First-Line treatment for transplant-ineligible newly diagnosed multiple myeloma: a Bayesian network meta-analysis of efficacy, safety, and high-risk subgroups.

Anti-CD38 monoclonal antibody-based regimens have emerged as the first-line standard of care for transplant-ineligible newly diagnosed multiple myeloma (NDMM), yet direct head-to-head comparisons between individual regimens remain limited. The systematic review identified 11 eligible randomised controlled trials; 6 of these, involving 3162 patients, entered the Bayesian network meta-analysis to systematically evaluate the efficacy, safety, and benefits in the cytogenetically high-risk subgroup across 7 treatment nodes, keeping the dexamethasone-sparing IFM2017-03 schedule (D-R-limited dexamethasone) separate from continuous D-Rd. All four anti-CD38-containing regimens improved progression-free survival (PFS) relative to lenalidomide-dexamethasone, with D-VRd ranking highest (SUCRA 81.5%). For overall survival (OS), D-R-limited dexamethasone ranked highest (SUCRA 87.4%), but OS follow-up is considerably less mature for the quadruplet trials, and no pairwise comparison among the anti-CD38-containing regimens reached significance for either outcome. High-risk subgroup estimates could not rank regimens against one another, but both daratumumab-lenalidomide regimens retained a progression-free survival benefit relative to lenalidomide-dexamethasone. Regarding safety, several anti-CD38-containing regimens increased grade ≥3 neutropenia, whereas infection signals were regimen- and endpoint-specific. This study provides comprehensive evidence to inform individualized first-line treatment decisions for transplant-ineligible NDMM patients.