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 Multiple Myeloma in North America
`Donna M. Weber, M.D., Christine Chen, M.D., Ruben Niesvizky, M.D.,
`Michael Wang, M.D., Andrew Belch, M.D., Edward A. Stadtmauer, M.D.,
`David Siegel, M.D., Ivan Borrello, M.D., S. Vincent Rajkumar, M.D.,
`Asher Alban Chanan-Khan, M.D., Sagar Lonial, M.D., Zhinuan Yu, Ph.D.,
`John Patin, M.S., Marta Olesnyckyj, R.N., Jerome B. Zeldis, M.D., Ph.D.,
`and Robert D. Knight, M.D., for the Multiple Myeloma (009) Study Investigators*
`
`ABS TR ACT
`
`Background
`Lenalidomide, an oral immunomodulatory drug that is similar to thalidomide but
`has a different safety profile, has clinical activity in relapsed or refractory multiple
`myeloma.
`
`Methods
`Patients in the United States and Canada who had received at least one previous
`therapy for multiple myeloma but who required additional treatment were randomly
`assigned to receive either 25 mg of lenalidomide or placebo on days 1 to 21 of a
`28-day cycle. Both groups also 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. Safety, clinical response, time to
`progression, and overall survival were assessed.
`
`Results
`We assigned 177 patients to the lenalidomide group and 176 to the placebo group.
`Complete, near-complete, or partial responses occurred in 108 patients (61.0%) in
`the lenalidomide group and in 35 patients (19.9%) in the placebo group (P<0.001);
`complete responses occurred in 14.1% and 0.6%, respectively (P<0.001). The median
`time to progression was 11.1 months in the lenalidomide group and 4.7 months in
`the placebo group (P<0.001). Median overall survival times in the two groups were
`29.6 months and 20.2 months, respectively (P<0.001). Grade 3 or 4 adverse events
`were reported in 85.3% of the lenalidomide group and in 73.1% of the placebo
`group; these events resulted in study discontinuation in 19.8% and 10.2%, respective-
`ly. Grade 3 or 4 neutropenia and venous thromboembolism were more common in
`the lenalidomide group than in the placebo group (41.2% vs. 4.6% and 14.7% vs.
`3.4%, respectively; P<0.001 for both comparisons).
`
`Conclusions
`Lenalidomide plus dexamethasone is superior to placebo plus dexamethasone in
`patients with relapsed or refractory multiple myeloma. (ClinicalTrials.gov number,
`NCT00056160.)
`
`From the M.D. Anderson Cancer Center,
`Houston (D.M.W., M.W.); Princess Mar-
`garet Hospital, Toronto (C.C.); Weill Cor-
`nell Medical College, New York (R.N.);
`Cross Cancer Institute, Edmonton, AB,
`Canada (A.B.); University of Pennsylvania
`Cancer Center, Philadelphia (E.A.S.); the
`Cancer Center at Hackensack University
`Medical Center, Hackensack, NJ (D.S.);
`Sidney Kimmel Comprehensive Cancer
`Center at Johns Hopkins, Baltimore (I.B.);
`Mayo Clinic Cancer Center, Rochester, MN
`(S.V.R.); Roswell Park Cancer Institute,
`Buffalo, NY (A.A.C.-K.); Emory University,
`Atlanta (S.L.); and Celgene, Summit, NJ
`(Z.Y., J.P., M.O., J.B.Z., R.D.K.). Address
`reprint requests to Dr. Weber at the De-
`partment of Lymphoma and Myeloma,
`M.D. Anderson Cancer Center, 1515 Hol-
`combe Blvd., Box 429, Houston, TX 77030,
`or at dmweber@mdanderson.org.
`
`*Other investigators in the Multiple My-
`eloma (009) Study are listed in the Ap-
`pendix.
`
`N Engl J Med 2007;357:2133-42.
`Copyright © 2007 Massachusetts Medical Society.
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`2133
`
`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. 1040, p. 0001
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Multiple myeloma causes nearly
`
`11,000 deaths annually in the United
`States.1 Treatment with the immuno-
`modulatory agent thalidomide or the proteasome
`inhibitor bortezomib has improved response rates,
`time to progression, and survival, but the side
`effects of fatigue, neuropathy, constipation, and
`thrombotic events remain a concern.2-6 In nearly
`all patients who receive these drugs or other che-
`motherapy, the disease eventually relapses and is
`subsequently resistant to treatment.
