Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma

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1 The new england journal of medicine 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 (00) Study Investigators* ABSTRACT Background Lenalidomide is a structural analogue of 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 35 patients who had received at least one previous antimyeloma therapy, 76 were randomly assigned to receive 25 mg of oral lenalidomide and 75 to receive placebo on days to 2 of a 28-day cycle. In addition, all patients received 40 mg of oral dexamethasone on days to 4, 9 to 2, and 7 to 20 for the first four cycles and subsequently, after the fourth cycle, only on days 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 lenalidomide plus dexamethasone (lenalidomide group) than in those who received placebo plus dexamethasone (placebo group) (median,.3 months vs. 4.7 months; P<0.00). A complete or partial response occurred in 06 patients in the lenalidomide group (60.2%) and in 42 patients in the placebo group (24.0%, P<0.00), with a complete response in 5.9% and 3.4% of patients, respectively (P<0.00). 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 0% of patients in the lenalidomide group were neutropenia (29.5%, vs. 2.3% in the placebo group), thrombocytopenia (.4% vs. 5.7%), and venous thromboembolism (.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 Universitario 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 528, Greece, or at mdimop@med.uoa.gr. *Other investigators who participated in the Multiple Myeloma (00) Study are listed in the Appendix. This article (0.056/NEJMoa070594) was updated on July 29, 2009, at NEJM.org. N Engl J Med 2007;357: 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, NCT ) n engl j med 357;2 november 22,

2 The new england journal of medicine Multiple myeloma, the second most common hematologic cancer, caused more than 9,000 deaths in Europe in To improve the outcome of treatment, new agents are needed. 2 The immunomodulatory drug has activity in about one third of patients with relapsed or refractory multiple myeloma; response rates are increased when is combined with dexamethasone or chemotherapy. 3-7 Treatment with 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, 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, 0, and dexamethasone plus lenalidomide is more effective than either agent alone in refractory multiple myeloma. 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 8 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 containing high-dose dexamethasone (total month ly 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 (22 μmol per liter), and an absolute neutrophil count of at least 000 per cubic 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 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 lenalidomide or placebo on days to 2 of a 28-day cycle; all patients received 40 mg of oral dexamethasone on days to 4, 9 to 2, and 7 to 20 for the first four cycles. After the fourth cycle, 40 mg of dexamethasone was administered only on days 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 β 2 - microglobulin level (<2.5 mg per liter or 2.5 mg per liter), previous stem-cell transplantation (none or ), and the number of previous antimyeloma regimens ( or 2). Toxic effects were graded according to the National 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, ) 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 (daily subcutaneous injection of 5 μg of 224 n engl j med 357;2 november 22, 2007

3 Lenalidomide for Relapsed or Refractory Myeloma granulocyte colony-stimulating factor per kilogram of body weight and 25 mg of lenalidomide); sequential reductions of the lenalidomide dose were 5 mg (dose level, 2), 0 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 and 5 (and day 8 of cycle ) during cycles to 3 and on day of each cycle thereafter. Serum and urinary levels of M protein were assessed on day 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. 2 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 plasmacytoma or an increase in the size of such lesions; or the development of hypercalcemia (serum calcium level, >.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 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 (5 in each group), which would provide a statistical power of 85% to detect a hazard ratio of.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 94 patients had died. An interim analysis of safety and efficacy was planned when disease had progressed in 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;2 november 22,

