Relative Efficacy of Treatment Options in Newly Diagnosed Multiple Myeloma: Results from a Systematic Literature Review and Network Meta-Analysis
Authors: Ramasamy Karthik , Thom Howard , D'Souza Vijay K. , Buchanan Vanessa , Dhanasiri Sujith 
Published: October 2019

Abstract
Background: For patients with newly diagnosed multiple myeloma (NDMM), the combination of lenalidomide and dexamethasone (Rd) provides for an oral, melphalan-free approach to treatment. Although the treatment practices for these patients have been rapidly evolving, the goal to gain and maintain as deep a response as possible still remains. Autologous stem cell transplantation (ASCT) has been proven to be beneficial for NDMM patients, irrespective of age (Pawlyn C, et al. HemaSphere 2018;2:S106); however, many NDMM patients are not selected for ASCT due to poor fitness; ASCT may also be delayed due to availability of effective first-line therapy options. For these patients, current standard first-line therapeutic options include lenalidomide and bortezomib, although thalidomide is still used in some countries. Recently, many studies have aimed to assess the benefits of new therapeutic options, including triplet therapy with Rd and bortezomib (RVd) (Durie BG, et al. Lancet. 2017;389:519-27), and daratumumab in combination with bortezomib, melphalan, and prednisone (VMP+D) (Mateos MV, et al. N Engl J Med. 2018;378:518-28).
The aim of this study was to estimate the relative treatment effects on progression-free survival (PFS) and overall survival (OS) in patients with NDMM not intended for ASCT and/or aged &gt; 65 years, using a systematic literature review (SLR) and network meta-analysis (NMA) of randomized controlled trials (RCTs), including emerging therapies.
Methods: According to predefined study selection criteria and literature search strategies, relevant studies were identified from MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases as well as the conference proceedings of the European Society for Medical Oncology, American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, International Multiple Myeloma Workshop, and International Society for Pharmacoeconomics and Outcomes Research. Only regimens commonly used in clinical practice were included, with a dosing schedule in line with the respective regimens' Summary of Product Characteristics (SmPC) for licensed treatments.
A Bayesian fixed-effect NMA was conducted on hazard ratios (HRs) for PFS and OS to determine the comparative efficacy of treatments. NMA allows estimation of the relative treatment effects for all pairs of interventions, even for those without head-to-head comparison data from clinical trials. This is possible as long as they are included in a connected network of comparisons. Results are presented as mean HRs for PFS and OS with their credible intervals (CrIs), where an HR &lt; 1 indicates a beneficial effect. Where HR data were unavailable, it was estimated from median or probability of survival outcomes assuming an exponential distribution. Analyses were carried out on an intention-to-treat basis.
Results: The systematic literature review yielded 39 publications describing 23 RCTs. We adopted a conservative approach to constructing the evidence network and excluded trials on the basis of relevance to clinical practice and/or adherence to the SmPC. This resulted in 7 trials representing 6 regimens being included in the NMA (ALCYONE, VISTA, IFM 01/01, IFM 99-06, MM-03, FIRST, and SWOG S0777), of which 6 had data available for OS.
Compared with Rd, only RVd significantly improved PFS (HR 0.72; 95% CrI 0.56, 0.9) (Figure 1A). For OS, RVd was the only therapy to show statistically significant superiority over Rd (HR 0.72, 95% CrI 0.52, 0.96) (Figure 1B). Results for PFS and OS of VMP+D versus Rd were inconclusive.
A limitation of this analysis was that a small number of patients in the SWOG S0777 (Durie BG, et al. Lancet. 2017;389:519-27) trial, which examined the effect of RVd versus Rd, received ASCT, although transplantation had not been planned a priori. Future research could consider sensitivity analysis through matching adjusted indirect comparison, adjusting for this and other differences across the included studies.
Conclusions: This analysis confirms Rd to be superior to other licensed treatments currently available, in terms of both PFS and OS. Of emerging treatment options, based on current published evidence, only RVd significantly extends PFS and OS.

Disclosures
Ramasamy: Celgene Corp.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thom:Celgene Corp.: Consultancy. Dhanasiri:Celgene International: Employment, Equity Ownership.