Leukemia (2009) 23, 2147–2152
`& 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00
`
`www.nature.com/leu
`
`ORIGINAL ARTICLE
`
`Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials
`of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple
`myeloma
`
`MA Dimopoulos1, C Chen2, A Spencer3, R Niesvizky4, M Attal5, EA Stadtmauer6, MT Petrucci7, Z Yu8, M Olesnyckyj8,
`JB Zeldis8, RD Knight8 and DM Weber9
`
`1Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 2Department of Medical
`Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada; 3Department of Clinical Haematology and
`Bone Marrow Transplantation, The Alfred Hospital, Melbourne, Australia; 4Department of Medicine, Weill Cornell Medical
`College, New York, NY, USA; 5Department of Hematology, C.H.U. Purpan, Toulouse, France; 6Abramson Cancer Center,
`University of Pennsylvania, Philadelphia, PA, USA; 7Department of Cellular Biotechnologies and Hematology, University
`‘Sapienza’, Rome, Italy; 8Celgene Corporation, Summit, NJ, USA and 9Department of Lymphoma and Myeloma, The M.D.
`Anderson Cancer Center, Houston, TX, USA
`
`We present a pooled update of two large, multicenter MM-009
`and MM-010 placebo-controlled randomized phase III trials that
`included 704 patients and assessed lenalidomide plus dex-
`amethasone versus dexamethasone plus placebo in patients
`with relapsed/refractory multiple myeloma (MM). Patients in
`both studies were randomized to receive 25 mg daily oral
`lenalidomide or identical placebo, plus 40 mg oral dexametha-
`sone. In this pooled analysis, using data up to unblinding (June
`2005 for MM-009 and August 2005 for MM-010), treatment with
`lenalidomide plus dexamethasone significantly improved over-
`all response (60.6 vs 21.9%, Po0.001), complete response rate
`(15.0 vs 2.0%, Po0.001), time to progression (median of 13.4 vs
`4.6 months, Po0.001) and duration of response (median of 15.8
`months vs 7 months, Po0.001) compared with dexamethasone-
`placebo. At a median follow-up of 48 months for surviving
`patients, using data up to July 2008, a significant benefit in
`overall survival (median of 38.0 vs 31.6 months, P¼ 0.045) was
`retained despite 47.6% of patients who were randomized to
`dexamethasone-placebo receiving lenalidomide-based treat-
`ment after disease progression or study unblinding. Low
`b2-microglobulin and low bone marrow plasmacytosis were
`associated with longer survival.
`In conclusion,
`these data
`confirm the significant response and survival benefit with
`lenalidomide and dexamethasone.
`Leukemia (2009) 23, 2147–2152; doi:10.1038/leu.2009.147;
`published online 23 July 2009
`Keywords: multiple myeloma; lenalidomide; dexamethasone;
`myelosuppression
`
`Introduction
`
`Multiple myeloma (MM) is an incurable plasma-cell malignancy
`that causes approximately 20% of all deaths attributed to all
`hematological malignancies and 2% of deaths caused by all types
`of cancer.1 The median survival of patients with MM was
`approximately 33 months before the advent of new therapies.2
`On the basis of surveillance, epidemiology and end result
`estimates, nearly 20 000 individuals (11 190 men and 8730
`
`Correspondence: Dr MA Dimopoulos, Department of Clinical Thera-
`peutics, University of Athens School of Medicine, Alexandra Hospital,
`80 Vas. Sofias, Athens 11528, Greece.
