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Lenalidomide (Revlimid ®)

Lenalidomide in Relapsed/Refractory Multiple Myeloma
Studies with lenalidomide among patients with relapsed and refractory MM demonstrate that this analogue can overcome drug resistance, including thalidomide resistance.1,2 Two phase I trials of lenalidomide demonstrated promising activity as well as decreased toxicity in heavily pretreated patients with relapsed, refractory myeloma. From a phase I study published by Richardson and colleagues, the safety and tolerability of lenalidomide at doses of 5-50 mg daily was investigated in patients with refractory/relapsed MM.1 These patients failed to respond to ≥ 2 previous chemotherapy regimens. Patients with MM with prior thalidomide therapy were allowed, provided no intolerance or hypersensitivity had occurred. Dose levels were 5, 10, 25 or 50 mg daily of oral lenalidomide for 21 days followed by a 1-week rest period and repeated every 28 days. Twenty-seven patients (median age, 57 years) had received a median of 3 previous regimens (range, 2-6 regimens); all had relapsed disease, and 18 (72%) were refractory to salvage treatment. Two patients were removed from the study on day 1 because of rapid disease progression. Fifteen of the remaining 25 patients (60%) had undergone previous high-dose chemotherapy with peripheral stem cell transplantation, and 16 (64%) had received previous thalidomide therapy. The first cohort (receiving 5 mg daily; n = 3) was treated for 28 days without any dose-limiting toxicity (DLT). In the second cohort (10 mg daily), 1 patient had dose-limiting grade 3 leukopenia and neutropenia. Three additional patients were enrolled on the second cohort and tolerated therapy without significant toxicity. No patients on the third (25 mg daily; n = 3) or fourth (50 mg daily; n = 13) cohorts developed DLT in the first 28 days. However, 2 patients from the third cohort did develop grade 3 thrombocytopenia and grade 4 neutropenia, respectively, during the second month or therapy and were subsequently removed from the study. The overall median duration of therapy was 6 months. The side effects related to thalidomide, namely, somnolence, constipation, and neuropathy, were not encountered; however, other adverse events included grades 1 and 2 rash, fatigue, lightheadedness, and leg cramps. As a result of grade 3/4 myelosuppression developing beyond the first 4 weeks of therapy in 12 of the 13 patients at the 50-mg-daily cohort, the authors concluded that 25 mg daily was the maximum tolerated dose (MTD) for lenalidomide. Stable disease (SD) or minor response ( 25% reduction in myeloma protein) was observed among 19 of 24 patients (79%) who received ≥ 28 days of therapy, including 11 patients (46%) who had received previous thalidomide. The median time to best response with the use of single-agent lenalidomide was 2 months (range, 1-11 months), with a median duration of response of 6 months (range, 2-14 months). In another phase I trial by Zangari et al of 15 patients with advanced MM, the MTD of 25 mg daily of lenalidomide was confirmed. These studies established the MTD and a firm foundation for continuing trials with lenalidomide alone or in combination with other active agents in MM.2

Combination of Lenalidomide and Dexamethasone and Chemotherapy
Preliminary results of a randomized, phase III, double-blind, placebo-controlled study (North American trial MM-009) of lenalidomide/dexamethasone versus dexamethasone alone in patients with relapsed/refractory MM was reported at the 10th International Myeloma Workshop in Sydney, Australia.3 The MM-009 trial enrolled 341 patients (170 on the combined arm and 171 on the dexamethasone alone arm). Lenalidomide 25 mg daily was administered along with dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 every 28 days versus dexamethasone (same dose as outlined above) with placebo in the other group. The combination yielded a significantly higher response rate (RR; 61% vs. 23%; P < 0.001). In the combination arm, 27% of patients exhibited a complete response (CR), 35% exhibited a partial response (PR), and 28% exhibited SD. Time to progression (TTP) was significantly prolonged by the addition of lenalidomide to dexamethasone (> 15 months vs. 5.1 months, respectively; P < 0.0000001). Toxicities included grade 3/4 neutropenia (24%), thrombocytopenia (11%), anemia (11%), and VTD (10%). The incidence of VTD was comparable with the general MM population observed in retrospective analyses.4 In an updated report at the 41st Annual Meeting of the American Society of Clinical Oncology in Orlando, Florida, Weber et al presented data from the European sister study (MM-010).5 In this study, 351 patients were enrolled (176 on the combination and 175 on the dexamethasone alone arm). The overall RR was similar at 58%. Complete response and TTP rates were lower compared with the MM-009 study (14% vs. 27% and 13.3 months vs. > 15 months, respectively). The incidence of VTD was also lower compared with the North American study (8.5% vs. 15% [updated]). The toxicity profile revealed very low incidence of fatigue, constipation, and neuropathy but increased grade 3/4 hematologic events. Due o the increased incidence of VTD, the authors recommended consideration of prophylactic anticoagulation.

