Clinical Trials: Relapsed and Refractory Myeloma
A number of clinical trials have demonstrated the safety and efficacy of Revlimid in relapsed and refractory myeloma. These studies have evaluated Revlimid alone or in combination with dexamethasone, and other combinations are being investigated. Revlimid-dexamethasone is now listed as a recommended option for relapsed and refractory myeloma in the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines for multiple myeloma.
In combination with dexamethasone: Expanded Access Program (EAP). Celgene's EAP was a multicenter, open-label Phase IV trial that was initiated prior to Revlimid's approval to allow previously treated myeloma patients access to the drug. Patients were eligible to enroll in the trial if their disease was progressing after at least two cycles of anti-myeloma treatment or had relapsed with progressive disease after treatment. Patients received the combination of Revlimid and high-dose dexamethasone in 4-week cycles until disease progression. The EAP enrolled patients at more than 100 sites throughout the U.S. and Canada before Revlimid was approved.
Preliminary data from this EAP were presented at ASH in 2006 and are summarized in the table below. This EAP provides a model of how government, advocacy groups, healthcare providers, and industry can work together to quickly provide an effective treatment to patients while waiting for its approval.
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Preliminary Results of Revlimid EAP: ASH 2006 |
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In combination with dexamethasone. In March 2005, the two ongoing pivotal Phase III clinical trials of Revlimid in patients with relapsed or refractory myeloma were unblinded early because they were found to exceed the pre-specified interim efficacy endpoint (p<0.0015) for disease progression. The External Independent Data Monitoring Committee noted a statistically significant improvement in time to disease progression in patients receiving Revlimid plus dexamethasone compared with patients receiving dexamethasone alone.
Based on this data, the trials were unblinded many months earlier than anticipated and all patients currently not on Revlimid had the opportunity to add Revlimid to their dexamethasone regimen.
The identical US (Study MM-009) and International trials (Study MM-010) enrolled a total of 705 patients and was conducted in 97 sites in the United States, Canada, Europe, and Australia. Patients were randomized to receive Revlimid (25 mg/day) and high-dose dexamethasone or an identically-appearing placebo and high-dose dexamethasone. Patients achieving a response or stable disease continued on therapy until progression of disease. The trials included a primary endpoint of time-to-disease progression calculated as the time from randomization to the first documentation of progressive disease based on Bladé criteria. (EBMT/IBMTR/ABMTR criteria; Bladé J et al. Br J Haematol. 1998;102(5):1115-1123.). View the Bladé Criteria
Updated results. Interim results from the trials were presented at the American Society of Clinical Oncology (ASCO) meeting in May 2005, and updated results were presented at ASH in December 2005. (Dimopoulos et al. Blood. 2005;106(11). Abstract 6.) Data from both the International and North American trials showed that the combination led to statistically significant improvement in median time to disease progression; data from the North American trial also showed statistically significant improvement in overall survival. As of June 2005, median survival in patients treated with the combination had not been reached; the median overall survival in the dexamethasone-placebo arm was 104 weeks, a statistically significant difference. The table below summarizes data from the International trial.
Revlimid International Phase III Trial (MM-010):
Updated Results as of June 2005 |
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* Statistically significant difference between treatment arms (P≤0.001)
In both trials, patients treated with lenalidomide plus dex had an increase in side effects as compared to those treated with dex alone. The most common side effects with the combination were constipation, diarrhea, and neutropenia. In general, this toxicity profile is superior to that seen with thalidomide, with sedation, constipation, and neuropathy being less common and less severe.
The most common Grade 3/4 adverse events seen in the International trial are shown in the table below.
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Revlimid International Phase III Trial (MM-010):
Grade 3/4 Adverse Events |
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Additional interim data from both trials were reported at the 2006 American Society of Clinical Oncology (ASCO) Annual Meeting. Updated clinical data from the North American trial continued to show significantly improved overall survival (p<0.0001) in addition to median time to disease progression (p<0.0001) in patients receiving lenalidomide plus dexamethasone compared to patients receiving dexamethasone plus placebo. (Weber et al. J Clin Oncol. 2006 ASCO Annual Meeting Proceedings Part I. 2006;24(18S). Abstract 7521.) The updated clinical data from the International trial again reported significantly improved overall survival in patients receiving lenalidomide plus placebo (p=0.03). As of June 2006, median overall survival in the International trial in patients treated with lenalidomide plus dexamethasone has not been reached as compared to 20.6 months with dexamethasone plus placebo.
Updated results from the North American trial are summarized in the table below.
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Revlimid North American Phase III Trial (MM-009):
Updated Results as of June 2006 |
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* Statistically significant difference between treatment arms (P≤0.0001)
As seen in the International trial, the most common side effects observed in the North American trial with lenalidomide plus dexamethasone were constipation, diarrhea and neutropenia. Grade 3/4 toxicities included neutropenia, thrombocytopenia, and anemia. Deep vein thrombosis and pulmonary embolism occurred in 17.5 percent of patients treated with lenalidomide plus dexamethasone, compared to 3.4 percent of patients treated with dexamethasone plus placebo.