`E-mail: mdimop@med.uoa.gr
`Received 5 March 2009; revised 1 May 2009; accepted 19 June 2009;
`published online 23 July 2009
`
`women) were expected to be diagnosed with myeloma, and
`approximately 11 000 patients were expected to die from the
`disease in the United States during 2008.3 Recent benefits in
`survival
`for patients with MM have been demonstrated after
`treatment with novel agents (for example, thalidomide, bortezo-
`mib and lenalidomide) administered alone or in combination.4–7
`In MM patients diagnosed between 1997 and 2006, the median
`survival for patients treated with one or more of these novel agents
`after relapse is more than double than that of patients not treated
`with the novel agents (30.9 months vs 14.8 months; Po0.001).8
`Lenalidomide (Revlimid; Celgene Corporation, Summit, NJ,
`USA) is an oral IMiD classified as an immunomodulatory drug that
`has undergone rapid clinical development in MM.9–11 After phase
`I and II trials showed promising activity of lenalidomide alone or
`in combination with dexamethasone,12–13 two large, multicenter,
`randomized, placebo-controlled phase III trials were initiated:
`MM-009 in North America and MM-010 in Europe, Australia and
`Israel. These studies already demonstrated the superiority of
`lenalidomide plus dexamethasone over dexamethasone-placebo
`in relapsed or refractory patients at
`the preplanned interim
`analysis, at which time the data monitoring committee decided to
`unblind the study and allow patients to cross-over. Near identical
`results from these phase III trials in patients with previously treated
`myeloma showed that
`the addition of
`lenalidomide to dex-
`amethasone, compared with dexamethasone alone, significantly
`improved overall response rate, progression-free survival (PFS),
`time to progression (TTP) and overall survival (OS).6,7
`On the basis of the MM-009 and MM-010 trials, lenalidomide
`in combination with dexamethasone has been approved by the
`US Food and Drug Administration and European Medicines
`Agency for the treatment of MM in patients who have received
`at least one earlier therapy. Results were initially published with
`a median follow-up of 17.6 months for the MM-009 trial and
`16.4 months for the MM-010 trial. We now report an updated
`pooled data analysis of 704 patients from the MM-009 and
`MM-010 phase III trials with an extended median follow-up of
`48 months for OS.
`
`Materials and methods
`
`For the purposes of the present analysis, we evaluated pooled
`data from patients enrolled in the MM-009 and MM-010 phase
`
`ALVOGEN, Exh. 1044, p. 0001
`
`

`

`Long-term follow-up of Len in relapsed MM
`MA Dimopoulos et al
`
`2148
`
`III clinical trials. Protocols have been described in detail in the
`primary publications.6,7
`
`Patient selection
`Patient selection has been previously described.6,7 In brief,
`eligible patients were aged at least 18 years, had progressive
`MM after one or more treatments, a serum creatinine level
`of less than 2.5 mg per 100 ml and a measurable disease that
`was not resistant to a total monthly dexamethasone dose of
`4200 mg.
`
`Treatment
`Patients were randomized to receive either oral lenalidomide
`25 mg per day or placebo on days 1–21 of each 28-day cycle.
`All patients received 40 mg oral dexamethasone on days 1–4,
`9–12 and 17–20 of each 28-day cycle (for 4 cycles) until disease
`progression. After four cycles, dexamethasone (40 mg/day) was
`limited to days 1–4 only. As the O’Brien–Fleming boundary for
`superiority of lenalidomide over placebo was crossed at the
`preplanned interim analysis by the data monitoring committee,
`the study was unblinded and patients originally randomized to
`receive dexamethasone-placebo were allowed to receive
`lenalidomide or
`lenalidomide plus dexamethasone either
`immediately or after disease progression occurred. If patients
`experienced grade 3 or 4 adverse events, lenalidomide was held
`until
`the adverse events were resolved and treatment was
`restarted with a dose reduced to 15 mg/day, with further
`reductions at decrements of 5 mg/day. For grade 3 or 4 neutro-
`penia without other toxicity, patients received a subcutaneous
`injection of granulocyte colony-stimulating factor 5 mg/kg/day
`with the first dose-modification step. The dexamethasone dose
`was adjusted for adverse events at
`the discretion of
`the
`investigator. Dexamethasone reductions were 40 mg/day for
`4 days every 2 weeks, then 40 mg/day for 4 days every 4 weeks,
`then 20 mg daily for 4 days every 4 weeks.
