The Efficacy and Safety of Immunomodulatory Drugs in Multiple Myeloma Maintenance Therapy: Results of a Meta-Analysis

Abstract

Objective: To evaluate the efficacy and safety of immunomodulatory drugs (IMiDs) in maintenance therapy of multiple myeloma through meta-analysis of randomized controlled trials (RCTs).Patients and methods: PubMed, Web of Science, ASCO, ESMO and ASH databases were searched for RCTs that investigated the treatment outcomes (overall survival [OS], progression-free survival [PFS] and/or event-free survival [EFS] and/or time to progression [TTP]) of maintenance therapy with IMiDs in patients with multiple myeloma. Study endpoints included OS, PFS/EFS/TTP, and grade 3 or 4 adverse events. Pooled hazard ratios (HRs) for survival outcomes and risk ratios (RRs) for dichotomous data with 95% confidence interval (CI) were calculated using Comprehensive MetaAnalysis (v2). The random-effect model was utilized in view of clinical heterogeneity in the study population.Results: Eighteen RCTs comprising a total of 6562 patients were included in this meta-analysis. IMiDs used in the RCTs included thalidomide (14 trials) and lenalidomide (4 trials). Overall, IMiD-based maintenance therapy significantly improved OS (HR = 0.91, 95% CI = 0.84 - 0.99, P = 0.027) and PFS (HR = 0.63, 95% CI = 0.60 - 0.68, P < 0.001). Notably, IMiDs maintenance therapy increased OS in the setting of ASCT but showed no OS prolongation without ASCT. On further stratification, thalidomide-based maintenance therapy demonstrated OS benefit only in the setting of ASCT, while lenalidomide-based maintenance therapy did not show OS benefit regardless of transplantation status. For PFS however, both thalidomide- and lenalidomide-based maintenance therapies demonstrated significant survival benefits, regardless of transplantation status (Table 1). IMiD-based maintenance therapy increased the risk of developing grade 3 or 4 neutropenia (RR = 3.04, 95% CI = 2.49 - 3.70, P < 0.001), thrombocytopenia (RR = 2.68, 95% CI = 1.90 - 3.79, P < 0.001), anemia (RR = 1.97, 95% CI = 1.23 - 3.15, P = 0.005), infection (RR = 1.53, 95% CI = 1.22 - 1.92, P < 0.001), fatigue (HR = 1.71, 95% CI = 1.24 - 2.36, P = 0.001), constipation (RR = 2.04, 95% CI = 1.15 - 3.62, P = 0.015), and peripheral neuropathy (RR = 2.02, 95% CI = 1.20 - 3.39, P = 0.008).Conclusions: IMiD-based maintenance therapy results in significant improvement in OS and PFS in multiple myeloma patients but increased the risk of developing some grade 3 or 4 adverse events. While thalidomide-containing maintenance therapy regimens showed OS benefits in the setting of ASCT, lenalidomide-containing maintenance therapy did not prolong OS regardless of transplantation status. Both thalidomide- and lenalidomide-based maintenance therapies increased PFS in multiple myeloma patients independent of transplantation status. When more data on lenalidomide and the newer agent pomalidomide become available, further analysis will be warranted to analyze the efficacy and safety of IMiDs in multiple myeloma maintenance therapy.Table 1Effects of IMiD-based maintenance therapy on OS and PFS in multiple myeloma patientsIMiDASCT statusSurvivalNumber of trialsHR95% CIP valueThalidomide/LenalidomidecombinedOS180.910.84 - 0.990.027with ASCTOS100.880.78 - 0.990.036without ASCTOS90.940.83 - 1.060.299ThalidomidecombinedOS140.920.84 - 1.010.090with ASCTOS80.870.77 - 1.000.049without ASCTOS70.970.85 - 1.100.640LenalidomidecombinedOS40.840.67 - 1.040.102with ASCTOS20.890.66 - 1.200.457without ASCTOS20.780.57 - 1.060.114Thalidomide/LenalidomidecombinedPFS170.630.60 -0.68< 0.001with ASCTPFS90.620.57 - 0.67< 0.001without ASCTPFS90.660.60 - 0.73< 0.001ThalidomidecombinedPFS130.670.63 - 0.72< 0.001with ASCTPFS70.660.60 - 0.72< 0.001without ASCTPFS70.690.62 -0.77< 0.001LenalidomidecombinedPFS40.500.43 - 0.58< 0.001with ASCTPFS20.490.41 - 0.58< 0.001without ASCTPFS20.520.40 - 0.67< 0.001 DisclosuresNo relevant conflicts of interest to declare.