Safety and Efficacy Outcomes with Lenalidomide Plus Dexamethasone in Relapsed or Refractory Multiple Myeloma Were Not Significantly Different for the Treatment of Patients with or without High-Risk Disease or Elderly Status

Introduction: Lenalidomide is effective in the treatment of multiple myeloma (MM). The MM-009 and MM-010 randomized, double-blind, placebo-controlled phase III trials showed that lenalidomide in combination with dexamethasone induced significantly higher overall response (OR), and longer median time-to-progression (TTP) than dexamethasone alone in patients with relapsed or refractory MM (Weber et al, NEJM 2007; Dimopoulos et al, NEJM 2007). Previously identified predictors of high-risk disease and poor prognosis in MM include age (≥ 65 vs. < 65 years), Eastern Cooperative Oncology Group (ECOG) performance status (ECOG score ≥ 1 vs. 0), IgA status (IgA MM vs. non-IgA MM), disease stage (Durie-Salmon stage III vs. I–II), and β2-microglobulin level (> 2.5 mg/L vs. ≤ 2.5 mg/L). Here, we compared safety and efficacy outcomes of lenalidomide plus dexamethasone in patients with or without these high-risk factors. Methods: Patients with or without high-risk factors, pooled from MM-009 and MM-010, were randomized to receive lenalidomide (25 mg/day on days 1–21 of each 28-day cycle) plus dexamethasone (40 mg/day on days 1–4, 9–12, and 17–20 of each 28-day cycle for 4 cycles, with 40 mg/day on days 1–4 only from cycle 5 onwards). OR and TTP were based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]). Results: OR rate and median TTP were comparable between low- and high-risk patients based on age, ECOG score, IgA status, and Durie-Salmon disease stage. Patients with β2-microglobulin ≤ 2.5 mg/L had significantly better OR and TTP than those with β2-microglobulin >2.5 mg/L (Table). Grade 3 or 4 adverse events for the different subgroups were similar to those observed for the overall study population. Most grade 3 or 4 adverse events were similar between high-risk and low-risk groups. Significant differences in grade 3 or 4 adverse events were neutropenia for patients with Durie-Salmon stage III vs. I–II (40% vs. 28%, p=0.03), thrombocytopenia for ≥ 65 years vs. < 65 years (17% vs. 9%, p=0.03) and those with β2-microglobulin ≤ 2.5 mg/L vs. >2.5 mg/L (16% vs. 7%, p=0.03), and anemia for those with β2-microglobulin ≤ 2.5 mg/L vs. >2.5 mg/L (15% vs. 1%, p=0.0001). Grade 3 or 4 peripheral neuropathy was uncommon (≤2%) for all subgroups and not significantly different between those with high- and those with low-risk features. Conclusion: High OR rates, long TTP and manageable adverse events were observed with lenalidomide plus dexamethasone for patients with high-risk features. Advanced age, high ECOG score, presence of IgA, and advanced Durie-Salmon stage did not affect efficacy outcomes. Patients with high β2-microglobulin levels did have lower efficacy and more adverse events. Risk group OR rate, % P Median, TTP months P < 65 years (n=192) 61 0.73 11.1 0.91 ≥ 65 years (n=161) 60 13.2 ECOG 0 (n=152) 59 0.52 10.2 0.30 ECOG ≥ 1 (n=192) 62 13.1 Non-IgA (n=72) 57 0.10 11.2 0.65 IgA (n=267) 68 10.2 Durie-Salmon I–II (n=123) 61 0.89 13.6 0.21 Durie-Salmon III (n=229) 60 10.6 β2-microglobulin ≤ 2.5 mg/L (n=103) 73 0.002 15.2 0.004 β2-microglobulin > 2.5 mg/L (n=250) 56 9.5