Prepublished online January 23, 2012;
doi:10.1182/blood-2011-11-374249
IMWG consensus on maintenance therapy in multiple myeloma
Heinz Ludwig, Brian GM Durie, Philip McCarthy, Antonio Palumbo, Jésus San Miguel, Bart Barlogie,
Gareth Morgan, Pieter Sonneveld, Andrew Spencer, Kenneth C. Andersen, Thierry Facon, Keith A
Stewart, Hermann Einsele, Maria-Victoria Mateos, Pierre Wijermans, Anders Waage, Meral Beksac, Paul
G. Richardson, Cyrille Hulin, Ruben Niesvizky, Henk Lokhorst, Ola Landgren, P. Leif Bergsagel, Robert
Orlowski, Axel Hinke, Michele Cavo and Michel Attal
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Blood First Edition Paper, prepublished online January 23, 2012; DOI 10.1182/blood-2011-11-374249
IMWG consensus on maintenance therapy in multiple
Myeloma
Heinz Ludwig1, Brian GM Durie2, Philip M cCarthy3, Antonio Palumbo4, Jésus San
Miguel5, Bart Barlogie6, Gareth Morgan7, Pieter Sonneveld8, Andrew Spencer9,
Kenneth C. Andersen10, Thierry Facon11, Keith A St ewart12, Hermann Einsele13,
Maria-Victoria Mateos5, Pierre Wijermans14, Anders Waage15, Meral Beksac16, Paul
G. Richardson10, Cyrille Hulin17, Ruben Niesvizky18, Henk Lokhorst19, Ola
Landgren20, P. Leif Bergsagel12, Robert Orlowski21, Axel Hinke22, Michele Cavo23,
Michel Attal24 *on behalf of the International Myeloma Working Group
1Department of Medicine I, Center for Oncology and Hematology, Wilhelminenspital, Vienna, Austria;
2Southwest Oncology Group, International Myeloma Foundation and Cedars Sinai Comprehensive
Cancer Center, Los Angeles, California, USA; 3Roswel Park Cancer Institute, Buffalo, New York,
USA; 4Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliera Universitaria
S. Giovanni Battista, Torino, Italy; 5University Hospital of Salamanca, Salamanca, Spain, 6Myeloma
Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA,
7Haemato-Oncology Unit, Roy al Marsden Hospital, London, UK; 8Department of Hematology,
Erasmus MC, Rotterdam, The Netherlands; 9Clinical Haematology/Bone Marrow Transplant
Department, Alfred Hospital, Melbourne, Victoria, Australia; 10Dana-Farber Cancer Institute, Medical
Oncology, Boston, Massachuset s, USA; 11Department of Hematology, Hospital Claude Huriez, Lil e,
France; 12Division of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 13Department of
Internal Medicine II, U niversity Hospital, Würzburg, Germany; 14Haga Hospital, the Hague, the
Netherlands; 15Department of Hematology, St Olavs Hospital, Norwegian University of Science and
Technology, Trondheim, Norway; 16Department of Microbiology and Clinical Microbiology, Ankara
University School of Medicine, Ibn-i Sina Hospital, Ankara, Turkey; 17Hematology Department,
University Hospital, Nancy, France; 18Weill Cornel Medical College, New York City, USA; 19University
Medical Center, Utrecht, The N etherlands; 20Metabolism Branch, National Cancer Institute, NIH,
Bethesda, Maryland, USA; 21Department of Lymphoma/Myeloma, Division of Cancer Medicine,
University of Texas M. D. Anderson Cancer Center, Houston, USA; 22WISP Research Institute,
Langenfeld, Germany; 23Serŕgnoli Institute of Haematology, Bologna School of Medicine, S. Orsola's
University Hospital, Bologna, Italy; 24Service d'Hématologie, Hospital Purpan, Toulouse, France
Correspondence:
Prof. Heinz Ludwig, MD
Department of Medicine I, Center for Oncology and Hematology, Wilhelminenspital
Montleartstrasse. 37, 1160 Vienna, Austria
Copyright © 2012
Abstract
Maintaining results of successful induction therapy is an important goal in m ultiple
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 progression-free survival (PFS) significantly in all six studies
and overall survival (OS) in t hree of them. In elderly patients, two trials showed a
significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed
a significant risk reduction for PFS/ event-free survival (EFS) and death. The role of
thalidomide maintenance after MPT is not well established. Two trials with
lenalidomide maintenance treatment after ASCT and o ne study after conventional
MPR induction therapy showed a significant risk reduction for PFS and an increase in
OS in one of the transplant trials. Maintenance therapy with single agent bortezomib
or in combination with thalidomide or prednisone has been studied. One trial
revealed a significantly increased OS with a b ortezomib-based induction and
bortezomib maintenance therapy compared to conventional induction and
thalidomide maintenance treatment. Maintenance treatment can be associated with
significant side effects and none of the drugs evaluated is approved for maintenance
therapy. Treatment decisions for individual patients must balance potential benefits
and risks carefully, as a widely agreed upon standard is not established.
Introduction
Maintaining the response of first-line therapy is an important objective in m ultiple
myeloma (MM), 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
2
relapse. Two different concepts regarding treatment following the initial induction
therapy exist: consolidation versus maintenance therapy. While consolidation therapy
typically consists of the application of a short course of treatment with the aim of
deepening the response achieved with the initial therapy, i.e. further reducing the
number of tumor cells, maintenance therapy is applied for a prolonged period of time
with the goal of preventing tumor progression. To date, no clinical trial has
specifically compared consolidation versus maintenance approaches to assess the
benefit of one approach over the other.
