Lenalidomide Benefits in Recurrent Myeloma Detailed



Donna M. Weber, M.D.Univ. of Texas M. D.Anderson Cancer Center
HOUSTON, Nov. 21 -- Patients with relapsed or refractory multiple myeloma had significantly improved progression-free and overall survival when treated with lenalidomide (Revlimid) and dexamethasone, compared with dexamethasone and placebo.So found results of trials in the North America and Europe, both reported in the Nov. 22 issue of the New England Journal of Medicine, that provided the basis for last year's FDA approval of combined lenalidomide, a potent thalidomide derivative, and dexamethasone for relapsed or refractory multiple myeloma.In both studies, patients treated with the drug duo had an overall response rate exceeding 60% compared with about 20% with dexamethasone and placebo. Time to progression was more than twice as long in lenalidomide-treated patients, and overall survival was about 30% better.
Action Points
Explain to interested patients that lenalidomide, a drug related to thalidomide, has demonstrated significant activity in patients with relapsed or refractory multiple myeloma.
Note that the authors of this study indicate that lenalidomide is less toxic than thalidomide.
"The superior results with lenalidomide were observed regardless of the number of previous therapies, the serum β2-microglobulin level, or the history with respect to treatment with thalidomide or bortezomib," Donna M. Weber, M.D., of the University of Texas M. D. Anderson Cancer Center, and colleagues concluded.
Treatment with thalidomide or the proteosome inhibitor bortezomib (Velcade) has improved response rates, time to progression, and survival in multiple myeloma. Additionally, thalidomide has demonstrated activity in relapsed or refractory myeloma. However, thalidomide-associated toxicity often complicates treatment.
Lenalidomide is a less toxic but more potent derivative of thalidomide. The drug's immunomodulatory properties include down-regulation of interleukin-6 and nuclear factor κ-B and activation of caspase 8.
Phase I and II trials of lenalidomide in patients with treatment-refractory multiple myeloma showed response rates approaching 30%. Adding dexamethasone led to responses in an additional 29% of patients who had not responded to lenalidomide alone (Blood 2002; 100: 3063-3067, Blood 2006; 108: 3458-3464).
Encouraging results from the preliminary clinical investigations provided impetus for two identically designed trials, in North America and Europe, to evaluate lenalidomide in patients with relapsed or refractory multiple myeloma.
In North America, Dr. Weber and colleagues studied 353 patients treated with dexamethasone and randomized them to lenalidomide or placebo. Endpoints were safety, clinical response, time to progression, and overall survival.
Lenalidomide was associated with an overall response rate of 61% compared with 19.9% in the dexamethasone-placebo group (P0.001). Complete responses occurred in 14.1% of lenalidomide patients and 0.6% of the placebo group (P0.001). The median time to progression was 11.1 months with lenalidomide and 4.7 months with placebo (P0.001). Median overall survival was 29.6 months with lenalidomide versus 20.2 months with placebo (P0.001).
Grade 3-4 adverse events occurred in 85.3% of lenalidomide patients and 73.1% of the placebo group, leading to discontinuation of 19.8% and 10.2% of patients, respectively. Grade 3-4 neutropenia and thromboembolism occurred in 41.2% and 14.7% of lenalidomide patients versus 4.6% and 3.4% of placebo patients (P0.001 for both comparisons).
The European trial, led by Meletios Dimopoulos, M.D., of the University of Athens, involved 351 patients. The primary endpoint of time to progression was 11.3 months with lenalidomide versus 4.7 months with placebo (P0.001).
Mirroring results of the North American trial, the overall response rate was 60.2% in the lenalidomide group and 24% in the placebo group (P0.001), including complete responses in 15.9% of lenalidomide patients and 3.4% of placebo patients (P0.001). Lenalidomide-treated patients had a 34% improvement in overall survival compared with the placebo group (P=0.03).
The most common grade 3-4 adverse events in the lenalidomide group were neutropenia (29.5% versus 2.3% with placebo), thrombocytopenia (11.4% versus 5.7%), and venous thromboembolism (11.4% versus 4.6%).
Akin to a phoenix rising from the ashes, the re-emergence of thalidomide has led to a new class of immunomodulatory drugs that have promising antineoplastic activity, Alan F. List, M.D., of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, commented in an accompanying editorial.
"Lenalidomide and the immunomodulatory drugs stand as prime examples of potentially dangerous chemical compounds that have been granted a second life with powerful therapeutic capability," wrote Dr. List.
Drs. Weber, Dimopoulos, and List disclosed relationships with Celgene, which sponsored the two clinical trials.Primary source: New England Journal of MedicineSource reference: Weber DM, et al “Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America”N Engl J Med 2007; 357: 2133-2142.Additional source: New England Journal of MedicineSource reference: Dimopoulos M, et al “Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma”N Engl J Med 2007; 357: 2123-2132. Additional source: New England Journal of MedicineSource reference: List AF, “Lenalidomide -- the phoenix rises”N Engl J Med 2007; 357: 2183-2186.