Author(s): M. Attal, C. Cristini, G. Marit, D. Caillot, T. Facon, C. Hullin, P. Moreau, C. Mathiot, H. Avet-Loiseau, J. L. Harousseau

ABSTRACT:

Background: High-dose therapy with autologous stem cell transplantation (ASCT) is a standard treatment for myeloma patients. However, a residual disease (RD) responsible for relapse is always present. Effective maintenance treatment would be required. However, such treatment is still to be defined. We previously reported that thalidomide reduced RD. However, neuropathy was a major limiting factor. Lenalidomide, a thalidomide analog devoid of neurological toxicity, was thus attractive to investigate.

Methods: Patients, under 65 years of age, with non-progressive disease after a first line ASCT (performed within the last 6 months) were randomized to receive a consolidation with lenalidomide (25 mg/d, 21 days/month, for 2 months) followed by a maintenance with either lenalidomide (10 to 15 mg/d) until relapse (Arm A) or placebo (Arm B). From July 2006 to August 2008, 614 patients were randomized. Patient's characteristics of each group were similar and no significant differences were found with regard to age (57 years), ISS stage, FISH analysis, induction regimen (VAD/bortezomib-dex/thalidomide-dex/others=49%/44%/3%/2%), diagnosis-randomization interval (10 months), and response at time of randomization.

Results: In December 2009, with a median follow up of 24 months from randomization, the first pre-planned interim analysis was performed. The independent data and safety monitoring committee recommended to unblind the trial due to the PFS superiority of arm B (primary end point). Consolidation improved the response in 20% of patients. Maintenance with LEN improved the 3-year PFS from randomization: 35% in arm A versus 68% in arm B (HR=0.46, p<10^-6). This benefit was observed both among patients achieving or not a complete response after ASCT. In multivariate analysis, PFS was related to response after consolidation, beta-2 microglobulin at diagnosis, and treatment arm. A strong interaction (p<0.04) was found between the efficacy of arm B and beta 2-microglobulin (HR=0.3, p <10^-4 for beta-2 m < 3 mg/l; HR=0.58, p<0.003 for beta-2 m > 3 mg/l). The 2-year survival was similar in both treatment arms (95%)

Conclusions: Lenalidomide is an effective maintenance treatment which prolongs PFS after ASCT.