The high efficacy of the three novel agents, thalidomide, bortezomib and
lenalidomide, observed in t he front-line and relapse settings has provided the
rationale to also test their 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). However, it
should be noted that the achievement of an OS benefit of a m aintenance therapy
may be dif ficult when effective salvage treatment is available at relapse. The
demonstration of a prolonged time to progression (TTP) seems to be a v alid
objective, provided the prolonged time span without progression of disease is
associated with better quality of life and evidently of benefit to the patient (1).
The first attempts with maintenance therapy were already undertaken with
conventional chemotherapy agents shortly after their effectiveness in MM had been
demonstrated (2-4). Results of these initial and of later studies (5-9) were
unsatisfactory, and so efforts to improve the outcome of maintenance concepts are
ongoing. Here we review current results obtained with novel drugs for maintenance
treatment.
3
Methodology and Statistics
Members of the International Myeloma Working Group met twice during the IMF
summits on the occasion of the European Hematology Association (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 t he literature or presented at meetings of the American Society of
Oncology, American Society of Hematology, EHA, and the International Myeloma
Workshop were considered.
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 (10). Standard techniques for meta-analysis
(11) were used to calculate the pooled estimates, as incorporated in the software
packages METASUB V. 1.1 (idv, Gauting, Germany) and R eview Manager V. 4.2
(Nordic Cochrane 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 remission phase and OS simply
continued chemotherapy after successful induction treatment with MP (2-4). This led Brian Durie on January 31, 2012.
4
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 (12),
and subsequent trials employed interferon for induction and for maintenance therapy.
Individual trials revealed variable results, with significant prolongation of remission
duration and also of survival in some, and negative outcomes in other studies. Two
meta-analyses, one on individual patient data (5) and the other using published data
(6), revealed a s ignificant but limited improvement in both remission duration and
survival of about 6 months. Due to toxicity and the inability to select those patients
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 (13) and
induce additive or synergistic activity in combination with other drugs (14). Berenson
(7) showed a significant increase in remission duration and in s urvival with 50 m g
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
(8). 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 after
dexamethasone (9). Taken together, the available evidence is insufficient for
recommending corticosteroid maintenance therapy.
5
bloo
Thalidomide
After the demonstration of the limited benefits of interferon (5, 6) and corticosteroids
(7-9) as maintenance therapy, thalidomide became the next logical candidate for
clinical evaluation. The absence of severe hematotoxicity and its availability as an
oral drug were favorable prerequisites for long-term use, but these advantages
proved partly abrogated by its specific toxicity profile, in particular neurotoxicity.
Thalidomide as maintenance treatment has mainly been studied in young patients
after ASCT.
Three (15, 16, and 22) of the six trials with thalidomide maintenance treatment after
ASCT (15-22) used thalidomide only as maintenance treatment. In two studies
thalidomide was administered both during the induction and maintenance phases
(18, 21), while in the MRC Myeloma IX study (17), approximately half of the patients
randomized to thalidomide maintenance treatment had thalidomide during induction
therapy (Table 1).
In the IFM 99 02 study, patients were randomized after double ASCT to thalidomide
plus pamidronate, to pamidronate alone, or to control (15). A significant improvement
in the quality of response was observed in the thalidomide-containing arm, with more
patients achieving very good partial response (VGPR) or complete response (CR)
compared to the two other groups. Furthermore, an inc reased event-free survival
(EFS), as well as improved OS could be s hown, 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 no t vary between the three study arms. After long-term follow-up of
6
patients with cytogenetics available (thereby excluding 90 patients) (20), 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 (16), 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, increased PFS and increased OS. OS after relapse did not differ between
the two groups
The MRC myeloma IX study consists of two trials, one in y ounger and the other in
older patients (17). In the entire patient group, no difference was noted in the
percentage of patients that upgraded response status. In the transplant study
thalidomide maintenance treatment resulted in increased PFS, while for the survival
rate at 3 years no improvement was obtained. Survival regarding FISH-defined
cytogenetic risk groups was assessed in both patient cohorts combined. In patients
with favorable FISH, PFS was significantly prolonged with thalidomide maintenance
therapy (P=0.004) with no ap parent improvement yet of OS (P=0.48), but survival
curves indicate a likely late survival benefit after longer follow up. Patients with
adverse FISH [t (4; 14), t (14; 16), t (14; 20), del17p, del (1p32), gain (1q21)] showed
similar PFS (9 vs. 12 months, P=0.48), but worse OS (P=0.009) with thalidomide
maintenance (17).
7
Barlogie and colleagues compared thalidomide in c ombination with total therapy II
(TT2) and pos t-transplant chemotherapy to the same chemotherapy without
thalidomide (18-20). Maintenance thalidomide was given until disease progression
(PD) or intolerance. After a median follow-up of 40 months, both a significantly higher
CR rate and EFS at 4 years were noted, while for OS no difference was observed.
After relapse, survival was significantly shorter in patients pre-exposed to thalidomide
(20). 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 (19). 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 y ears 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% v s. 6%, P=0.04), but was similar between
both treated and 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, final y 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 (20).
In the HOVON-50 study (20), 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
8
with interferon alpha. Maintenance treatment was given until progression. Patients
randomized to thalidomide maintenance achieved a significantly higher VGPR rate,
longer EFS and a tendency for improved OS. Survival after relapse was significantly
shorter in patients exposed to thalidomide induction and maintenance treatment. Fifty
percent of patients developed peripheral neuropathy (PNP), and 58% ha d dose
reductions or discontinued thalidomide.
