21

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IMWG consensus on maintenance therapy in multiple myeloma
those treated with conventional therapy (37). In elderly patients, a phase 2 trial with
MPR was the forerunner for the MM15 trial (49). Lenalidomide maintenance therapy
turned out to be effective even after extensive use during the induction phase, which
was comprised of 9 cycles of MPR. Lenalidomide maintenance treatment has
recently been shown to increase survival in the CALGB study (35). The results of this
and the other lenalidomide maintenance studies have as yet been presented at
meetings only and longer follow-up is needed to confirm whether the positive finding
in this CALGB study is robust and whether similar improvements will be seen in the
IFM study, which differed in respect to the patient population and treatment. If good-
risk patients benefit more from lenalidomide maintenance, survival curves should
start to diverge after prolonged follow-up.
In any event, a time span without progression of disease is associated with better
quality of life (50), and hence, of substantial benefit to the patient. Lenalidomide
maintenance therapy was well tolerated with almost negligible hematotoxicity, no
neurotoxicity, and no increase in thromboembolic complications or infections. The
observation of increased occurrence of second primary malignancies (SPM),
however, is of major concern. The incidence of SPM was highest in the IFM trial,
where a proportion of patients had been exposed to intensive induction therapy
incorporating DCEP, which contains drugs of known leukemogenic potential. Further
studies are needed to evaluate the true risk of this complication, to identify risk
factors for its development, and hopefully to develop strategies for prevention of
SPMs. Before more information is available, physicians and patients must carefully
weigh the impressive benefits of lenalidomide maintenance therapy against the low
but relevant risk of SPM.
22

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IMWG consensus on maintenance therapy in multiple myeloma
Two studies employed bortezomib in combination with thalidomide for maintenance
treatment either in comparison to control or to bortezomib plus prednisone
maintenance therapy (38, 39). Combining 2 drugs with significant neurotoxic potential
poses the risk of prohibitive toxicity, but contrary to such concerns, clinical
experience shows an acceptable tolerance if a 'low-dose intensity' concept is used.
Thalidomide was administered at a daily dose of 50 mg continuously, and the dose
intensity for bortezomib was 6 doses over three months in the Italian study and 4
doses over the same period in the Spanish study. VT maintenance treatment
resulted in a low rate of grade 1-2 neurotoxicity and a low discontinuation rate, as
well as a tendency for increased PFS in comparison to bortezomib plus prednisone
(32 vs. 24 months, P=0.1) in the PETHEMA study (39). In the GIMEMA trial (38),
there was a tendency for an increase in PFS (P=0.07) compared to control. OS did
not differ between VT and VP maintenance therapy in the Spanish study, and in the
Italian trial, no difference in the survival rates at 3 years were noted between patients
receiving VT maintenance therapy or those randomized to the control arm (88.1% vs.
89.2%, P=0.9). The manifold unresolved issues concerning the mode of action of
bortezomib during maintenance makes recommendations for its optimal use--in
particular scheduling, dosing, and combination with other drugs--difficult. Its
significant activity in patients with different risk profiles seems to particularly
predispose it for induction and consolidation treatments.
The comparison of PAD induction therapy followed by ASCT and bortezomib
maintenance with VAD/ASCT and thalidomide maintenance treatment in the
combined HOVON/GEMMG trial revealed a significantly better outcome with the
bortezomib-based induction and bortezomib maintenance therapy (41). Patients in
23

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IMWG consensus on maintenance therapy in multiple myeloma
this arm had better quality responses and longer PFS and OS, and this was also true
for patients with adverse cytogenetic features and renal impairment. However, a
direct comparison between bortezomib and thalidomide as maintenance treatment in
this trial is not possible, because both drugs had already been used in the respective
treatment arms during induction therapy. The study showed that bortezomib
maintenance therapy can be tolerated for up to 2 years, but dose reductions were
required in 27% of patients and 9% discontinued treatment because of toxicity.
Recommendations for clinical practice
Presently, in most countries none of the drugs evaluated for maintenance therapy is
approved for this indication. Nevertheless, patients will find access to the available
information and will query their treating physicians about possible treatment options
after induction therapy. Based on available scientific evidence (table 5), thalidomide
maintenance treatment after ASCT is a possible option that increases PFS and,
albeit to a lesser degree, OS. Thalidomide maintenance should not be offered to
patients with FISH-defined poor-risk cytogenetics, because those patients had
inferior outcome with thalidomide maintenance therapy compared to controls. The
lowest dose shown to be active is 50 mg daily, and the duration of therapy should
possibly be limited to one year or less in order to limit the risk of significant toxicity.
For elderly patients, the situation is less clear. In both studies conducted so far,
roughly half the patients had already been exposed to thalidomide during induction
therapy. Results showed a significant increase in PFS, but not in survival.
Thalidomide maintenance therapy in elderly patients therefore is also a valuable
option, but thalidomide tolerance decreases with increasing age. Results of some
studies suggest that thalidomide maintenance should preferentially be considered in
24

