B-cell Maturation Antigen-directed Therapies versus Standard Regimens in Lenalidomide-refractory Relapsed or Refractory Multiple Myeloma After 1-3 Prior Lines: A Systematic Review and Network Meta-analysis of Phase 3 Trials

The therapeutic landscape for relapsed or refractory multiple myeloma (RRMM) has evolved with the introduction of B-cell maturation antigen (BCMA)-directed agents and novel triplet combinations; however, robust comparative evidence in lenalidomide-refractory patients with early relapse remains limited. We conducted a systematic review and network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs) comparing BCMA-targeted therapies with standard regimens in adults with RRMM after 1-3 prior lines. MEDLINE, Embase, CENTRAL, and Web of Science were searched from inception through December 2025. The primary endpoint was progression-free survival (PFS), which was quantitatively synthesized using NMA; overall survival (OS), minimal residual disease (MRD) negativity, and grade ≥3 adverse events were summarized descriptively. Ten phase 3 RCTs met the inclusion criteria. Experimental regimens consistently improved PFS compared with control arms, with hazard ratios ranging from 0.31 to 0.70 across trials. Within the connected network, anti-CD38-based triplets demonstrated the most favorable PFS estimates. Although BCMA-directed therapies showed superior efficacy in direct comparisons, including deeper responses and higher MRD negativity rates, limited network connectivity precluded robust indirect comparisons across therapeutic classes. OS data were heterogeneous and frequently immature, and safety outcomes were not quantitatively synthesized. Multiple therapeutic strategies improve PFS in lenalidomide-refractory RRMM during early relapse. Anti-CD38-based triplets remain a cornerstone of care, while BCMA-directed therapies represent a promising alternative. However, structural limitations of the evidence network warrant cautious interpretation.