Updated data and additional analyses from these large Phase III trials are providing important information regarding optimal usage of this regimen. Some of the major findings presented at ASH in 2006 are listed in the table below.
Updated Results of Revlimid Phase III Trials and Subgroup Analyses |
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Phase II
Revlimid +/- dexamethasone. Final results of the multicenter Phase II trial of Revlimid in relapsed and refractory myeloma were published in 2006. (Richardson et al. Blood. 2006;108(10):3458-64.) A total of 25% of patients with refractory or relapsed disease achieved at least a minor response with Revlimid alone.
This trial evaluated the efficacy and safety of two Revlimid dose regimens when used alone or in combination with dexamethasone. Patients in the study were randomized into one of two groups. One group received oral Revlimid (30 mg) once a day, while the other received oral Revlimid (15 mg) twice a day. One cycle was 28 days, which included 3 weeks of treatment and 1 week off treatment. Dexamethasone was added on days 1 through 4 every 14 days if patients had progressive disease or if they had not experienced a greater than 25% reduction in their paraprotein levels after 8 weeks. Patients received treatment for up to 8 months and responses were assessed using the Bladé Criteria.
Analysis of the first 70 patients enrolled in the study showed increased Grade 3/4 myelosuppression in patients receiving 15 mg twice daily (41% versus 13%). Therefore, the additional 32 patients enrolled received 30 mg once daily. The median patient age was 60 years and patients had received a median of four prior therapies.
Both dose schedules of Revlimid resulted in comparable responses. Overall, 25% of patients responded (complete, partial, or minor response). Response and survival data from the study are summarized in the table below. Dexamethasone was added in 68 patients and 29% responded.
Phase II trial of Revlimid in Relapsed and Refractory Myeloma |
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During the study, the most common severe (Grade 3) or potentially life-threatening (Grade 4) toxicities were thrombocytopenia and neutropenia. At the conclusion of the study, no significant differences were detected in the proportion of patients experiencing Grade 3 or 4 myelosuppression between the two dosing groups (69% for once daily and 80% for twice daily), the time to the first occurrence was shorter in the twice-daily group (1.8 vs. 5.5 mos.). The most common other Grade 3 or higher toxicities included leukopenia, anemia, and fatigue. DVT was reported in 4% of patients receiving Revlimid in combination with dexamethasone.
Single agent, post-transplant salvage therapy. Results of a randomized Phase II study of Revlimid as post-transplant salvage therapy were also reported at ASH 2003. (Zangari et al. Blood. 2003;102(11). Abstract 1642.) The study included 58 patients with advanced and refractory myeloma who received one of two dosing regimens of Revlimid: 25 mg/day x 20 days, followed by an 8-day rest period (1 treatment cycle) or 50 mg/day x 10 days, followed by an 18-day rest period (1 treatment cycle). Response rates were higher in patients receiving the more prolonged (25 mg x 20 day) dose schedule. For example, following the 8th cycle of treatment, 40% of patients in this arm of the study achieved a 50% or greater reduction in M protein compared to 15% of patients in the 50 mg x 10 day dose arm.
In this study, low blood counts—particularly platelets—were the only dose-limiting (Grade 3 or 4) toxicity seen. The risk for low platelet counts was greater in patients who had counts lower than 100,000 at the start of the study (a normal platelet count is 150,000 to 450,000). Revlimid was not associated with sedative or neurotoxic effects in this study.
Single agent. A Phase II open-label study (Study 014) was conducted to further evaluate the effectiveness and safety of single-agent Revlimid in relapsed and refractory myeloma. (Richardson et al. Blood. 2005;106(11). Abstract 1565.) Preliminary results of the multicenter study, which were reported at ASH in December 2005, showed an overall best response rate (CR + PR) of 25% and stable disease in 71%.
Patients eligible for the study included those who had received at least two prior anti-myeloma therapies. Patients could have been previously treated with thalidomide, bortezomib (Velcade®), or stem cell transplant, but could not have received Revlimid before. Patients (n=222) received oral Revlimid (30 mg/day) in 28-day cycles for as long as they responded to therapy or achieved stable disease. Study endpoints included response rate, the length of time before disease progressed, and overall survival.
As the time of the meeting, median time to disease progression was 22.4 weeks and median survival was not reached. Toxicity has been manageable, with the most common side effects being upper respiratory tract infection, neutropenia, and thrombocytopenia. Side effects that most frequently led to dose reduction or interruption included neutropenia (40%), thrombocytopenia (23%), fatigue (5%), and anemia (5%).
