Talquetamab Shows Durable Responses in R/R MM at 3-Year Follow-Up

Talquetamab (Talvey) continued to produce high rates of deep, durable responses and promising overall survival (OS) in patients with relapsed/refractory multiple myeloma (R/R MM), according to a 3-year follow-up analysis published in Blood.¹

Findings come from the phase 1/2 MonumenTAL-1 trial (NCT03399799; NCT04634552), which evaluated the GPRC5D-directed bispecific antibody in 3 cohorts: patients naive to T-cell redirection therapy (TCR) who received talquetamab 0.4 mg/kg subcutaneously (SC) weekly (QW; n = 143) or 0.8 mg/kg SC every other week (Q2W; n = 154), and a separate cohort with prior TCR exposure who received either dose (n = 78). At a median follow-up of 38.2, 31.2, and 30.3 months, median progression-free survival (PFS) was 7.5 months (95% CI, 5.7-9.4), 11.2 months (95% CI, 7.7-14.6), and 7.7 months (95% CI, 4.1-14.5), in the respective QW, Q2W, and prior TCR cohorts.

Additional Efficacy Findings

The overall response rate (ORR), which previously supported the accelerated approval of talquetamab, was 74.1% in the QW cohort, 69.5% in the Q2W cohort, and 66.7% in the prior TCR cohort, with a complete response (CR) or better achieved by 32.9%, 40.3%, and 42.3% of patients, respectively.

Responses were deep and durable across cohorts. Median duration of response (DOR) was 9.5 months (95% CI, 6.7-13.4) in the QW cohort, 17.5 months (95% CI, 12.5-25.1) in the Q2W cohort, and 19.2 months (95% CI, 8.1-24.7) in the prior TCR cohort.

Median OS was 34.0 months (95% CI, 25.6-not estimable [NE]) in the QW cohort and was not reached in the Q2W cohort; 36-month OS rates were 49.3% (95% CI, 40.4-57.6) and 60.8% (95% CI, 51.5-68.8), respectively. In the prior TCR cohort, median OS was 28.3 months (95% CI, 19.5-NE), with a 36-month OS rate of 44.6% (95% CI, 31.4-57.0). Minimal residual disease negativity at a threshold of 10^-5 was achieved in 64.3%, 65.2%, and 57.1% of evaluable patients in the QW, Q2W, and prior TCR cohorts, respectively.

Outcomes by Prior T-Cell Redirection Therapy

Among patients with prior TCR exposure, outcomes trended more favorable for those who had received prior chimeric antigen receptor (CAR) T-cell therapy compared with prior bispecific antibody therapy, though the study authors cautioned that patient numbers were small. The ORR was 71.9% and median DOR was 19.2 in patients with prior CAR T-cell therapy, whereas the ORR was 57.7% and DOR was 8.1 months with prior bispecific antibody exposure, with a median PFS of 12.3 vs 4.1 months, respectively.

Safety Findings

The safety profile remained consistent with earlier reports, with no new discontinuations attributed to talquetamab-related adverse events (AEs) leading to death. The most common AEs across the 3 cohorts were cytokine release syndrome (CRS; 73.1%-79.0%; grade 3 or 4, 0.6%-2.1%), taste changes (72.0%-75.6%), and infections (60.8%-78.2%; grade 3 or 4, 20.1%-25.6%). Rates of dose reduction (10.4%-15.4%) and discontinuation (5.1%-9.7%) due to treatment-emergent AEs remained low.

Ataxia/balance disorders, a neurologic safety signal associated with GPRC5D-targeting therapies,² occurred in 5.3% of patients overall (4.8% grade 1 or 2, 0.5% grade 3), with no grade 4 or 5 events reported; these led to discontinuation in a single patient. The study authors noted that talquetamab continued to show lower rates of high-grade infections (21%-26%) relative to published rates for approved B-cell maturation antigen (BCMA)–targeting bispecific antibodies.¹

Study Design

MonumenTAL-1 enrolled patients with multiple myeloma measurable per International Myeloma Working Group criteria who had received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. Prior exposure to TCR therapy was permitted following a 3-month washout period and was evaluated in a dedicated cohort; among these patients, 73% had received prior CAR T-cell therapy, 33% had received a prior bispecific antibody, and 6% had received both. The primary end point was ORR by independent committee review per 2016 International Myeloma Working Group criteria; secondary end points included DOR, PFS, OS, minimal residual disease negativity, and AE incidence, with a data cutoff of September 2024.

Clinical Implications

Limitations cited by the authors include the trial’s single-arm design and the low proportion of Black patients enrolled relative to the broader R/R MM population.

The study authors concluded that the 0.8 mg/kg Q2W dosing schedule continued to outperform QW dosing across efficacy measures, supporting its use as the starting schedule in ongoing phase 3 trials of talquetamab. They further noted that talquetamab’s favorable infection profile, attributed to limited GPRC5D expression on normal B cells and plasma cells relative to BCMA, may help preserve patient fitness for subsequent antimyeloma therapies and support its use in combination regimens, several of which are currently in development.

REFERENCES

1. Rasche L, Schinke C, Touzeau C, et al. Talquetamab in patients with relapsed/refractory multiple myeloma: 3-year follow-up of the phase 1/2 MonumenTAL-1 study. Blood. Published online 2026. doi:10.1182/blood.2025031994

2. Pan D, Kumar A, Lipof JJ, et al. Emerging GPRC5D-targeted therapies for multiple myeloma: a comprehensive review. Expert Opin Investig Drugs. 2025;34(5):379-389. doi:10.1080/13543784.2025.2511179