A meta-analysis of phase III trials favors the use of a triplet drug regimen for patients with RRMM

Zhiqiang Sun and colleagues from the Department of Hematology, Shenzhen Hospital of Southern Medical University, Guangdong province, undertook a meta-analysis of data from previously published phase III randomized clinical trials, to assess the efficacy of doublet versus triplet drug regimens for the treatment of patients with Relapsed and Refractory Multiple Myeloma (RRMM). Their findings were published in Critical Reviews in Oncology Hematology in March 2017.

Study Design

• Four key databases used: Embase, Medline, Cochrane central register of RCTs, Cochrane database of systematic reviews
• Inclusion criteria: published before May 2016, written in English, RCTs, study population = previously treated RRMM, comparison of doublet vs triplet regimens, included information on HRs for progression free survival (PFS), time to progression (TTP) or overall survival (OS)
• 145 studies were identified; 10 reports retrieved for full-text evaluation; a total of 5 RCTs included with 3,179 patients in total

Key findings

Triplet vs doublet therapy:

• OS (3/5 trials): HR = 0.82(95%CI: 0.71–0.94, p = 0.004Fig. 2); fixed-effects model (I² = 0%, p = 0.77)
• PFS (5 trials): HR = 0.68 (95%CI: 0.62–0.74, p < 0.001Fig. 3); fixed-effects model (I² = 0%, p = 0.78)
• ORR (5 trials): RR = 1.19 (95%CI 1.10–1.27, P < 0.001); random-effects model (I² = 61.4%, p = 0.035)
• VGPR (5 trials): RR = 1.44 (95%CI: 1.17–1.77, p < 0.001)
• CR (5 trials): RR = 1.76 (95%CI: 1.04–2.97, p = 0.035)
• AEs ≥grade 3 (5 trials): RR = 1.11 (95%CI: 1.05-1.18, p=0.001)
  • infections (4 trials): RR = 1.33 (95%CI: 0.97-1.83, p= 0.079)
  • thrombocytopenia ≥ grade 3 (5 trials): RR = 1.64 (95%CI: 1.13-2.38, p=0.009)
  • neutropenia (5 trials): RR= 1.13 (95%CI: 0.71-1.81, p= 0.60)

In this analysis, a clear improvement in OS, PFS and CR was indicated for patients with RRMM when treated with a triplet drug regimen – in which a novel agent is added to a doublet combination of an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI). This therefore strengthens the case for triplet regimens as the standard of care in this patient population, although clinicians must be wary that the risk of resultant grade 3 and 4 AEs is heightened.

Abstract

During the past decades, several prospective trials had been conducted to assess the efficacy and toxicities of triplet versus doublet combination regimens for the treatment of relapsed or refractory multiple myeloma (RRMM), but the results were controversial. We thus performed a systematic literature search to identify relevant trials. Summary hazard ratios (HRs), relative risks (RRs), and 95% confidence intervals (95%CIs) were calculated. A total of 3197 RRMM patients were included for analysis. The pooled results demonstrated that triplet combination therapies significantly improve OS (HR 0.83, 95%CI: 0.71–0.94, p = 0.004) and PFS (HR 0.68, 95%CI: 0.62–0.74, p < 0.001). The pooled RRs of ORR, very good partial response (VGPR) and complete response (CR) with triplets vs. doublets were 1.19 (95%CI: 1.10–1.27), 1.44 (95%CI: 1.18–1.77), and 1.76 (95%CI: 1.04–2.97), respectively, indicating that the RRs of achieving deeper responses were higher with triplets, though the RRs of overall ≥ grade 3 adverse events (RR 1.11, p = 0.001) and ≥grade 3 thrombocytopenia (RR 1.64, p = 0.009) was higher with triplets. In conclusion, our meta-analysis demonstrated that triplet regimens result in improved OS, PFS, ORR, VGPR, and CR when compared to doublets, though the risk of grade 3 and 4 adverse events were higher with triplets.