The NCIC CTG trial (22) 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% f or the maintenance group and 60% f or the control group
(P=0.21). PFS was significantly longer for patients randomized to maintenance
therapy. Quality of life was inferior in patients on maintenance therapy in most
domains, with the exception of appetite and s leep, which were better with
thalidomide/prednisone therapy.
A recently presented meta-analysis of five of the six 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 (23). Grade
3/4 PNP (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.
9
Our meta-analysis of the published trial results revealed a significant reduction of the
risk for progression (HR:0.65, 95% C I: 0.59, 0.72) with thalidomide maintenance
therapy. Outcome did n ot differ between trials that used thalidomide during the
maintenance phase only and those that used thalidomide both for induction and
maintenance treatment. For OS a m ajor effect variability between trials was noted
(test for heterogeneity P=0.03). Therefore, the positive result for overall effect (HR:
0.84, 95%CI: 0.73 0.97, P=0.01) must be interpreted with caution. The most likely
explanation for this heterogeneity is the inclusion of elderly patients in the MRC and
GEMSG trial, where no improvement in OS was noted. The variability for OS in the
thalidomide trials might also be explained by the availability of novel agents at
relapse, which differed among countries and for different time periods.
The improvement in qu ality of response with thalidomide maintenance reported in
most trials (15, 16, 18, 21, and 22) supports a consolidation in addition to a
maintenance effect of thalidomide. Patients with unfavorable cytogenetics defined by
FISH did no t benefit from thalidomide maintenance in the IFM and the MRC IX
studies, in fact in the latter trial survival was significantly shorter in patients with FISH
defined adverse cytogenetics (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 (24). 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 grou
10
An interesting phenomenon of different outcomes at different periods of trial maturity
was noted in the TT2, the IFM and the MRC IX trials. In the TT2 study, OS was not
different after 42 months of follow up, became superior in patients with metaphase-
defined adverse cytogenetics after 70 m onths, and was significantly longer in t he
total group of patients after 87 months of follow-up (20). In the IFM study, an analysis
of 88% o f patients initially enrolled revealed an inverse pattern, with a s ignificant
advantage seen at first analysis that was lost at later follow-up (20). The pattern of
increasing benefit in the TT2 trial indicates the favorable impact of thalidomide
maintenance primarily in good-risk patients, because an ef fect in high-risk patients
should have become evident much earlier due to the reduced survival generally seen
in high-risk disease. This notion is also supported by the MRC IX trial, which
indicates a t endency for improved survival in FISH-favorable patients after long
follow-up. The conversion of survival curves after long-standing disease in the IFM
trial does not support this explanation, and may reflect a significant influence of
salvage therapy in good-risk patients on OS.
In two trials exploring the role of thalidomide maintenance treatment after
conventional therapy (17, 25), approximately 50% of patients had already been
exposed to thalidomide-containing induction regimens. In the CEMSG trial (25)
patients were randomized to thalidomide pus interferon or to interferon maintenance
therapy. The thalidomide-containing combination induced a s ignificant 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
older and younger patients (P=0.39). Survival after disease progression tended to be
shorter in patients exposed to thalidomide-interferon maintenance therapy (P=0.056).
11
Patients receiving thalidomide-interferon had more PNP (69% vs. 38%, P=0.0015),
constipation (44% vs. 19%, P=0.0004), skin toxicity (33% vs. 11%, P=0.0041) and
elevated creatinine (13% vs. 5%, P=0.026). In the MRC myeloma IX study, PFS was
significantly, but only moderately increased with thalidomide maintenance (11 vs. 9
months, P=0.014), while for OS no difference (38 vs. 39 months, P=0.995) was noted
(17). Survival after relapse was shorter in thalidomide exposed patients, but the
difference did no t reach statistical significance (21 vs. 26 m onths, P=0.25). When
novel drugs were selected for salvage therapy after relapse, survival was improved, a
finding which was also noted in younger patients (17).
Seven randomized trials have compared MPT with MP in elderly patients (26-33),
and in f our 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 O S with MPT followed by thalidomide maintenance therapy was
noted in the HOVON trial (28) (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 (31), and 26 vs. 28 months,
P=0.0655 (32), respectively, was observed.
The optimal dose of thalidomide should be t he 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 (30). As the results have been similar
12
in most trials, a dose of 50 to 100 mg/day may be recommended as an appropriate
dose.
The median duration of thalidomide treatment varied between 7 months in the MRC
IX trial (17), 13.2 months in the CEMSG study (25), 15 months in the IFM trial (15),
and almost 24 m onths in t he HOVON study (30), which used the lowest dose of
thalidomide and in which 47% of patients 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 (19). Limiting the
duration of thalidomide exposure should reduce the risk of severe side effects,
particularly PNP, the most relevant toxicity (15, 16). Other side effects are
constipation, fatigue, mood disturbances, and, particularly in elderly patients,
arrhythmias, bradycardia and thromboembolic complications.
Lenalidomide
Lenalidomide is an attractive drug for maintenance therapy with the advantage of oral
administration. It was found to be particularly active in patients with high IRF4
expression (34) and with higher cereblon expression (35). Dexamethasone enhances
the anti-myeloma effect of lenalidomide, but antagonizes the immunostimulatory
effects in a dose-dependent manner (36). Hence, single-agent lenalidomide seems to
be the logical choice for maintenance treatment when tumor load has already been
reduced significantly and c ontrol 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 (37).
