T h e ne w e ngl a nd jou r na l o f m e dicine
`
`original article
`
`Lenalidomide plus Dexamethasone
`for Relapsed or Refractory Multiple Myeloma
`Meletios Dimopoulos, M.D., Andrew Spencer, M.D., Michael Attal, M.D.,
`H. Miles Prince, M.D., Jean-Luc Harousseau, M.D., Anna Dmoszynska, M.D.,
`Jesus San Miguel, M.D., Andrzej Hellmann, M.D., Thierry Facon, M.D.,
`Robin Foà, M.D., Alessandro Corso, M.D., Zvenyslava Masliak, M.D.,
`Marta Olesnyckyj, R.N., Zhinuan Yu, Ph.D., John Patin, M.S.,
`Jerome B. Zeldis, M.D., Ph.D., and Robert D. Knight, M.D.,
`for the Multiple Myeloma (010) Study Investigators*
`
`ABS TR ACT
`
`Background
`Lenalidomide is a structural analogue of thalidomide with similar but more potent
`biologic activity. This phase 3, placebo-controlled trial investigated the efficacy of
`lenalidomide plus dexamethasone in the treatment of relapsed or refractory multiple
`myeloma.
`
`Methods
`Of 351 patients who had received at least one previous antimyeloma therapy, 176
`were randomly assigned to receive 25 mg of oral lenalidomide and 175 to receive
`placebo on days 1 to 21 of a 28-day cycle. In addition, all patients received 40 mg of
`oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles
`and subsequently, after the fourth cycle, only on days 1 to 4. Patients continued in
`the study until the occurrence of disease progression or unacceptable toxic effects.
`The primary end point was time to progression.
`
`Results
`The time to progression was significantly longer in the patients who received lena-
`lidomide plus dexamethasone (lenalidomide group) than in those who received
`placebo plus dexamethasone (placebo group) (median, 11.3 months vs. 4.7 months;
`P<0.001). A complete or partial response occurred in 106 patients in the lenalido-
`mide group (60.2%) and in 42 patients in the placebo group (24.0%, P<0.001), with
`a complete response in 15.9% and 3.4% of patients, respectively (P<0.001). Overall
`survival was significantly improved in the lenalidomide group (hazard ratio for death,
`0.66; P = 0.03). Grade 3 or 4 adverse events that occurred in more than 10% of pa-
`tients in the lenalidomide group were neutropenia (29.5%, vs. 2.3% in the placebo
`group), thrombocytopenia (11.4% vs. 5.7%), and venous thromboembolism (11.4%
`vs. 4.6%).
`
`Conclusions
`Lenalidomide plus dexamethasone is more effective than high-dose dexametha-
`sone alone in relapsed or refractory multiple myeloma. (ClinicalTrials.gov number,
`NCT00424047.)
`
`From the University of Athens School of
`Medicine, Athens (M.D.); Alfred Hospital
`(A.S.) and Peter MacCallum Cancer Insti-
`tute (H.M.P.) — both in Melbourne, Aus-
`tralia; Centre Hospitalier Universitaire
`Purpan, Toulouse, France (M.A.); Centre
`Hospitalier Hôtel-Dieu, Nantes, France
`(J.-L.H.); University School of Medicine,
`Lublin, Poland (A.D.); Hospital Univer-
`sitario de Salamanca, Salamanca, Spain
`(J.S.M.); Medical University of Gdansk,
`Gdansk, Poland (A.H.); Hôpital Claude
`Huriez, Lille, France (T.F.); University “La
`Sapienza,” Rome (R.F.); Fondazione Isti-
`tuto Ricovero e Cura a Carattere Scientif-
`ico, Policlinico San Matteo, Pavia, Italy
`(A.C.); Institute of Blood Pathology and
`Transfusion Medicine, Lviv, Ukraine (Z.M.);
`and Celgene, Summit, NJ (M.O., Z.Y., J.P.,
`J.B.Z., R.D.K.). Address reprint requests
`to Dr. Dimopoulos at the University of
`Athens School of Medicine, Alexandra
`Hospital, Vas. Sophias 80, Athens 11528,
`Greece, or at mdimop@med.uoa.gr.
`
`*Other investigators who participated in
`the Multiple Myeloma (010) Study are list-
`ed in the Appendix.
`
`This article (10.1056/NEJMoa070594) was
`updated on July 29, 2009, at NEJM.org.
`
`N Engl J Med 2007;357:2123-32.
`Copyright © 2007 Massachusetts Medical Society.
