Multinomial network meta-analysis using response rates: relapsed/refractory multiple myeloma treatment rankings differ depending on the choice of outcome.

BACKGROUND: Due to the fast growing relapsed/refractory multiple myeloma (RRMM) treatment landscape, a comparison of all the available treatments was warranted. For clinical practice it is important to consider both immediate effects such as response quality and prolonged benefits such as progression-free survival (PFS) in a meta-analysis. The objective of this study was to assess the impact of the choice of outcome on the treatment rankings in RRMM. METHODS: A multinomial logistic network meta-analysis was conducted to estimate the ranking of sixteen treatments based on both complete and objective response rates (CRR and ORR). Seventeen phase III randomized controlled trials from a previously performed systematic literature review were included. Treatment ranking was based on the surface under the cumulative ranking curve (SUCRA). Sensitivity analysis was conducted. RESULTS: The ranking of treatments differed when comparing PFS hazard ratios rankings with rankings based on CRR. Pomalidomide, bortezomib and dexamethasone ranked highest, while a substantial lower ranking was observed for the triplet elotuzumab, lenalidomide, dexamethasone. The ranking of treatments did not differ when comparing PFS hazard ratios and ORR. The scenario analyses showed that the results were robust. In all scenarios the top three was dominated by the same triplets. The treatment with the highest probability of having the best PFS and ORR was the triplet daratumumab, lenalidomide plus dexamethasone in the base case. CONCLUSION: This analysis shows that depending on the chosen outcome treatment rankings in RRMM may differ. When conducting NMAs, the response rate, a clinically recognized outcome, should therefore be more frequently considered.

Efficacy of first-line treatments for multiple myeloma patients not eligible for stem cell transplantation: a network meta-analysis.

Decision making for patients with multiple myeloma (MM) not transplant eligible (NTE) is complicated by a lack of head-to-head comparisons of standards of care, the increase in the choice of treatment modalities, and the promising results that are rapidly evolving from studies with novel regimens. To support evidence-based decision making, we performed a network meta-analysis for NTE MM patients that synthesizes direct and indirect evidence and enables a comparison of all treatments. Relevant randomized clinical trials were identified by a systematic literature review in EMBASE®, MEDLINE®, MEDLINE®-in-Process and the Cochrane Central Register of Controlled Trials for January 1999 to March 2016. Efficacy outcomes [i.e. the hazard ratio (HR) and 95% confidence interval (95%CI) for progression-free survival] were extracted and synthesized in a random effects network-meta analysis. In total, 24 studies were identified including 21 treatments. According to the network-meta analysis, the HR for progression-free survival was favorable for all NTE MM treatments compared to dexamethasone (HR: 0.19-0.90). Daratumumab-bortezomib-melphalan-prednisone and bortezomib-melphalan-prednisone-thalidomide with bortezomib-thalidomide maintenance were identified as the most effective treatments (HR: 0.19, 95%CI: 0.08-0.45 and HR: 0.22, 95%CI: 0.10-0.51, respectively). HR and 95%CI for currently recommended treatments, bortezomib-lenalidomide-dexamethasone, bortezomib-melphalan-prednisone, and lenalidomide-dexamethasone compared to dexamethasone, were 0.31 (0.16-0.59), 0.39 (0.20-0.75), and 0.44 (0.29-0.65), respectively. In addition to identifying the most effective treatment options, we illustrate the additional value and evidence of network meta-analysis in clinical practice. In the current treatment landscape, the results of network meta-analysis may support evidence-based decisions and ultimately help to optimize treatment and outcomes of NTE MM patients.

Cost-effectiveness of Novel Treatment Sequences for Transplant-Ineligible Patients With Multiple Myeloma.

Importance: Although the number of treatments for elderly patients with non-transplant-eligible (NTE) multiple myeloma (MM) has increased substantially, evidence is lacking on the clinical effectiveness and cost-effectiveness of novel treatment sequences. Objective: To determine the optimal sequence of treatment for patients with NTE MM from the perspective of the patient, physician, and society. Design, Setting, and Participants: Using data from a Dutch observational registry, this economic evaluation combined evidence from network meta-analyses in a patient-level simulation model and modeled time-to-event and types of events from a hospital perspective with a lifetime horizon. Data analysis was performed from June 2019 to September 2020. Interventions: Thirty treatment sequences, including up to 3 lines of therapy, were compared with bortezomib-melphalan-prednisone (VMP)-lenalidomide-dexamethasone (LenDex)-pomalidomide-dexamethasone (PomDex). Main Outcomes and Measures: The primary outcomes of the model were overall survival (OS), quality-adjusted life-years (QALYs), costs, and cost-effectiveness. Results: Sequences starting with daratumumab-VMP (second line: carfilzomib-lenalidomide-dexamethasone or elotuzumab-lenalidomide-dexamethasone) or bortezomib-melphalan-prednisone-thalidomide-maintenance bortezomib-thalidomide (VMPT-VT) (second line: daratumumab-lenalidomide-dexamethasone) had the largest expected OS (7.5 years), which is 3.5 additional life-years compared with VMP-LenDex-PomDex. Total costs per patient for these sequences ranged between $786 024 and $1 085 794. The sequence VMPT-VT-carfilzomib-lenalidomide-dexamethasone-panobinostat-bortezomib-dexamethasone had the most favorable cost-effectiveness ratio ($98 585 per life-year gained and $132 707 per QALY gained vs VMP-LenDex-PomDex). Conclusions and Relevance: These findings suggest that sequences including novel treatments were highly effective, but the cost-effectiveness ratios were above currently accepted willingness-to-pay thresholds. Treating MM with novel agents necessitates either a large increase in budget or a substantial reduction of drug costs by price negotiations, and these findings can support these reimbursement decisions and price negotiations.

Systematic Literature Review and Network Meta-Analysis of Treatment Outcomes in Relapsed and/or Refractory Multiple Myeloma.

Purpose Since 2000, many new treatment options have become available for relapsed and/or refractory multiple myeloma (R/R MM) after a long period in which dexamethasone and melphalan had been the standard treatment. Direct comparisons of these novel treatments, however, are lacking. This makes it extremely difficult to evaluate the relative added value of each new treatment. Our aim was to synthesize all efficacy evidence, enabling a comparison of all current treatments for R/R MM. Methods We performed a systematic literature review to identify all publicly available phase III randomized controlled trial evidence. We searched Embase, MEDLINE, MEDLINE In-Process, Cochrane Central Register of Controlled Clinical Trials, and the Web site www.ClinicalTrials.gov . In addition, two trials presented at two international hematology congresses (ie, ASCO 2016 and European Hematology Association 2016) were added to include the most recent evidence. In total, 17 randomized controlled trials were identified, including 18 treatment options. The evidence was synthesized using a conventional network meta-analysis. To include all treatments within one network, two treatment options were combined: (1) bortezomib monotherapy and bortezomib plus dexamethasone, and (2) thalidomide monotherapy and thalidomide plus dexamethasone. Results The combination of daratumumab, lenalidomide, and dexamethasone was identified as the best treatment. It was most favorable in terms of (1) hazard ratio for progression-free survival (0.13; 95% credible interval, 0.09 to 0.19), and (2) probability of being best (99% of the simulations). This treatment combination reduced the risk of progression or death by 87% versus dexamethasone, 81% versus bortezomib plus dexamethasone, and 63% versus lenalidomide plus dexamethasone. Conclusion Our network meta-analysis provides a complete overview of the relative efficacy of all available treatments for R/R MM. Until additional data from randomized studies are available, on the basis of this analysis, the combination of daratumumab, lenalidomide, and dexamethasone seems to be the best treatment option.