`
`Response
`Complete response, very good partial response and partial
`response (PR) of progressive disease were assessed every 4
`weeks according to modified European Group for Blood and
`Marrow Transplantation criteria.14 TTP was measured from the
`date of randomization to the date of the first assessment showing
`progression. For patients who were given another anti-myeloma
`therapy without documented disease progression, TTP was
`censored at the last adequate response assessment date before
`taking another anti-myeloma therapy. OS was calculated as time
`from randomization until death from any cause. OS was
`censored at the last date of patient follow-up. Data for OS were
`updated up to 23 July 2008 for MM-009 and 2 March for
`MM-010 (median follow-up of 48 months for surviving patients).
`Overall
`response rate, TTP and PFS were assessed up to
`unblinding, which occurred in June 2005 for study MM-009
`and in August 2005 for study MM-010, for a median follow-up
`of 17.5 months for ongoing patients. Toxic effects were graded
`according to the National Cancer Institute’s Common Toxicity
`Criteria, version 2.
`
`Statistical analysis
`Baseline characteristics were compared between groups using a
`pooled t-test for continuous variables (that is, age, time since
`diagnosis) and Fisher’s exact test for categorical variables (all
`other variables). Fisher’s exact
`tests were used to compare
`
`Leukemia
`
`response rates; TTP, PFS and OS were estimated by Kaplan–
`Meier methods and compared between treatment groups using
`log-rank tests stratified by study. Exploratory analysis was
`performed to identify the predictors of OS among patients
`treated with lenalidomide plus dexamethasone. The univariate
`Cox proportional hazards model was used to determine
`potential prognostic variables predictive for OS. Variables
`assessed in the univariate analysis included age, gender, race,
`number of earlier therapies, earlier use of thalidomide, radiation
`therapy, dexamethasone and other baseline disease character-
`istics such as b2-microglobulin, disease duration, lytic bone
`lesion, ECOG performance status, Durie–Salmon disease stage
`and percentage of plasma cells in bone marrow samples.
`Cytogenetic abnormalities were not routinely recorded and
`were therefore not included in the analysis. Only those variables
`that differed at the 0.20 level by the univariate analysis were
`included in the multivariate Cox regression model. For the
`multivariate analysis, a forward selection stepwise procedure
`was used to identify the subset of relevant factors. Statistical
`significance was determined at the 0.05 alpha level. TTP was the
`primary efficacy end point specified in the protocol. Other
`analyses were considered secondary without adjustment
`for
`multiplicity. Analyses were performed using Statistical Analysis
`Software (SAS) Version 9.1 (SAS Institute, Cary, NC, USA).
`
`Results
`
`Patient characteristics
`Baseline characteristics were well balanced between patients
`treated with lenalidomide plus dexamethasone and those
`treated with dexamethasone-placebo (P40.05 for all; Table 1).
`
`Efficacy
`Up to study unblinding, TTP was significantly longer in patients
`treated with lenalidomide plus dexamethasone than in those
`treated with dexamethasone-placebo (median of 13.4 vs 4.6
`months, respectively; Po0.001; Figure 1; Table 2). PFS was
`significantly longer in patients treated with lenalidomide plus
`dexamethasone than in those treated with dexamethasone-
`placebo (median of 11.1 vs 4.6 months, respectively; Po0.001;
`Figure 2; Table 2). The time to first response was similar in
`patients treated with lenalidomide plus dexamethasone than in
`those treated with dexamethasone-placebo (median of 1.9 vs
`2.0 months,
`respectively); however, patients
`treated with
`lenalidomide plus dexamethasone had a substantially longer
`duration of response than did those treated with dexametha-
`sone-placebo (median of 15.8 vs 7.0 months, Po0.001; Table 2).
