Results of a multicenter, randomized, double-blind phase 2/3 study of lenalidomide in the treatment of pretreated relapsed or refractory metastatic malignant melanoma




The results of an international, multicenter, randomized, double-blind, controlled study assessing the efficacy and safety of lenalidomide treatment in patients with refractory stage IV metastatic malignant melanoma are reported.


The study compared treatment with lenalidomide (25 mg/d on Days 1-21 of a 28-day cycle) to placebo in 306 patients with metastatic malignant melanoma. Treatment was continued until progression of disease or unacceptable toxicity.


There were no significant differences between lenalidomide and placebo in overall survival (median 5.9 months vs 7.4 months, respectively; P = .32), time to progression (median 3.0 months vs 2.1 months; P = .19), or Response Evaluation Criteria in Solid Tumors tumor response (5.3% vs 5.8%; P = .82). None of the patients given placebo discontinued treatment because of treatment-related adverse events, compared with 4.6% of those treated with lenalidomide. Treatment-related myelosuppression was observed in 2.0% of patients treated with placebo and 7.3% of patients treated with lenalidomide.


This study showed that treatment with lenalidomide (25 mg/d) has a manageable safety profile in patients with previously treated metastatic malignant melanoma but no benefit in tumor response, time to progression, or overall survival in these patients. Future trials for treatment of metastatic malignant melanoma with lenalidomide should focus on its use in combination therapies. Cancer 2010. © 2010 American Cancer Society.

Melanoma is a cancer that originates from melanocytes in the skin, which are responsible for skin and hair pigmentation. In 2002, according to statistics from the GLOBOCAN database, 160,177 people worldwide (79,043 men and 81,134 women) were diagnosed with melanoma, and 40,781 died from the disease.1

The Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC) has developed a staging system that categorizes patients according to their clinical and pathological characteristics.2 In its early stages, melanoma has a high curative rate, predominantly by surgical resection; however, once it has metastasized, melanoma is extraordinarily resistant to currently available therapies, and patients have a poor prognosis.3, 4 Malignant melanoma patients who are free of disease but have a high risk for systemic recurrence can be treated with interferon (IFN)-α2b, a US Food and Drug Administration (FDA)-approved postsurgical adjuvant therapy that prolongs disease-free survival.4, 5

In the AJCC staging system, evidence of distant metastases indicates a stage IV disease classification.2 Median survival of patients with stage IV disease is <9 months, and only a minority of them survive beyond 12 months.2, 4 At present, the only FDA-approved treatments for stage IV metastatic malignant melanoma are dacarbazine and high-dose interleukin (IL)-2.4, 6 Although these treatments have exhibited modest tumor response rates, neither treatment provides significant improvement in overall survival (OS), and IL-2 is associated with significant toxicity.4, 6 A phase 3 trial of temozolomide, an oral analogue of dacarbazine, showed it had comparable efficacy to that of dacarbazine in advanced metastatic malignant melanoma patients. Median OS was 7.7 months with temozolomide, which was equivalent to the 6.4 months seen with dacarbazine, and hence no significant improvement was seen for patients in terms of OS.7 Nevertheless, because of its ease of administration, oral temozolomide treatment is now generally preferred over intravenous dacarbazine where funded.4

Other drugs have been tested in clinical trials against metastatic malignant melanoma, including the proteasome inhibitor bortezomib, the endothelin receptor antagonist bosentan, the multikinase inhibitor sorafenib, the angiogenesis inhibitor ABT-510, and the immunomodulatory drug thalidomide.8-14 None of the drugs tested has had higher response rates than the current treatments with dacarbazine and IL-2, and to date no treatment has led to prolonged OS for patients with malignant metastatic melanoma. Thus, despite extensive research efforts, the prognosis of patients with stage IV metastatic malignant melanoma remains poor, and new treatment regimens are sought.4 In the United States, the National Comprehensive Cancer Network recommends that patients with unresectable stage IV metastatic malignant melanoma be enrolled in clinical trials, either as a first-line therapy or as a second-line therapy, in preference over other existing treatments.15

One new compound under investigation for the treatment of metastatic malignant melanoma is lenalidomide (Revlimid, Celgene Corporation, Summit, NJ). Lenalidomide is an oral drug that has shown antitumor activity against metastatic malignant melanoma in an animal model.16 Phase 1 studies have demonstrated the safety and tolerability of lenalidomide and have suggested its potential for clinical activity in the treatment of metastatic malignant melanoma.17, 18 A phase 2/3 trial (MEL-001) comparing the efficacy and safety of 2 daily doses of lenalidomide (5 mg vs 25 mg) in the treatment of stage IV metastatic malignant melanoma showed no significant differences between the doses on response rates or progression-free survival (submitted for publication). This study demonstrated an acceptable safety profile for lenalidomide used at either dose.