13
The CALGB 100104 study randomized 460 patients after ASCT to lenalidomide
maintenance therapy or to placebo (38). 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, median TTP was 48 months in t he
lenalidomide maintenance, and 30.9 months in the placebo group (HR: 0.39, 95% CI,
0.27 - 0.56, P<0.0001) (Table 3). 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 of the study in January
2010. Twenty-three deaths were observed in the treatment and 39 in the control arm
(P=0.018). Patients receiving lenalidomide maintenance therapy had significantly
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 plac ebo came off therapy due t o AEs and
20% of patients on lenalidomide and 7% on plac ebo 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. An EF S analysis, with events defined as progression, second
cancers and deaths, demonstrated a median EFS of 42 months in the lenalidomide
arm and 22 months in the placebo arm.
14
In the IFM-2005-02 lenalidomide maintenance trial, 614 patients who had single or
double ASCT were treated with two cycles of lenalidomide consolidation therapy, and
were thereafter randomized to lenalidomide maintenance therapy or placebo (39).
After a median follow-up of 24 m onths following randomization to maintenance, an
independent data monitoring committee recommended stopping and unblinding the
trial because of a dramatically improved PFS in the lenalidomide maintenance arm.
Consolidation therapy with lenalidomide resulted in an upgrading 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). With a median follow up of 36 months after randomization (46
months from diagnosis), median PFS was significantly 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 independently of the quality of response at
randomization, type of induction regimen, and ß-2 microglobulin. PFS and OS were
shorter in patients with FISH-defined unfavorable cytogenetics compared to the
standard-risk group. For patients progressing on 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) (40). The median interval
between time of progression and death was relatively short (11 vs. 13 months).
Patients on lena lidomide maintenance therapy had an increased incidence of
secondary malignancies (26 vs. 6 cases). Common toxicities were relatively low with
21% of patients on lenalidomide and 15% on plac ebo discontinuing therapy due to
toxicity.
15
The results of the lenalidomide maintenance studies require longer follow-up to
confirm whether the positive finding in t he CALGB study will prove robust, and
whether similar improvements will be seen in the IFM study, which differed with
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 usually is associated with
better quality of life (1), and hence, is 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 an increased occurrence of second primary
malignancies (SPM), however, is notable. The incidence of SPM was slightly higher
in the IFM trial, where a proportion of patients had been exposed to 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 the prevention of
SPMs. Before more information is available, a firm recommendation cannot be made.
Physicians and patients must weigh the benefits of lenalidomide maintenance
therapy against the low but relevant risk of SPM.
In elderly patients, a phase 2 trial with MPR was the forerunner for the MM-015 trial
(41). 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 c ycles of MPR, or M P without maintenance therapy (42). The MPR regimen
16
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) (Table 3). Sixty percent of
responses were achieved within 3 months following induction treatment initiation, but
improvements in t he 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 27 months, PFS was significantly longer with
lenalidomide maintenance treatment (31 vs. 14 vs. 13 months for MPR-R, MPR, and
MP, respectively; MPR-R vs. MP, HR: 0.395, P<0.001) (43). A la ndmark analysis
conducted from the beginning of cycle 10 demonstrated the significant impact of
maintenance therapy regarding PFS for the MPR-R compared to the MPR arm (HR:
0.34, P<0.001). In addition, a subgroup landmark analysis showed that the significant
benefit of MPR-R over MPR was maintained regardless of ISS stage (ISS I and II
versus ISS III), response ( VGPR versus PR) and age (65-75 years versus >75
years old). With a median follow-up of 41 months for OS, the OS rate at four years
was similar between the three groups (58%-59%). 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 (42). Overall 20% of patients in the MPR-R, 16% in the MPR,
and 8% in the MP group discontinued therapy due to adverse events. Notably, the
rate of discontinuation was higher in pat ients > 75 years old than in t hose 65-75
years old (22% vs. 12%, respectively), indicating that treatment tolerance is reduced
in the very elderly population. A subsequent analysis revealed an increased rate of
17
.
secondary malignancies in t he MPR-R and MPR compared to the MP group (12
(8.0%), 10 (6.6%), and 4 (2.6%) patients respectively).
Our meta-analysis of the published results of the three lenalidomide maintenance
studies, which included a total of 1380 patients, revealed a 65% risk reduction for
progression for patients on lenalidomide maintenance therapy (Figure 1C) (HR: 0.45,
CI: 0.37, 0.54, P<0.00001). The significant increase in PFS with a reduction of the
relative risk of relapse by 65% as a result of lenalidomide maintenance is
unprecedented. Lenalidomide maintenance therapy is effective both in pat ients
subjected to high-dose therapy with ASCT (38, 39) and in those treated with
conventional therapy (42), but is unable to overcome the adverse prognosis of FISH
defined high risk cytogenetics (39).
Bortezomib
Two studies employed bortezomib in combination with thalidomide for maintenance
treatment either in c omparison to control or to bortezomib plus prednisone
maintenance therapy (44, 45). The Spanish PETHEMA trial randomized 260 patients
aged 65 years or older to either VMP or VTP for induction treatment (44) (Table 4).
The induction therapy consisted of one 6-week cycle with biweekly bortezomib
followed by five 5-week cycles with weekly bortezomib to reduce toxic side effects.
After induction, 178 patients were randomized to either VT or VP maintenance
therapy. Bortezomib maintenance was administered every three months using the
conventional day 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
18
treatment improved the quality of response with the CR (IF-) rate rising from 24% to
46% in patients on the former and to 39% in patients on the latter therapy. After a
median follow-up of 46 months from first randomization, PFS was 39 m onths for
patients receiving VT and 32 m onths for those treated with VP (P=0.1). The non-
significant benefit of VT maintenance therapy was independent of the type of
induction therapy. OS did not differ between the two groups (not reached vs. 60
months, P=0.1, for VT vs. VP, respectively). During maintenance treatment, grade
3/4 neutropenia was seen in 1 % of patients receiving VT. No further grade 3 or
higher hematological toxicities were noted in either arm. Grade 3/4 PN was seen in
3% of patients in the VP and 9% in the VT group.