`The median duration of treatment was 10.1 months for patients
`treated with lenalidomide plus dexamethasone compared with
`5.3 months for patients treated with dexamethasone-placebo
`(Po0.0001). The pooled overall response rate was significantly
`higher in patients treated with lenalidomide plus dexametha-
`sone than in those treated with dexamethasone-placebo (60.6 vs
`21.9%, respectively; Po0.001; Table 2). Among patients treated
`with lenalidomide plus dexamethasone, complete response was
`observed in 15.0% and very good partial response in 17.3%,
`which was significantly higher compared with treatment with
`dexamethasone-placebo (2.0 and 2.8%, respectively; Po0.001 for
`the comparison of complete responseþ very good partial response
`between treatment groups).
`After a median follow-up of 48 months, 199 patients (56.4%)
`died in the lenalidomide plus dexamethasone group and 219
`patients (62.4%) died in the dexamethasone monotherapy
`
`ALVOGEN, Exh. 1044, p. 0002
`
`

`

`Table 1
`
`Baseline characteristics
`
`Characteristic, n (%)
`
`Lenalidomide+
`dexamethasone
`(n¼ 353)
`
`Dexamethasone+
`placebo
`(n¼ 351)
`
`Age, years
`Median
`Range
`
`Sex
`Male
`Female
`
`63.0
`33–86
`
`63.0
`37–85
`
`210 (59.5)
`143 (40.5)
`
`207 (59.0)
`144 (41.0)
`
`Time since diagnosis, years
`Median
`Range
`
`3.2
`0.4–15.7
`
`3.5
`0.0–26.6
`
`Durie–Salmon stage
`I
`II
`III
`
`17 (4.8)
`106 (30.0)
`229 (64.9)
`
`13 (3.7)
`112 (31.9)
`226 (64.4)
`
`Eastern Cooperative Oncology Group performance status
`0
`152 (43.1)
`150 (42.7)
`1
`155 (43.9)
`162 (46.2)
`2
`37 (10.5)
`33 (9.4)
`
`Number of earlier therapies/stem cell transplantations
`1
`65 (18.4)
`X2
`288 (81.6)
`Earlier thalidomide treatment
`127 (36.0)
`Earlier bortezomib treatment
`27 (7.6)
`Earlier stem cell transplantation
`206 (58.4)
`
`73 (20.8)
`278 (79.2)
`147 (41.9)
`27 (7.7)
`203 (57.8)
`
`b2-Microglobulin level, mg/l
`p2.5
`42.5
`
`103 (29.2)
`250 (70.8)
`
`99 (28.2)
`252 (71.8)
`
`No significant differences between the two groups for any of the
`characteristics (P40.05) were found based on pooled t-test
`for
`continuous variables (age, time since diagnosis) and Fisher’s exact test
`for categorical variables (all other variables in the table).
`
`Figure 1 The Kaplan–Meier estimate of time-to-progression for the
`intent-to-treat population. The estimate of time-to-progression for the
`intent-to-treat population of the lenalidomide plus dexamethasone-
`placebo groups. Len/Dex denotes lenalidomide plus dexamethasone;
`Placebo/Dex denotes dexamethasone-placebo. Survival curves were
`compared using log-rank test stratified by study (Po0.001).
`
`2149
`
`Long-term follow-up of Len in relapsed MM
`MA Dimopoulos et al
`
`The Cox proportional hazards regression model for multi-
`variate analysis showed that
`treatment
`remained a highly
`significant predictor of OS (P¼ 0.0008, in favor of lenalidomide
`In addition, baseline b2-microglobulin
`plus dexamethasone).
`levels higher than 2.5 mg/l, a baseline ISS (International Staging
`System) score 41, a high baseline percentage of plasma cells
`and more than one earlier anti-myeloma were among significant
`predictors of short OS after controlling for treatment
`factor
`(Table 3).
