Developments in the treatment of multiple myeloma (MM) with proteasome inhibitors have led to improved outcomes. Moreover, frontline treatment and maintenance with lenalidomide have exposed progressively greater numbers of patients to this therapy prior to relapse. As a result, treatment of patients with lenalidomide-refractory MM has become an increasing area of concern. In the absence of studies directly comparing treatment regimens for lenalidomide-refractory MM, a systematic review was conducted to identify randomized controlled trials (RCTs) that included subgroup analyses of outcomes in lenalidomide-refractory patients. The objective of this network meta-analysis study was to compare the efficacy of novel treatment regimens in RCTs among patients with lenalidomide-refractory MM.
The MEDLINE/PubMed, Embase, and Cochrane registry of controlled trials databases were queried using the keywords “multiple myeloma” and “randomized controlled trial” for all studies published between January 1, 2005, and December 30, 2019. The primary outcome of this meta-analysis was progression- free survival (PFS). All studies were reviewed by independent investigators and conflicts were resolved through mutual discussion.
Direct and indirect comparisons among various treatment groups were generated by performing a network meta-analysis using a random-effects model. Interventions were ranked and P-scores were generated using a frequentist method. Using this method, a higher P-score would indicate greater PFS. In addition, hazard ratios (HRs) were calculated with 95% confidence intervals (CIs). Heterogeneity between the studies, as defined by the Cochrane Handbook for Systematic Reviews of Interventions, was assessed using the I2 statistic. An I2 value >50% was considered as significant heterogeneity.
The initial search strategy returned 1171 results. This number was reduced to 123 RCTs after excluding duplicates, trials in progress, subset analysis, and nonrandomized studies. Of these, only 8 studies adequately reported outcomes of patients with lenalidomide-refractory MM, and 7 studies with a total of 1698 patients were included in the final analysis of 2 discrete networks.
The results from Network 1 showed that the combinations of pomalidomide + bortezomib + dexamethasone (HR, 0.65; 95% CI, 0.50-0.84), daratumumab + bortezomib + dexamethasone (HR, 0.36; 95% CI, 0.21-0.63), and daratumumab + carfilzomib + dexamethasone (HR, 0.38; 95% CI, 0.21-0.69) all improved PFS when compared with bortezomib + dexamethasone alone. When these interventions were ranked, the daratumumab + bortezomib + dexamethasone and daratumumab + carfilzomib + dexamethasone combinations were the most efficacious (P-scores = .8758 and .8514, respectively), followed by pomalidomide + bortezomib + dexamethasone (P-score = .4791), carfilzomib + dexamethasone (P-score = .2707), and bortezomib + dexamethasone (P-score = .0231).
Results from Network 2 showed that the combinations of pomalidomide + dexamethasone (HR, 0.50; 95% CI, 0.40-0.62), isatuximab + pomalidomide + dexamethasone (HR, 0.30; 95% CI, 0.20-0.44), and elotuzumab + pomalidomide + dexamethasone (HR, 0.27; 95% CI, 0.16-0.45) all improved PFS compared with dexamethasone alone. When these interventions were ranked, the elotuzumab + pomalidomide + dexamethasone and isatuximab + pomalidomide + dexamethasone combinations were the most efficacious (P-scores of .8716 and .7932, respectively), followed by pomalidomide + dexamethasone (P-score = .3352).
Results from this network meta-analysis among 1698 lenalidomide-refractory MM patients across 7 RCTs demonstrated that triple therapy is superior to dual therapy. Furthermore, the highest efficacy for these patients was triple therapy that included a monoclonal antibody (eg, daratumumab, elotuzumab, or isatuximab).
Reference
Abstract 2557. ASH 2020. December 6, 2020. A Systematic Review and Network Meta-Analysis of Randomized Data on Efficacy of Novel Therapy Combinations in Patients with Lenalidomide Refractory Multiple Myeloma.