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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.

SUBMITTER: Botta C

PROVIDER: S-EPMC5738982 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Botta Cirino C Ciliberto Domenico D Rossi Marco M Staropoli Nicoletta N Cucè Maria M Galeano Teresa T Tagliaferri Pierosandro P Tassone Pierfrancesco P

Blood advances 20170227 7

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 ( ...[more]

PMID: 29296961

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Project description:Background: In recent years, chimeric antigen receptor-modified T (CAR-T) cell therapy for B-cell leukemia and lymphoma has shown high clinical efficacy. Similar CAR-T clinical trials have also been carried out in patients with refractory/relapsed multiple myeloma (RRMM). However, no systematic review has evaluated the efficacy and safety of CAR-T cell therapy in RRMM. The purpose of this study was to fill this literature gap. Methods: Eligible studies were searched in PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, and WanFang from data inception to December 2019. For efficacy assessment, the overall response rate (ORR), minimal residual disease (MRD) negativity rate, strict complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) were calculated. The incidence of any grade cytokine release syndrome (CRS) and grade ≥3 adverse events (AEs) were calculated for safety analysis. The effect estimates were then pooled using an inverse variance method. Results: Overall, 27 studies involving 497 patients were included in this meta-analysis. The pooled ORR and MRD negativity rate were 89% (95% Cl: 83-94%) and 81% (95% Cl: 67-91%), respectively. The pooled sCR, CR, VGPR, and PR were 14% (95% Cl: 5-27%), 13% (95% Cl: 4-26%), 23% (95% Cl: 14-33%), and 15% (95% Cl: 10-21%), respectively. Subgroup analyses of ORR by age, proportion of previous autologous stem cell transplantation (ASCT), and target selection of CAR-T cells revealed that age ≤ 55 years (≤55 years vs. > 55 years, p = 0.0081), prior ASCT ≤70% (≤70% vs. > 70%, p = 0.035), and bispecific CAR-T cells (dual B-cell maturation antigen (BCMA)/BCMA + CD19 vs specific BCMA, p = 0.0329) associated with higher ORR in patients. Subgroup analyses of remission depth by target selection suggested that more patients achieved a better response than VGPR with dual BCMA/BCMA + CD19 CAR-T cells compared to specific BCMA targeting (p = 0.0061). In terms of safety, the pooled incidence of any grade and grade ≥ 3 CRS was 76% (95% CL: 63-87%) and 11% (95% CL: 6-17%). The most common grade ≥ 3 AEs were hematologic toxic effects. Conclusion: In heavily treated patients, CAR-T therapy associates with promising responses and tolerable AEs, as well as CRS in RRMM. However, additional information regarding the durability of CAR-T cell therapy, as well as further randomized controlled trials, is needed.

Project description:ObjectivesThe current study aims to evaluate the safety and efficacy of anti-CD38 monoclonal antibodies (mAbs) among patients with relapsed/refractory multiple myeloma (RRMM) through meta-analysis.MethodsAs of June 2023, we searched PubMed, Web of Science, Embase and the Cochrane Library. Randomized controlled trials (RCTs) which compared the clinical outcomes of anti-CD38 mAbs plus immunomodulatory drugs (IMiDs) or proteasome inhibitors (PIs) plus dexamethasone and IMiDs (or PIs) and dexamethasone alone for RRMM patients were included. Efficacy outcomes were mainly evaluated with progression-free survival (PFS) and overall survival (OS). The safety was analyzed with hematologic and nonhematologic treatment-emergent adverse events (TEAEs). All results were pooled using hazard ratio (HR), relative risk (RR), and their 95% confidence interval (CI) and prediction interval (PI).ResultsThis meta-analysis included 11 RCTs in total. Compared with IMiDs (or PIs) and dexamethasone alone, anti-CD38 mAbs in combination with IMiDs (or PIs) and dexamethasone significantly prolonged PFS (HR: 0.552, 95% CI = 0.461 to 0.659, 95% PI = 0.318 to 0.957) and OS (HR: 0.737, 95% CI = 0.657 to 0.827, 95% PI = 0.626 to 0.868) in patients with RRMM. Additionally, RRMM patients receiving anti-CD38 mAbs in combination with IMiDs (or PIs) and dexamethasone achieved higher rates of overall response (RR: 1.281, 95% CI = 1.144 to 1.434, 95% PI = 0.883 to 1.859), complete response or better (RR: 2.602, 95% CI = 1.977 to 3.424, 95% PI = 1.203 to 5.628), very good partial response (VGPR) or better (RR: 1.886, 95% CI = 1.532 to 2.322, 95% PI = 0.953 to 3.731), and minimum residual disease (MRD)-negative (RR: 4.147, 95% CI = 2.588 to 6.644, 95% PI = 1.056 to 16.283) than those receiving IMiDs (or PIs) and dexamethasone alone. For TEAEs, the rates of hematologic and nonhematologic TEAEs, including thrombocytopenia, neutropenia, upper respiratory tract infection (URTI), pneumonia, bronchitis, dyspnea, diarrhea, pyrexia, back pain, arthralgia, fatigue, insomnia, and hypertension, were higher in the anti-CD38 mAbs in combination with IMiDs (or PIs) and dexamethasone group than in the IMiDs (or PIs) and dexamethasone group.ConclusionOur study showed that anti-CD38 mAbs in combination with IMiDs (or PIs) and dexamethasone improved PFS and OS, and achieved higher rates of overall response, complete response or better, VGPR or better, and MRD-negative, as well as higher rates of thrombocytopenia, neutropenia, URTI, pneumonia, bronchitis, dyspnea, diarrhea, pyrexia, back pain, arthralgia, fatigue, insomnia, and hypertension in RRMM patients.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023431071.

Project description:ObjectivesTo systematically review and meta-analyse the evidence for effect modification by refractory status and number of treatment lines in relapsed/refractory multiple myeloma (RRMM); and to assess whether effect modification is likely to invalidate network meta-analyses (NMA) that assume negligible modification.DesignSystematic review, meta-analysis and simulation.Data sourcesWe systematically searched the literature (e.g., OVID Medline) to identify eligible publications in February 2020 and regularly updated the search until January 2022. We also contacted project stakeholders (including industry) ELIGIBILITY CRITERIA: Phase 2 and 3 randomised controlled trials reporting stratified estimates for comparisons with at least one of a prespecified set of treatments relevant for use in Norwegian RRMM patients.OutcomesWe used meta-analysis to estimate relative HRs (RHRs) for overall survival (OS) and progression-free survival (PFS) with respect to refractory status and number of treatment lines. We used the estimated RHRs in simulations to estimate the percentage of NMA results expected to differ significantly in the presence versus absence of effect modification.ResultsAmong the 42 included publications, stratified estimates were published by and extracted from up to 18 (43%) publications and on as many as 8364 patients. Within-study evidence for effect modification is very weak (p>0.05 for 47 of 49 sets of stratified estimates). The largest RHR estimated was 1.32 (95% CI 1.18 to 1.49) for the modifying effect of refractory status on HR for PFS. Simulations suggest that, in the worst case, this would result in only 4.48% (95% CI 4.42% to 4.54%) of NMA estimates differing statistically significantly in the presence versus absence of effect modification.ConclusionsBased on the available evidence, effect modification appears to be sufficiently small that it can be neglected in adequately performed NMAs. NMAs can probably be relied on to provide estimates of HRs for OS and PFS in RRMM, subject to caveats discussed herein.

Dataset Information

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

Publications

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

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