`Lenalidomide is a thalidomide derivative that
`down-regulates interleukin-6 and nuclear factor
`κ-B and activates caspase 8 in vitro. The drug is up
`to 50,000 times as potent as its parent molecule
`in inhibiting tumor necrosis factor α.7 Phase 1
`and 2 trials of lenalidomide in patients with
`treatment-refractory multiple myeloma showed a
`partial-response rate of 24 to 29%.8-10 Moreover,
`an additional 29% of patients who had not had
`a response to lenalidomide alone had a partial
`remission after the addition of pulsed doses of
`dexamethasone.10 We report here on a random-
`ized, phase 3 trial that compared lenalidomide
`plus dexamethasone with placebo plus dexameth-
`asone in patients with relapsed or refractory mul-
`tiple myeloma.
`
`Methods
`
`Patients
`Patients were eligible for the study if they were
`at least 18 years of age, had progressive multiple
`myeloma after at least one previous treatment,
`and had measurable disease that was not resis-
`tant to dexamethasone. Patients were considered
`to have disease that was resistant to dexametha-
`sone if they had had progression during previous
`therapy containing high-dose dexamethasone
`(total monthly dose, >200 mg). Measurable dis-
`ease was defined as a serum monoclonal protein
`(M protein) level of at least 0.5 g per deciliter or
`a urinary Bence Jones protein level of at least 0.2 g
`per day. Additional eligibility criteria included an
`Eastern Cooperative Oncology Group performance
`status of no more than 2, a serum aspartate amino-
`transferase or alanine aminotransferase level that
`was no more than 3 times the upper limit of the
`normal range, a serum bilirubin level that was no
`more than 2 times the upper limit of the normal
`range, a serum creatinine level of less than 2.5 mg
`per deciliter (221 μmol per liter), an absolute neu-
`trophil count of at least 1000 per cubic millime-
`
`ter, and a platelet count of 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 childbear-
`ing potential were eligible if they agreed to use
`contraception, had a negative pregnancy test be-
`fore enrollment, and agreed to undergo monthly
`pregnancy testing until 4 weeks after the discon-
`tinuation of the study drug.
`
`Study Design
`In this multicenter, double-blind, placebo-con-
`trolled, randomized, phase 3 trial, patients re-
`ceived 25 mg of daily oral lenalidomide or placebo
`on days 1 to 21 of each 28-day cycle. All patients
`also received 40 mg of daily oral dexamethasone
`on days 1 to 4, 9 to 12, and 17 to 20. After the
`fourth cycle, 40 mg of dexamethasone was ad-
`ministered only on days 1 to 4. Treatment was
`continued until the occurrence of disease progres-
`sion or unacceptable toxic effects. Central random-
`ization was performed with a block size of 4 and
`the use of an integrated voice-response system.
`The assignment of patients was stratified accord-
`ing to the level of serum β2-microglobulin (<2.5
`mg per liter vs. ≥2.5 mg per liter), previous stem-
`cell transplantation (none vs. ≥1), and the number
`of previous antimyeloma therapies (1 vs. ≥2).
`The primary end point was the time to disease
`progression. Secondary end points included over-
`all survival and the response rate.
`Toxic effects were graded according to the
`National Cancer Institute’s Common Toxicity
`Criteria, version 2.11 In the case of a grade 3 or 4
`adverse event, treatment was withheld and restart-
`ed at the next lower daily dose. The dose of lena-
`lidomide was modified as follows: 15 mg (dose
`level, –1), 10 mg (dose level, –2), or 5 mg (dose
`level, –3). For grade 3 or 4 neutropenia without
`other toxic effects, the first dose-modification
`step was dose level –1 (daily subcutaneous injec-
`tion of 5 μg of granulocyte colony-stimulating
`factor per kilogram of body weight and 25 mg of
`lenalidomide); sequential dose reductions of lena-
`lidomide were 15 mg (dose level, –2), 10 mg (dose
`level, –3), and 5 mg (dose level, –4) plus the daily
`administration of 5 μg per kilogram of granulo-
`cyte colony-stimulating factor at the investigator’s
`discretion. Thromboprophylaxis was not required,
`although it was used on an individual basis.