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IMWG consensus on maintenance therapy in multiple myeloma
patients who have not been exposed to thalidomide during induction therapy, but this
has not been confirmed by the MRC trial (16).
Lenalidomide after ASCT is associated with significantly increased PFS (35, 36, 38),
and in one study (35), also with a significant survival benefit. It is well tolerated and
active in all risk groups including FISH-defined cytogenetic risk, with the exception of
patients with del 17p (37). The starting dose should be 10 mg daily, with dose
modification between 5 to 15 mg being feasible. Both continuous treatment as well as
a three weeks on, one week off regimen have been shown to be effective. So far,
treatment has been continued until PD or untoward toxicity. It is not clear whether
shorter therapy would render similar effects. In elderly patients, only one prospective
randomized trial has been presented as yet. Results are essentially identical to those
obtained in younger patients; thus, the same recommendations apply to elderly and
younger patients. Recent updates of all three studies indicate that exposure to
lenalidomide confers an increased risk for secondary malignancies. Whether
lenalidomide maintenance therapy should be routinely offered to patients is
controversial among experts. Some consider the marked gain in PFS and the
survival advantage observed in one of the two studies in younger patients as strong
argument for therapy, while others weigh the increased incidence of SPMs as a
serious risk and prefer to wait for more solid data before making a firm
recommendation.
Data on single-agent bortezomib maintenance treatment are available only in
patients who had already been exposed to bortezomib during induction therapy (41).
Twice-weekly bortezomib maintenance therapy is feasible and can be tolerated for
25

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IMWG consensus on maintenance therapy in multiple myeloma
up to 2 years, but dose reductions may be necessary in up to one third of patients.
Although a significant benefit of bortezomib maintenance therapy is likely, the design
of the study allows only the conclusion that a bortezomib - based induction regimen
followed by ASCT and bortezomib maintenance is superior to VAD induction followed
by ASCT and thalidomide maintenance therapy. Bortezomib maintenance in
combination with thalidomide has been shown to yield superior PFS compared to
control (38) or (although not statistically significant) compared to bortezomib plus
prednisone in elderly patients (39). Further studies, particularly in patients not
previously exposed to these drugs during induction phase, are warranted.
26

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IMWG consensus on maintenance therapy in multiple myeloma
References
1. Alabamian R, Balderas 5, Behan E, Haut A, Hewlett J. Remission maintenance
therapy for multiple myeloma. Arch Intern Med 1975. 135:147-152.
2. Alabamian R, Behan E, Haut A, Saiki J, Wick J. Unmaintained remissions in
multiple myeloma. Blood. 1978; 51(6):1005-11.
3. Belch A, Shelley W, Bergsagel D, et al. A randomized trial of maintenance versus
no maintenance melphalan and prednisone in responding multiple myeloma
patients. Br J Cancer. 1988; 57(1):94-9.
4. Myeloma Trialists' Collaborative Group. Interferon as therapy for multiple
myeloma: an individual patient data overview of 24 randomized trials and 4012
patients. Br J Haematol. 2001; 113(4):1020-34.
5. Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis
of 30 randomized trials among 3948 patients. Ann Oncol. 2000; 11(11):1427-36.
6. Kumar S, Lacy MQ, Dispenzieri A, et al. Single agent dexamethasone for pre-
stem cell transplant induction therapy for multiple myeloma. Bone Marrow
Transplant. 2004; 34(6):485-90.
7. Rosignol L, Oriol A, Mateos MV, et al. Phase II PETHEMA Trial of alternating
bortezomib and dexamethasone as induction regimen before autologous stem-
cell transplantation in younger patients with multiple myeloma: Efficacy and
clinical implications of tumor response kinetics. J Clin Oncol. 2007; 25(28):4452-8
8. Berenson JR, Crowley JJ, Grogan TM, et al. Maintenance therapy with alternate-
day prednisone improves survival in multiple myeloma patients. Blood. 2002;
99(9):3163-8.
27

---

IMWG consensus on maintenance therapy in multiple myeloma
9. Shustik C, Belch A, Robinson S, et al. A randomized comparison of melphalan
with prednisone or dexamethasone as induction therapy and dexamethasone or
observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J
Haematol. 2007; 136(2):203-11.
10. Alexanian R, Weber D, Dimopoulos M, Delasalle K, Smith TL. Randomized trial
of alpha-interferon or dexamethasone as maintenance treatment for multiple
myeloma. Am J Hematol. 2000; 65(3):204-9.
11. Whitehead A: Meta-analysis of controlled clinical trials. Wiley, Chichester,
England, 2002
12. Parmar MK, Torri V, Stewart L.Extracting summary statistics to perform meta-
analyses of the published literature for survival endpoints. Stat Med. 1998;
30;17(24):2815-34
13. Mellstedt H, Aahre A, Bjørkholm M, et al. Interferon therapy in myelomatosis.
Lancet. 1979; 2(8144):697.
14. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide
improves survival in patients with multiple myeloma. Blood 2006; 108:3289-94.
15. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose
thalidomide and prednisolone prolongs the survival of multiple myeloma patients
undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol
2009; 27:1788-93.
16. Morgan GJ, Davies FE, Gregory WM, et al. The Addition of Thalidomide to the
Induction Treatment of Newly Presenting Myeloma Patients Increases the CR
Rate Which Is Likely to Translate Into Improved PFS and OS. Blood (ASH Annual
Meeting) 2009; 114, 22, abstract 352
28