A GIMEMA (45) 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
bortezomib was reduced to a o nce-weekly schedule to enhance the 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,
was similar in both groups (89% vs. 87%, P=0.77). Patients in the VMPT arm
experienced more grade 3 and 4 ne
utropenia (38% vs. 28%, P=0.02),
thromboembolic events (5% vs. 2%, P=0.08), and cardiologic side effects (10% vs.
5%, P=0.04). However, the evaluation of the benefit of maintenance treatment in this
trial is difficult since different induction treatments had been used in the two arms.
19
Combining two drugs with significant neurotoxic potential poses the risk of substantial
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 d oses over the same period in t he
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 in the PETHEMA study (44). In the
GIMEMA trial (45), a tendency for an increase in PFS (P=0.07) compared to control
was observed. 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 joint HOVON/GMMG trial randomized 613 patients to bortezomib-doxorubicin-
dexamethasone (PAD) or VAD induction therapy followed by single or double ASCT
(46). Patients started on PAD received bortezomib maintenance (1.3 mg/m2,
biweekly for two years) and those randomized to VAD were treated with thalidomide
maintenance therapy (50 mg, daily for two years). After a median follow-up of 40
months, the 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 42% and 71%
20
in the PAD/ASCT/bortezomib/group, respectively. 67% of patients in t he
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 ot her reasons (2%).
In the bortezomib arm, 47% discontinued maintenance because of PD (29%), toxicity
(9%), or other reasons (9%) and 27% re quired dose reductions. In essence, the
PAD/ASCT/bortezomib protocol was in all study objectives superior to the
VAD/ASCT/thalidomide regimen, including patients with renal impairment (47) and
with adverse FISH-determined cytogenetics (t [4; 14], amplification of 1q21, and del
17p) (48). The study showed that bortezomib maintenance therapy can be tolerated
for up to two years, but the design of the study does not allow a clear dissection of
the role of bortezomib maintenance therapy.
As several questions regarding the optimal use of bortezomib, in p articular
scheduling, dosing, duration of therapy, combination with other drugs, remain
unresolved, specific recommendations cannot be made for bortezomib maintenance
therapy at this point of time.
Considerations for clinical practice
Presently, in most countries none of the novel 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 besides a wait and see strategy, which remains a
valuable alternative. Based on present scientific evidence (Table 5), thalidomide
maintenance treatment after ASCT is a p ossible option that increases PFS and,
albeit to a les ser degree, OS. Thalidomide maintenance should not be of fered to
21
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
potentially 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 of the patients had already been exposed to thalidomide during induction
therapy. Results showed a significant increase in PFS, but not in OS. Thalidomide
maintenance therapy in elderly patients with favorable cytogenetics 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 patients who have not been exposed to thalidomide during induction
therapy, but this observation was not confirmed in the MRC trial (17).
Lenalidomide after ASCT is associated with a significantly increased PFS (38, 39),
and in one study (38) with a significant survival benefit. It is well tolerated and active
in most risk groups, with the exception of FISH-defined high-risk patients (39). The
starting dose should be 10 mg daily, with dose modification between 5 t o 15 m g
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
22
.
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 a strong argument for therapy, while others weigh the increased
incidence of SPMs as an important risk and so prefer to wait for more mature survival
data before making specific recommendations.
Data on s ingle-agent bortezomib maintenance treatment are available only in
patients who had already been exposed to bortezomib during induction therapy (46).
Twice-weekly bortezomib maintenance therapy is feasible and can be tolerated for
up to two years, but dose reductions may be necessary in up to one third of patients.
While 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 s hown to yield superior PFS compared to
control (45) or ( although not statistically significant) compared to bortezomib plus
prednisone in elder ly patients (44). Further studies, particularly in pat ients not
previously exposed to these drugs during induction phase, are warranted.
Acknowledgments
The experts meetings on maintenance therapy were supported by the International
Myeloma Foundation. In addition, we wish to thank the members of the International
Myeloma Foundation who reviewed the manuscript and provided comments. Part of
this study was supported by a grant from the Austrian Forum against Cancer.
23
Authorship
Contribution: H.L. designed the outline and prepared the first draft of the manuscript.
B.G.M.D. organized and chaired two experts meetings on maintenance therapy
during IFM summits. Axel Hinke conducted the meta-analysis. Al authors
participated significantly in the development of the manuscript, provided critical
review and edits and gave approval to the f nal manuscript.
Conflict-of-interest disclosure
K.C.A Honoraria from ONYX, Millennium, Celgene, Novartis, BMS and Merck. Co-
founder for Acetylon. B.B. Honoraria from Celgene, IMF, MMRF, Millennium, and
Genzyme. Research funding from Celgene, Novartis, NCI, Millennium, Johnson &
Johnson, Centocor, Onyx, and Icon. M. B. Honoraria from Celgene and Janssen-
Cilag. P.L.B. Honoraria from Celgene. M.C. Honoraria from Celgene and Janssen-
Cilag. B.G.M.D. Honoraria from Celgene and Millennium. H.E. Honoraria from
Celgene and Janssen-Cilag. T.F. Honoraria from Celgene, Merck, Onyx, BMS and
Janssen-Cilag. H.L. Honoraria from Celgene. H.L. Honoraria from Celgene, Janssen-
Cilag, Mundipharma and research funding from Celgene, Janssen-Cilag and
Mundipharma. M.-V.M. Honoraria from Janssen-Cilag, Celgene and Millennium.