4 The new england journal of medicine Table. Demographic and Clinical Characteristics of the Patients.* Characteristic Age yr Lenalidomide (N = 76) Results Placebo (N = 75) Median Range Male sex % Lytic bone lesions no. (%) 36 (77.3) 40 (80.0) Time since first diagnosis yr Median Range Durie Salmon stage no. (%) I (6.2) 8 (4.6) II 50 (28.4) 57 (32.6) III 5 (65.3) 0 (62.9) Eastern Cooperative Oncology Group performance status no. (%) 0 78 (44.3) 65 (37.) 72 (40.9) 79 (45.) 2 23 (3.) 27 (5.4) 3 0 (0.6) Missing data 3 (.7) 3 (.7) Previous therapy no. (%) No. of therapies 56 (3.8) 57 (32.6) 2 20 (68.2) 8 (67.4) Type of therapy Thalidomide 53 (30.) 67 (38.3) Bortezomib 8 (4.5) 7 (4.0) Stem-cell transplantation 97 (55.) 95 (54.3) β 2 -microglobulin level no. (%) <2.5 mg per liter 5 (29.0) 48 (27.4) 2.5 mg per liter 25 (7.0) 27 (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 00 because of rounding. Lower numbers indicate better performance. Patients and Treatments Between September 22, 2003, and September 5, 2004, a total of 35 patients (intention-to-treat population) were enrolled at 4 centers in Europe, 6 centers in Australia, and 3 centers in Israel. Of these patients, 76 were randomly assigned to receive lenalidomide plus dexamethasone (the lenalidomide group) and 75 to receive placebo plus dexamethasone (the placebo group). Baseline characteristics were well balanced between the two groups (Table ). Previous therapies included stem-cell transplantation,, dexamethasone, 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 included all data obtained before unblinding in August 2005, the median follow-up was 6.4 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 Efficacy The median time to progression was.3 months in the lenalidomide group and 4.7 months in the placebo group (P<0.00) (Fig. A). The hazard ratio for time to progression was 2.85 (95% confidence interval [CI], 2.6 to 3.76; P<0.00) in favor of the lenalidomide group. Patients in the lenalidomide 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. months in the lenalidomide group and 4.7 months in the placebo group (P<0.00). The median time to progression for patients who had previously undergone treatment with (30.% of the patients in the lenalidomide 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<0.00). Among patients with no previous exposure to, the median time to progression was 3.5 months in the lenalidomide group and 4.7 months in the placebo group (P<0.00) (Fig. B). In the lenalidomide group, the median time to progression was not significantly related to previous exposure to (hazard ratio, 0.65; 95% CI, 0.42 to.02; P = 0.06). Among patients in whom the disease had progressed during previous treatment, the median time to 226 n engl j med 357;2 november 22, 2007

5 Lenalidomide for Relapsed or Refractory Myeloma A Lenalidomide Placebo Patients (%) Months to Progression B Lenalidomide without previous Patients (%) Lenalidomide with previous Placebo without previous Placebo with previous Months to Progression Figure. 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 (.3 months in the lenalidomide group and 4.7 months in the placebo group) (P<0.00 by the log-rank test). Panel B shows the median time to disease progression among patients in the two study groups who received before study entry and those who did not receive (in the lenalidomide group, 3.5 months among patients who did not receive and 8.4 months among those who did receive ; in the placebo group, 4.7 months and 4.6 months, respectively; P<0.00 by the log-rank test for both between-group comparisons of patients who did and those who did not receive ). progression was 9.5 months in the lenalidomide group and 3.7 months in the placebo group (P<0.00). The median time to progression was.3 months among patients who had undergone stem-cell transplantation and.4 months among patients who had not undergone stem-cell transplantation. A total of 06 patients (60.2%) in the lenalidomide group and 42 patients (24.0%) in the placebo group had at least a partial response (P<0.00); 28 patients (5.9%) in the lenalidomide group and 6 patients (3.4%) in the placebo group had a complete response (P<0.00) (Table 2). The median time to the first response was 2. months in the lenalidomide group and.6 months in the placebo group. The median time to a complete or near-complete response was 5. months in the lenalidomide group and 6.9 months in the placebo group. The median duration of the response was longer in the lenalidomide group (6.5 months) than in the placebo group (7.9 months, P = 0.02). The analysis of overall response rates (complete, near-complete, and partial responses) for each stratification group and for patients with and those without previous treatment showed a higher response rate among patients receiving lenalidomide in all the subgroups (Table 2). In the lenalidomide group, the overall response rate was higher in patients who had not received than in those who had received (65.0% vs. 49.%, P = 0.07). Survival As of May 2006, 47 patients (26.7%) in the lenalidomide 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;2 november 22,

