Continuous Lenalidomide/Dexamethasone Improves Progression-Free  Survival in Transplant-Ineligible Patients With Myeloma


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[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 MPT among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation.

—Lotfi Benboubker, MD, and colleagues

In the phase III FIRST trial reported in The New England Journal of Medicine, Lotfi Benboubker, MD, Service d’Hématologie et Thérapie Cellulaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire (CHRU), Tours, France, and colleagues found that continuous lenalidomide (Revlimid) plus dexamethasone significantly improved progression-free survival vs MPT (melphalan, prednisone, thalidomide [Thalomid]) in transplant-ineligible myeloma patients.1 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 MPT for 72 weeks (n = 547). Patients were either aged ≥ 65 years or both < 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 MPT.

The three patient groups were generally balanced for age (median, 73 years in all, 94%–95% ≥ 65 years), sex (50%–55% male), race/ethnicity (89%–90% white, 7%–8% Asian), Eastern Cooperative Oncology Group performance status (0 in 29%–30%, 1 in 48%–50%), International Staging System stage (I or II in 59%–60%), myeloma subtype (IgG in 61%-64%, IgA in 22%–26%), lactate dehydrogenase level (< 200 U/L in 79%–84%), creatinine clearance (< 30 mL/min in 8%–10%, ≥ 60 mL/min in 50%–53%), history of bone lesions (71%–72%), and high-risk cytogenetic profile (17%–20% in 248–261 assessed patients).

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 MPT, with hazard ratios (HRs) of 0.72 (P < .001) for continuous lenalidomide/dexamethasone vs MPT and 0.70 (P < .001) for continuous lenalidomide/dexamethasone vs 18 cycles of lenalidomide/dexamethasone.

There was no difference in progression-free survival between the 18-cycle lenalidomide/dexamethasone group and the MPT group (HR = 1.03, P = .70). The progression-free survival benefit of continuous lenalidomide/dexamethasone vs 18 cycles of lenalidomide/dexamethasone was greatest among patients with very good partial response or complete response.

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 MPT, and 4-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 MPT (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 = .31).

Benefits of continuous lenalidomide/dexamethasone vs MPT for both progression-free and overall survival were observed in most subgroups, including younger patients and those 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.

Responses

Response rates were 75% with continuous lenalidomide/dexamethasone, 73% with 18 cycles of lenalidomide/dexamethasone, and 62% with MPT (< .001 for comparisons with both lenalidomide regimens); rates of very good partial response were 44%, 43%, and 28%, and rates of complete response were 15%, 14%, and 9%.

Median time to response was significantly shorter in the two lenalidomide groups vs the MPT group (1.8 months in both vs 2.8 months, P < .001). Responses were more durable with continuous lenalidomide/dexamethasone vs 18 cycles of lenalidomide/dexamethasone or MPT (P < .001 for both comparisons).

Second-line therapy was used in 43% of patients in the continuous lenalidomide/dexamethasone group, 55% of the group receiving 18 cycles of lenalidomide/dexamethasone, and 56% of the MPT group. Time to second-line therapy was 39.1, 28.5 months (P < .001 vs continuous lenalidomide), and 26.7 months (P < .001 vs continuous lenalidomide).

The progression-free survival benefit of continuous lenalidomide/dexamethasone continued through the second-line of therapy, with median progression-free survival including second-line treatment being 42.9 months in the initial continuous lenalidomide group vs 36.3 months in the initial MPT group (HR = 0.78, P = .005).

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 MPT 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%).

Febrile neutropenia occurred in 1%, 3%, and 3% of patients. Deep-vein thrombosis or pulmonary embolism occurred in 8%, 6%, and 5%. Peripheral sensory neuropathy occurred in ≤ 1% of lenalidomide recipients vs 9% of MPT recipients. Cataracts occurred in 6%, 3%, and 1% of patients. 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%.

Most adverse events in the continuous lenalidomide/dexamethasone group occurred during the first 18 months of treatment.

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 MPT 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. ■

Disclosure: The study was funded by Intergroupe Francophone du Myélome and Celgene. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Benboubker L, Dimopoulos MA, Dispenzieri A, et al: N Engl J Med 371:906-917, 2014.


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