`Modifications in the dose of dexamethasone be-
`cause of toxic effects were 40 mg daily for 4 days
`
`2134
`
`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. 1040, p. 0002
`
`

`

`Lenalidomide for Relapsed Myeloma in North America
`
`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).
`Blood counts and physical examination were
`performed 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 protein electropho-
`resis studies were performed on day 1 of each
`cycle and at the end of treatment. Survival status
`was determined every 6 months after the discon-
`tinuation of treatment.
`The study was designed as a collaborative ef-
`fort by Dr. Weber, the coinvestigators, and the
`sponsor, Celgene. The sponsor collected the data
`and performed the final analysis in collaboration
`with an independent data monitoring committee
`and Dr. Weber. All authors had full access to the
`primary data and the final analysis. Dr. Weber
`wrote the first draft of the manuscript and vouch-
`es for the completeness and accuracy of the clini-
`cal results and the reporting of adverse events. An
`independent data and safety monitoring commit-
`tee reviewed ongoing safety and efficacy data
`throughout the study.
`
`Response Criteria
`The response of patients was assessed according
`to the criteria of the European Group for Blood
`and Marrow Transplantation.12 A partial response
`was defined as a reduction of M protein by at
`least 50% in serum, 90% in urine, or both, as
`confirmed by at least two electrophoretic mea-
`surements. A complete response was defined as
`the complete disappearance of M protein in serum
`and urine by immunofixation, as confirmed by
`two measurements, and the presence of less than
`5% marrow plasma cells; the criteria for near-
`complete remission were identical to those for
`complete remission but without confirmation of
`marrow plasmacytosis of less than 5% or the dis-
`appearance of M protein.
`The time to progression was measured from
`randomization to the date of the first assessment
`showing disease progression. Progressive disease
`was defined as an increase of at least 25% in
`M protein from nadir; an absolute increase in se-
`rum M protein of more than 500 mg per decili-
`ter, as compared with the nadir value; an absolute
`increase in urinary M protein of more than 200 mg
`per 24-hour period; or either a new bone lesion
`or plasmacytoma (or an increase in the size of
`such lesions), or a serum calcium level of more
`than 11.5 mg per deciliter (2.9 mmol per liter).
`
`Table 1. Demographic and Clinical Characteristics of the Patients.*
`
`Characteristic
`
`Age — yr
`
`Median
`
`Range
`
`Male sex — %
`
`Time since diagnosis — yr
`
`Median
`
`Range
`
`Durie–Salmon stage — no. (%)
`
`I
`
`II
`
`III
`
`Missing data
`
`Eastern Cooperative Oncology Group
`performance status — no. (%)†
`
`0
`
`1
`
`2
`
`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 = 177)
`
`Placebo
`(N = 176)
`
`64
`
`36–86
`
`59.9
`
`3.1
`
`0.5–14.7
`
`6 (3.4)
`
`56 (31.6)
`
`114 (64.4)
`
`1 (0.6)
`
`74 (41.8)
`
`83 (46.9)
`
`14 (7.9)
`
`6 (3.4)
`
`62
`
`37–85
`
`59.1
`
`3.1
`
`0–19.7
`
`5 (2.8)
`
`55 (31.2)
`
`116 (65.9)
`
`0
`
`83 (47.2)
`
`80 (45.5)
`
`6 (3.4)
`
`7 (4.0)
`
`68 (38.4)
`
`109 (61.6)
`
`67 (38.1)
`
`109 (61.9)
`
`74 (41.8)
`
`19 (10.7)
`
`80 (45.5)
`
`20 (11.4)
`
`109 (61.6)
`
`108 (61.4)
`
`52 (29.4)
`
`125 (70.6)
`
`51 (29.0)
`
`125 (71.0)
`
`* There were no significant differences between the two groups according to a
`pooled t-test for continuous variables (age and time since first pathological
`diagnosis) and Fisher’s exact test for categorical variables (all other variables
`in the table) (P>0.05). Percentages may not total 100 because of rounding.
`† Lower numbers indicate better performance.