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`2123
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 29, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1037, p. 0001
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Multiple myeloma, the second most
`
`common hematologic cancer, caused
`more than 19,000 deaths in Europe in
`2004.1 To improve the outcome of treatment,
`new agents are needed.2 The immunomodulatory
`drug thalidomide has activity in about one third
`of patients with relapsed or refractory multiple
`myeloma; response rates are increased when tha-
`lidomide is combined with dexamethasone or
`chemotherapy.3-7 Treatment with thalidomide is
`associated with sedation, fatigue, constipation,
`rash, deep-vein thrombosis, and peripheral neu-
`ropathy. These toxic effects often require dose re-
`duction and, in some instances, discontinuation
`of the drug.8
`Lenalidomide, a derivative of thalidomide, is
`less toxic and more potent than the parent drug.9
`In patients with relapsed or refractory multiple
`myeloma, lenalidomide can overcome resistance
`not only to conventional chemotherapy but also to
`thalidomide,10,11 and dexamethasone plus lena-
`lidomide is more effective than either agent alone
`in refractory multiple myeloma.11 We report on a
`randomized, phase 3 trial in which lenalidomide
`plus dexamethasone was compared with placebo
`plus dexamethasone in patients with relapsed or
`refractory multiple myeloma.
`
`Methods
`
`Patients
`Patients with multiple myeloma in Europe, Israel,
`and Australia were eligible to participate in the
`study if they were at least 18 years of age and had
`been treated with at least one previous antimye loma
`regimen. Patients were excluded if they had had
`disease progression during previous therapy con-
`taining high-dose dexamethasone (total month ly
`dose, >200 mg). Measurable disease was defined
`as a level of serum monoclonal protein (M pro-
`tein) of at least 0.5 g per deciliter or a level of
`urinary Bence Jones protein of at least 0.2 g per
`day. Additional eligibility criteria included an East-
`ern Cooperative Oncology Group performance
`status of 2 or less, a serum aspartate aminotrans-
`ferase or alanine aminotransferase level that was
`no more than three times the upper limit of the
`normal range, a serum bilirubin level that was no
`more than two times the upper limit of the nor-
`mal range, a serum creatinine level of less than
`2.5 mg per deciliter (221 μmol per liter), and an
`absolute neutrophil count of at least 1000 per cu-
`
`bic millimeter. The platelet count needed to be
`more than 75,000 per cubic millimeter for patients
`with less than 50% bone marrow plasma cells
`and more than 30,000 per cubic millimeter for
`patients with 50% or more bone marrow plasma
`cells.
`Women of childbearing potential were eligible
`if they agreed to use contraception during the
`study, had a negative pregnancy test before en-
`rollment, and agreed to undergo pregnancy test-
`ing every 4 weeks from enrollment until 4 weeks
`after discontinuation of the assigned study drug.
`Patients were excluded if they had previously had
`hypersensitivity to or uncontrollable side effects
`associated with previous use of thalidomide or
`dexamethasone. All patients gave written informed
`consent, and an ethics committee at each study
`site approved the protocol.
`
`Study Design
`The primary end point of this multicenter, ran-
`domized, placebo-controlled, phase 3 trial was
`the time to disease progression. Secondary end
`points included overall survival, the rate of re-
`sponse, and safety.
`Patients received either 25 mg of oral lenalido-
`mide or placebo on days 1 to 21 of a 28-day cycle;
`all patients received 40 mg of oral dexamethasone
`on days 1 to 4, 9 to 12, and 17 to 20 for the first
`four cycles. After the fourth cycle, 40 mg of dexa-
`methasone was administered only on days 1 to 4.
`Patients continued to receive the assigned drug
`regimen until the occurrence of disease progres-
`sion or unacceptable toxic effects. Patients were
`stratified according to the baseline serum β2-
`microglobulin level (<2.5 mg per liter or ≥2.5 mg
`per liter), previous stem-cell transplantation (none
`or ≥1), and the number of previous antimyeloma
`regimens (1 or ≥2).
`Toxic effects were graded according to the Na-
`tional Cancer Institute’s Common Toxicity Crite-
`ria, version 2. For grade 4 adverse events, treat-
`ment was withheld and restarted at the next lower
`dose after resolution of the toxic effects. The
`dexamethasone dose was modified because of
`toxic effects at the investigator’s discretion as fol-
`lows: 40 mg daily for 4 days every 2 weeks (dose
`level, −1) or every 4 weeks (dose level, −2) or 20 mg
`daily for 4 days every 4 weeks (dose level, −3).
