Choosing optimal therapy for relapsed refractory multiple myeloma: A systematic review and network meta-analysis.

e20037 Background: Several treatment options are available for relapsed refractory multiple myeloma(RRMM). However, in the absence of direct-comparative trials, it is unclear how to choose optimal therapy in RRMM. We conducted a network meta-analysis (NMA) to assess the comparative efficacy of different treatment options in RRMM. Methods: Standard electronic databases were searched for abstract and full-text publications of phase 2/3 randomized controlled trials (RCTs) assessing treatment regimens in RRMM. Progression free survival (PFS) , overall survival (OS), complete response (CR), and very good partial response (VGPR) were analyzed. Mixed treatment comparisons were made using fixed-effect network meta-analysis (NMA) within the frequentist framework due to sparse direct evidence. Sensitivity analyses were conducted using the Bayesian approach. Publication bias was assessed by visual inspection of comparison-adjusted funnel plots. P-score plots were used to assess relative rankings of the treatments. R statistical software v 4.0.3 was used to conduct the analyses. Results: After a review of 1137 citations, A total of 37 relevant studies were included in systematic review and 30 studies were analyzed in the network meta-analysis (29 contributed for PFS; 18 for OS; 23 for CR; 25 for VGPR). Mixed treatment comparisons showed high likelihood of PFS benefit with triplet regimens; Isatuximab-Carfilzomib-Dexamethasone (Isa-Kd; P-score: 0.98), followed by Daratumumab-Carfilzomib-Dexamethasone (DKd; P-score: 0.93), Daratumumab-Bortezomib-Dexamethasone (DVd P-score: 0.92), Elotuzumab-Pomalidomide-Dexamethasone (EPd); P-score: 0.84), and Isatuximab-Pomalidomide-Dexamethasone (Isa-Pd; P-score: 0.80) when compared to monotherapy and different doublet regimens. Isa-Kd and DKd continued to show significant PFS advantage when compared to Kd doublet. High likelihood of OS benefit was observed with Carfilzomib-Lenalidomide-Dexamethasone (KRd); P-score: 0.86) followed by Kd (P-score: 0.83), and DVd (P-score: 0.82). However, trials did not consistently report data for OS and most of the mixed treatment comparisons were statistically insignificant. Similar results were observed for CR and VGPR with triplet regimens showing better likelihood for achieving CR and VGPR. Conclusions: This NMA provide most updated evidence on different treatment options in RRMM and can serve as a contemporary guidance in the absence of head-to-head trials. The weight of current evidence favors the use of triplet regimens. Isa-Kd, DKd, DVd, EPd and Isa-Pd showed no statistically significant difference in terms of PFS in RRMM.

Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis

Background: Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. Methods: We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: −0.89 to −0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: −0.97 to −0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: −3.96 to −0.75). Memantine was effective for negative symptoms (standardised mean difference: −0.56 95% confidence interval: −0.93 to −0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses. Conclusions: On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.