`
`Data for patients who died before there was evi-
`dence of disease progression were censored at the
`time of the last evaluation for assessment of time
`to progression. Overall survival was calculated as
`the time from randomization until death from
`any cause or the date of the last visit.
`
`Statistical Analysis
`The number of patients was calculated so that a
`one-sided log-rank test at the 0.025 level, allowing
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`2135
`
`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. 1040, p. 0003
`
`

`

`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. (%)
`
`Lenalidomide
`(N = 177)
`
`Placebo
`(N = 176)
`
`P Value*
`
`<0.001
`
`<0.001
`
`Overall response
`
`108 (61.0)
`
`35 (19.9)
`
`Complete response
`
`Near-complete response
`
`Partial response
`
`Stable disease
`
`Progressive disease
`
`Response could not be evaluated
`
`Overall response in selected sub-
`groups — no./total no. (%)†
`
`Previous use of thalidomide
`
`25 (14.1)
`
`18 (10.2)
`
`65 (36.7)
`
`54 (30.5)
`
`5 (2.8)
`
`10 (5.6)
`
`1 (0.6)
`
`2 (1.1)
`
`32 (18.2)
`
`102 (58.0)
`
`25 (14.2)
`
`14 (8.0)
`
`Yes
`
`No
`
`42/74 (56.8)
`
`10/80 (12.5)
`
`<0.001
`
`66/103 (64.1)
`
`25/96 (26.0)
`
`<0.001
`
`Previous use of bortezomib
`
`Yes
`
`No
`β2-microglobulin level
`<2.5 mg per liter
`
`13/19 (68.4)
`
`2/20 (10.0)
`
`<0.001
`
`95/158 (60.1)
`
`33/156 (21.2)
`
`<0.001
`
`39/52 (75.0)
`
`14/51 (27.5)
`
`<0.001
`
`≥2.5 mg per liter
`
`69/125 (55.2)
`
`21/125 (16.8)
`
`<0.001
`
`Previous no. of therapies
`
`1
`
`≥2
`
`Previous stem-cell transplantation
`
`44/68 (64.7)
`
`15/67 (22.4)
`
`<0.001
`
`64/109 (58.7)
`
`20/109 (18.3)
`
`<0.001
`
`Yes
`
`No
`
`72/109 (66.1)
`
`21/108 (19.4)
`
`<0.001
`
`36/68 (52.9)
`
`14/68 (20.6)
`
`<0.001
`
`* P values were calculated with the use of a continuity-corrected Pearson chi-
`square test.
`† There was no stratum-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 within selected subgroups of the intention-to-treat
`population.
`
`for one interim analysis, would have a statistical
`power of 85% to detect a difference between the
`time to progression for each group with a con-
`stant hazard ratio of 1.5, reflecting an increase
`of 50% in the median time to progression. The
`number of events required was 222. On the basis
`of the planned accrual rate, a log-rank test of over-
`all survival that was performed 18 months after
`the last patient had been enrolled, when 194 deaths
`were expected, would have a power of 80% to de-
`tect a hazard ratio for death of 0.67. An interim
`analysis to evaluate safety and efficacy was planned
`
`when 111 patients had disease progression; if the
`predetermined O’Brien–Fleming boundary for the
`superiority of lenalidomide over placebo was
`crossed, the study would be unblinded and pa-
`tients would be allowed to cross over to open-label
`administration of lenalidomide at progression or
`at the investigator’s discretion.
`All primary analyses were based on the inten-
`tion-to-treat population, and subgroup analyses
`were planned on the basis of stratification vari-
`ables. An unstratified log-rank test was used to
`compare the time-to-event variables between the
`two study groups. Both the time to progression
`and overall survival were estimated by Kaplan–
`Meier methods, and a Cox proportional-hazards
`regression model was used to assess the effect
`of demographic and prognostic variables on dif-
`ferences in treatment responses between the two
`study groups. Exact tests were used to compare re-
`sponse rates. All reported P values are two-sided.
`
`R esults
`
`Patients
`From February 27, 2003, to April 14, 2004, a total
`of 353 patients were enrolled at 44 centers in the
`United States and 4 in Canada. Of those patients,
`177 were assigned to receive lenalidomide plus
`dexamethasone (lenalidomide group) and 176 to
`receive placebo plus dexamethasone (placebo
`group). Baseline characteristics were well balanced
`between the two groups (Table 1). Previous treat-
`ments included radiotherapy, myeloablative ther-
`apy with stem-cell transplantation, and various
`combinations of dexamethasone, melphalan, doxo-
`rubicin, thalidomide, bortezomib, and other che-
`motherapy agents.
