Network meta-analysis of randomized trials in multiple myeloma: efficacy and safety in relapsed/refractory patients

Abstract

Despite major therapeutic advancements, multiple myeloma (MM) is still incurable and relapsed/refractory multiple myeloma (RRMM) remains a challenge; the rational choice of the most appropriate regimen in this setting is currently undefined. We performed a systematic review and 2 standard pairwise meta-analyses to evaluate the efficacy of regimens that have been directly compared with bortezomib or immunomodulatory imide drugs (IMiDs) in head-to-head clinical trials and a network meta-analysis (NMA) to determine the relevance of each regimen on the basis of all the available direct and indirect evidence. Sixteen trials were included in the pairwise meta-analyses, and 18 trials were included in the NMA. Pairwise meta-analyses showed that a 3-drug regimen (bortezomib- or IMiD-based) was superior to a 2-drug regimen in progression-free-survival (PFS) and overall response rate (ORR). NMA showed that an IMiD backbone associated with anti-MM monoclonal antibodies (mAbs) (preferably) or proteasome inhibitors had the highest probability of being the most effective regimen with the lowest toxicity. The combination of daratumumab, lenalidomide, and dexamethasone ranked as the first regimen in terms of activity, efficacy, and tolerability according to the average value between surface under the cumulative ranking curve of PFS, overall survival, ORR, complete response rate, and safety. This is the first NMA comparing all currently available regimens evaluated in published randomized trials for the treatment of RRMM, but our results need to be interpreted taking into account differences in their patient populations. Our analysis suggests that IMiDs plus new anti-MM mAb-containing regimens are the most active therapeutic option in RRMM.

Graphical abstract

Figure 1.

PRISMA flowchart for study selection and review. MA, meta-analysis; PRISMA, preferred reporting items for systematic reviews and meta‐analyses (checklist); SEER, Surveillance, Epidemiology, and End Results (program).

Figure 2.

Forest plots of comparisons between experimental treatments and standard treatments in terms of PFS and OS. Bortezomib (BORT) with or without dexamethasone represents the standard treatment (ST) in (A) PFS and (C) OS; IMiDs represent the standard treatment in (B) PFS and (D) OS. Subgroups have been created according to drug classes. CARF, carfilzomib; ET, experimental treatment; W, weight.

Figure 3.

Network of the comparisons and comparative efficacy and tolerance results. (A) Network plot of all treatment groups evaluated in the NMA for PFS. The number of studies that analyzed each treatment group is shown inside the circles; the overall numbers of patients included in the analysis for each group are provided in parentheses. (B) Effect estimates of the treatment in terms of PFS (column headings being compared with row headings) and safety (row headings being compared with column headings). PFS is reported as HR and safety is reported as RR (95% credible intervals are in parentheses). Statistically significant comparisons are shown in bold. DEX, dexamethasone.

Figure 4.

Ranking of treatments based on NMA results. (A,C) Distribution of the probabilities of being at each rank, together with mean rank. Cumulative ranking probabilities for each treatment evaluated in term of (B) PFS and (D) OS. (E) All of the SUCRA values for each regimen in regard to PFS, OS, ORR, CR, and toxicity (TOX; in this case, the higher the SUCRA, the safer the regimen is for patients). An average SUCRA and the average ranking are provided. BEV, bevacizumab; DAR, daratumumab; DEX, dexamethasone; ELO, elotuzumab; IXA, ixazomib; PAN, panobinostat; PLD, pegylated liposomal doxorubicin; SILT, siltuximab; VOR, vorinostat.