Continuous Lenalidomide/Dexamethasone Improves Progression-Free Survival in Transplant-Ineligible Patients With Myeloma
In the phase III FIRST trial reported in The New England Journal of Medicine, Benboubker et al found that continuous lenalidomide (Revlimid) plus dexamethasone significantly improved progression-free survival vs melphalan/prednisone/thalidomide (Thalomid) in transplant-ineligible myeloma patients. An interim analysis suggested an overall survival benefit with continuous lenalidomide/dexamethasone.
Study Details
In this open-label trial, 1,623 patients from 246 treatment centers in 18 countries in Europe, North America, and the Asia-Pacific region were randomly assigned between August 2008 and March 2011 to receive continuous lenalidomide plus dexamethasone in 28-day cycles until disease progression (n = 535), lenalidomide/dexamethasone for 72 weeks (18 cycles) (n = 541), or melphalan/prednisone/thalidomide for 72 weeks (n = 547). Patients were either aged ≥ 65 years or were aged < 65 years and ineligible for stem cell transplantation. Lenalidomide was given at 25 mg on days 1 to 21 and dexamethasone was given at 40 mg on days 1, 8, 15, and 22 of each 28-day cycle. The primary endpoint was progression-free survival with continuous lenalidomide/dexamethasone vs melphalan/prednisone/thalidomide.
Improved Progression-Free Survival
Median duration of follow-up among surviving patients was 37.0 months. Median progression-free survival was 25.5 months with continuous lenalidomide/dexamethasone, 20.7 months with 18 cycles of lenalidomide/dexamethasone, and 21.2 months with melphalan/prednisone/thalidomide, with hazard ratios (HRs) of 0.72 (P < .001) for continuous lenalidomide/dexamethasone vs melphalan/prednisone/thalidomide and 0.70 (P < .001) for continuous lenalidomide/dexamethasone vs 18 cycles of lenalidomide/dexamethasone.
Overall Survival Interim Analysis
On interim analysis, 3-year overall survival was 70% with continuous lenalidomide/dexamethasone, 66% with 18 cycles of lenalidomide/dexamethasone, and 62% with melphalan/prednisone/thalidomide. Four-year overall survival was 59%, 56%, and 51%, respectively. The difference in overall survival did not cross the prespecified superiority boundary (P < .0096), but the hazard ratio for death favored continuous lenalidomide/dexamethasone vs melphalan/prednisone/thalidomide (0.78, P = .02). Continuous lenalidomide/dexamethasone was not associated with significantly different 4-year overall survival vs 18 cycles of lenalidomide/dexamethasone (HR = 0.90, P = 0.31).
Benefits of continuous lenalidomide/dexamethasone vs melphalan/prednisone/thalidomide for both progression-free survival and overall survival were observed in most subgroups, including younger patients and patients aged > 75 years. Benefit was questionable in subgroups with poor prognostic features, including patients with high-risk cytogenetic profiles and those with elevated lactate dehydrogenase.
Toxicity
Grade 3 or 4 adverse events occurred in 85% of the continuous lenalidomide/dexamethasone group, 89% of the 18-cycle lenalidomide/dexamethasone group, and 89% of the melphalan/prednisone/thalidomide group. The most common hematologic grade 3 or 4 adverse events were neutropenia (28%, 26%, and 45%) and anemia (18%, 16%, and 19%). The most common nonhematologic grade 3 or 4 adverse events were infection (29%, 22%, and 17%) and cardiac disorders (12%, 7%, and 9). Invasive second primary cancers were found in 3%, 6%, and 5% of patients, with hematologic cancers found in < 1%, < 1%, and 2% and solid tumors found in 3%, 5%, and 3%.
The investigators concluded: “[T]reatment with continuous lenalidomide-dexamethasone, an alkylator-free doublet oral regimen, significantly improved progression-free survival, as compared with the alkylator-based triplet regimen [melphalan/prednisone/thalidomide] among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. A survival benefit was also seen with continuous lenalidomide-dexamethasone in an interim analysis….[The findings thus far suggest that patients] who are elderly or are ineligible for stem-cell transplantation may benefit from continuous therapy.”
Thierry Facon, MD, of Centre Hospitalier Régional Universitaire de Lille, France, is the corresponding author for The New England Journal of Medicine article.
The study was funded by Intergroupe Francophone du Myélome and Celgene. For full disclosures of the study authors, visit www.nejm.org.
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