P.McC. Honoraria from Celgene and Onyx. R.N. Honoraria from Celgene,
Millennium. Research funding from Celgene, Onyx and Millennium. A.P. Honoraria
from Celgene, Janssen-Cilag, Merck and AMGEN. P.G.R. Honoraria from Celgene,
Millennium and Johnson and Johnson. J.S.M. Honoraria from Celgene, Millennium
and Janssen-Cilag. K.A.S. Honoraria from Celgene, Millennium and ONYX and
research funding from Millenium. A.W. Honoraria from Janssen-Cilag, Celgene and
Mundipharma. The other authors declared no competing financial interests.
Correspondence
Heinz Ludwig, Department of Medicine I, Center of Oncology and Hematology,
Wilhelminenhospital,
Montleartstrasse
37,
Vienna,
Austria;
e-mail:
Heinz.ludwig@aon.at.
24
.
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Legends:
Table 1.
Thalidomide maintenance studies after ASCT and conventional therapy
Table 2.
Tials comparing MPT plus thalidomide maintenance versus MP
Table 3.
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 thalidomide or thalidomide combinations in young
and older patients. 1C progression-free survival with lenalidomide
maintenance therapy in young and older patients
32
Table 1.
Study group
Age
Induction Therapy
Maintenance
Improveme
EFS or PFS
OS
Survival after
Thalidomide
(median)
Dose, duration of TX
nt in quality
relapse
Tolerance
# of Pts
of
response
IFM 99-02
Mean 59
VAD: 3-4 cycles,
A) Thalidomide
VGPR
3-year EFS:
4-year OS:
1- year OS:
39% stopped
Attal et al.,
± 8
single ASCT
400mg/d until PD
A) 67%
A) 52%
A) 87%
A) 75%
Thal due to side
2006 [15]
Pamidronate 90mg,
effects, mostly
N = 597
q4w, until PD
PNP, all grades
of PNP 68%,
B) Pamidronate
B) 55%
B) 37%
B) 74%
B) 73%
G3-4: 7%
90mg, 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
A) 65%
estimate:
estimate:
estimate:
therapy due to
al., 2009
N= 243
months
A) 42%
A) 86%
A) 79%
intolerance
[16]
Prednisolone 50mg
B) 77%
(mostly PNP),
on alternate days
P=0.237
10% G3-4 PNP
until PD
and 9% stopped
due to PD
B) Prednisolone
B) 44%
B) 23%
B) 75%)
50mg on alternate
P=0.001
P<0.001
P=0.004
days until PD
MRC
Intensive
CVAD vs. CTD,
No
52.2%
myeloma IX, 59 yrs
single ASCT
difference
PFS
3-year OS
A) 20 months
discontinued
Morgan et
N=493
A) Thalidomide, 50
in the
A) 30 months
A) 75%
maintenance
al., 2010
100mg/d, until PD*
percentage
B) 36 months
before PD mainly
[17]
of patients
B) 27 months
B) 80%
(P=0.003)
due to adverse
B) None*
that
(P=0.003)
(P=0.26)
events, median
upgraded
duration of
response
treatment: 7
status
months**
Non-
CTD attenuated
A) Thalidomide, 50
(P=0.19)
PFS
A) 38 months A) 21 months
intensive
vs. MP
100mg/d, until PD*
A) 11 months
73 yrs
B) 39 months B) 26 months
N=327
B) None*
B) 9 months
(P=0.995)
(P=0.25
(P=0.014)
.
TT2
75 yrs
A) 4 induction
A) Thalidomide
CR
4-year EFS
OS
Median OS
30% stopped
33
Study group
Age
Induction Therapy
Maintenance
Improveme
EFS or PFS
OS
Survival after
Thalidomide
(median)
Dose, duration of TX
nt in quality
relapse
Tolerance
# of Pts
of
response
Barlogie et
cycles,
100mg during the first A) 62%
A) 65%
A) not stated
A) 1.1 yrs
Thal within 2 yrs
al., 2006
Median
double ASCT
year, thereafter 50mg
[18]
n.a.
4 consolidation
on alternate days,
N = 668
cycles,
until PD
Thalidomide
400mg/d during
Median
induction, 100mg
follow up:
between ASCT,
42 months 200mg with
consolidation
B) Same induction
B) None
B) 43%
B) 44%
B) not stated
B) 2.7 yrs
without
P=0.001
P=0.01
P=0.9
P=0.001
thalidomide
TT2
CR
EFS Median:
8-year OS
5-year OS
80% stopped
Barlogie et
Median
A) 64%*
A) 6.0 yrs
estimate:
estimate:
Thal due toxicity
al., 2008
fol ow up:
A) 57%
A) 27%
within 2 years*
[19]
70 months
B) 43%
B) 4.1 yrs
B) 44%
B) 23%
P=0.001
P=0.001
P=0.09
P=0.11
TT2
Median
n.a
EFS Median
OS Median
7.2-year OS
n.a
Barlogie et
follow up:
4.8 years
9 years
estimate
al.