`For grade 3 or 4 neutropenia without other toxic
`effects, the first dose-modification step was dose
`level −1 (daily subcutaneous injection of 5 μg of
`
`2124
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 29, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1037, p. 0002
`
`

`

`Lenalidomide for Relapsed or Refractory Myeloma
`
`granulocyte colony-stimulating factor per kilo-
`gram of body weight and 25 mg of lenalidomide);
`sequential reductions of the lenalidomide dose
`were 15 mg (dose level, −2), 10 mg (dose level, −3),
`and 5 mg (dose level, −4), with 5 μg of granulo-
`cyte colony-stimulating factor per kilogram daily
`at the investigator’s discretion.
`Patients underwent a blood count and physi-
`cal examination on days 1 and 15 (and day 8 of
`cycle 1) during cycles 1 to 3 and on day 1 of
`each cycle thereafter. Serum and urinary levels
`of M protein were assessed on day 1 of each cycle
`and at the end of treatment. Transfusion of plate-
`lets and red cells and the administration of neu-
`trophil growth factors and epoetin alfa were
`allowed as needed. All patients were allowed to
`receive bisphosphonates. Prophylactic anticoagu-
`lation was not recommended.
`The study was designed as a collaborative ef-
`fort by Dr. Dimopoulos, the coinvestigators, and
`the sponsor, Celgene. The sponsor collected the
`data and performed the final analysis, in collabo-
`ration with an independent data monitoring com-
`mittee and Dr. Dimopoulos. All authors had full
`access to the primary data and the final analysis.
`Dr. Dimopoulos vouches for the accuracy and com-
`pleteness of the published results. The first draft
`was written by Dr. Dimopoulos; subsequent drafts
`were written by Dr. Dimopoulos with editorial
`assistance from an employee of the sponsor. All
`authors had input before submission of both the
`original and revised manuscripts. An independent
`data monitoring committee reviewed safety and
`efficacy data throughout the study.
`
`Assessments
`The response of patients to treatment was as-
`sessed according to the criteria of the European
`Group for Blood and Marrow Transplantation.12
`The time to progression was measured from ran-
`domization to the date of the first assessment
`showing progression. Progressive disease was de-
`fined as any of the following: an absolute increase
`of more than 500 mg of serum M protein per
`deciliter, as compared with the nadir value, or an
`absolute increase of more than 200 mg of urinary
`M protein in 24 hours; a new bone lesion or plasma-
`cytoma or an increase in the size of such lesions;
`or the development of hypercalcemia (serum cal-
`cium level, >11.5 mg per deciliter [2.9 mmol per
`liter]). Responses were designated as complete
`
`(defined as the absence of M protein in serum and
`urine, as confirmed by immunofixation in two
`samples, and <5% marrow plasma cells) or par-
`tial (defined as a reduction in the level of M pro-
`tein in serum of at least 50% and a reduction in
`urine of at least 90%). Complete and partial re-
`sponses were confirmed by repeated measure-
`ments of M protein in serum and urine after
`6 weeks, and progressive disease was confirmed
`by repeated measurements of M protein in serum
`and urine after 1 to 3 weeks. Near-complete re-
`sponse, a subcategory of partial response, was de-
`fined as a complete response without confirma-
`tion of a decrease in marrow plasma cells to less
`than 5% by bone marrow biopsy, confirmation of
`the disappearance of M protein in serum or urine
`by repeat immunofixation, or both.
`
`Statistical Analysis
`The accrual goal was the enrollment of 302 pa-
`tients (151 in each group), which would provide a
`statistical power of 85% to detect a hazard ratio
`of 1.5 for the time to progression with the use of
`a two-sided log-rank test with an overall signifi-
`cance level of 0.05, adjusted for one interim analy-
`sis. Full information that was necessary for a log-
`rank test to have a power of 85% would be
`achieved when approximately 222 patients had
`disease progression in the two study groups. For
`overall survival, the trial had a power of approxi-
`mately 80% to detect a difference of 50% in me-
`dian overall survival for an analysis performed
`when at least 194 patients had died.
`An interim analysis of safety and efficacy was
`planned when disease had progressed in 111 pa-
`tients. If the predetermined O’Brien–Fleming
`boundary for the superiority of lenalidomide over
`placebo was crossed, the study would be un-
`blinded, and patients would be allowed to receive
`lenalidomide at the time of disease progression
`or at the investigator’s discretion. All primary
`analyses were based on the intention-to-treat
`population, and subgroup analyses were planned
`on the basis of stratification variables. An un-
`stratified log-rank test was used to compare
`time-to-event variables between groups. Both the
`time to progression and overall survival were es-
`timated with the use of Kaplan–Meier methods.
