Background: Talquetamab (Tal), a GPRC5D-targeting bispecific antibody, has emerged as a promising therapy for heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), including those with triple-class refractory disease. In the MonumenTAL-1 trial, Tal demonstrated an overall response rate of 73%, with high efficacy even in triple-class exposed patients. However, real-world data on survival outcomes and treatment-related toxicities remain limited. This study aimed to evaluate real-world outcomes using the TriNetX global health research network.

Methods: We conducted a retrospective study of RRMM patients treated with Talquetamab between database inception and June 2025 using TriNetX. This analysis utilized TriNetX data from 176M patients across 152 healthcare organizations, predominantly academic centers in the U.S. Inclusion criteria included confirmed RRMM diagnosis, documented Tal exposure, and a minimum 30-day follow-up. Outcomes included 6-month overall survival (OS), hematologic toxicities, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Adverse events were graded per CTCAE v5.0. Kaplan-Meier analysis was used to estimate OS; other outcomes were reported as proportions.

Results: A total of 426 RRMM patients treated with Tal were included, with a mean age of 65.6 years (±9); 55.7% were male and 66.0% were White. Treatment patterns reflected a triple-class refractory population, with high prior exposure to proteasome inhibitors (bortezomib 52%, carfilzomib 48%), IMiDs (lenalidomide 66%, pomalidomide 63%), and anti-CD38 antibodies (daratumumab 51%). Additionally, 35% had received CAR T-cell therapy, 39% underwent ASCT, 24% were treated with Teclistamab, and extramedullary disease and plasma cell leukemia were reported in 11% and 13% of patients, respectively.

At 6 months, the all-cause mortality rate was 17.2%, with a Kaplan-Meier estimated OS of 82.8% (95% CI: 79.1–86.5%), comparable to MonumenTAL-1 trial findings. Median overall survival was not reached at 6-month follow-up. Grade ≥3 CRS and ICANS occurred in <10 patients each (2.4%), and 24% received tocilizumab for CRS. Hematologic toxicities were frequent: grade ≥3 neutropenia (45.1%), anemia (45.3%), and thrombocytopenia (38.9%). CMV reactivation occurred in 5%. Non-hematologic toxicities were lower than in clinical trials: skin rash (12%), dysgeusia/anosmia (21%), and nail disorders (5%), likely due to underreporting of mild adverse events in structured real-world data compared to the rigorous monitoring of clinical trials.

Conclusion: In this large, real-world cohort, Talquetamab demonstrated favorable short-term survival and a manageable safety profile, consistent with clinical trial data. The higher mortality observed may reflect the heavily pretreated, triple-class refractory population with advanced disease features and comorbidities often seen in real-world settings. Hematologic toxicities remained significant, while lower observed rates of non-hematologic side effects likely reflect differences in documentation practices. These findings support Talquetamab's integration into RRMM treatment strategies with attention to toxicity monitoring in routine practice.

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2025
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