Efficacy of Bispecific Antibodies in Relapsed or Refractory Multiple Myeloma With Extramedullary Disease: A Systematic Review and Meta-Analysis.

Extramedullary disease (EMD) in multiple myeloma refers to soft-tissue plasmacytomas that spread hematogenously and grow independently of bone, an aggressive phenotype that has been associated with poorer responses and shorter survival across successive treatment eras. Bispecific antibodies are highly active in relapsed or refractory multiple myeloma (RRMM), but their efficacy in patients with baseline EMD has not been quantitatively synthesized. We performed a systematic review and meta-analysis, reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance, of prospective trials of B-cell maturation antigen (BCMA)- or G protein-coupled receptor class C group 5 member D (GPRC5D)-directed CD3 bispecific antibodies in RRMM that reported the objective response rate (ORR) in patients with baseline EMD. One estimate per trial was included; proportions were pooled using a random-effects model on the logit scale with restricted maximum-likelihood estimation of between-study variance, and heterogeneity was assessed with the Cochran Q test and the I-squared statistic; fixed-effect and leave-one-out sensitivity analyses were performed, and risk of bias was appraised for each EMD subgroup. Four prospective studies comprising 144 patients with baseline EMD were included. Study-level ORRs were 58.3% for teclistamab, 38.5% for elranatamab, 52.6% for linvoseltamab, and 44.6% for talquetamab when recommended phase 2 dose cohorts were combined. The random-effects pooled ORR was 45.2% (95% CI, 37.2-53.4), with no observed between-study heterogeneity (I-squared = 0%); estimates were identical under a fixed-effect model, and leave-one-out pooled ORRs ranged narrowly from 44.0% to 47.6%. BCMA- and GPRC5D-directed bispecific antibodies produce objective responses in approximately half of patients with RRMM and baseline EMD, with broadly similar activity across agents despite high-risk biology, although the small number of trials and their differing, sometimes paramedullary-inclusive, definitions of EMD warrant caution in interpreting this estimate. These pooled estimates provide a benchmark for patient counseling and trial design and support combination strategies to improve outcomes in this population.