87 months
A) 45,2%
2010 [20]
B) 42.2%
P=0.27
HOVON 50
56
VAD vs. TAD
A) Thalidomide,
VGPR
EFS:
Median
Median OS
PNP G2-4:50%
Lokhorst et
N = 536
Single or double
50mg/d, until PD
A) 66%
A) 34 months
A) 73 months A) 20 months
Treatment
al., 2010
ASCT
B) 22 months,
discontinued or
[21]
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
PFS:
P=0.77
P=0.009
A) 34 months
B) 25 months
P<0.001
34
Study group
Age
Induction Therapy
Maintenance
Improveme
EFS or PFS
OS
Survival after
Thalidomide
(median)
Dose, duration of TX
nt in quality
relapse
Tolerance
# of Pts
of
response
NCIC CTG
58 yrs
Induction therapy
A) Thalidomide
PFS:
4-year OS
Increased
MY.10
not specified
200mg/d and
A) 28 months
estimate
toxicity including
Stewart et al N=332
Single ASCT
alternate day
A) 68%
PNP and
2010 [22]
prednisone 50mg,
reduced QOL,
until PD
improved
appetite and
B) none
B) 17 months
B) 60%
sleep
P<0.0001
P=0.21
VTE: 7%
VTE:0%
CEMSG
72 yrs
Thal/Dex vs. MP
A) Thalidomide
A) PR to
PFS:
A) 52.6
OS after PD:
PNP G3-4: 11%
Ludwig et
200mg up to max.
VGPR or
A) 27.7 months
months
A) 8.1 months
al., 2010
N = 124
tolerated dose, until
CR: 8%
[25]
PD
B) IFN -2b, 3 Mega
B) PR to
B) 13.2 months
B) 51.4
B) 25.5 months,
U, TIW
VGPR or
P=0.0068
months
P=0.056
CR: 2%
P=0.81
* Same regimen for intensive and non-intensive patients, **Results for intensive and non-intensive group combined
median unless otherwise stated
35
Table 2.
Study group
Age
Induction Therapy
Maintenance
Improvement
EFS or PFS
OS
Survival after
Thalidomide
(median)
Dose, duration
in quality of
relapse
Tolerance
# of Pts
of TX
response
GIMEMA
72 yrs
A) MPT
Thalidomide
CR + PR
2-year EFS
3-year OS:
n.a.
G 3-4 AEs
Palumbo et
Thalidomide
100mg/day until
A) 76.0%
A) 54%
A) 80%
A) 48%
al.,
N=255
100mg/day
relapse
B) 47.6%
B) 25%
2006 [26]
6 cycles
P=0·0002
nCR/CR
B) MP
A) 27.9%
B) 27%
B) 64%
6 cycles
None
B) 7.2%
P=0·0006
P=0.19
GIMEMA
72 yrs
A) MPT
Thalidomide
CR+VGPR
PFS
A) 45 months
A) 11.5
G 3-4
Palumbo et
6 cycles
100mg/day until
A) 44.9%
A) 21.8 months
months
A) 55%
al., 2008
N=331
relapse
[27]
B) MP
None
B) 14.7%
B) 14.5 months
B) 47.6 months
B) 24.3 months B) 22%
6 cycles
P<0.001
P=0.001
P=0.79
P=0.01
HOVON
72 yrs
A) MPT
Thalidomide
>PR
EFS
A) 40 months
n.a.
G 2 toxicities
Wijermans
Thalidomide
50mg/day
A) 66%
A) 13 months
B) 31 months
A) 87%
et al.
N=333
50mg/day
until relapse
B) 45%
B) 9 months
P=0.05
B) 60%
2010 [30]
8 cycles
P<0.001
P<0.001
2-year OS:
B) MP
VGPR
PFS
67 vs. 61%
8 cycles
None
A) 27%
A) 33%
B) 10%
B) 21%
4-year 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 to
200mg/day until
A) 57%
A) 15 months
B) 32 months
hematological
2010 [31]
N=357
400mg/day
relapse
B) 40%
B) 14 months
P=0.16
A) 40%
cycles were given until
P=0.84*
B) 19%
plateau phase
VGPR
PNP A) 6%
A) 23%
B)1%
B) MP
B) 7%
TVT A) 8%
cycles were given until None
P<0.0001
B) 8%
plateau phase
TMSG
N=122
A) MPT,
Thalidomide
PR
DFS
A) 26 months
Infections (G3-4)
Beksac et al.
Thalidomide 100mg,
100mg/day
A) 57.9%
A) 21.0 months
B) 28 months
22.4%
2011 [32]
12 months
continuously
B) 37.5%
B) 14.0 months
P = 0.655
B) 7%
B) MP,12 months
None
P = 0.03.
P = 0.342
*P value form oral presentation, definite value not stated in final publication, n.a =not available, n.s. not significant , median unless otherwise stated
36
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
median
Any, fol owed by
A) 10 mg/d with
n.a
A) TTP,
Number of
n.a
Discontinuation
McCarthy et
n.a.
ASCT (M 200)
dose adaptations
median 42
deaths
78% of eligible
due to AEs 12%
al. 2011 [38]
N=460
(5-15 mg/d)
months
A) 23
patients of the
Due to other
continuously*
control group
reasons: 13%
had been
SPM: 15
crossed over to
B) placebo
B) 22 months
B) 39
lenalidomide
Due to AEs 2%
P<0.0001
P=0.018
TX
Due to other
reasons: 6%
SPM: 6
IFM
55 yrs
VAD, Vel-Dex and
A)
10-15
A) CR: 25%*
A) 42 months
5 years OS
A)12 months
Discontinuation
Attal et al.,
N=614
other induction
mg/d
VGPR: 76%**
A) 79%
due to AEs
2010 [39, 40]
therapy, single or
continuously*
A)21%
double ASCT
SPM: 26
Consolidation:
lenalidomide
B) placebo
B) CR: 23%*
B) 24 months
B) 73%
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
71 yrs
A) MPR R
A) 10 mg/d, d 1-
A) 77%
A) 31 months
4-year OS
n.a.