`Because the O’Brien–Fleming boundary for the
`superiority of lenalidomide over placebo was
`crossed at the interim analysis, the data and safe-
`ty monitoring committee recommended that the
`study be unblinded. The results presented here
`for response and time to progression are based
`on data obtained before unblinding, and the re-
`sults for safety are based on data obtained be-
`fore December 31, 2005. Median follow-up was
`17.6 months.
`
`Response Rate
`Among 177 patients in the lenalidomide group,
`108 (61.0%) had a response (complete, near-com-
`plete, or partial), as compared with 35 of 176
`patients (19.9%) in the placebo group (P<0.001)
`
`2136
`
`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. 1040, p. 0004
`
`

`

`Lenalidomide for Relapsed Myeloma in North America
`
`(Table 2). A complete response occurred in 25
`patients (14.1%) in the lenalidomide group and
`in 1 patient (0.6%) in the placebo group (P<0.001);
`a near-complete response occurred in 18 patients
`(10.2%) in the lenalidomide group and in 2 pa-
`tients (1.1%) in the placebo group (P<0.001). The
`median time to a response was similar in the two
`groups, but the median duration of the response
`was significantly longer in the lenalidomide group
`than for those in the placebo group (15.8 months
`vs. 5.1 months, P<0.001). The overall response rate
`was higher for patients who received lenalido-
`mide, regardless of the stratification group (Ta-
`ble 2). In addition, previous treatment with thalido-
`mide did not affect the response to lenalidomide;
`56.8% of patients who had received thalidomide
`had a complete, near-complete, or partial response,
`as compared with 64.1% who had not received
`
`thalidomide (P = 0.33). Similarly, previous treatment
`with bortezomib did not affect the response to
`lenalidomide (Table 2).
`
`Time to Progression
`The median time to progression was significant-
`ly longer in the lenalidomide group (11.1 months)
`than in the placebo group (4.7 months), with a
`hazard ratio of 0.35 (95% confidence interval [CI],
`0.27 to 0.47; P<0.001) (Fig. 1A). The median time
`to progression was significantly larger in all
`subgroups of patients who received lenalidomide,
`as compared with those who received placebo
`(P<0.001 for all comparisons), including patients
`who had received one previous therapy (median
`time not reached vs. 5.1 months) or two or more
`previous therapies (10.2 months vs. 4.6 months).
`Among the 154 patients who had been ex-
`
`Lenalidomide
`Placebo
`
`Lenalidomide without previous
`thalidomide
`
`Lenalidomide with previous
`thalidomide
`Placebo without previous
`thalidomide
`Placebo with previous thalidomide
`
`10
`15
`20
`Months to Progression
`
`25
`
`30
`
`10
`15
`20
`Months to Progression
`
`25
`
`30
`
`5
`
`5
`
`100
`
`75
`
`50
`
`25
`
`0
`
`0
`
`100
`
`75
`
`50
`
`25
`
`0
`
`0
`
`Patients (%)
`
`Patients (%)
`
`A
`
`B
`
`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 the curves for time to progression for the intention-to-treat population (a median of 11.1 months in
`AUTHOR:
`Weber
`1st
`RETAKE
`ICM
`the lenalidomide group and 4.7 months in the placebo group, P<0.001 by the log-rank test). Panel B shows the time
`2nd
`FIGURE:
`1 of 2
`REG F
`to disease progression among patients in the two study groups who received thalidomide before study entry and
`3rd
`CASE
`Revised
`those who did not receive thalidomide. In the lenalidomide group, the median time was 14.2 months among patients
`Line
`4-C
`SIZE
`EMail
`who did not receive thalidomide and 8.5 months among those who received thalidomide; in the placebo group, the
`ARTIST:
`ts
`H/T
`H/T
`33p9
`Enon
`median time was 4.7 months and 4.1 months, respectively (P<0.001 by the log-rank test for both between-group
`Combo
`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.