`Continuity-corrected Pearson chi-square tests were
`used to compare the proportions of patients in
`the two groups who had a response to treatment.
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`2125
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`The New England Journal of Medicine
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`Downloaded from nejm.org on July 29, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1037, p. 0003
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 1. Demographic and Clinical Characteristics of the Patients.*
`
`Characteristic
`
`Age — yr
`Median
`Range
`Male sex — %
`Lytic bone lesions — no. (%)
`Time since first diagnosis — yr
`Median
`Range
`Durie–Salmon stage — no. (%)
`I
`II
`III
`Eastern Cooperative Oncology Group per-
`formance status — no. (%)†
`
`0
`1
`2
`3
`Missing data
`Previous therapy — no. (%)
`No. of therapies
`1
`≥2
`Type of therapy
`Thalidomide
`Bortezomib
`Stem-cell transplantation
`β2-microglobulin level — no. (%)
`<2.5 mg per liter
`≥2.5 mg per liter
`
`Lenalidomide
`(N = 176)
`
`Placebo
`(N = 175)
`
`63
`33–84
`59.1
`136 (77.3)
`
`64
`40–82
`58.9
`140 (80.0)
`
`3.4
`0.4–15.7
`
`4.0
`0.3–26.6
`
`11 (6.2)
`50 (28.4)
`115 (65.3)
`
`8 (4.6)
`57 (32.6)
`110 (62.9)
`
`78 (44.3)
`72 (40.9)
`23 (13.1)
`0
`3 (1.7)
`
`65 (37.1)
`79 (45.1)
`27 (15.4)
`1 (0.6)
`3 (1.7)
`
`56 (31.8)
`120 (68.2)
`
`57 (32.6)
`118 (67.4)
`
`53 (30.1)
`8 (4.5)
`97 (55.1)
`
`67 (38.3)
`7 (4.0)
`95 (54.3)
`
`51 (29.0)
`125 (71.0)
`
`48 (27.4)
`127 (72.6)
`
`* There were no significant differences between the two groups according to
`a pooled t-test for continuous variables (age, time from first pathological
`diagnosis, percent plasma cells) and Fisher’s exact test for categorical vari-
`ables (all other variables in the table) (P>0.05). Percentages may not total
`100 because of rounding.
`† Lower numbers indicate better performance.
`
`R esults
`
`Patients and Treatments
`Between September 22, 2003, and September 15,
`2004, a total of 351 patients (intention-to-treat
`population) were enrolled at 41 centers in Europe,
`6 centers in Australia, and 3 centers in Israel. Of
`these patients, 176 were randomly assigned to
`receive lenalidomide plus dexamethasone (the
`
`lenalidomide group) and 175 to receive placebo
`plus dexamethasone (the placebo group). Baseline
`characteristics were well balanced between the
`two groups (Table 1). Previous therapies included
`stem-cell transplantation, thalidomide, dexameth-
`asone, melphalan, doxorubicin, and bortezomib.
`Patients in the two groups had received a median
`of two previous therapies. The average time from
`initial diagnosis to study entry was more than
`4 years. At the time of the analysis, which includ-
`ed all data obtained before unblinding in August
`2005, the median follow-up was 16.4 months.
`Median daily doses of study drugs in the two
`groups were 25 mg of lenalidomide and 40 mg of
`dexamethasone. The O’Brien–Fleming boundary
`for the superiority of lenalidomide had been
`passed at the time of the interim analysis in Sep-
`tember 2004.
`
`Efficacy
`The median time to progression was 11.3 months
`in the lenalidomide group and 4.7 months in the
`placebo group (P<0.001) (Fig. 1A). The hazard ra-
`tio for time to progression was 2.85 (95% confi-
`dence interval [CI], 2.16 to 3.76; P<0.001) in favor
`of the lenalidomide group. Patients in the lenalido-
`mide group had a significantly longer time to
`progression than patients in the placebo group
`in all stratified subgroups. The median time to
`progression for patients who had undergone one
`previous therapy was not reached in the lenalido-
`mide group and was 4.7 months in the placebo
`group. Among patients who had undergone at
`least two previous therapies, the median time to
`progression was 11.1 months in the lenalidomide
`group and 4.7 months in the placebo group
`(P<0.001).
