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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*

A BS T R AC T 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 lenalidomide 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 patients 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%).

From the University of Athens School of Medicine, Athens (M.D.); Alfred Hospital (A.S.) and Peter MacCallum Cancer Institute (H.M.P.) — both in Melbourne, Australia; 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 Istituto Ricovero e Cura a Carattere Scientifico, 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. N Engl J Med 2007;357:2123-32. Copyright © 2007 Massachusetts Medical Society.

Conclusions

Lenalidomide plus dexamethasone is more effective than high-dose dexamethasone alone in relapsed or refractory multiple myeloma. (ClinicalTrials.gov number, NCT00424047.)

n engl j med 357;21  www.nejm.org  november 22, 2007

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ultiple 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 thalidomide is combined with dexamethasone or chemotherapy.3-7 Treatment with thalidomide is associated with sedation, fatigue, constipation, rash, deep-vein thrombosis, and peripheral neuropathy. These toxic effects often require dose reduction 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.

Me thods 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 antimye­loma regimen. Patients were excluded if they had had disease progression during previous therapy containing high-dose dexamethasone (total month­ly dose, >200 mg). Measurable disease was defined as a level of serum monoclonal protein (M protein) 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 Eastern Cooperative Oncology Group performance status of 2 or less, a serum aspartate aminotransferase 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 normal 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 cu2124

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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 enrollment, and agreed to undergo pregnancy testing 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, randomized, placebo-controlled, phase 3 trial was the time to disease progression. Secondary end points included overall survival, the rate of response, 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 dexamethasone was administered only on days 1 to 4. Patients continued to receive the assigned drug regimen until the occurrence of disease progression or unacceptable toxic effects. Patients were stratified according to the baseline serum β2microglobulin 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 Criteria, version 2. For grade 4 adverse events, treatment 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 follows: 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

n engl j med 357;21  www.nejm.org  november 22, 2007


Lenalidomide for Relapsed or Refr actory Myeloma

granulocyte colony-stimulating factor per kilogram 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 granulocyte colony-stimulating factor per kilogram daily at the investigator’s discretion. Patients underwent a blood count and physical 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 platelets and red cells and the administration of neutrophil growth factors and epoetin alfa were allowed as needed. All patients were allowed to receive bisphosphonates. Prophylactic anticoagulation was not recommended. The study was designed as a collaborative effort by Dr. Dimopoulos, 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. Dimopoulos. All authors had full access to the primary data and the final analysis. Dr. Dimopoulos vouches for the accuracy and completeness 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 assessed according to the criteria of the European Group for Blood and Marrow Transplantation.12 The time to progression was measured from randomization to the date of the first assessment showing progression. Progressive disease was defined 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 calcium 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 partial (defined as a reduction in the level of M protein in serum of at least 50% and a reduction in urine of at least 90%). Complete and partial responses were confirmed by repeated measurements 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 response, a subcategory of partial response, was defined as a complete response without confirmation 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 patients (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 significance level of 0.05, adjusted for one interim analysis. Full information that was necessary for a logrank 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 approximately 80% to detect a difference of 50% in median 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 patients. If the predetermined O’Brien–Fleming boundary for the superiority of lenalidomide over placebo was crossed, the study would be unblinded, 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 unstratified log-rank test was used to compare time-to-event variables between groups. Both the time to progression and overall survival were estimated 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

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Table 1. Demographic and Clinical Characteristics of the Patients.* Lenalidomide (N = 176)

Placebo (N = 175)

Median

63

64

Range

33–84

40–82

Male sex — %

59.1

58.9

136 (77.3)

140 (80.0)

Median

3.4

4.0

Range

0.4–15.7

0.3–26.6

11 (6.2)

8 (4.6)

Characteristic Age — yr

Lytic bone lesions — no. (%) Time since first diagnosis — yr

Durie–Salmon stage — no. (%) I II

50 (28.4)

57 (32.6)

III

115 (65.3)

110 (62.9)

0

78 (44.3)

65 (37.1)

1

72 (40.9)

79 (45.1)

2

23 (13.1)

27 (15.4)

Eastern Cooperative Oncology Group performance status — no. (%)†

3

0

1 (0.6)

Missing data

3 (1.7)

3 (1.7)

Previous therapy — no. (%) No. of therapies 1

56 (31.8)

57 (32.6)

≥2

120 (68.2)

118 (67.4)

Thalidomide

53 (30.1)

67 (38.3)

Bortezomib

8 (4.5)

7 (4.0)

97 (55.1)

95 (54.3)

Type of therapy

Stem-cell transplantation β2-microglobulin level — no. (%) <2.5 mg per liter

51 (29.0)

48 (27.4)

≥2.5 mg per liter

125 (71.0)

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 variables (all other variables in the table) (P>0.05). Percentages may not total 100 because of rounding. † Lower numbers indicate better performance.

