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

Abstract

Key Points• Different therapeutic agents are currently available for the treatment of RRMM.• By performing an NMA, we identified a lenalidomidedexamethasone 1 mAb regimen as the most active therapeutic option in this setting.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). NMAshowed 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.

The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma

“…Previous analyses have attempted to solve the problem of disconnected networks by grouping regimens and assuming equal efficacy for each group [3, 31]. While this approach allows for the estimation of relative effects across the entire evidence base, the uncertainty associated with the assumption is not incorporated.…”

“…We validated our method by comparing our analysis with estimates from previous inter network comparisons [3, 29, 31, 39]. …”

“…Armoiry et al have recently highlighted the disagreement between published matched pair analyses and the assumption of equal efficacy applied here [30]. Botta et al obtained relative effects across the network by grouping regimens into nine groups [31]. An analysis of independent treatments is also provided, however, still assuming equal efficacy of bortezomib monotherapy and bortezomib plus dexamethasone as well as thalidomide, thalidomide plus dexamethasone and lenalidomide plus dexamethasone.…”

Plasma cell diseases and organ transplant: A comprehensive review

“…[28][29][30] Proteasome inhibitors include bortezomib, ixazomib, and carfilzo- Myeloma therapy can have clinically significant acute and longterm side effects. 35,36 A thorough discussion of post-ASCT complications is beyond the scope of this paper, but immunocompromised state lasts well beyond engraftment, and infectious complications may occur up to a 35,36 Proteasome inhibitors such as bortezomib have a risk of neuropathy, and immune suppression leading to reactivation of shingles.…”

“…Immunomodulatory drugs lenalidomide and pomalidomide can cause rash, cytopenias, increased risk for thromboembolism, and an increased risk for secondary malignancies. 35,36 Proteasome inhibitors such as bortezomib have a risk of neuropathy, and immune suppression leading to reactivation of shingles. 35,36 A thorough discussion of post-ASCT complications is beyond the scope of this paper, but immunocompromised state lasts well beyond engraftment, and infectious complications may occur up to a…”