`The median time to progression for patients
`who had previously undergone treatment with
`thalidomide (30.1% of the patients in the lenalido-
`mide group and 38.3% of those in the placebo
`group) was 8.4 months in the lenalidomide group
`and 4.6 months in the placebo group (P<0.001).
`Among patients with no previous exposure to
`thalidomide, the median time to progression was
`13.5 months in the lenalidomide group and 4.7
`months in the placebo group (P<0.001) (Fig. 1B).
`In the lenalidomide group, the median time to
`progression was not significantly related to pre-
`vious exposure to thalidomide (hazard ratio, 0.65;
`95% CI, 0.42 to 1.02; P = 0.06). Among patients
`in whom the disease had progressed during pre-
`vious thalidomide treatment, the median time to
`
`2126
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 29, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1037, p. 0004
`
`

`

`Lenalidomide for Relapsed or Refractory Myeloma
`
`Lenalidomide
`Placebo
`
`Lenalidomide without previous
`thalidomide
`
`Lenalidomide with previous
`thalidomide
`Placebo without previous
`thalidomide
`Placebo with previous
`thalidomide
`
`100
`
`75
`
`50
`
`25
`
`Patients (%)
`
`0
`
`0
`
`2.5
`
`5
`
`7.5
`
`10
`15
`12.5
`Months to Progression
`
`17.5
`
`20
`
`22.5
`
`25
`
`A
`
`B
`
`100
`
`75
`
`50
`
`25
`
`Patients (%)
`
`0
`
`0
`
`5
`
`10
`15
`20
`Months to Progression
`
`25
`
`30
`
`Figure 1. Kaplan–Meier Curves for the Time to Disease Progression among All Patients and in Subgroups
`with and without Previous Exposure to Thalidomide.
`Panel A shows estimates of the median time to disease progression for the intention-to-treat population (11.3 months
`AUTHOR:
`Dimopoulos
`1st
`RETAKE
`ICM
`in the lenalidomide group and 4.7 months in the placebo group) (P<0.001 by the log-rank test). Panel B shows the
`2nd
`FIGURE:
`1 of 2
`REG F
`3rd
`median time to disease progression among patients in the two study groups who received thalidomide before study
`CASE
`Revised
`entry and those who did not receive thalidomide (in the lenalidomide group, 13.5 months among patients who did
`Line
`4-C
`SIZE
`EMail
`ARTIST:
`ts
`not receive thalidomide and 8.4 months among those who did receive thalidomide; in the placebo group, 4.7 months
`H/T
`H/T
`22p3
`Enon
`Combo
`and 4.6 months, respectively; P<0.001 by the log-rank test for both between-group comparisons of patients who did
`and those who did not receive thalidomide).
`AUTHOR, PLEASE NOTE:
`Figure has been redrawn and type has been reset.
`Please check carefully.
`was longer in the lenalidomide group (16.5 months)
`progression was 9.5 months in the lenalidomide
`JOB:
`35721
`ISSUE:
`11-22-07
`group and 3.7 months in the placebo group
`than in the placebo group (7.9 months, P = 0.02).
`(P<0.001). The median time to progression was
`The analysis of overall response rates (com-
`11.3 months among patients who had undergone
`plete, near-complete, and partial responses) for
`stem-cell transplantation and 11.4 months among
`each stratification group and for patients with
`patients who had not undergone stem-cell trans-
`and those without previous thalidomide treat-
`plantation.
`ment showed a higher response rate among pa-
`A total of 106 patients (60.2%) in the lenalido-
`tients receiving lenalidomide in all the subgroups
`mide group and 42 patients (24.0%) in the place-
`(Table 2). In the lenalidomide group, the overall
`bo group had at least a partial response (P<0.001);
`response rate was higher in patients who had
`28 patients (15.9%) in the lenalidomide group
`not received thalidomide than in those who had
`and 6 patients (3.4%) in the placebo group had
`received thalidomide (65.0% vs. 49.1%, P = 0.07).
`a complete response (P<0.001) (Table 2). The me-
`dian time to the first response was 2.1 months
`in the lenalidomide group and 1.6 months in the
`placebo group. The median time to a complete
`or near-complete response was 5.1 months in the
`lenalidomide group and 6.9 months in the place-
`bo group. The median duration of the response
`
`Survival
`As of May 2006, 47 patients (26.7%) in the lena-
`lidomide group had died (30 from progressive
`disease), as had 60 patients (34.3%) in the placebo
`group (49 from progressive disease). At the time
`of the last analysis, median overall survival had
`
`n engl j med 357;21 www.nejm.org november 22, 2007
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`2127
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`The New England Journal of Medicine
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`Downloaded from nejm.org on July 29, 2016. For personal use only. No other uses without permission.
