Impact of extramedullary plasmacytoma on outcomes in patients with relapsed refractory multiple myeloma treated with talquetamab: U.S. Myeloma Immunotherapy Consortium.

Talquetamab, a GPRC5D-targeting bispecific antibody, shows promising activity in relapsed-refractory multiple myeloma. However, real-world outcomes in patients with extramedullary disease (EMD) remain poorly described. We studied 360 patients treated with talquetamab at 15 U.S. centers by Dec 2024. Soft tissue plasmacytomas (STP) were classified as EMD (not contiguous with bone) or paraskeletal disease (PSD; contiguous with bone). If both were present, patients were assigned to the EMD category. Of those, 97 (27%) had EMD, 22 (6%) had PSD, and 241 (67%) had No-STP. Median follow-up was 12.8 months. Overall response rates were 68% in EMD, 63% in PSD, and 65% in No-STP (p = 0.8). Median progression-free survival was 4.3, 4.5, and 7.8 months, respectively (p = 0.009), and median overall survival was 10.3 months, 13.0 months, and not reached (p = 0.070). These findings demonstrate that EMD and PSD are associated with preserved response rates but shorter PFS and OS with talquetamab. While systemic markers of tumor burden and inflammation-particularly lactate dehydrogenase (LDH) and ferritin-emerged as independent predictors of inferior PFS, elevated LDH also retained independent prognostic significance for OS. While EMD was associated with shorter PFS and OS on univariate analysis, it did not retain independent prognostic significance on multivariable analysis, suggesting that inferior outcomes are driven by aggressive disease biology rather than by lesion anatomy alone. These findings are hypothesis-generating and require prospective validation. Talquetamab retains clinical utility in this high-risk population with EMD, though outcomes are suboptimal with a need for further refinement of treatment approaches.