Phase I/II
In combination with Velcade. The safety and efficacy of Revlimid in combination with Velcade (bortezomib) in the treatment of relapsed and relapsed/refractory myeloma was evaluated in a Phase I trial. The primary objective was to evaluate the safety of the combination and determine the maximum tolerated dose (MTD) and recommended dose for future study.
Patients with relapsed or refractory myeloma who had received at least one prior therapy received Revlimid (5-20 mg) on days 1 to 14 of a 21-day cycle in combination with Velcade (1.0 or 1.3 mg/m² on days 1, 4, 8, and 11 of each 21-day cycle) for a maximum of 8 cycles, with an extension phase for responding patients. Dexamethasone could be added if patients experienced progressive disease. A total of 8 cohorts (one for each dose combination) of 3 to 6 patients were enrolled, with an additional 10 patients at the MTD.
Final results of this study were presented at ASH in 2006 (Richardson et al. Blood. 2006;108(11). Abstract 405.) The toxicity with the combination was manageable and Revlimid 15 mg and Velcade 1.0 mg/m² were identified as the MTD. One DLT (low serum sodium level, Grade 3 in severity) was reported in cohort 4 (10 mg Revlimid and 1.3 mg/m² Velcade). Two DLTs (a secondary Grade 3 shingles infection that delayed treatment and Grade 4 neutropenia) were reported in cohort 6 (up to 15 mg Revlimid and 1.3 mg/m² Velcade). No Grade 3/4 fatigue or neuropathy were reported.
The combination was shown to be active, with durable responses (median, 8 months) seen in heavily pretreated patients, including patients who had had prior Revlimid, Velcade, thalidomide, and/or stem cell transplant. The overall response (n=36 evaluable patients) was 58%, including 6% CR/nCR and 33% PR. Dexamethasone was added in 15 patients who experienced progressive disease, resulting in PR, minor response, or stable disease in 11 (73%) of these patients.
Phase 2 studies of combination Velcade, Revlimid, and dex are currently underway in both relapsed and/or refractory disease as well as in newly diagnosed myeloma.
In combination with Doxil / vincristine / reduced frequency dexamethasone (DVd-R).
Revlimid was evaluated in combination with Doxil® (liposomal doxorubicin, Ortho-Biotech), vincristine, and reduced frequency dexamethasone (DVd) in relapsed and refractory myeloma in a Phase I/II study at the Cleveland Clinic.
(Baz et al. Ann Oncol. 2006;17(12):1766-71.)
The first phase of the study identified 10 mg Revlimid daily as the maximum tolerated dose (MTD) in combination with a fixed dose of DVd. Patients received up to four 28-day cycles of therapy, followed by maintenance with Revlimid +/- prednisone.
All patients also received prophylactic aspirin, amoxicillin, and acyclovir.
After 7.5 months of follow-up, this regimen resulted in a response rate by SWOG criteria of 75% in this chemotherapy-resistant population, with 29% of patients achieving a CR or near-CR. The median progression-free survival was 12 months, while the median overall survival was not reached at the time of publication. Grade 3 and 4 adverse events included leukopenia, infections, thrombocytopenia, neuropathy, and tumor lysis syndrome. Other adverse events included DVT and pulmonary embolism.
Single-agent. Two Phase I trials of Revlimid in relapsed and refractory myeloma were conducted at the Dana-Farber Cancer Institute (DFCI) and the Arkansas Cancer Research Center.
Results from the DFCI study were published in the November 2002 issue of Blood (Richardson, et al. Blood 2002;100:3063-3067). These investigators investigated Revlimid doses of 5 to 50 mg/day to determine the maximal tolerated dose. Patients enrolled in the study had received an average of three prior regimens. All patients who had received the 50-mg/day dose had severely reduced blood cell counts after the first 28 days of therapy. After the dose was reduced to 25 mg/day, there were no significant side effects, thus this dose was identified as the maximum tolerated dose. No significant sleepiness, constipation, or neuropathy was noted at any dose level.
Altogether, 19 of 24 patients (79 percent) achieved stable disease or better (at least a 25% reduction in M protein). Seventy-one percent of patients experienced a ≥25 percent reduction in M protein levels, including 46% of patients who had previously received thalidomide, showing a lack of cross-resistance between thalidomide and Revlimid. The results are summarized in the table below.
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Results: Revlimid (CC-5013) Phase I Trial at DFCI
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The Revlimid study at Arkansas included 15 patients. Preliminary results presented at the 43rd Annual Meeting of the American Society of Hematology (ASH) in December 2001 were similar.
Eight patients experienced a >25% reduction in M protein and 1 patient achieved a complete response.
The drug had a manageable side effect profile, which included mild skin rash and some instances of reduced blood cell counts at higher doses. No significant sleepiness, constipation, or neuropathy was reported.
The drug had a manageable side effect profile, which included mild skin rash and some instances of reduced blood cell counts at higher doses. No significant sleepiness, constipation, or neuropathy was reported.