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IMWG consensus on maintenance therapy in multiple myeloma
17. Morgan GJ, Davies FE, Gregory WM et al., Cyclophosphamide, thalidomide, and
dexamethasone (CTD) as initial therapy for patients with multiple myeloma
unsuitable for autologous transplantation. BLOOD; 118(5), 1231-8.
18. Morgan GJ, Davies FE, Gregory WM et al. Thalidomide Maintenance Significantly
Improves Progression-Free Survival (PFS) and Overall Survival (OS) of Myeloma
Patients When Effective Relapse Treatments Are Used: MRC Myeloma IX
Results, BLOOD (ASH annual meeting) 2010; 116, 21, abstract 623
19. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell
transplantation for multiple myeloma. N Engl J Med. 2006; 354(10):1021-30.
20. Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of total therapy
2 improves complete remission duration and survival in myeloma patients with
metaphase cytogenetic abnormalities. Blood 2008; 112:3115-3121.
21. Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation
trials for multiple myeloma: update of protocols conducted by the Intergroupe
Francophone du Myelome, Southwest Oncology Group, and University of
Arkansas for Medical Sciences. J Clin Oncol. 2010; 28(7):1209-14
22. Lokhorst HM, Schmidt-Wolf I, Sonneveld P, et al. Thalidomide in induction
treatment increases the very good partial response rate before and after high-
dose therapy in previously untreated multiple myeloma. Haematologica 2008;
93:124-127.
23. Stewart KA, Trudel S, Bahlis NJ et al. A Randomized Phase III Trial of
Thalidomide and Prednisone as Maintenance Therapy Following Autologous
Stem Cell Transplantation (ASCT) In Patients with Multiple Myeloma (MM): The
NCIC CTG MY.10 Trial. BLOOD (ASH annual meeting) 2010; 116, 21, abstract
39.
29

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IMWG consensus on maintenance therapy in multiple myeloma
24. Hahn-Ast C, Lilienfeld-Toal M, Heteren P et al. Improved progression-free and
overall survival with thalidomide maintenance therapy after autologous stem cell
transplantation in multiple myeloma: A meta-analysis of five randomized trials:
Hematologica 2011; 96 (s2), EHA abstract 884.
25. Ludwig H, Adam Z, Tóthová E, et al. Thalidomide maintenance treatment
increases progression-free but not overall survival in elderly patients with
myeloma. Haematologica. 2010; 95(9):1548-54.
26. Palumbo A, Bringhen S, Caravita T, et al. Italian Multiple Myeloma Network,
GIMEMA. Oral melphalan and prednisone chemotherapy plus thalidomide
compared with melphalan and prednisone alone in elderly patients with multiple
myeloma: randomized controlled trial. Lancet. 2006; 367(9513):825-31.
27. Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and
thalidomide in elderly patients with multiple myeloma: updated results of a
randomized, controlled trial. Blood 2008; 112: 3107-14.
28. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide
versus melphalan and prednisone alone or reduced-intensity autologous stem cell
transplantation in elderly patients with multiple myeloma (IFM 99-06): a
randomise trial. Lancet 2007; 370:1209-18.
29. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus
thalidomide in patients older than 75 years with newly diagnosed multiple
myeloma: IFM 01/01 Trial. J Clin Oncol. 2009; 27(22):3664-70.
30. Wijermans PW, Schaafsma M, Termorshuizen F, et al. Phase III study of the
value of thalidomide added to melphalan plus prednisone in elderly patients with
newly diagnosed multiple myeloma: The HOVON 49 Study. J Clin Oncol. 2010;
28(19):3160-6.
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IMWG consensus on maintenance therapy in multiple myeloma
31. Waage A, Gimsing P, Fayers P, et al. Melphalan and prednisone plus thalidomide
or placebo in elderly patients with multiple myeloma. Blood. 2010; 116(9):1405-
12.
32. Beksac M, Haznedar R, Firatli-Tuglular T, et al. Addition of thalidomide to oral
melphalan/prednisone in patients with multiple myeloma not eligible for
transplantation: results of a randomized trial from the Turkish Myeloma Study
Group. Eur J Haematol. 2011; 86(1): 16­22
33. Fayers P, Palumbo A, Hulin C et al. Thalidomide for previously untreated
untreated elderly patients with multiple myeloma: A meta-analysis of 1,682
individual patient data from six randomized clinical trials. BLOOD; 2011,
118:1239-1247
34. Kapoor P, Rajkumar SV, Dispenzieri A, Gertz MA, Lacy MQ. Melphalan and
prednisone versus melphalan, prednisone and thalidomide for elderly and/or
transplant
ineligible
patients
with
multiple
myeloma:
a
meta-analysis.
Leukemia 2011; 25(4):689-96.
35. McCarthy PL, Owzar K, Anderson KC. et al. Phase III Intergroup study of
lenalidomide versus placebo maintenance therapy following single autologous
hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM):
CALGB ECOG BMT-CTN 100104. Haematologica 2011; 96; (s1): IMW 2011,
abstract s23.
36. Attal M, Cances Lauwers V, Marit G, et al. Maintenance treatment with
lenalidomide after transplantation for myeloma: final analysis of the IFM 2005-02.
BLOOD (ASH annual meeting) 2010; 116, 21, abstract 310.
37. Attal M, Olivier F, Cances Lauwers V. et al. Maintenance treatment with
lenalidomide
after
transplantation
for
myeloma:
Analysis
of
secondary
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---