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` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1037, p. 0005
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 2. Response among Patients in the Intention-to-Treat Population and in Selected Subgroups.*
`
`Variable
`
`Response in the intention-to-treat population — no. (%)
`
`Overall response
`
`Complete response
`
`Near-complete response
`
`Partial response
`
`Stable disease
`
`Progressive disease
`
`Response could not be evaluated
`
`Overall response in subgroups — no./total no. (%)†
`
`Previous exposure to thalidomide
`
`Yes
`
`No
`β2-microglobulin — mg per liter
`<2.5
`
`≥2.5
`
`Previous no. of therapies
`
`1
`
`≥2
`
`Previous stem-cell transplantation
`
`Yes
`
`No
`
`Lenalidomide
`(N = 176)
`
`Placebo
`(N = 175)
`
`106 (60.2)
`
`28 (15.9)
`
`15 (8.5)
`
`63 (35.8)
`
`53 (30.1)
`
`3 (1.7)
`
`14 (8.0)
`
`42 (24.0)
`
`6 (3.4)
`
`3 (1.7)
`
`33 (18.9)
`
`97 (55.4)
`
`25 (14.3)
`
`11 (6.3)
`
`26/53 (49.1)
`
`11/67 (16.4)
`
`80/123 (65.0)
`
`31/108 (28.7)
`
`36/51 (70.6)
`
`18/48 (37.5)
`
`70/125 (56.0)
`
`24/127 (18.9)
`
`37/56 (66.1)
`
`17/57 (29.8)
`
`69/120 (57.5)
`
`25/118 (21.2)
`
`60/97 (61.9)
`
`46/79 (58.2)
`
`27/95 (28.4)
`
`15/80 (18.8)
`
`P Value
`
`<0.001
`
`<0.001
`
`0.002
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`* P values were calculated with the use of a continuity-corrected Pearson chi-square test. There was no subgroup-by-treatment
`interaction for response rates with the use of the Breslow–Day test for homogeneity.
`† Percentages are for the rate of overall response among patients in selected subgroups of the intention-to-treat population.
`
`not been reached in the lenalidomide group and
`was 20.6 months in the placebo group (hazard
`ratio for death in the lenalidomide group, 0.66;
`95% CI, 0.45 to 0.96; P = 0.03) (Fig. 2A). Overall
`survival was also significantly improved in the
`lenalidomide group among patients who had pre-
`viously received thalidomide (hazard ratio, 2.07;
`95% CI, 1.02 to 4.21; P = 0.04) (Fig. 2B).
`
`Adverse Events
`The most frequently reported adverse events were
`neutropenia, muscle cramps, constipation, nausea,
`tremor, and dizziness. Table 3 lists all grade 3 or
`4 adverse events. Patients in the lenalidomide
`group had a higher incidence of grade 3 neutro-
`penia (25.0%) than did those in the placebo
`group (2.3%). However, grade 3 or 4 febrile neu-
`tropenia was rare (occurring in 3.4% of the pa-
`tients in the lenalidomide group and in none of
`those in the placebo group). Grade 3 or 4 thrombo-
`
`cytopenia was twice as frequent in the lenalido-
`mide group as in the placebo group (11.4% vs.
`5.7%). The incidence of grade 3 or 4 somnolence,
`constipation, or peripheral neuropathy (all toxic ef-
`fects of thalidomide) was less than 10% in the two
`groups and rarely resulted in a dose reduction.
`Lenalidomide was associated with higher inci-
`dences of deep-vein thrombosis (4.0% vs. 3.5%)
`and pulmonary embolism (4.5% vs. 1.2%) than
`was placebo. The rate of grade 3 or 4 thrombo-
`embolic complications was unrelated to the con-
`comitant administration of erythropoietin. Such
`events occurred in 3 of 38 patients (7.9%) who
`received erythropoietin and 17 of 138 patients
`(12.3%) who did not receive erythropoietin in
`the lenalidomide group (P = 0.57) and in 3 of 36
`patients (8.3%) who received erythropoietin and
`5 of 139 patients (3.6%) who did not receive
`erythropoietin in the placebo group (P = 0.36).