R e sult s 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 2126

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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 September 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 ratio for time to progression was 2.85 (95% confidence 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 lenalidomide 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 previous 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 previous thalidomide treatment, the median time to

n engl j med 357;21  www.nejm.org  november 22, 2007


Lenalidomide for Relapsed or Refr actory Myeloma

A

Patients (%)

100

Lenalidomide Placebo

75 50 25 0

0

2.5

5

10

7.5

12.5

15

17.5

20

22.5

25

Months to Progression

B

Patients (%)

100 75

Lenalidomide without previous thalidomide

50

Lenalidomide with previous thalidomide Placebo without previous thalidomide

25 0

Placebo with previous thalidomide 0

5

10

15

20

25

30

Months to Progression

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 showsICM estimates of theDimopoulos median time to disease progression 1st for the intention-to-treat population (11.3 months RETAKE AUTHOR: 2nd(P<0.001 by the log-rank test). Panel B shows the in the lenalidomide group and 4.7 months in the placebo group) FIGURE: 1 of 2 REG F median time to disease progression among patients in the two3rd 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 EMail SIZE ARTIST: ts months not receive thalidomide and 8.4 among H/T those who22p3 did receive thalidomide; in the placebo group, 4.7 months H/T Enon and 4.6 months, respectively; P<0.001Combo 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.

progression was 9.5 months in the lenalidomide was longer in the lenalidomide group (16.5 months) 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 (com11.3 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 treatplantation. ment showed a higher response rate among paA 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 median time to the first response was 2.1 months Survival in the lenalidomide group and 1.6 months in the As of May 2006, 47 patients (26.7%) in the lena­ placebo group. The median time to a complete lidomide group had died (30 from progressive or near-complete response was 5.1 months in the disease), as had 60 patients (34.3%) in the placebo lenalidomide group and 6.9 months in the place­ group (49 from progressive disease). At the time bo group. The median duration of the response of the last analysis, median overall survival had n engl j med 357;21  www.nejm.org  november 22, 2007

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Table 2. Response among Patients in the Intention-to-Treat Population and in Selected Subgroups.* Variable

Lenalidomide (N = 176)

Placebo (N = 175)

P Value

106 (60.2)

42 (24.0)

<0.001

28 (15.9)

6 (3.4)

<0.001

Response in the intention-to-treat population — no. (%) Overall response Complete response Near-complete response

15 (8.5)

3 (1.7)

Partial response

63 (35.8)

33 (18.9)

53 (30.1)

97 (55.4)

3 (1.7)

25 (14.3)

14 (8.0)

11 (6.3)

Stable disease Progressive disease Response could not be evaluated Overall response in subgroups — no./total no. (%)† Previous exposure to thalidomide Yes

26/53 (49.1)

11/67 (16.4)

0.002

No

80/123 (65.0)

31/108 (28.7)

<0.001

β2-microglobulin — mg per liter <2.5

36/51 (70.6)

18/48 (37.5)

<0.001

≥2.5

70/125 (56.0)

24/127 (18.9)

<0.001

Previous no. of therapies 1

37/56 (66.1)

17/57 (29.8)

<0.001

≥2

69/120 (57.5)

25/118 (21.2)

<0.001

Yes

60/97 (61.9)

27/95 (28.4)

<0.001

No

46/79 (58.2)

15/80 (18.8)

<0.001

Previous stem-cell transplantation

* 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 previously 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 neutropenia (25.0%) than did those in the placebo group (2.3%). However, grade 3 or 4 febrile neutropenia was rare (occurring in 3.4% of the patients in the lenalidomide group and in none of those in the placebo group). Grade 3 or 4 thrombo­ 2128

cytopenia was twice as frequent in the lenalidomide 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 incidences 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 thromboembolic complications was unrelated to the concomitant 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

n engl j med 357;21  www.nejm.org  november 22, 2007


Lenalidomide for Relapsed or Refr actory Myeloma

A 100

Lenalidomide Placebo

Patients (%)

75 50 25 0

0

5

10

15

20

25

30

35

14 3

2 1

2 1

40

Months No. at Risk Lenalidomide Placebo

176 175

142 140

116 104

82 50

44 20

B

Patients (%)

100 75

Lenalidomide with previous thalidomide

50

Lenalidomide without previous thalidomide Placebo without previous thalidomide

25 0

Placebo with previous thalidomide 0

5

10

15

20

25

30

35

9 6 3 1

1 2 1 1

1 2 1 1

40

Months No. at Risk Lenalidomide without thalidomide Lenalidomide with thalidomide Placebo without thalidomide Placebo with thalidomide