IMWG consensus on maintenance therapy in multiple myeloma
malignancies within the IFM 2005-02 trial. Heamatologica 2011; 96 (s1): IMW
2011, abstract s23
38. Palumbo A, Delforge M, Catalano J, et al. A phase 3 study evaluating the efficacy
and safety of lenalidomide combined with melphalan and prednisone in patients
65 years with newly diagnosed multiple myeloma (NDMM): continuous use of
lenalidomide vs fixed-duration regimens. BLOOD (ASH annual meeting) 2010;
116, 21, abstract 622.
39. Mateos MV, Oriol A, Martínez-López J, et al. Bortezomib, melphalan, and
prednisone versus bortezomib, thalidomide, and prednisone as induction therapy
followed by maintenance treatment with bortezomib and thalidomide versus
bortezomib and prednisone in elderly patients with untreated multiple myeloma: a
randomised trial. Lancet Oncol. 2010;11(10):934-41.
40. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-
thalidomide followed by maintenance with bortezomib-thalidomide compared with
bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a
randomized controlled trial. J Clin Oncol. 2010;28(34):5101-9.
41. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMG-HD4
Randomized Phase III Trial Comparing Bortezomib, Doxorubicin, Dexamethasone
(PAD) vs VAD Followed by High-Dose Melphalan (HDM) and Maintenance with
Bortezomib or Thalidomide In Patients with Newly Diagnosed Multiple Myeloma
(MM). BLOOD (ASH annual meeting) 2010; 116, 21, abstract 40.
42. Scheid C, Sonneveld P, Ingo Schmidt-Wolf I, et al. Influence of renal function on
outcome of VAD or bortezomib, doxorubicin, dexamethasone (PAD) induction
treatment followed by high-dose melphalan (HDM): A subgroup analysis from the
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HOVON-65/GMMG-HD4 randomized phase III trial for newly diagnosed multiple
myeloma. BLOOD (ASH annual meeting) 2010; 116, 21, abstract 2396.
43. Goldschmidt H, Neben K, Bertsch U, et al. Bortezomib-Based Induction Therapy
Followed by Autologous Stem Cell Transplantation and Maintenance Therapy
with Bortezomib Improves Outcome In Myeloma Patients with Gain 1q21 and t(4;
14) - a Subgroup Analysis of the HOVON-65/GMMG-HD4 Trial. BLOOD (ASH
annual meeting) 2010; 116, 21, abstract 305.
44. Zhou Y, Barlogie B, Shaughnessy JD Jr. The molecular characterization and
clinical management of multiple myeloma in the post-genome era. Leukemia.
2009; 23(11):1941-56.
45. Gandhi K, Kang A, Capone J, et al. Dexamethasone Synergizes with
Lenalidomide
to
Inhibit
Multiple
Myeloma
Tumor
Growth,
But
Reduces
Lenalidomide-Induced Immunomodulation of T and NK Cell Function. Current
Cancer Drug Targets 2010; 10:155-167. 51
46. Lopez-Girona A. Heintel E. Zhang L. et al. Lenalidomide downregulates the cell
survival factor interferon regulatory factor-4, providing a potential mechanistic link
for predicting response. Br. J. Haematol 2011, 154(3):325-36.
47. Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone is
more effective than dexamethasone alone in patients with relapsed or refractory
multiple myeloma regardless of prior thalidomide exposure. Blood. 2008;
112(12):4445-51.
48. Palumbo A, Gay F, Falco P, et al. Bortezomib as induction before autologous
transplantation, followed by lenalidomide as consolidation-maintenance in
untreated multiple myeloma patients. J Clin Oncol. 2010; 28(5):800-7.
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IMWG consensus on maintenance therapy in multiple myeloma
49. Palumbo A, Falco P, Corradini P, et al.; Melphalan, prednisone, and lenalidomide
treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian
Multiple Myeloma Network. GIMEMA--Italian Multiple Myeloma Network. J Clin
Oncol. 2007; 25(28):4459-65.
50. Dimopoulos MA, Delforge M, Hájek R,et al. Lenalidomide plus melphalan and
prednisone followed by lenalidomide maintenance provides favorable efficacy and
health related quality-of-life in newly diagnosed multiple myeloma patients over 65
years. Heamatologica 2011; 96 (s2), EHA Congress, abstract 880.
Legends:
Table 1.
Thalidomide maintenance studies after ASCT and conventional therapy
Table 2.
MPT versus MP trials. Four of the six trials incorporated thalidomide
maintenance therapy
Table 2.
Maintenance studies with lenalidomide in patients after ASCT and after
conventional chemotherapy
Table 4.
Maintenance and consolidation studies with bortezomib in combination
with thalidomide or prednisone
Table 5.
Summary of benefits and limitations of maintenance therapy with novel
drugs for clinical decision making
Figure 1.
Meta-analysis of maintenance studies. 1A progression free survival with
thalidomide or thalidomide combinations in young and older patients. 1B
overall survival with or thalidomide combinations in young and older
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IMWG consensus on maintenance therapy in multiple myeloma
patients. 1C progression-free survival with lenalidomide maintenance
therapy in young and older patients
35

