PF611 MULTIPLE DRUG COMBINATIONS FOR FIRST‐LINE TREATMENT IN TRANSPLANT‐INELIGIBLE MULTIPLE MYELOMA PATIENTS: A SYSTEMATIC REVIEW AND NETWORK META‐ANALYSIS
Authors: V. Piechotta, B. Scheckel, P. Langer, I. Monsef, C. Scheid, L.J. Estcourt, A. Adams, K. Kuhr, N. Skoetz
Journal: HemaSphere (2019)

Background: Multiple drug combinations have been studied in randomized controlled trials (RCT) and are currently recommended for first‐line treatment of transplant‐ineligible multiple myeloma patients. However, direct head‐to‐head comparisons are rare, which allow statements on the relative importance of the different combinations. Aims: The aim of this study was to compare different agent‐combinations for first‐line myeloma therapy for transplant‐ineligible patients to rank treatments according to efficacy and safety. Methods: MEDLINE, CENTRAL, study registries and conference proceedings were systematically searched for RCTs including newly diagnosed multiple myeloma patients in non‐transplant settings (search date 02/2019). Outcomes of interest were overall survival, progression‐free survival, grade 3 and 4 adverse events, serious adverse events, and quality of life. Methodological quality of studies was assessed with the Cochrane Risk of Bias Tool. The GRADE approach was used to rate the certainty of the evidence. Studies were selected, extracted, and evaluated in duplicate. Treatment effects are given as hazard ratios (HR) and risk ratios (RR), respectively with corresponding 95% confidence intervals (CI). A HR/RR &lt;1 indicates an advantage for the intervention. For network meta‐analyses, we used the frequentist graph‐theoretical approach. Melphalan and prednisone was used as main comparator. Results: We included 30 studies comprising 13,884 patients and 19 treatment regimens. Overall risk of bias was generally high across studies due to the open‐label study design. The certainty of evidence in survival outcomes was low to moderate for pre‐selected comparisons. A clinically meaningful improvement in overall survival was shown for VTMP (HR: 0.48 [95% CI: 0.26–0.88]), and VRD (HR: 0.54 [95% CI: 0.32–0.91]) compared to MP, respectively (figure 1). The certainty of the evidence was low for VTMP and VRD, due to high heterogeneity within the network and large confidence intervals. The highest benefit on progression‐free survival was shown for Dara‐VMP (HR: 0.27 [95% CI: 0.15–0.47]), VTMP (HR: 0.31 [95% CI: 0.18–0.53]), and Dara‐RD (HR: 0.36 [95% CI: 0.22–0.60]) compared to MP, respectively. Overall, drug combinations consisting of two or more novel agents, showed a large benefit on progression‐free survival compared to MP. The certainty of the evidence was moderate for Dara‐VMP, VTMP, and Dara‐RD, due to high risk of bias. Assessment and reporting of adverse events and quality of life differed between studies. No discernible trend favored any treatment‐combination. The risk for polyneuropathies is lower for patients receiving lenalidomide‐ and thalidomide‐based therapies compared to bortezomib‐based therapies (RR: 0.00 [95% CI: 0.00–0.09] to 0.05 [95% CI: 0.00–0.95]). Network estimates showed a significantly lower thrombocytopenia ‐risk for all treatment‐combinations, except ERD and SVMP, than for MPR (RR: 0.04 [95% CI: 0.01–0.18] to 0.45 [95% CI: 0.24–0.82]). Summary/Conclusion: This is the first network meta‐analysis comparing all RCT‐tested novel agent combinations for the treatment of newly diagnosed transplant‐ineligible multiple myeloma patients. VTMP shows the highest benefit on overall survival and high benefit on progression‐free survival. Dara‐VMP and Dara‐RD show similar large benefits on PFS. These results may best be confirmed by additional direct comparisons of multiple drug combinations. Further trials should focus on consistent reporting of safety outcomes and should use a standardized instrument to evaluate quality of life to ensure comparability of treatment‐combinations. image