`Of the 351 patients treated with dexamethasone-placebo, 167
`(47.6%) received lenalidomide-based therapy after unblinding
`of the study or after disease progression. Of those, 147 (41.9%)
`patients crossed over to lenalidomide alone (as part of the MM-
`012 trial) after disease progression before study unblinding and
`20 (5.7%) crossed over to lenalidomide plus dexamethasone
`after official study unblinding of the study; median time to
`crossover was 9.6 months. Among the 20 patients who received
`lenalidomide plus dexamethasone after study unblinding, 6
`(30.0%) did so immediately after study unblinding and the
`remaining 14 (70.0%) crossed over after disease progression. Of
`the 32 patients in the placebo-dexamethasone arm ongoing at
`study unblinding, 12 did not cross-over to lenalidomide plus
`dexamethasone. Of these 12 patients, three patients remained
`on the dexamethasone regimen and then progressed, and the
`remaining patients were either responding or in the plateau
`phase at
`the time of data cutoff. After the crossover to a
`lenalidomide-based therapy, a X PR was achieved in 53
`(31.7%) patients who were previously randomized to dexa-
`methasone-placebo.
`
`Safety
`At least one grade 3 or 4 adverse event was observed in 83.3%
`of patients treated with lenalidomide plus dexamethasone and
`in 69.7% of
`those treated with dexamethasone-placebo
`(Po0.0001). Neutropenia and thrombocytopenia were the most
`common grade 3 or 4 adverse events among those treated with
`lenalidomide plus dexamethasone and were significantly higher
`than
`in
`patients
`treated with
`dexamethasone-placebo
`(Po0.001); grade 3 or 4 hyperglycemia was the most common
`event noted among those treated with dexamethasone-placebo
`(Table 4). As previously reported, thromboembolic events were
`significantly higher in patients treated with lenalidomide plus
`dexamethasone in the absence of a prophylactic use of an
`(Po0.001). Patients treated with lenalidomide
`anticoagulant
`plus dexamethasone experienced grade 2 (1.4%) and grade 3
`(1.4%) peripheral neuropathy. Patients in the dexamethasone
`group experienced grade 2 (1.7%) and grade 3 (0.6%) peripheral
`neuropathy and there were no grade 4 events in both groups.
`
`Dosing
`The median dose of lenalidomide or placebo was 25 mg and
`40 mg for dexamethasone. Among the patients treated with
`lenalidomide plus dexamethasone, 38.8% had at least one dose
`reduction of lenalidomide and 30.9% had at least one dose
`reduction of dexamethasone; 15.7% of patients treated with
`dexamethasone-placebo required at least one dose reduction.
`
`group. OS was significantly longer in patients treated with
`lenalidomide plus dexamethasone than in those treated with
`dexamethasone-placebo (median of 38.0 vs 31.6 months,
`respectively; P¼ 0.045; Table 2; Figure 3).
`
`Initial publication of MM-009 and MM-010, two randomized,
`placebo-controlled, phase III trials reported a significant benefit
`in response and TTP for patients with relapsed or refractory MM
`
`Discussion
`
`Leukemia
`
`ALVOGEN, Exh. 1044, p. 0003
`
`

`

`2150
`
`Table 2
`
`Response rates, time-to-progression, progression-free survival and overall survival
`
`Long-term follow-up of Len in relapsed MM
`MA Dimopoulos et al
`
`Lenalidomide+dexamethasone
`(n¼ 353)
`
`Dexamethasone+placebo
`(n¼ 351)
`
`Up to Unblinding (median FU¼ 17.5 months)
`Response rate, %
`ORR
`CR
`VGPR
`PR
`Median TTP, months
`Median DOR, months
`Median PFS, months
`Extended FU (Median FU¼ 48 months)
`Median OS, months
`
`60.6
`15.0
`17.3
`28.3
`13.4
`15.8
`11.1
`38.0
`
`21.9
`2.0
`2.8
`17.1
`4.6
`7.0
`4.6
`31.6
`
`P-value
`
`o0.001
`o0.001
`
`o0.001
`o0.001
`o0.001
`0.045
`
`Abbreviations: CR, complete response; DOR, duration of response; FU, follow-up; ORR, overall response rate; OS, overall survival; PFS,
`progression-free survival; PR, partial response; TTP, time-to-progression; VGPR, very good partial response.