---

IMWG consensus on maintenance therapy in multiple myeloma
Table 1.
Study group
Age
Induction Therapy
Maintenance
Improve
EFS or PFS
OS
Survival
after
Thalidomide
Dose, duration of TX
ment
in
relapse
Tolerance
# of Pts
quality of
response
IFM 99-02
<65 yrs
VAD: 3-4 cycles,
A)
Thalidomide
VGPR
3-year EFS:
4-year OS:
1- year OS:
39%
stopped
Attal et al.,
single ASCT
400mg/d until PD
A) 67%
A) 52%
A) 87%
A) 75%
Thal due to side
2006 [14]
N = 597
Pamidronate
90mg,
effects,
mostly
q4w, until PD
PNP, all grades
of PNP 68%,
B) Pamidronate 90mg,
B) 55%
B) 37%
B) 74%
B) 73%
G3-4: 7%
q4w, until PD
C) None
C) 57%
C) 36%
C) 77%
C) 78%
P=0.03
P<0.009
P<0.04
P=0.7
ALLG
MM6
70 yrs
Mostly VAD
A) Thalidomide 100 -
VGPR
3-year
PFS
3-year
OS
1-year
OS
30%
stopped
Spencer
et
single ASCT
200mg/d, for 12 months
A) 65%
estimate:
estimate:
estimate:
therapy
due
to
al.,
2009
N= 243
Prednisolone 50mg on
A) 42%
A) 86%
A) 79%
intolerance
[15]
alternate days until PD
(mostly
PNP),
10% G3-4 PNP
B) Prednisolone 50mg
B) 44%
B) 23%
B) 75%)
B) 77%
and 9% stopped
on alternate days until
P=0.001
P<0.001
P=0.004
P=0.237
due to PD
PD
MRC
Median:
Young
patients:
A)
Thalidomide,
50
17%
Significant.
No significant
Significantly
n.a
myeloma IX,
59 yrs
CVAD
vs.
CTD,
100mg/d, until PD
increase
improvement
in
difference
reduced OS from
Morgan
et
and
single ASCT
in
CR
PFS
with
Thal
relapse after Thal
al.,
2010
median:
older Patients:
rate
P=0.003
exposure.
[16]
73 yrs
CTD attenuated vs.
B) None
for
<VGPR
after
P=0.05,
more
MP
ASCT (P=0.007);
pronounced
in
N = 820
worse
outcome
FISH
high
risk
with Thal in pts with
patients
del17p
TT2
75 yrs
4 induction cycles,
A) Thalidomide 100mg
CR
4-year EFS
OS
Median OS
30%
stopped
Barlogie
et
double ASCT
during the first year,
A) 62%
A) 65%
A) not stated
A) 1.1 yrs
Thal within 2 yrs
al.,
2006
N = 668
4
consolidation
thereafter
50mg
on
[18]
cycles,
alternate days, until PD
Thalidomide
400mg/d
during
induction,
100mg
between
ASCT,
36

---

IMWG consensus on maintenance therapy in multiple myeloma
Study group
Age
Induction Therapy
Maintenance
Improve
EFS or PFS
OS
Survival
after
Thalidomide
Dose, duration of TX
ment
in
relapse
Tolerance
# of Pts
quality of
response
200mg
with
consolidation
Same
induction
B) None
B) 43%
B) 44%
B) not stated
B) 2.7 yrs
without thalidomide
P=0.001
P=0.01
P=0.9
P=0.001
TT2
CR
EFS Median:
8-year
OS
5
yrs
OS
80% stopped
Barlogie
et
A) 64%*
A) 6.0 yrs
estimate:
estimate:
Thal due toxicity
al.,
2008
A) 57%
A) 27%
within 2 years*
[19]
B) 43%
B) 4.1 yrs
B) 44%
B) 23%
P=0.001
P=0.001
P=0.09
P=0.11
TT2
n.a
EFS
Median
OS
Median
7,2
yrs
OS
n.a
Barlogie
et
4.8 years
9 years
estimate
al.
A) 45,2%
2010 [20,21]
B) 42.2%
P=0.27
HOVON 50
65 yrs
VAD vs. TAD
A)
Thalidomide,
VGPR
EFS:
Median
Median OS
PNP G2-4:50%
Lokhorst
et
Single
or
double
50mg/d, until PD
A) 66%
A) 34 months
A) 73 months
A) 20 months
Treatment
al.,
2010
N = 536
ASCT
B)
22
months,
discontinued
or
[22]
P<0.001
dose
reduced:
B) IFN, 3 Mega U,
B) 54%
B) 60 months
B) 31 months
58%
TIW, until PD
P=0.005
P=0.77
P=0.009
PFS:
A) 34 months
B) 25 months
P<0.001
NCIC
CTG
58 yrs
Induction
therapy
A)
Thalidomide
PFS:
4-year
OS
Increased
MY.10
not specified
200mg/d and alternate
A) 28 months
estimate
toxicity including
Stewart et al
N=332
Single ASCT
day prednisone 50mg,
A) 68%
PNP
and
2010 [23]
until PD
reduced
QOL,
improved
appetite
and
sleep
VTE: 7%
B) none
B) 17 months
B) 60%
VTE:0%
37

