Lenalidomide plus Dexamethasone Delays Progression and Improves Survival in High-risk Smoldering Multiple Myeloma


Key Points

  • Induction lenalidomide/dexamethasone plus maintenance lenalidomide significantly prolonged time to disease progression.
  • Treatment was associated with a significant overall survival benefit.
  • The oral regimen was associated with an acceptable safety profile.

In a study reported in The New England Journal of Medicine, María-Victoria Mateos, MD, PhD, of the Universidad de Salamanca, and colleagues compared induction lenalidomide (Revlimid) plus dexamethasone followed by maintenance lenalidomide with observation in patients with high-risk smoldering multiple myeloma. Active treatment was associated with delayed progression to symptomatic disease and improved overall survival with acceptable toxicity.

Study Details

In this open-label, phase III trial, 119 patients with high-risk smoldering multiple myeloma were randomly assigned to treatment (n = 57) or observation (n = 62). The treatment group received an induction regimen of lenalidomide at 25 mg/d on days 1 to 21 plus dexamethasone at 20 mg/d on days 1 to 4 and days 12 to 15 at 4-week intervals for nine cycles, followed by a maintenance regimen of lenalidomide at 10 mg/d on days 1 to 21 of each 28-day cycle for 2 years. The primary endpoint was time to progression to symptomatic disease.

Patients had to have been diagnosed within the prior 5 years. High-risk disease was defined as plasma-cell bone marrow infiltration of at least 10% and a monoclonal component (IgG ≥ 3 g/dL, IgA ≥ 2 g/dL, or urinary Bence Jones protein > 1 g per 24 hours) or one of these two criteria plus at least 95% phenotypically aberrant plasma cells in the bone marrow plasma-cell compartment with reductions in one or two uninvolved immunoglobulins of more than 25% compared with normal values.

The treatment and observation groups were generally well matched for age (median, 63 and 69 years), sex (56% and 55% female), time since diagnosis (> 6 months in 56% and 58%), and criteria for high risk (monoclonal component and plasma-cell bone marrow infiltration in 18% and 13%, ≥ 95% aberrant plasma cells plus immunoparesis in 40% and 39%, and both criteria in 42% and 48%).

Delayed Progression, Improved Survival

After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group (median not reached vs 21 months, hazard ratio [HR] = 0.18, P < .001). Symptomatic disease developed in 23% of the treatment group and in 76% of the observation group.

Three-year overall survival was significantly higher in the treatment group (94% vs 80%, HR = 0.31, P = .03) . Analysis of overall survival from time of diagnosis of smoldering myeloma, with a median follow-up of 46 months, also indicated significant improvement in the treatment group (5-year overall survival, 94% vs 78%, HR = 0.28, P = .02). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase.


Toxic effects were mainly grade 2 or lower. The most frequently reported grade 3 events during induction therapy were infection (6%), asthenia (6%), neutropenia (5%), and rash (3%). A total of 10 patients required a reduction in lenalidomide dose from 25 mg to 15 mg due to grade 3 events; 6 required reductions in dexamethasone dose to 20 mg on days 1 through 4.

The rate of serious adverse events during induction therapy was higher in the treatment group (12% vs 3%). Four patients in the treatment group and one in the observation group had infection resulting in serious adverse events. In the treatment group, one patient died from a grade 5 respiratory infection, and four patients discontinued study medications due to treatment-related adverse events. The incidence of adverse events was lower during maintenance. The rate of grade 1 or 2 infections was 18% in the treatment group and 8% in the observation group. No dose reductions were needed during maintenance therapy.

The investigators concluded: “[The study] showed that early treatment with lenalidomide and dexamethasone, followed by maintenance therapy with lenalidomide, in patients with high-risk smoldering multiple myeloma significantly delayed the time to progression to symptomatic disease and resulted in an overall survival benefit. The orally administered treatment regimen was associated with an acceptable toxicity profile.”

The study was funded by Celgene.

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