6 The new england journal of medicine Table 2. Response among Patients in the Intention-to-Treat Population and in Selected Subgroups.* Variable Lenalidomide (N = 76) Placebo (N = 75) P Value Response in the intention-to-treat population no. (%) Overall response 06 (60.2) 42 (24.0) <0.00 Complete response 28 (5.9) 6 (3.4) <0.00 Near-complete response 5 (8.5) 3 (.7) Partial response 63 (35.8) 33 (8.9) Stable disease 53 (30.) 97 (55.4) Progressive disease 3 (.7) 25 (4.3) Response could not be evaluated 4 (8.0) (6.3) Overall response in subgroups no./total no. (%) Previous exposure to Yes 26/53 (49.) /67 (6.4) No 80/23 (65.0) 3/08 (28.7) <0.00 β 2 -microglobulin mg per liter <2.5 36/5 (70.6) 8/48 (37.5) < /25 (56.0) 24/27 (8.9) <0.00 Previous no. of therapies 37/56 (66.) 7/57 (29.8) < /20 (57.5) 25/8 (2.2) <0.00 Previous stem-cell transplantation Yes 60/97 (6.9) 27/95 (28.4) <0.00 No 46/79 (58.2) 5/80 (8.8) <0.00 * 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 (hazard ratio, 2.07; 95% CI,.02 to 4.2; 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 thrombocytopenia was twice as frequent in the lenalidomide group as in the placebo group (.4% vs. 5.7%). The incidence of grade 3 or 4 somnolence, constipation, or peripheral neuropathy (all toxic effects of ) was less than 0% 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..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 7 of 38 patients (2.3%) 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 39 patients (3.6%) who did not receive erythropoietin in the placebo group (P = 0.36). The proportion of patients who required more 228 n engl j med 357;2 november 22, 2007

7 Lenalidomide for Relapsed or Refractory Myeloma A Lenalidomide Placebo Patients (%) Months No. at Risk Lenalidomide Placebo B Patients (%) Lenalidomide with previous Lenalidomide without previous Placebo without previous Placebo with previous Months No. at Risk Lenalidomide without Lenalidomide with Placebo without Placebo with 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<0.00 by the log-rank test). Panel B shows the median overall survival among patients in the two study groups who received before study entry and those who did not receive (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 and 8.2 months among those who did receive ; P = 0.04 by the log-rank test for the between-group comparison of patients who received and P = 0.2 for the between-group comparison of patients who did not receive ). than one dose reduction or interruption of lenalidomide or dexamethasone was similar in the two groups. The mean time until the first dose reduction or interruption of a study drug was also similar in the two groups (25 days in the lenalidomide group and 28 days in the placebo group). Dose reduction or interruption because of adverse events was more common in the lenalidomide group (occurring in 76.% of the patients) than in the placebo group (56.9%, P<0.00). There were deaths that were possibly related to a study drug: 5 in the lenalidomide group ( from cardiac arrest, from pulmonary embolism, from leukoencephalopathy, from pneumonia bacteria, and from sudden death) and 6 in the placebo group (3 from sepsis, from hepatic failure, from a cerebrovascular event, and from gastrointestinal hemorrhage). The primary reason for the discontinuation of treatment in the two groups was disease progression; 3 patients in the two groups (8.8%) discontinued treatment early because of adverse events. Granulocyte colony-stimulating factor was administered if only grade 3 or 4 myelosuppression occurred; with other grade 3 or 4 adverse events, the lenalidomide dose was reduced. In the n engl j med 357;2 november 22,