`The proportion of patients who required more
`
`2128
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 29, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1037, p. 0006
`
`

`

`Lenalidomide
`Placebo
`
`Lenalidomide with previous
`thalidomide
`Lenalidomide without previous
`thalidomide
`
`Placebo without previous
`thalidomide
`Placebo with previous
`thalidomide
`
`Lenalidomide for Relapsed or Refractory Myeloma
`
`5
`
`10
`
`15
`
`20
`Months
`
`25
`
`30
`
`35
`
`40
`
`100
`
`75
`
`50
`
`25
`
`0
`
`0
`
`Patients (%)
`
`21
`
`21
`
`176
`175
`
`142
`140
`
`116
`104
`
`82
`50
`
`44
`20
`
`14
`3
`
`No. at Risk
`Lenalidomide
`Placebo
`
`A
`
`B
`
`100
`
`75
`
`50
`
`25
`
`Patients (%)
`
`5
`
`10
`
`15
`
`20
`Months
`
`25
`
`30
`
`35
`
`40
`
`1211
`
`1211
`
`9631
`
`98
`45
`87
`54
`
`80
`38
`66
`39
`
`59
`24
`33
`18
`
`33
`12
`17
`4
`
`0
`
`0
`
`124
`52
`108
`67
`
`No. at Risk
`Lenalidomide without thalidomide
`Lenalidomide with thalidomide
`Placebo without thalidomide
`Placebo with thalidomide
`
`EMail
`
`Figure 2. Kaplan–Meier Curves for Overall Survival among All Patients and in Subgroups with and without Previous Exposure to Thalidomide.
`Panel A shows the estimates of median overall survival for the intention-to-treat population (not yet reached in the lenalidomide group
`and 20.6 months in the placebo group, P<0.001 by the log-rank test). Panel B shows the median overall survival among patients in the
`two study groups who received thalidomide before study entry and those who did not receive thalidomide (in the lenalidomide group,
`the median was not yet reached in either subgroup; in the placebo group, 23.5 months among those who did not receive thalidomide
`AUTHOR:
`Dimopoulos
`1st
`RETAKE
`ICM
`and 18.2 months among those who did receive thalidomide; P = 0.04 by the log-rank test for the between-group comparison of patients
`2nd
`FIGURE:
`2 of 2
`REG F
`3rd
`who received thalidomide and P = 0.21 for the between-group comparison of patients who did not receive thalidomide).
`CASE
`Revised
`4-C
`Line
`SIZE
`ARTIST:
`ts
`H/T
`H/T
`22p3
`Enon
`Combo
`1 from leukoencephalopathy, 1 from pneumonia
`than one dose reduction or interruption of lena-
`AUTHOR, PLEASE NOTE:
`lidomide or dexamethasone was similar in the
`bacteria, and 1 from sudden death) and 6 in the
`Figure has been redrawn and type has been reset.
`Please check carefully.
`two groups. The mean time until the first dose
`placebo group (3 from sepsis, 1 from hepatic
`reduction or interruption of a study drug was
`failure, 1 from a cerebrovascular event, and 1 from
`JOB:
`35721
`11-22-07
`ISSUE:
`also similar in the two groups (125 days in the
`gastrointestinal hemorrhage). The primary reason
`lenalidomide group and 128 days in the placebo
`for the discontinuation of treatment in the two
`group). Dose reduction or interruption because
`groups was disease progression; 31 patients in
`of adverse events was more common in the lena-
`the two groups (8.8%) discontinued treatment
`lidomide group (occurring in 76.1% of the pa-
`early because of adverse events.
`tients) than in the placebo group (56.9%, P<0.001).