`
`JOB:
`
`35721
`
`ISSUE:
`11-22-07
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`2137
`
`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. 1040, p. 0005
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`posed to thalidomide, the median time to pro-
`gression was also significantly improved in the
`lenalidomide group (8.5 months), as compared
`with the placebo group (4.1 months, P<0.001)
`(Fig. 1B). The median time to progression did
`not differ significantly between patients who had
`been exposed to thalidomide and those who had
`not been exposed to thalidomide (P = 0.08). The
`median time to progression among the 39 pa-
`tients who had received previous treatment with
`bortezomib was longer in the lenalidomide group
`(10.3 months) than in the placebo group (3.3
`months, P<0.001).
`
`In the two study groups, prognostic factors for
`significant improvement in the time to progres-
`sion were a serum β2-microglobulin level of less
`than 2.5 mg per liter, only one previous antimye-
`loma therapy, and a lower baseline level of bone
`marrow plasmacytosis, according to Cox regres-
`sion analysis.
`
`Survival
`As of May 2006, a total of 49 patients (27.7%) had
`died in the lenalidomide group (40 from progres-
`sive disease), as had 63 patients (35.8%) in the
`placebo group (53 from progressive disease). The
`
`Lenalidomide
`Placebo
`
`Lenalidomide without previous
`thalidomide
`
`Lenalidomide with previous
`thalidomide
`Placebo without previous
`thalidomide
`Placebo with previous thalidomide
`
`30
`
`35
`
`71
`
`30
`
`35
`
`5311
`
`25
`
`34
`5
`
`25
`
`25
`10
`
`42
`
`100
`
`75
`
`50
`
`25
`
`Patients (%)
`
`0
`
`0
`
`5
`
`10
`
`15
`
`20
`Months
`
`No. at Risk
`Lenalidomide
`Placebo
`
`177
`175
`
`164
`144
`
`144
`115
`
`109
`51
`
`74
`26
`
`100
`
`75
`
`50
`
`25
`
`Patients (%)
`
`A
`
`B
`
`No. at Risk
`Lenalidomide without thalidomide
`Lenalidomide with thalidomide
`Placebo without thalidomide
`Placebo with thalidomide
`
`0
`
`0
`
`103
`74
`95
`80
`
`5
`
`98
`67
`83
`62
`
`10
`
`86
`59
`66
`49
`
`15
`
`20
`Months
`
`70
`40
`27
`25
`
`51
`24
`15
`12
`
`Figure 2. Kaplan–Meier Curves for Overall Survival for All Patients and in Subgroups with and without Previous Exposure to Thalidomide.
`Weber
`AUTHOR:
`1st
`RETAKE
`Panel A shows the curves for overall survival for the intention-to-treat population (a median of 29.6 months in the lenalidomide group
`ICM
`2nd
`2 of 2
`FIGURE:
`and 20.2 months in the placebo group, P<0.001 by the log-rank test). Panel B shows the overall survival among patients in the two study
`REG F
`3rd
`groups who received thalidomide before study entry and those who did not receive thalidomide. In the lenalidomide group, the median
`CASE
`Revised
`Line
`4-C
`time was 29.6 months among those who did not receive thalidomide, and the median was not yet reached among those who received
`SIZE
`EMail
`ARTIST:
`ts
`H/T
`H/T
`thalidomide; in the placebo group, the median time was 20.5 months among those who did not receive thalidomide and 16.8 months
`22p3
`Enon
`Combo
`among those who received thalidomide (P<0.001 by the log-rank test for the between-group comparison of patients who did not receive
`AUTHOR, PLEASE NOTE:
`thalidomide and P = 0.03 for the between-group comparison of patients who received thalidomide).
`Figure has been redrawn and type has been reset.
`Please check carefully.
`
`2138
`
`JOB:
`
`35721
`
`ISSUE:
`
`11-22-07
`
`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. 1040, p. 0006
`
`

`

`Lenalidomide for Relapsed Myeloma in North America
`
`median follow-up from randomization to data
`cutoff for the surviving patients was 26.2 months
`in the lenalidomide group and 12.9 months in the
`placebo group. The median overall survival was
`significantly longer for patients in the lenalido-
`mide group (29.6 months) than for those in the
`placebo group (20.2 months), with a hazard ratio
`of 0.44 (95% CI, 0.30 to 0.65; P<0.001) (Fig. 2A).