`
`Figure 2 The Kaplan–Meier estimate of progression-free survival for
`the intent-to-treat population. The estimate of progression-free survival
`for the intent-to-treat population of the lenalidomide plus dexametha-
`sone-placebo groups. Len/Dex denotes lenalidomide plus dexametha-
`sone; Placebo/Dex denotes dexamethasone-placebo. Survival curves
`were compared using log-rank test stratified by study (Po0.001).
`
`Predictors of overall survival in patients treated using the
`Table 3
`Cox regression model
`
`Treatment (dexamethasone+placebo vs
`lenalidomide+dexamethasone treatment)
`Baseline plasma cells percentage
`(high vs low)
`High baseline b2-microglobulin
`(42.5 vs p2.5 mg/l)
`Duration of multiple myeloma
`Lytic bone lesion at baseline (Y vs N)
`Number of earlier anti-myeloma therapies
`Previously treated with HDT/SCT (Y vs N)
`Earlier dexamethasone therapy (Y vs N)
`ISS score at baseline (III vs II vs I)
`
`Abbreviations: HDT, high-dose therapy;
`System; SCT, stem cell transplant.
`
`Hazard ratio
`(95% CIs)
`
`P-value
`
`1.4 (1.2–1.7)
`
`0.0008
`
`1.0 (1.0–1.0) o0.0001
`1.6 (1.2–2.1) o0.0022
`
`0.9 (0.9–1.0)
`0.0008
`1.3 (1.0–1.6)
`0.064
`1.2 (1.0–1.3)
`0.026
`1.2 (1.0–1.5)
`0.053
`1.3 (1.1–1.7)
`0.017
`1.5 (1.3–1.7) o0.0001
`ISS,
`International Staging
`
`Table 4
`patients
`
`Grade X3 adverse events occurring in more than 5% of
`
`Adverse event, n (%)
`
`Lenalidomide+
`dexamethasone
`(n¼ 353)
`
`Dexamethasone+
`placebo
`(n¼ 351)
`
`Neutropenia
`Thrombocytopenia
`Anemia
`Pneumonia
`All thromboembolic events
`Hyperglycemia
`Fatigue
`Muscle weakness
`Hypokalemia
`Asthenia
`* Po0.001; ** Po0.05.
`
`125 (35.4)**
`46 (13.0)**
`38 (10.8)*
`32 (9.1)
`56 (15.9)**
`27 (7.6)
`23 (6.5)
`20 (5.7)
`20 (5.7)
`17 (4.8)
`
`12 (3.4)
`22 (6.3)
`21 (6.0)
`19 (5.4)
`19 (5.4)
`27 (7.7)
`17 (4.9)
`11 (3.1)
`5 (1.4)
`18 (5.1)
`
`Figure 3 The Kaplan–Meier estimate of overall survival for the intent-
`to-reat population. The estimate of overall survival for the intent-
`to-treat population of
`the lenalidomide plus dexamethasone and
`dexamethasone-placebo groups. Len/Dex denotes
`lenalidomide
`plus dexamethasone; Placebo/Dex denotes dexamethasone-placebo.
`Survival curves were compared using log-rank test stratified by study
`(P¼ 0.045).
`
`treated with lenalidomide plus dexamethasone compared with
`treatment with dexamethasone.6,7 OS was also significantly
`longer for patients treated with lenalidomide plus dexametha-
`sone in both trials; however, the median follow-up was short at
`17.6 and 16.4 months for the MM-009 and MM-010 phase III
`
`Leukemia
`
`ALVOGEN, Exh. 1044, p. 0004
`
`

`

`trials, respectively. Both studies were unblinded early by the
`data monitoring committee when the O’Brien–Fleming bound-
`ary for superiority of lenalidomide over placebo was crossed
`at the first planned interim analysis. We now present a pooled
`analysis of the MM-009 and MM-010 phase III trials with a
`median follow-up of 48 months for OS, which demonstrates
`a continued prolongation of OS for the lenalidomide and
`dexamethasone arm versus the dexamethasone single-agent
`arm, despite a crossover of almost half of
`the patients to
`either lenalidomide or lenalidomide plus dexamethasone as
`subsequent salvage therapies.