Here, we report the results from the phase 2/3 trial MEL-002. The objective of MEL-002 was to compare the efficacy and safety of placebo with 25 mg of lenalidomide, in the treatment of refractory stage IV metastatic malignant melanoma in patients whose disease had progressed after treatment with dacarbazine, IL-2, IFN-α, and/or IFN-β).


Study Design

The protocol for this international, multicenter, randomized, double-blind, placebo-controlled study was designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. Institutional review boards or ethics committees at each participating center approved the study protocol. Patients from Australia, Estonia, Germany, Israel, Latvia, Lithuania, the Netherlands, South Africa, Ukraine, and the United Kingdom were enrolled in the study. All patients provided written informed consent. Patients were randomized using an interactive voice response system. Data from all randomized patients who received at least 1 dose of study drug were included in the safety analyses. Response was determined using Response Evaluation Criteria in Solid Tumors. Disease progression was defined according to the Response Evaluation Criteria in Solid Tumors criteria. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria version 2.


Patients aged ≥18 years with stage IV refractory metastatic malignant melanoma were eligible. Disease stage IV patients who had relapsed or had refractory disease after 1 to ≥6 standard metastatic treatments were included. These patients had previously been treated with therapies such as dacarbazine, IL-2, IFN-α, and/or IFN-β for stage IIIb, IIIc, or IV disease. Patients also had to have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2. Patients were excluded from the trial for concurrent or recent (within past 28 days) cancer treatments, pregnancy, serious mental or physical illness other than that being treated, human immunodeficiency virus, hepatitis, hypersensitivity to thalidomide, brain disease, and previous treatment with lenalidomide. On the basis of previously published prognostic indicators for metastatic malignant melanoma,19 patients were stratified into subgroups based on the following variables: sex; ECOG performance status score; metastatic sites of stage IV melanoma (AJCC stage M1, M2, or M3); serum lactate dehydrogenase (LDH) level (normal or elevated); serum albumin level; alkaline phosphatase level; and platelet count.


Patients were split into 2 arms. Patients in arm A were treated with placebo administered daily; patients in arm B were treated with lenalidomide (25 mg) administered orally for Days 1-21 of a 28-day cycle, and placebo for the other 7 days. Pill distribution was administered in a double-blind fashion with the same number and pill appearance for all subjects in the study. Concurrent treatment with filgrastim was recommended for the treatment of neutropenia, and patients received full supportive care, including transfusions, antibiotics, and antiemetics when appropriate. Patients were monitored for adverse events, with treatment withheld for serious adverse events (grade 3 or higher nonhematological, and grade 4 or higher hematological events). Treatment continued until disease progression or unacceptable adverse events. With no maximum study limit, all discontinuations of treatment were considered early discontinuations.

Statistical Analysis

Primary outcome was OS with secondary endpoints of time to tumor progression (TTP) and tumor response rate. OS and TTP endpoints were assessed using the Kaplan-Meier product limit method. Cox proportional hazards were used to assess variable effects on treatment. Comparisons for response between treatments and between subgroups were assessed using Fisher exact test. Sample size was selected to provide 80% power for the comparison between the 2 arms using a 1-tailed test at the .025 level (adjusted for 1 interim analysis). A 1-sided test was used to facilitate the interim futility analysis, with a .025 alpha value equivalent to a 2-sided test with a .05 alpha value. The sample size was chosen to provide at least 196 total events, with an allowance of 12 ineligible patients. Also, as the hypothesis was a directional hypothesis, 1-sided testing is warranted.


Patient Characteristics

Of the 308 patients enrolled in the MEL-002 trial, 306 were included in the intent-to-treat data analyses; 2 patients died after screening but before randomization. Overall, patients' characteristics were well balanced over the 2 study arms (Table 1). Of the 154 patients treated with placebo, 49.4% were men, compared with 54.6% of 152 patients treated with lenalidomide. Groups were similar in terms of patients who had received prior treatments, with 25.3% of patients having had prior radiation in the placebo group, compared with 25.7% of patients in the lenalidomide group; nearly all patients had received prior surgery for their cancer. Of the 306 patients from both treatment arms, 50% had received prior chemotherapy, 5% had received prior immunotherapy, and 46% had received both prior chemotherapy and immunotherapy. Baseline patient characteristics were similar for ECOG performance status, sites of stage IV melanoma, prior antineoplastic regimens, and LDH level.