---

IMWG consensus on maintenance therapy in multiple myeloma
Study group
Age
Induction Therapy
Maintenance
Improve
EFS or PFS
OS
Survival
after
Thalidomide
Dose, duration of TX
ment
in
relapse
Tolerance
# of Pts
quality of
response
P<0.0001
P=0.21
CEMSG
Median:
Thal/Dex vs. MP
A) Thalidomide 200mg
A) PR to
PFS:
A)
52.6
OS after PD:
PNP G3-4: 11%
Ludwig
et
72 yrs
up to max. tolerated
VGPR or
A) 27.7 months
months
A)
8.1
months
al.,
2010
dose, until PD
CR: 8%
[24]
N = 124
B) IFN -2b, 3 Mega U,
B) PR to
B) 13.2 months
B)
51.4
B) 25.5 months,
TIW
VGPR or
P=0.0068
months
P=0.056
CR: 2%
P=0.81
38

---

IMWG consensus on maintenance therapy in multiple myeloma
Table 2.
Study group
Age (median)
Induction
Maintenance
Improvement in
EFS or PFS
OS
Survival
after
Thalidomide
Therapy
Dose, duration
quality
of
relapse
Tolerance
# of Pts
of TX
response
GIMEMA
65 yrs (72 A) MPT
Thalidomide
CR + PR
2-year EFS
3-yrs OS:
A) 11.5 months
G 3-4 AEs
Palumbo et al.,
yrs)
Thalidomide
100mg/day
A) 76.0%
A) 54%
A) 80%
B) 24.3 months
A) 48%
2006 [26]
100mg/day
until relapse
B) 47.6%
B) 27%
B) 64%
P=0.01
B) 25%
N=255
6 cycles
P=0·0006
P=0.19
P=0·0002
nCR/CR
B) MP
A) 27.9%
6 cycles
B) 7.2%
GIMEMA
(72 yrs)
A) MPT
Thalidomide
CR+VGPR
PFS
A) 45 months
n.a
G 3-4
Palumbo et al.,
6 cycles
100mg/day
A) 44.9%
A) 21.8 months
B) 47.6 months
A) 55%
2008 [27]
N=331
until relapse
B) 14.7%
B) 14.5 months
P=0.79
B) 22%
B) MP
P<0.001
P=0.001
6 cycles
IFM
65-75 years
A) MPT
no
A) 27.5 months
A) 51.6 months
Similar
G3-4,
Facon et al
N=445
Thalidomide
B) 17.8 months
B) 33.2 months
between
TVT: A) 12%
2007 [28]
400mg stopped
C) 19.4 months
C) 38.2 months
groups
B) 4%
after 12 cycles
A
vs.
B,
A
vs.
B,
C) 8%
of MPT
P=0.0001
P=0.0006
Somnolence
A) 8%
B) MP
B) 0
12 cycles
C) 0
C) HDM
Cardiac
A) 2%
B) 0.5%
C) 10%
IFM
75 years
A) MPT
no
CR+VGPR
PFS
A) 44 months
A) 11.5 months
G2-4
Hulin et al
N=232
Thalidomide
A) 21%
A) 24.1 months
B) 29.1 months
B) 9.7 months
PNP
2009 [29]
100mg/day
B) 7%
B) 18.5 months
A vs. B,
P= 0.89
20%
12 cycles
P<0.001
A vs. B,
P=0.028
5%
P=0.001
P<0.01
G3-4
B) MP
Neutropenia
12 cycles
23%
9%
P=0.03
39

---

IMWG consensus on maintenance therapy in multiple myeloma
Study group
Age (median)
Induction
Maintenance
Improvement in
EFS or PFS
OS
Survival
after
Thalidomide
Therapy
Dose, duration
quality
of
relapse
Tolerance
# of Pts
of TX
response
HOVON
>65 years (72
A) MPT
Thalidomide
>PR
EFS
A) 40 months
n.a.
G 2 toxicities
Wijermans
et
yrs)
Thalidomide
50mg/day
A) 66%
A) 13 months
B) 31 months
A) 87%
al.
50mg/day
until relapse
B) 45%
B) 9 months
P=0.05
B) 60%
2010 [30]
N=333
8 cycles
P<0.001
P<0.001
2-yrs
OS:
B) MP
VGPR
PFS
67 vs. 61%
8 cycles
A) 27%
A) 33%
B) 10%
B) 21%
4-yrs
OS:
P<0.001
P=0.05
43% vs. 30%,
2 year-PFS:
A) 34%
B) 14%
NMSG
74.5 yrs
A) MPT
Thalidomide
PR
PFS
A) 29 months
n.a.
G3-4
Non-
Waage et al.
Thalidomide up
200mg/day
A) 57%
A) 15 months
B) 32 months
hematological
2010 [31]
N=357
to 400mg/day
until relapse
B) 40%
B) 14 months
P=0.16
A) 40%
cycles
were
P=0.84*
B) 19%
given
until
VGPR
PNP A) 6%
plateau phase
A) 23%
B)1%
B) 7%
TVT A) 8%
B) MP
P<0.0001
B) 8%
cycles
were
given
until
plateau phase
TMSG
N=122
MPT
Thalidomide
PR
DFS
A) 26 months
Infections (G3-4)
Beksac et al.
Thalidomide
100mg/day
A) 57.9%
A)
21.0
B) 28 months
22.4%
2011 [32]
100mg
continuously
B) 37.5%
months
P = 0.655
B) 7%
12 months
P = 0.03.
B) 14.0 months
MP
P = 0.342
12 months
*P value form oral presentation, definite value not stated in final publication, n.a =not available, n.s. not significant
40

