Beyond dual targeting: redefining the treatment horizon for true extramedullary myeloma? – a critical appraisal

The management of relapsed/refractory multiple myeloma with true extramedullary disease (EMD) remains a critical challenge. The phase 2 RedirecTT-1 study evaluated the combination of two bispecific antibodies, talquetamab (anti-GPRC5D) and teclistamab (anti-BCMA), in this high-risk population. While the reported overall response rate of 79% and 12-month progression-free survival of 61% are promising, a balanced interpretation requires caution. The single-arm design, short follow-up (12.6 months), and indirect comparisons with CAR-T therapy preclude definitive conclusions about comparative effectiveness. Notably, grade 3-4 infections occurred in 31% of patients, with five treatment-related deaths - a toxicity burden that may limit real-world implementation outside specialized centers. Responses were observed after prior BCMA-directed CAR-T therapy, but heterogeneity within this subgroup (time from CAR-T to progression ranging from 98 to 1030 days) tempers enthusiasm for universal sequencing strategies. Key unresolved questions include optimal sequencing with CAR-T, mechanisms of resistance, predictive biomarkers, and the feasibility of delivering this intensive regimen in routine practice. This commentary argues that dual bispecific therapy is a potent but still investigational option for EMD, and its definitive positioning requires randomized data and head-to-head comparisons.