Table 1. Patient Characteristics in the Intent-to-Treat Population
CharacteristicLenalidomide 25 mg, n=152, No. (%)Placebo, n=154, No. (%)
  • ECOG indicates Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase.

  • *

    Defined as at least 1 regimen for metastatic disease.

Median age, y62.056.0
 Men83 (54.6)76 (49.4)
 Women69 (45.4)78 (50.6)
Prior cancer surgery  
 Yes151 (99.3)152 (98.7)
 Missing1 (0.7)2 (1.3)
ECOG performance status score  
 046 (30.3)41 (26.6)
 175 (49.3)78 (50.6)
 230 (19.7)33 (21.4)
 301 (0.6)
 Missing1 (0.7)1 (0.6)
Metastatic sites of stage IV melanoma  
 M139 (25.7)38 (24.7)
 M223 (15.1)27 (17.5)
 M390 (59.2)89 (57.8)
 Normal90 (59.2)90 (58.4)
 Elevated62 (40.8)64 (41.6)
No. of prior antineoplastic regimens*  
 166 (43.4)69 (44.8)
 249 (32.2)49 (31.8)
 321 (13.8)21 (13.6)
 49 (5.9)8 (5.2)
 55 (3.3)4 (2.6)
 ≥62 (1.3)3 (1.9)
Prior chemotherapy145 (95.4)146 (94.8)
Prior immunotherapy75 (49.3)80 (51.9)

Response Evaluation Criteria in Solid Tumors Tumor Response Rate

Of the 152 patients treated with lenalidomide, 128 patients were evaluable according to Response Evaluation Criteria in Solid Tumors criteria (Table 2). Among these patients, no significant differences between treatment (5.3%) and placebo (5.8%) were observed in overall Response Evaluation Criteria in Solid Tumors response rates (P = .82). Most patients in the study had stable disease or progression of disease as their best response. Stable disease as best response was observed in 65 (42.8%) patients treated with lenalidomide and 51 (33.1%) patients treated with placebo. Figure 1 shows the occurrence of stable disease over time. Throughout the course of treatment, patients treated with lenalidomide showed a higher rate of stable disease than patients treated with placebo.

Table 2. RECIST Response, Overall Survival, and Time to Progression
 Lenalidomide 25 mg, n=152*Placebo, n=154*P
  • RECIST indicates Response Evaluation Criteria in Solid Tumors; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group.

  • *

    The number of evaluable patients in the lenalidomide- and placebo-treated groups were 128 and 127, respectively.

  • The P value is based on a chi-square test of differences between groups.

  • The P value is based on a 1-tailed, unstratified log-rank test of curve differences between groups.

  • §

    Hazard ratio for placebo vs lenalidomide comparison.

  • The P value is based on a 1-tailed, log-rank test of curve differences between groups.

RECIST response, No. (%)   
 Overall response8 (5.3)9 (5.8).82
 Complete response01 (0.6)
 Partial response8 (5.3)8 (5.2)
 Stable disease65 (42.8)51 (33.1)
 Progression of disease55 (36.2)67 (43.5)
Overall survival  .32
 Median, mo (range)5.9 (5.1-7.7)7.4 (5.5-8.2)
 Hazard ratio (95% CI)0.86 (0.63-1.16)§ 
 Subgroup median, mo   
  ECOG performance status score  .27
   0 or
  Lactate dehydrogenase  .34
  Metastatic sites of stage IV melanoma  .48
Time to progression  .19
 Median, mo (range)3.0 (2.0-3.7)2.1 (1.9-2.8)
 Hazard ratio (95% CI)1.18 (0.9-1.5)§
Figure 1.

The occurrence of stable disease over time is shown.

Time to Progression

Kaplan-Meier product limit estimation of TTP is shown in Figure 2. Median TTP was 3.0 months for the patients treated with lenalidomide and 2.1 months for those treated with placebo. No significant difference in TTP was observed between lenalidomide treatment and placebo (P = .19; Table 2).

Figure 2.

Kaplan-Meier product limit estimation of time to progression is shown.