---

IMWG consensus on maintenance therapy in multiple myeloma
Table 3.
Study group
Age
Induction
Maintenance
Improvement
in
TTP or PFS
OS
Survival
after
Lenalidomide
(median),
Consolidation
Dose, duration of
quality
of
relapse
Tolerance
# of Pts
Therapy
TX
response
CALGB
<70 yrs
Any,
followed
by
A) 10 mg/d with
n.a
A)
TTP,
Number
of
n.a
Discontinuation
McCarthy
et
(median
ASCT (M 200)
dose adaptations
median
42.3
deaths
78% of eligible
due to AEs 12%
al. 2011 [35]
n.a.)
(5-15
mg/d)
months
A) 23
patients of the
Due
to
other
N=460
continuously*
control
group
reasons: 13%
had
been
SPM: 15
crossed over to
B) placebo
B)
21.8
B) 39
lenalidomide
Due to AEs 2%
months
P=0.018
TX
Due
to
other
P<0.0001
reasons: 6%
SPM: 6
IFM
<65
yrs
VAD, Vel-Dex and
10-15
mg/d
A)
CR:
25%*
A) 42 months
5 years OS
A)12 months
Discontinuation
Attal et al.,
(55 yrs)
other
induction
continuously*
VGPR: 76%**
A) 79%
due to AEs
2010 [35]
N=614
therapy,
single
or
A)21%
double ASCT
SPM: 26
Consolidation:
lenalidomide
B) placebo
B)
CR:
23%*
B) 24 months
B) 733%
B) 12 months
B) 15%
25mg/d, d 1-21, q
VGPR: 71%**
P<10-8
SPM: 6
28 days, 2 cycles
*P=0.49,
**P=0.13
MM015
65
yrs A) MPR R
10 mg/d, d 1-21,
A) 77%
A) 31 months
2 year OS
n.a.
Discontinuation
Palumbo et al.
(71 yrs)
continuously*
estimate
due to AEs
2010 [37]
N=459
A,
B,
C)
A) 20%
75%-82%
SPM: 8%
B) MPR
B) placebo
B) 68%
B) 14 months.
B)16%
SPM: 5.9%
C) MP
C) placebo
C) 50%
C) 13 months
C) 2.9%
A
vs.
C,
SPM: 2.6%
P<0.00001
SPM: Secondary primary malignancies, *until PD or intolerance, ** Patients on placebo were not allowed to cross over to Lenalidomide after PD
41

---

IMWG consensus on maintenance therapy in multiple myeloma
Table 4.
Study group
Age
Induction
Maintenance Dose, duration of
Improvement
EFS or PFS
OS
Tolerance
(media
Therapy
TX
in quality of
n),
response
# of Pts
PETHEMA
73 yrs
VMP vs. VTP
A) VT: Bortezomib 1.3mg/m2 d
CR IF-
PFS
2-year
OS
G3 and G4 PNP
Mateos et al.,
N=260
1, 4, 8, 11 q12 wks for 3 years
A) 23 44%
A) 32 months
estimate
A) 7%
2010 [38]
Thalidomide 50mg/d for 3 years
A) 86%
B) 2%
Discontinuation due to AEs
A) 8%
B) 5%
B) VP: Bortezomib as above
B)
23%
B) 24 months
B) 81%
Prednisone 50mg q 2 day for 3
39%
HR 1.4, 95%
P=0.7
years
CI 0.8-2.1
P=0.1
GIMEMA
71 yrs
VMPT-VT
Bortezomib 1.3mg/m2, d 1, 15,
CR
3-year PFS
3-year OS
G3 and G4 Neutropenia*
Palumbo et al.,
N=511
q 4 wks
A) 38%
A) 60%
A) 88.8%
A) 38%
2010 [39]
Thalidomide 50mg/d
B) 28.1%
Until PD or intolerance
Cardiologic*
VMP
B) 24%
B) 42%
B) 89.2%
A) 10.4%
P=0.0008
P<0.07
P=0.9
B) 5.5%
HOVON/GMMG
N=613
PAD
Bortezomib 1.3mg/m2 biweekly,
A) CR/nCR
3-year PFS
3-year OS
G 3 and G4 PNP
Sonneveld et al.
for 2 yrs.
50%
A) 48%
A) 78%
A) 16%
2010 [41]
VGPR 65%
VAD
Thal 50mg/d for 2 yrs
B) CR/nCR
B) 42%
B) 71%
B) 7%
38%
P=0.047
P=0.048
VGPR 61%
* p values not given, ** Only high risk pts defined by ß-2m>5.5µg/ml. and/or labeling index>1, and/or del13q by metaphase cytogenetics
42