Pegylated Doxorubicin (Doxil ®) in combination with Lenalidomide
At Cleveland Clinic, we combined pegylated doxorubicin (Doxil®), vincristine, and dexamethasone regimen with lenalidomide in a phase I/II study of patients with refractory/relapsed MM.6 Study objectives included MTD, safety, and efficacy. Lenalidomide was administered orally at doses of 5, 10, and 15 mg daily for 21 days every 28 days in cohorts of 3-6 patients. Patients were treated for ≥ 4 cycles and a maximum of 2 cycles after best response. Maintenance therapy included continuation of lenalidomide with the addition of prednisone 50 mg every other day until disease progression. Low-dose acetylsalicylic acid (81 mg) was administered for VTD prophylaxis. Twenty-four patients were enrolled on the study (18 of whom had refractory disease). The overall RR was 70% (CR or near CR, 36.5%). An additional 32.5% of patients exhibited SD. Grade 3/4 adverse events included neutropenic fever (9%), neurologic events (14%), VTD (9%), and tumor lysis (9%). This novel combination appears to be active with manageable toxicities.

Lenalidomide and Dexamethasone in the First-Line Setting
The encouraging results in the relapsed/refractory setting resulted in a phase II trial to assess the response rate and toxicity of the lenalidomide/dexamethasone combination in the first-line setting.7 In this recent phase II trial, lenalidomide was combined with dexamethasone in 34 newly diagnosed, previously untreated patients with MM. Lenalidomide 25 mg daily was administered orally on days 1-21 of a 28-day cycle. Dexamethasone 40 mg daily was given orally on days 1-4, 9-12, 17-20 of each cycle. Thirty-one of 34 patients attained an objective response; 2 patients (6%) exhibited a CR, and 11 (32%) met criteria for both very good PR and near CR, resulting in an overall objective RR of 91%. Of the 3 patients without an objective response, 2 experienced a minor response and 1 exhibited SD. Forty-seven percent of patients developed grade ≥ 3 nonhematologic toxicity, including fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%), and rash (6%).
Myelosuppression was minimal, most likely reflecting the preserved bone marrow reserve in this group of previously untreated patients. All patients were placed on acetylsalicylic acid prophylaxis, based on the efficacy of acetylsalicylic acid in preventing VTD among patients treated on the thalidomide/dexamethasone regimen.8 Only 1 patient developed a VTD. No disease progression was noted to date (10 months after the last patient was enrolled). The lenalidomide/dexamethasone combination appeared to be a useful pre-transplantation conditioning regimen, because there was no adverse effect on stem cell mobilization among these patients.
With successful responses and better tolerability obtained from early phase I trials, as well as in large randomized trials, lenalidomide is rapidly being incorporated into first-line regimens. The Southwest Oncology Group and Eastern Cooperative Oncology Group (ECOG) have ongoing randomized trials assessing lenalidomide/dexamethasone as primary therapy in the first-line setting. The ECOG compares lenalidomide/dexamethasone versus lenalidomide with low-dose dexamethasone in an attempt to further diminish adverse events, while maintaining the response rate.
Conclusion
IMiDs appear to have a different safety profile from thalidomide. Significant sleepiness, constipation, or neuropathy is much less frequent. From the published data, lenalidomide appears to have manageable side effects. The most common grade 3/4 toxicities include myelosuppression (neutropenia, thrombocytopenia) and VTD. Mild side effects include diarrhea, fever, muscle cramps, rash, and fatigue.
Multiple myeloma has become a paradigm for translational research in the past few years, with significant advances in the translation of novel biologically derived therapies from bench to bedside. Studies of lenalidomide and CC-4047 have shown a significant clinical benefit in MM, along with an improved safety profile and probable improved activity compared with thalidomide. It is anticipated that lenalidomide and other IMiDs will become a significant addition to the therapeutic armamentarium for MM therapy because of their more potent immunomodulatory properties and their better tolerability. Further studies of these orally bioavailable agents in patients with MM are warranted not only in combination with other biologics and chemotherapeutic agents but with thalidomide as well.
 

References

1. 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;100:3063-3067.
2. Zangari M, Tricot, G, Zeldis, J, et al. Results of a phase I study of CC-5013 for the treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy (HDCT). Blood. 2001;98:3226a.
3. Weber D, Chen C, Niesvizky R, et al. A Multicenter, Randomized, Parallel-Group, Double-Blend, Placebo-Controlled Study of Lenalidomide Plus Dexamethasone Versus Dexamethasone Alone in Previously Treated Subjects with Multiple Myeloma. The 10th International Myeloma Workshop. Sydney, Australia; 2005:Abstract #738.
4. Srkalovic G, Cameron MG, Rybicki L, Deitcher SR, Kattke-Marchant K, Hussein MA. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer. 2004;101:558-566.
5. Weber D. IMiDs- Results of Phase III studies in relapsed/refractory myeloma. American Society of Clinical Oncology. Orlando, FL; 2005.
6. Hussein MA, Karam M, Brand C, et al. Doxil (D), Vincristine (V), Reduced Frequency Dexamethasone (d) and Revlimid(R) (DVd-R) a Phase I/II Trial in Advanced Relapsed/Refractory Multiple Myeloma (RMM) Patients. Blood (ASH Annual Meeting Abstracts), Nov 2004; 104(11):208.
7. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (REV/DEX) for newly diagnosed myeloma. Blood. 2005 (preprinted ahead online).
8. Baz R, Li L, Kottke-Marchant K, et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc. 2005;80:1568-1574.

 
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