Study of Lenalidomide Plus Dexamethasone Versus Dexamethasone Alone in Relapsed or Refractory Multiple Myeloma (MM): Results of a Phase 3 Study (MM-010).

Abstract

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.

Alternate day pomalidomide retains anti‐myeloma effect with reduced adverse events and evidence of in vivo immunomodulation

“…The incidence of venous thromboembolism in association with the use of single agent thalidomide or lenalidomide is low and has been reported in up to 5% of patients (Singhal et al, 1999;Hussein, 2006;Richardson et al, 2006). Interestingly, the use of combination therapy, especially with dexamethasone, appears to increase this risk (Dimopoulos et al, 2005;Hussein, 2006;Knight et al, 2006). In this phase 1 study, there were no deep vein thromboses reported either for patients who received single agent pomalidomide or those who subsequently received pomalidomide and dexamethasone.…”

Current status of new drugs for the treatment of patients with multiple myeloma

“…The MM010 (Europe and Australia) recruited 351 patients from 50 clinical sites with a median age of 63 years in the study arm and 64 years in the control arm. 50 In both the MM010 and MM009 (USA and Canada) trials, those receiving lenalidomide had significantly better ORR (61.2 and 58%, respectively) compared with dexamethasone alone (21.7 and 22.8%, respectively) with a further 28.2 and 33.5%, respectively, achieving stable disease. 51 There was also a significantly prolonged median time to progression (TTP) of 60.1 and 53.4 weeks (MM009 and MM010) in those receiving active drug, more than double that of dexamethasone-treated and placebotreated patients (20.7 and 20.6 weeks, respectively).…”

United Kingdom myeloma forum position statement on the use of lenalidomide in multiple myeloma

“…Two key phase III randomized, multicentre, double blind placebo controlled studies using identical protocols have been carried out (Dimopoulos et al, 2005;Weber et al, 2006a) with updated results recently reported (Dimopoulos et al, 2007;Weber et al, 2007). The randomization compared lenalidomide 25 mg daily on 21 days of a 28-day cycle plus dexamethasone with dexamethasone alone.…”

“…Myelosuppression has been identified as the most important adverse effect of lenalidomide therapy. Grade 3/4 neutropenia is reported in 16.5-24% of patients and thrombocytopenia in 11-17% patients (Dimopoulos et al, 2005;Weber et al, 2006a,b;Dimopoulos et al, 2007;Weber et al 2007, Celgene data on file). As a consequence, we recommend blood counts be carried out at two weekly intervals during the first 1-2 months of treatment and as clinically appropriate during subsequent cycles.…”

“…The use of lenalidomide/dexamethasone to treat myeloma significantly increases the risk of venous thrombosis (8.5% with lenalidomide/dexamethasone vs. 4.5% with dexamethasone alone; Dimopoulos et al, 2005). The use of erythropoietin may increase the incidence of venous thrombosis further, but data supporting this is not strong (Knight, DeLap & Zeldis, 2006) and erythropoietin may be used clinically if appropriate.…”