`Patients experienced improved responses, with a total of
`32.3% of patients achieving very good partial response or better
`with lenalidomide plus dexamethasone versus 4.8% with
`dexamethasone-placebo. The median duration of response of
`15.8 months with lenalidomide plus dexamethasone was shown
`to be nearly twice as long as that noted with dexamethasone-
`placebo. The TTP of 13.4 months with lenalidomide plus
`dexamethasone was also almost
`thrice as
`long as with
`dexamethasone-placebo. The PFS of 11.1 months with lenali-
`domide plus dexamethasone was more than twice as long as
`with dexamethasone-placebo.
`With a median follow-up of 17.6 months, an approximately
`9 month improvement was observed in the median OS in patients
`treated with lenalidomide plus dexamethasone compared with
`that in patients treated with dexamethasone in the MM-009 trial
`(median OS 29.6 vs 20.2 months, respectively; Po0.001).7 The
`median OS was not reached in the MM-010 trial at the 17.6
`month follow-up; however, a similar significant improvement in
`OS was observed.6 In the current analysis with a longer follow-up
`of 48 months, we now report an improvement in the median
`OS to 38.0 months for patients treated with lenalidomide plus
`dexamethasone versus 31.6 months for those receiving dexa-
`methasone-placebo (P¼ 0.045). Low serum b2-microglobulin, a
`low ISS score at baseline and low plasma cell infiltration of the
`bone marrow were associated with longer survival.
`As an IMiD immunomodulatory compound,
`the effect of
`lenalidomide might be more pronounced at the early stages of
`disease management when the cellular immune system and
`stroma are less compromised by other
`therapeutic agents.
`A recent subset analysis of the MM-009 and MM-010 trials
`demonstrated a significant clinical benefit in patients with one
`earlier therapy compared with those with X2 earlier therapies,
`further supporting the earlier use of lenalidomide and dexa-
`methasone.15 On the basis of the above results, investigation of
`lenalidomide plus dexamethasone combination is also ongoing
`in patients with newly diagnosed MM. As current therapies are
`achieving response rates approaching 100% and an impressive
`OS (1–year OS, 86–96%) in MM patients, the challenge in this
`disease is to understand the function of immunomodulation in
`long-term therapy.16,17,18
`In conclusion, results from this pooled analysis of data from
`the MM-009 and MM-010 trials, with a median extended
`follow-up of 48 months, confirm significant response outcomes
`and significant OS benefit with manageable toxicities for
`patients treated with lenalidomide and dexamethasone in
`relapsed or refractory MM. In addition, these data show for
`the first time that this significant OS benefit was still achieved
`despite nearly half of the patients in the control arm of the study
`receiving lenalidomide at the time of disease progression or
`study unblinding. These data, together with the results recently
`reported by Stadtmauer et al.,15 indicate that the greatest benefit
`occurs with early use of lenalidomide and dexamethasone in
`patients with relapsed or refractory MM, and demonstrate the
`long-term significant clinical benefit of lenalidomide treatment.
`
`Long-term follow-up of Len in relapsed MM
`MA Dimopoulos et al
`
`Conflict of interest
`
`2151
`
`MAD, CC and RN had a consultant role and have received
`honoraria from Celgene Corporation; CC and RN received
`research funding from Celgene Corporation; EAS and AS have
`received consulting and lecture fees from Celgene Corporation;
`MA is a member of
`the Board of Directors or Advisory
`Committee for Celgene Corporation; MTP has no relevant
`conflicts of interest to disclose; ZY, MO, JBZ and RDK are
`employed by Celgene Corporation; DMW received honoraria
`from and has been an occasional
`speaker
`for Celgene
`Corporation.
`
`Acknowledgements
`
`We received editorial support in the preparation of this article,
`funded by Celgene. We, however, were fully responsible for
`content and editorial decisions for this article.
`
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