124 52 108 67

98 45 87 54

80 38 66 39

59 24 33 18

33 12 17 4

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, 23.5RETAKE months among those who did not receive thalidomide 1st AUTHOR: Dimopoulos ICM 2nd and 18.2 months among those who did REG receive thalidomide; P = 0.04 by the log-rank test for the between-group comparison of patients FIGURE: 2 of 2 F 3rddid not receive thalidomide). who received thalidomide and P = 0.21 for the between-group comparison of patients who CASE

EMail Enon

ARTIST: ts

Line H/T Combo

4-C H/T

Revised

SIZE 22p3

than one dose reduction or interruption of lena­ 1 from leukoencephalopathy, 1 from pneumonia AUTHOR, PLEASE NOTE: lidomide or dexamethasone was similar bacteria, and from Figure in has the been redrawn and type has1been reset.sudden death) and 6 in the check carefully. two groups. The mean time until the first dosePleaseplacebo group (3 from sepsis, 1 from hepatic reduction or interruption of a study drug was failure, 1 fromISSUE: a cerebrovascular event, and 1 from JOB: 35721 11-22-07 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 myelosuppresa 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

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Table 3. Grade 3 and 4 Adverse Events.* Event

Placebo (N = 175)

Lenalidomide (N = 176) Grade 3

Grade 4

Grade 3

Grade 4

number (percent) Hematologic disorder Neutropenia

44 (25.0)

8 (4.5)

4 (2.3)

0

Anemia

14 (8.0)

1 (0.6)

12 (6.9)

0

Thrombocytopenia

17 (9.7)

3 (1.7)

7 (4.0)

3 (1.7)

Febrile neutropenia

5 (2.8)

1 (0.6)

0

0

Gastrointestinal disorder Constipation

3 (1.7)

0

2 (1.1)

0

Diarrhea

5 (2.8)

0

4 (2.3)

0

Nausea

2 (1.1)

0

0

0

Dyspnea

4 (2.3)

1 (0.6)

2 (1.1)

1 (0.6)

General disorder Asthenia

11 (6.2)

0

Fatigue

11 (6.2)

1 (0.6)

10 (5.7) 6 (3.4)

0 0

Pyrexia

1 (0.6)

0

6 (3.4)

0

Peripheral edema

2 (1.1)

0

3 (1.7)

0

3 (1.7)

0

0

0

2 (1.1)

9 (5.1)

2 (1.1)

0

1 (0.6)

0

Infection Upper respiratory infection All other infection†

15 (8.5)

Weight loss

3 (1.7)

Musculoskeletal or connective-tissue disorder Muscle cramp

1 (0.6)

0

0

0

Back pain

4 (2.3)

0

3 (1.7)

0

Bone pain Muscle weakness Arthralgia

5 (2.8)

0

3 (1.7)

0

13 (7.4)

0

8 (4.6)

0

1 (0.6)

0

3 (1.7)

0

Neurologic disorder Headache

1 (0.6)

0

1 (0.6)

0

Tremor

2 (1.1)

0

2 (1.1)

0

Dizziness

1 (0.6)

0

1 (0.6)

0

Paresthesia

1 (0.6)

0

0

0

Insomnia

2 (1.1)

0

1 (0.6)

0

Respiratory, thoracic, or mediastinal disorder Cough

2 (1.1)

0

1 (0.6)

0

Nasopharyngitis

1 (0.6)

0

0

0 1 (0.6)

Vascular disorder Deep-vein thrombosis

6 (3.4)

1 (0.6)

5 (2.9)

Pulmonary embolism

2 (1.1)

6 (3.4)

1 (0.6)

1 (0.6)

13 (7.4)

7 (4.0)

6 (3.5)

2 (1.1)

Venous thromboembolism‡

* 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, nasopharyngitis, febrile neutropenia, oral candidiasis, oral fungal infection, primary atypical pneumonia, fungal sinusitis, herpes simplex, 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 infarction, thrombosis, phlebothrombosis, thrombophlebitis, superficial thrombophlebitis, venous thrombosis, thromboembolism, splenic-vein thrombosis, phlebitis, and superficial phlebitis.

2130

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Lenalidomide for Relapsed or Refr actory 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 neutropenia until the last follow-up visit, as long as that period of time was at least 3 months.