Overall Survival

Figure 3 shows Kaplan-Meier product limit estimation of OS. There were no significant differences in OS observed between lenalidomide and placebo (P = .32; Table 2). Median OS for patients in the lenalidomide treatment group was 5.9 months, compared with 7.4 months for placebo. There were no significant differences in OS observed for subgroup variables (Table 2).

Figure 3.

Kaplan-Meier product limit estimation of overall survival is shown.

Adverse Events

None of the placebo-treated patients discontinued as a result of treatment-related adverse events, compared with 4.6% of patients treated with lenalidomide. Although there were several instances where study medication was temporarily stopped during a treatment cycle, adverse events leading to dose reduction were not observed in any patients. There were 3 patients who received concurrent filgrastim for the treatment of neutropenia. Only 1 patient treated with lenalidomide experienced treatment-related thrombocytopenia (grade 3 or 4). In total, treatment-related myelosuppression was observed in 2.6% of patients treated with placebo and 10% of patients treated with lenalidomide. The most common treatment-related adverse events in placebo-treated patients were nausea, vomiting, anorexia, fatigue, and cancer pain, whereas in those treated with lenalidomide, fatigue, nausea, constipation, neutropenia, and diarrhea were the most commonly observed treatment-related grade 3 or 4 adverse events (Table 3).

Table 3. Treatment-Related Grade 3 or 4 Adverse Events
Adverse EventLenalidomide 25 mg, n=151, No. (%)Placebo, n=153, No. (%)
  1. NOS indicates not otherwise specified.

Blood and lymphatic system disorders
 Anemia NOS1 (0.7)0
 Leukopenia NOS5 (3.3)2 (1.3)
 Neutropenia9 (6.0)2 (1.3)
Gastrointestinal disorders
 Abdominal pain NOS3 (2.0)3 (2.0)
 Constipation10 (6.6)2 (1.3)
 Diarrhea NOS9 (6.0)2 (1.3)
 Dyspepsia01 (0.7)
 Nausea12 (7.9)15 (9.8)
 Vomiting NOS8 (5.3)7 (4.6)
General disorders and administration site conditions
 Asthenia3 (2.0)3 (2.0)
 Edema peripheral
 Fatigue13 (8.6)4 (2.6)
 Fatigue aggravated
 Pain exacerbated
 Pain NOS
 Pyrexia1 (0.7)2 (1.3)
Infections and infestations
 Lower respiratory tract infection NOS1 (0.7)0
 Weight decreased
 Aspartate aminotransferase increased1 (0.7)0
 Alanine aminotransferase increased1 (0.7)0
Metabolism and nutrition disorders
 Anorexia3 (2.0)6 (3.9)
Musculoskeletal and connective tissue disorders
 Back pain01 (0.7)
 Neck pain
 Pain in limb2 (1.3)0
Neoplasms benign, malignant, and unspecified
 Cancer pain1 (0.7)4 (2.6)
Nervous system disorders
 Paresthesia6 (4.0)0
Psychiatric disorders
 Insomnia1 (0.7)3 (2.0)
Respiratory, thoracic, and mediastinal disorders
 Dyspnea NOS3 (2.0)0
 Pleural effusion
Skin and subcutaneous tissue disorders
 Rash, pruritic6 (4.0)0

No treatment-related adverse events led to the death of any patients treated with placebo, compared with 0.7% of patients treated with lenalidomide. A patient died on September 30, 2003 after being in the study for 39 days as a result of treatment-related dyspnea (not otherwise specified).


Figure 4 shows the patient flow through the study. In total, 139 (92.1%) of patients treated with lenalidomide and 153 (100%) of patients treated with placebo discontinued study treatment. The discontinuations were mainly because of lack of effect. More than half of the patients in each arm had discontinued treatment by the start of cycle 4 (41.4% of patients treated with lenalidomide started cycle 4, compared with 33.8% of those treated with placebo). Throughout all cycles the median dose received by patients was 25 mg in both the lenalidomide- and placebo-treated patients, with only 1 (0.7%) patient treated with lenalidomide requiring a single dose reduction at cycle 5. Dose reduction was because of a combination of adverse events during the time frame that included hypersensitivity rash, cough, neutropenia, and constipation.

Figure 4.

Patient flow is shown. *Arm A = placebo; Arm B = lenalidomide 25 mg. ITT indicates intent to treat.