8 The new england journal of medicine Table 3. Grade 3 and 4 Adverse Events.* Event Lenalidomide (N = 76) Placebo (N = 75) Grade 3 Grade 4 Grade 3 Grade 4 number (percent) Hematologic disorder Neutropenia 44 (25.0) 8 (4.5) 4 (2.3) 0 Anemia 4 (8.0) (0.6) 2 (6.9) 0 Thrombocytopenia 7 (9.7) 3 (.7) 7 (4.0) 3 (.7) Febrile neutropenia 5 (2.8) (0.6) 0 0 Gastrointestinal disorder Constipation 3 (.7) 0 2 (.) 0 Diarrhea 5 (2.8) 0 4 (2.3) 0 Nausea 2 (.) General disorder Asthenia (6.2) 0 0 (5.7) 0 Fatigue (6.2) (0.6) 6 (3.4) 0 Pyrexia (0.6) 0 6 (3.4) 0 Peripheral edema 2 (.) 0 3 (.7) 0 Infection Upper respiratory infection 3 (.7) All other infection 5 (8.5) 2 (.) 9 (5.) 2 (.) Weight loss 3 (.7) 0 (0.6) 0 Musculoskeletal or connective-tissue disorder Muscle cramp (0.6) Back pain 4 (2.3) 0 3 (.7) 0 Bone pain 5 (2.8) 0 3 (.7) 0 Muscle weakness 3 (7.4) 0 8 (4.6) 0 Arthralgia (0.6) 0 3 (.7) 0 Neurologic disorder Headache (0.6) 0 (0.6) 0 Tremor 2 (.) 0 2 (.) 0 Dizziness (0.6) 0 (0.6) 0 Paresthesia (0.6) Insomnia 2 (.) 0 (0.6) 0 Respiratory, thoracic, or mediastinal disorder Cough 2 (.) 0 (0.6) 0 Nasopharyngitis (0.6) Dyspnea 4 (2.3) (0.6) 2 (.) (0.6) Vascular disorder Deep-vein thrombosis 6 (3.4) (0.6) 5 (2.9) (0.6) Pulmonary embolism 2 (.) 6 (3.4) (0.6) (0.6) Venous thromboembolism 3 (7.4) 7 (4.0) 6 (3.5) 2 (.) * Listed are data that were available on December 3, Percentages may not total 00 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. 230 n engl j med 357;2 november 22, 2007

9 Lenalidomide for Relapsed or Refractory Myeloma lenalidomide group, 38 patients (2.6%) 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, 2 (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. Discussion 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.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 myeloma. 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. Our data indicate that lenalidomide can be administered to patients who have received previous treatment with without deterioration of preexisting -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, 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 and dexamethasone, this finding is encouraging for patients with disease that is resistant to 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. In summary, we found that therapy with lena lidomide 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 (Pierre- Bénite), 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. Boyle P, Ferlay J. Cancer incidence and mortality in Europe, Ann Oncol 2005;6: Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002;2: Singhal S, Mehta J, Desikan R, et al. Antitumor activity of in refractory multiple myeloma. N Engl J Med 999;34: [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: Dimopoulos MA, Zervas K, Kouvatseas G, et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol 200;2:99-5. n engl j med 357;2 november 22,

10 Lenalidomide for Relapsed or Refractory Myeloma 6. Garcia-Sanz R, González-Porras JR, Hernández JM, et al. The oral combination of, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 2004;8: Kumar S, Anderson KC. Drug insight: as a treatment for multiple myeloma. Nat Clin Pract Oncol 2005;2: Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of administration in patients with neoplastic diseases. Am J Med 2004;7: Marriott JB, Clarke IA, Dredge K, Muller G, Stirling D, Dalgleish AG. Thalidomide 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; 30: Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-503 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002;00: 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;08: 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 transplan tation. Br J Haematol 998;02:5-23. Copyright 2007 Massachusetts Medical Society. 232 n engl j med 357;2 november 22, 2007