Dis cus sion We found that in patients with relapsed or refractory multiple myeloma, lenalidomide plus dexamethasone increased the time to progression, the rate of response (both overall and complete responses), and overall survival, as compared with placebo plus dexamethasone. The median time to progression of 11.3 months and the 60.2% response rate in the lenalidomide group are among the highest values that have been reported in the treatment of relapsed or refractory multiple mye­ loma. These findings support the early use of lenalidomide in patients with progressive multiple myeloma. In addition, nearly one third of patients in our trial had previously received thalidomide. Our data indicate that lenalidomide can be administered to patients who have received previous treatment with thalidomide without deterioration of preexisting thalidomide-related neuropathy;

in our study, nearly 50% of such patients had a response to lenalidomide, with a median time to progression of 8.4 months. As compared with patients who had not been exposed to thalidomide, patients who had previously been treated with the drug had received an additional year of treatment and had also received one more previous therapy. Given that current therapy includes thalidomide and dexamethasone, this finding is encouraging for patients with disease that is resistant to thalidomide treatment. The primary toxic effects of the lenalidomide regimen were hematologic, and we found them to be manageable with adjustment of the dose of lenalidomide. Neutropenia was managed with dose adjustments, the administration of granulocyte colony-stimulating factor, or both, whereas thromboembolic events were managed with anticoagulants. Lenalidomide was not associated with the peripheral neuropathy that is caused by long-term treatment with thalidomide. In summary, we found that therapy with lena­lidomide plus dexamethasone was more effective in patients with relapsed or refractory multiple myeloma than was therapy with placebo plus dexamethasone. Supported by Celgene. Drs. Dimopoulos, Harousseau, and San Miguel report receiving consulting and lecture fees from Celgene; Drs. Prince, Hellmann, and Facon, receiving consulting fees from Celgene; and Drs. Yu, Patin, Zeldis, and Knight, being employees of and holding equity in Celgene. No other potential conflict of interest relevant to this article was reported. We thank all the patients who participated in this trial, along with the nurses, the study contributors, and the investigators who recruited patients.

Appendix In addition to the authors, the following investigators (listed according to city and country) participated in the study: Austria — H. Ludwig (Vienna); Australia — J. Catalano (Frankston), J. Szer (Melbourne), K. Taylor (Brisbane), P. Wood (Herston); Belgium — M. Delforge (Leuven), A. Ferrant (Brussels); England — J. Bird (Bristol), M. Streetly and K. Yong (London); France — B. Coiffer (PierreBénite), J.-P. Fermand (Paris); Germany — R. Fenk (Dusseldorf), H. Goldschmidt (Heidelberg), H. Gollasch and U. Schneider (Berlin), M. Kropff (Muenster), A.D. Rascu (Erlangen); Israel — D. Ben-Yehuda (Jerusalem), A. Nagler (Tel Hashomer), J.M. Rowe (Haifa); Italy — M. Baccarani (Bologna), R. Fanin (Udine), M. Gobbi (Genoa), E. Morra (Milan); Northern Ireland — M. Drake (Belfast); Poland — L. Konopka (Warsaw); Spain — A. Algere and J.-J. Lahuerta (Madrid), J. Baro (Valdecilla), J. Blade (Barcelona), F. Prosper (Pamplona); Switzerland — F. Hitz (St. Gallen), C. Taverna (Zurich); Ukraine — P. Kaplan (Dnepropetrovsk), E. Karamanesht (Kiev), T. Lysaya (Zhitomir), G. Pilipenko (Cherkassy). References 1. Boyle P, Ferlay J. Cancer incidence and

mortality in Europe, 2004. Ann Oncol 2005;16:481-8. 2. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002;2:927-37.

3. Singhal S, Mehta J, Desikan R, et al.

Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565-71. [Erratum, N Engl J Med 2000;342:364.] 4. Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome

drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000;96:2943-50. 5. Dimopoulos MA, Zervas K, Kouvatseas G, et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol 2001;12:991-5.

n engl j med 357;21  www.nejm.org  november 22, 2007

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Lenalidomide for Relapsed or Refr actory Myeloma 6. Garcia-Sanz R, González-Porras JR,

Hernández JM, et al. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 2004;18:856-63. 7. Kumar S, Anderson KC. Drug insight: thalidomide as a treatment for multiple myeloma. Nat Clin Pract Oncol 2005;2: 262-70. 8. Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of thalidomide administration in patients with neoplastic diseases. Am J Med 2004;117:508-15.

9. Marriott JB, Clarke IA, Dredge K,

Muller G, Stirling D, Dalgleish AG. Thalido­ mide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during costimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol 2002; 130:75-84. 10. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002;100:30637. 11. Richardson PG, Blood E, Mitsiades

CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006;108:3458-64. 12. Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplan­tation. Br J Haematol 1998;102:1115-23. Copyright © 2007 Massachusetts Medical Society.

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Estudio Revlimid MM-10  

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