---

IMWG consensus on maintenance therapy in multiple myeloma
Table 5.
Drug
Dose/regimen
Duration of
Impact on
Risk Groups
Tolerance
Level
of
Comments
Therapy
Evidence/
Quality of
PFS
OS
Grade
of
Response
Recommen
dation
Thalidomide
50
(100)
Up to one
Yes
Yes
Yes
No benefit
PNP,
I/A
Poor tolerance in some
mg/day
year*,
Preferent
In
FISH
defined
fatigue and
(particularly
elderly)
no
ially if not
high risk patients***
other
patients
correlation
part
of
Possible benefit in
limiting
.
between
the
pts with abnormal
dose
and
Not recommended for
duration
induction
metaphase
duration of
patients
with
FISH
and
regimen,
cytogenetics
and
therapy
defined high risk profile
outcome**
yes
in
GEP defined high
meta-
risk
analysis
Lenalidomide
10
(5-15)
Until PD
(Yes)
Yes
Presently
Active in all hitherto
Few
I/A
Unprecedented
mg/day
or
shown in
investigated
high
discontinua
extension
of
PFS,
continuously or
intolerance
1/3
risk
groups
tions due to
increase in OS in 1/3
day 1-21, q 28
studies
including
FISH
AEs
studies
days
defined cytogenetic
Usually well tolerated,
high risk
increased
risk
for
secondary
primary
malignancies
Bortezomib****
1.3
mg
2 years or
(Yes****)
(Yes****) (Yes****)
Active in
patients
PNP G3-4:
Not
Only
comparison
biweekly
until PD or
with
renal
failure
16%
applicable
between PAD ­ ASCT
intolerance
and
cytogenetic
bortezomib with VAD ­
risk groups
ASCT
thalidomide
available
Bortezomib-
GIMEMA:
Bortezomib-Thalidomide
yielded
increased
PFS
compared
to
control.
Thalidomide
PETHEMA: Bortezomib-Thalidomide resulted in a tendency for increased PFS compared to VP. In both studies an impact on OS was not
observed. Results of ongoing trials need to be awaited
* Spencer et al. [15] limited Thalidomide therapy to 12 months, **Barlogie [18], *** Morgan [16] showed shortened survival in del17p patients, ****different
regimens during induction therapy limit comparability with the thalidomide maintenance arm
43

---

IMWG consensus on maintenance therapy in multiple myeloma
Figure 1A. Thalidomide, Progression-free survival
Study
Maintenance
Control
Hazard ratio (fixed)
Hazard ratio (fixed)
N
N
95% CI
95% CI
Attal
201
396
0.69 [0.54, 0.88]
Barlogie
232
345
0.70 [0.57, 0.86]
Spencer
114
129
0.50 [0.35, 0.71]
Ludwig
64
64
0.55 [0.36, 0.85]
MRC-My-IX
409
409
0.73 [0.62, 0.87]
NCIC MY.10
166
166
0.56 [0.43, 0.73]
Total (95% CI)
1186
1509
0.66 [0.60, 0.73]
0.2
0.5
1
2
5
Test for heterogeneity: Chi² = 6.63, df = 5 (P = 0.25), I² = 24.6%
Favors treatment
Favors control
Test for overall effect: Z = 8.26 (P < 0.00001)
44

---

IMWG consensus on maintenance therapy in multiple myeloma
Figure 1 B. Thalidomide, Overall Survival
Study
Maintenance
Control
hazard ratio (fixed)
hazard ratio (fixed)
N
N
95% CI
95% CI
Attal
201
396
0.59 [0.37, 0.93]
Barlogie
323
345
0.81 [0.64, 1.03]
Spencer
114
129
0.41 [0.22, 0.76]
Ludwig
64
64
0.93 [0.53, 1.65]
NCIC MY.10
166
166
0.77 [0.53, 1.12]
Total (95% CI)
868
1100
0.74 [0.63, 0.88]
0.2
0.5
1
2
5
Favors treatment
Favors control
Test for heterogeneity: Chi² = 5.71, df = 4 (P = 0.22), I² = 30.0%
Test for overall effect: Z = 3.49 (P = 0.0005)
45

---

IMWG consensus on maintenance therapy in multiple myeloma
Figure 1 C. Lenalidomide
Study
Maintenance
Control
Hazard ratio (fixed)
Weight
Hazard ratio (fixed)
or sub-category
N
N
Log [Hazard ratio] (SE)
95% CI
%
95% CI
CALGB 100104
231
229
-0.9416 (0.1861)
5.66
0.39 [0.27, 0.56]
Palumbo
152
154
-0.6931 (0.2111)
4.40
0.50 [0.33, 0.76]
IFM 2005-02
307
307
-0.7765 (0.1348)
10.78
0.46 [0.35, 0.60]
Subtotal (95% CI)
690
690
20.83
0.45 [0.37, 0.54]
Test for heterogeneity: Chi² = 0.86, df = 2 (P = 0.65), I² = 0%
0.2
0.5
1
2
5
Test for overall effect: Z = 8.29 (P < 0.00001)
Favors treatment
Favors control
.
46

---