`Overall survival was also significantly improved
`in the lenalidomide group, as compared with the
`placebo group, among patients who had been
`treated with thalidomide (hazard ratio, 0.56; 95%
`CI, 0.34 to 0.95; P = 0.03) (Fig. 2B).
`
`Adverse Events
`The most frequently reported nonhematologic ad-
`verse events were fatigue, insomnia, diarrhea, con-
`stipation, muscle cramps, and infection. Infec-
`tions were more common in the lenalidomide
`group than in the placebo group (67.8% vs. 44.0%,
`P<0.001) but were usually grade 2 or less; grade 3
`or 4 infections were noted in 38 patients (21.5%)
`and 21 patients (12.0%), respectively (P = 0.14)
`(Table 3). Among patients with grade 3 or 4 in-
`fections in the lenalidomide group and the place-
`bo group, 31 and 17 patients, respectively, required
`antibiotics; 3 and 1, respectively, required anti-
`viral therapy; and 3 and 4, respectively, required
`antifungal therapy. The most frequently reported
`infections were upper respiratory tract infections
`and pneumonia. In the lenalidomide group, grade
`3 or 4 peripheral neuropathy, constipation, and
`diarrhea developed in 1.7%, 2.8%, and 3.4% of
`patients, respectively (Table 3).
`Venous thromboembolic events were more
`common in the lenalidomide group than in the
`placebo group (14.7% vs. 3.4%, P<0.001). There
`were no deaths due to venous thromboembolic
`events. The dose of lenalidomide was reduced in
`seven patients, and eight stopped treatment after
`the event. In a post hoc analysis among 98 patients
`in the lenalidomide group who were receiving con-
`current epoetin alfa or darbepoetin, 18.4% had
`thrombotic events, as compared with 10.1% of
`patients not receiving these agents (P = 0.14). In
`the placebo group, among patients with and those
`without concomitant administration of these
`drugs, thromboembolic complications occurred in
`5 of 69 patients (7.2%) and 1 of 106 patients
`(0.9%), respectively (P = 0.04).
`Grade 3 or 4 hematologic toxic effects oc-
`curred in 52.5% of patients in the lenalidomide
`
`group and in 13.7% of patients in the placebo
`group (P<0.001). Grade 3 or 4 neutropenia was
`more common in the lenalidomide group (41.2%)
`than in the placebo group (4.6%, P<0.001), as was
`thrombocytopenia (14.7% vs. 6.9%, P = 0.02).
`Sixty-eight patients (38.4%) in the lenalido-
`mide group and 126 patients (71.6%) in the pla-
`cebo group discontinued the study drug because
`of disease progression, and 35 (19.8%) and 18
`(10.2%), respectively, discontinued the study drug
`because of adverse events. The proportion of pa-
`tients who required at least one dose reduction or
`interruption of a study drug because of adverse
`events was higher in the lenalidomide group than
`in the placebo group (76.8% vs. 57.7%). There
`were four deaths that were considered to be pos-
`sibly related to a study drug: three in the lena-
`lidomide group (two from sepsis and one from
`a cerebrovascular accident) and one in the placebo
`group (pneumonia). Neutropenia and thrombo-
`cytopenia were the primary reasons for dose re-
`duction in the lenalidomide group, but less than
`5% of patients had neutropenia or thrombocyto-
`penia resulting in discontinuation of the study
`drug. The median time to the first dose reduction
`or interruption was approximately 2 months in
`the two study groups.
`Granulocyte colony-stimulating factor was ad-
`ministered if grade 3 or 4 myelosuppression oc-
`curred without the occurrence of other adverse
`events; with additional grade 3 or 4 adverse events,
`the dose of lenalidomide was reduced. Among the
`177 patients in the lenalidomide group, 60 (33.9%)
`received granulocyte colony-stimulating factor
`during the study. Among these 60 patients, 28
`(46.7%) received granulocyte colony-stimulating
`factor as the first step in dose reduction because
`of grade 3 or 4 neutropenia, to maintain the 25-mg
`dose level. Among these 28 patients, 12 (42.9%)
`were able to continue with the 25-mg dose level
`of lenalidomide. The dose of dexamethasone was
`reduced in 31.1% of patients receiving lenalido-
`mide and in 15.4% receiving placebo.