Discontinuation
Palumbo et al. N=459
21, continuously* P<0.001
estimate
due to AEs
2010 [42, 43]
A, B, C)
A) 20%
58%-59%
SPM: 8%
B) MPR
B) placebo
B) 68%
B) 14 months.
B)16%
SPM: 6.6%
C) MP
C) placebo
C) 50%
C) 13 months
C) 2.9%
A vs. C,
SPM: 2.6%
P<0.001
SPM: Secondary primary malignancies, *until PD or intolerance, ** Patients on placebo were not al owed to cross over to Lenalidomide after PD
median unless otherwise stated
37
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
A) not
G3 and G4 PNP
Mateos et al.,
N=260
1, 4, 8, 11 q12 wks for 3 years
A) 24%
A) 39 months reached
A) 9%
2010 [44]
Thalidomide 50mg/d for 3 years 46%
B) 3%
B) 60 months Discontinuation due to AEs
B) VP: Bortezomib as above
B) 32 months P=0.1
A) 13%
Prednisone 50mg q 2 day for 3
B) 24%
P=0.1
B) 9%
years
39%
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 [45]
Thalidomide 50mg/d
B) 28.1%
Until PD or intolerance
Cardiologic*
B) 24%
B) 42%
B) 89.2%
A) 10.4%
VMP
P=0.0008
P<0.07
P=0.9
B) 5.5%
HOVON/GMMG
57
PAD
Bortezomib 1.3mg/m2,
A) CR/nCR
3-year PFS
3-year OS
G 3 and G4 PNP
Sonneveld et al.
N=613
biweekly, for 2 yrs.
50%
A) 48%
A) 78%
A) 16%
2010 [46]
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
median unless otherwise stated
38
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 Does not overcome Few
I/A
Unprecedented
mg/day
or
shown in
negative impact of
discontinua
extension of PFS,
continuously or
intolerance
1/3
FISH defined
tions due to
increase in OS in 1/3
day 1-21, q 28
studies
unfavorable
AEs
studies
days
cytogenetics
Usually wel tolerated,
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
(based on
bortezomib with VAD
risk groups
iv.admini-
ASCT thalidomide
stration)
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 unfavorable FISH patients,
****different regimens during induction therapy limit comparability with the thalidomide maintenance arm, §Lowest dose shown to be effective and therefore
recommended, several studies used 100mg or higher doses, §§ recommended starting dose, doses have been adapted to 5-15mg in the CALGB study
39
Figure 1A. Thalidomide, Progression-free survival
Study
Maintenance
Control
Hazard ratio (fixed)
Hazard ratio (fixed)
N
N
95% CI
95% CI
IFM 99 02 (15)
201
396
0.69 [0.54, 0.88]
TT 2 (18)
323
345
0.70 [0.57, 0.86]
Australian (16)
114
129
0.50 [0.35, 0.71]
CEMSG (25)
64
64
0.55 [0.36, 0.85]
MRC-My-IX (17)
408
410
0.69 [0.58, 0.82]
NCIC MY.10 (22)
166
166
0.56 [0.43, 0.73]
Total (95% CI)
1276
1510
0.65 [0.59, 0.72]
0.2
0.5
1
2
5
Test for heterogeneity: Chi˛ = 5.20, df = 5 (P = 0.39),
Favors treatment
Favors
I˛ = 3.9%, Test for overal effect: Z = 8.63 (P < 0.00001)
control
40
Figure 1 B. Thalidomide, Overall Survival
Study
Maintenance
Control
Hazard ratio (fixed)
Hazard ratio (fixed)
N
N
95% CI
95% CI
IFM 99 02 (15)
201
396
0.59 [0.37, 0.93]
0.81 [0.64, 1.03]
TT 2 (18)
323
345
Australian (16)
114
129
0.41 [0.22, 0.76]
64
64
0.93 [0.53, 1.65]
CEMSG (25)
MRC-My-IX (17)
408
410
1.10 [0.86, 1.41]
NCIC MY.10 (22)
166
166
0.77 [0.53, 1.12]
Total (95% CI)
1276
1510
0.84 [0.73, 0.97]
Test for heterogeneity: Chi˛ = 12.46, df = 5 (P = 0.03),
0.2
0.5
1
2
5
I˛ = 59.9%, Test for overall effect Z = 2.45 (P=0.01)
Favours treatment
Favours control
41
Figure 1 C. Lenalidomide, Progression- (Event-) free survival
Study
Maintenance
Control
Log [Hazard ratio] (SE)
Hazard ratio (fixed)
Weight
Hazard ratio (fixed)
N
N
95% CI
%
95% CI
CALGB 100104 (38)
231
229
-0.9416 (0.1861)
5.66
0.39 [0.27, 0.56]
MM 015* (42, 43)
152
154
-0.6931 (0.2111)
4.40
0.50 [0.33, 0.76]
IFM 2005-02 (39, 40)
307
307
-0.7765 (0.1348)
10.78
0.46 [0.35, 0.60]
Total (95% CI)
690
690
20.83
0.45 [0.37, 0.54]
Test for heterogeneity: Chi˛ = 0.86, df = 2 (P = 0.65), I˛ = 0%
0.2
0.5
1
2
5
Test for overall effect: Z = 8.29 (P < 0.00001)
Favors treatment
Favors control
*comparison between MPR followed with lenalidomide maintenance therapy with MP without maintenance
42