`Granulocyte colony-stimulating factor was
`There were 11 deaths that were possibly related to
`administered if only grade 3 or 4 myelosuppres-
`a study drug: 5 in the lenalidomide group (1 from
`sion occurred; with other grade 3 or 4 adverse
`cardiac arrest, 1 from pulmonary embolism,
`events, the lenalidomide dose was reduced. In the
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`2129
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 29, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1037, p. 0007
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 3. Grade 3 and 4 Adverse Events.*
`
`Event
`
`Hematologic disorder
`Neutropenia
`Anemia
`Thrombocytopenia
`Febrile neutropenia
`Gastrointestinal disorder
`Constipation
`Diarrhea
`Nausea
`General disorder
`Asthenia
`Fatigue
`Pyrexia
`Peripheral edema
`Infection
`Upper respiratory infection
`All other infection†
`Weight loss
`Musculoskeletal or connective-tissue disorder
`Muscle cramp
`Back pain
`Bone pain
`Muscle weakness
`Arthralgia
`Neurologic disorder
`Headache
`Tremor
`Dizziness
`Paresthesia
`Insomnia
`Respiratory, thoracic, or mediastinal disorder
`Cough
`Nasopharyngitis
`Dyspnea
`Vascular disorder
`Deep-vein thrombosis
`Pulmonary embolism
`Venous thromboembolism‡
`
`Placebo (N = 175)
`Lenalidomide (N = 176)
`Grade 3
`Grade 4
`Grade 3
`Grade 4
`number (percent)
`
`44 (25.0)
`14 (8.0)
`17 (9.7)
`5 (2.8)
`
`3 (1.7)
`5 (2.8)
`2 (1.1)
`
`11 (6.2)
`11 (6.2)
`1 (0.6)
`2 (1.1)
`
`3 (1.7)
`15 (8.5)
`3 (1.7)
`
`1 (0.6)
`4 (2.3)
`5 (2.8)
`13 (7.4)
`1 (0.6)
`
`1 (0.6)
`2 (1.1)
`1 (0.6)
`1 (0.6)
`2 (1.1)
`
`2 (1.1)
`1 (0.6)
`4 (2.3)
`
`6 (3.4)
`2 (1.1)
`13 (7.4)
`
`8 (4.5)
`1 (0.6)
`3 (1.7)
`1 (0.6)
`
`0
`0
`0
`
`0
`1 (0.6)
`0
`0
`
`0
`2 (1.1)
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`1 (0.6)
`
`1 (0.6)
`6 (3.4)
`7 (4.0)
`
`4 (2.3)
`12 (6.9)
`7 (4.0)
`0
`
`2 (1.1)
`4 (2.3)
`0
`
`10 (5.7)
`6 (3.4)
`6 (3.4)
`3 (1.7)
`
`0
`9 (5.1)
`1 (0.6)
`
`0
`3 (1.7)
`3 (1.7)
`8 (4.6)
`3 (1.7)
`
`1 (0.6)
`2 (1.1)
`1 (0.6)
`0
`1 (0.6)
`
`1 (0.6)
`0
`2 (1.1)
`
`5 (2.9)
`1 (0.6)
`6 (3.5)
`
`0
`0
`3 (1.7)
`0
`
`0
`0
`0
`
`0
`0
`0
`0
`
`0
`2 (1.1)
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`1 (0.6)
`
`1 (0.6)
`1 (0.6)
`2 (1.1)
`
`* Listed are data that were available on December 31, 2005. Percentages may not total 100 because of rounding.
`† This condition was also described in the following terms: infections not otherwise specified, pneumonia, upper respiratory
`tract infection, upper respiratory viral infection, sepsis, bacterial infection, urinary tract infection, pharyngitis, nasopharyn-
`gitis, febrile neutropenia, oral candidiasis, oral fungal infection, primary atypical pneumonia, fungal sinusitis, herpes sim-
`plex, herpes zoster, herpes encephalitis, herpes viral infection, cytomegalovirus pneumonia, and viral infection.
`‡ This condition was also described in the following terms: deep-vein thrombosis, pulmonary embolism, pulmonary infarc-
`tion, thrombosis, phlebothrombosis, thrombophlebitis, superficial thrombophlebitis, venous thrombosis, thromboem-
`bolism, splenic-vein thrombosis, phlebitis, and superficial phlebitis.
`
`2130
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 29, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1037, p. 0008
`
`

`

`Lenalidomide for Relapsed or Refractory Myeloma
`
`lenalidomide group, 38 patients (21.6%) received
`granulocyte colony-stimulating factor during the
`study. Of these patients, 23 (60.5%) received
`granulocyte colony-stimulating factor as the first
`step after having grade 3 or 4 neutropenia to
`maintain the 25-mg dose level. Among these 23
`patients, 12 (52.2%) were able to continue with
`the 25-mg dose level of lenalidomide from the
`time of the first episode of grade 3 or 4 neutro-
`penia until the last follow-up visit, as long as that
`period of time was at least 3 months.
`
`Discussion
`
`We found that in patients with relapsed or refrac-
`tory multiple myeloma, lenalidomide plus dexa-
`methasone increased the time to progression, the
`rate of response (both overall and complete re-
`sponses), and overall survival, as compared with
`placebo plus dexamethasone. The media