Triplet versus doublet combination regimens for the treatment of relapsed or refractory multiple myeloma: A meta-analysis of phase III randomized controlled trials

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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.

Section snippets

What’s new?

The treatment of RRMM remains a significant clinical challenge worldwide. Currently, whether triplet combination therapy would improve the prognosis of RRMM remains undetermined. The present study demonstrates 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 are higher with triplets. The pooled estimates of response and survival strongly favor triplets in the RRMM patients.

Study design

We developed a protocol that defined inclusion criteria, search strategy, outcomes of interest, and analysis plan. The reporting of this systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements (Moher et al., 2009).

Data source

To identify studies for inclusion in our systematic review and meta-analysis, we did a broad search of four databases, including Embase, Medline, the Cochrane Central Register of Controlled Trials, and the Cochrane

Search results

A total of 145 studies were identified from the database search, of which 10 reports were retrieved for full-text evaluation. 135 of which were excluded for the reasons shown in Fig. 1. Finally, a total of 5 RCTs were included. Table 1, Table 2 summarized the baseline and disease characteristics of all included studies. A total of 3179 patients were available for the meta-analysis. According to the inclusion criteria of each trial, patients were required to have an adequate renal, hepatic and

Discussion

Multiple myeloma (MM) is the second most common lymphoid malignancy with 102 826 new cases of MM are diagnosed in 2008 (Ferlay et al., 2010). During the past decades, the introduction of targeted agents such as IMiDs and proteasome inhibitors improves treatment outcomes. However, MM remains incurable and patients eventually relapse (Kumar et al., 2012, Rajkumar, 2011). The prognosis of RRMM patients, particularly those that are refractory to bortezomib and are relapsed from, refractory to or

Funding

None.

Conflicts of interest statement

All authors declare that they have no potential conflicts of interests.

Contributions

Z.S. and F.Z. conceived and designed the experiments. Z. S. and S.W. wrote the main manuscript text. Y. L. and H.G. extracted and analyzed the data: Y.L. and Z.S. prepared the figures; all authors reviewed the manuscript.

Zhiqiang Sun is a medical oncologist (Department of Hematology, Shenzhen Hospital of Southern Medical University). He has interests in the field of novel targeted agents for the treatment refractory or relapsed multiple myeloma.

References (21)

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Zhiqiang Sun is a medical oncologist (Department of Hematology, Shenzhen Hospital of Southern Medical University). He has interests in the field of novel targeted agents for the treatment refractory or relapsed multiple myeloma.

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