The currently available and approved drugs for the treatment of stage IV metastatic malignant melanoma are inadequate for the treatment of this disease. To date, no drug treatment has been shown to produce a clinically meaningful improvement in the treatment of patients with a very poor prognosis. Unfortunately, in the present study lenalidomide as a single agent did not result in a clinical benefit for these patients either; the results of this study show no significant benefit in OS, TTP, or tumor response rate.

Myelosuppression was a commonly observed adverse event with lenalidomide treatment, as was the case in MEL-001 (submitted for publication). In general, the treatment with lenalidomide resulted in manageable adverse events, with no need for dose reductions.

Although lenalidomide does not seem to be beneficial in the treatment of stage IV refractory metastatic malignant melanoma as a single agent, future attempts to integrate this drug in the treatment of refractory metastatic malignant melanoma should focus on combination therapy, where rationale exists. Preclinical studies using lenalidomide in combination therapy suggest a promising role for lenalidomide in metastatic melanoma. It has been shown that lenalidomide in combination with tyrosine kinase inhibitors such as sunitinib or sorafenib, or low-dose cyclophosphamide, is efficacious in both ocular melanoma and cutaneous melanoma xenograft models. Such findings warrant further investigation of lenalidomide combination therapy for the treatment of metastatic melanoma.20, 21

Of note, both thalidomide and bortezomib similarly failed to demonstrate clinically meaningful benefits as a single agent in the treatment of metastatic melanoma,8, 12-14 but are currently being tested as part of combination therapies.22-26 It must also be noted that the patients included in the present study had advanced disease, and that there was no difference in effect between those with low and high levels of LDH or M stage, as observed in other studies.

The lack of efficacy of lenalidomide could be because of the advanced stage of disease in the malignant melanoma patients. Immunomodulatory agents such as cytotoxic T lymphocyte-associated protein 4 monoclonal antibodies have been shown to have a limited impact in advanced disease, which could be because of tumor-induced immunosuppression.27 Outcome could be improved by finding synergistic combinations with other agents that allow an immunomodulatory agent to act on a highly tumor-burdened patient, or by treating patients at an earlier stage of disease.

The selected dose of lenalidomide in the present study (25 mg/d on Days 1-21 of each 28-day cycle) is the dose/schedule used in hematological malignancies. However, whether this dose is appropriate for single-agent use in solid malignances remains to be confirmed. There are data emerging from 2 different studies indicating that the dose used in this study may not be optimal. In a phase 1 trial of patients with advanced solid tumors, the dose of lenalidomide has reached 25 mg in combination with 75 mg/m2 docetaxel on a 3-weekly schedule, without the maximum tolerated dose (MTD) of lenalidomide being achieved.28 In another phase 1 trial, the MTD was not established in a cohort of patients treated with a dose-escalated regimen of lenalidomide (25 mg daily for the first 7 days, the daily dose rising each week up to a maximum daily dose of 150 mg).18 Higher doses of single-agent lenalidomide may be feasible, if there is a dose-response relationship for this agent. Suboptimal dosing may be 1 reason that the current study did not show any benefit using lenalidomide.

Currently, lenalidomide treatment in combination with dacarbazine is being tested in a phase 1, single-center dose-escalation study (MEL-003). Preliminary results show a MTD for the combination of 2 drugs, 25 mg lenalidomide plus 800 mg/m2 dacarbazine, and indicate manageable side effects in patients with metastatic malignant melanoma who are untreated with systemic chemotherapy. At the MTD, the combination treatment resulted in a promising tumor control rate of 42%.29

In all, 25 mg of single-agent lenalidomide resulted in outcomes comparable to placebo, and did not lead to a clinically meaningful improvement in the treatment of refractory stage IV metastatic malignant melanoma. Lenalidomide remains an agent with potential in the treatment of solid tumors. As lenalidomide toxicity was minimal and easily managed, further studies are warranted to establish optimal dose, and to explore its potential as a combination therapy.


The MEL-002 study was funded by Celgene Corporation, Summit, New Jersey. The authors received editorial support in the preparation of this article, which was funded by Celgene Corporation. The authors, however, were fully responsible for content and editorial decisions for this article.

Tim Eisen has attended advisory boards for and received honoraria and research support from Celgene Corporation. Uwe Trefzer, Anne Hamilton, Peter Hersey, Michael Millward, and John Glaspy have no conflicts of interest to disclose. Robert D. Knight and Jarl U. Jungnelius are employees of Celgene Corporation.