High-dose dexamethasone (Dex) remains a standard therapy for relapsed or refractory MM. Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when combined with Dex. In this phase 3, multicenter, randomized, double-blind trial, 351 patients with relapsed or refractory MM were enrolled from clinical centers in Europe, Israel, and Australia. Patients were treated with Dex 40 mg daily on days 1–4, 9–12, and 17–20 every 28 days and were randomized to receive either lenalidomide 25 mg daily orally on days 1–21 every 28 days or placebo. Beginning at cycle 5, the dose intensity of Dex was reduced to 40 mg daily on days 1–4 only every 28 days. Patients resistant to Dex were excluded. Patients were stratified with respect to B2M (≤ 2.5 vs. > 2.5 mg/mL), prior stem cell transplant (none vs. ≥1), and number of prior regimens (1 vs > 1). A pre-planned interim analysis of time to progression (TTP; primary endpoint), response (Blade criteria), and safety data was performed by an independent Data Monitoring Committee (IDMC) when at least half the number of disease progressions required for full statistical power had occurred (50% information). The treatment arms were well balanced for prognostic features. With a study duration of 18 months, the median TTP for patients treated with the combination of lenalidomide plus Dex was 13.3 months compared to 5.1 months for patients treated with Dex and placebo (p < 0.000001). The overall response rate was greater in patients who received lenalidomide plus Dex than in patients who were given Dex alone (58% vs. 22%; p < 0.001). Grade 3 or 4 neutropenia adverse events were reported more frequently in patients given combination therapy than in patients treated Dex alone (16.5% vs. 1.2%), however grade 3 or 4 infections were reported with similar frequencies between treatment groups. Thromboembolic events occurred in 8.5% of patients in the lenalidomide/Dex group and in 4.5% of patients in the Dex alone group. Otherwise, the safety profile of lenalidomide/Dex was similar to that of Dex alone.

Conclusion: Combination lenalidomide/Dex is a relatively well-tolerated and active oral regimen for patients with relapsed or refractory MM. The difference in TTP between the 2 arms surpassed the pre-specified O’Brien-Fleming boundary for superior efficacy (p < 0.0015) and the IDMC recommended the data be released to all study participants. Prophylactic antithrombotic therapy should be considered for patients undergoing treatment with lenalidomide/Dex. These data support further evaluation of this combination in previously untreated patients with MM.

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