`
`Discussion
`
`In our randomized phase 3 study, we found that
`lenalidomide plus dexamethasone had significant
`clinical activity in patients with relapsed or re-
`fractory multiple myeloma. Lenalidomide plus
`dexamethasone was superior to high-dose dexa-
`methasone alone in terms of the overall response
`
`n engl j med 357;21 www.nejm.org november 22, 2007
`
`2139
`
`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. 1040, p. 0007
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 3. Grade 3 or 4 Adverse Events (Safety Population).*
`
`Event
`
`Hematologic disorder
`
`Neutropenia
`
`Anemia
`
`Thrombocytopenia
`
`Febrile neutropenia
`
`Gastrointestinal disorder
`
`Diarrhea
`
`Constipation
`
`Nausea
`
`Dyspepsia
`
`General and administration-site disorder
`
`Lenalidomide (N = 177)
`
`Grade 3
`
`Grade 4
`
`Placebo (N = 175)
`
`Grade 3
`
`Grade 4
`
`number (percent)
`
`62 (35.0)
`
`19 (10.7)
`
`24 (13.6)
`
`5 (2.8)
`
`6 (3.4)
`
`5 (2.8)
`
`5 (2.8)
`
`1 (0.6)
`
`11 (6.2)
`
`4 (2.3)
`
`2 (1.1)
`
`1 (0.6)
`
`0
`
`0
`
`0
`
`0
`
`6 (3.4)
`
`6 (3.4)
`
`12 (6.9)
`
`0
`
`0
`
`0
`
`2 (1.1)
`
`1 (0.6)
`
`11 (6.3)
`
`2 (1.1)
`
`3 (1.7)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Fatigue
`
`Peripheral edema
`
`Pyrexia
`
`Asthenia
`
`Infection or infestation
`
`Any infection†
`
`Upper respiratory infection
`
`Pneumonia
`
`Metabolism or nutrition disorder
`
`Hyperglycemia
`
`Hypokalemia
`
`Anorexia
`
`11 (6.2)
`
`4 (2.3)
`
`4 (2.3)
`
`6 (3.4)
`
`33 (18.6)
`
`2 (1.1)
`
`19 (10.7)
`
`15 (8.5)
`
`10 (5.6)
`
`1 (0.6)
`
`0
`
`0
`
`0
`
`0
`
`5 (2.8)
`
`0
`
`3 (1.7)
`
`4 (2.3)
`
`1 (0.6)
`
`0
`
`1 (0.6)
`
`6 (3.4)
`
`6 (3.4)
`
`16 (9.1)
`
`2 (1.1)
`
`10 (5.7)
`
`10 (5.7)
`
`2 (1.1)
`
`3 (1.7)
`
`0
`
`0
`
`0
`
`5 (2.9)
`
`0
`
`3 (1.7)
`
`5 (2.9)
`
`0
`
`0
`
`rate (61.0% vs. 19.9%, P<0.001), median time to
`progression (11.1 months vs. 4.7 months, P<0.001),
`and median overall survival (29.6 months vs.
`20.2 months, P<0.001). It is notable that patients
`with multiple myeloma that was refractory to stan-
`dard treatments had a median time to progres-
`sion of more than 10 months. In addition, there
`was a prolongation of overall survival. This benefit
`was evident even though 58.0% of patients in the
`placebo group later received lenalidomide or lena-
`lidomide plus dexamethasone after disease pro-
`gression or after the unblinding of the trial but
`were analyzed on an intention-to-treat basis in
`the placebo group.
`The superior results with lenalidomide were
`observed regardless of the number of previous
`therapies, the serum β2-microglobulin level, or the
`history with respect to treatment with thalido-
`mide or bortezomib. Response rates were higher
`in subgroups with a β2-microglobulin level of less
`
`than 2.5 mg per liter and only one previous anti-
`myeloma therapy, suggesting that treatment early
`in the course of disease may also be beneficial.
`Most results of treatment with lenalidomide plus
`dexamethasone were superior even among pa-
`tients treated previously with thalidomide. How-
`ever, the shorter time to progression in these pa-
`tients suggests some degree of cross-resistance
`betwe