Talquetamab Combo Yields High Responses in Heavily Pretreated Myeloma

The combination of talquetamab (Talvey) and daratumumab (Darzalex) demonstrated promising and robust clinical activity for the treatment of patients with heavily pretreated, relapsed/refractory multiple myeloma, according to data from the phase 1b TRIMM-2 study (NCT04108195).¹

At the recommended phase 2 dose of 0.8 mg/kg of talquetamab plus 1800 mg of daratumumab every 2 weeks, the overall response rate (ORR) was 82.4%, with 57% of patients achieving a complete response or better and 73% achieving a very good partial response or better. The median progression-free survival (PFS) was 21.2 months.

About the TRIMM-2 Study

TRIMM-2 is an ongoing, open-label, multicohort study designed to investigate antimyeloma combination regimens. This analysis focuses on the cohorts receiving talquetamab plus daratumumab for relapsed/refractory multiple myeloma.

Talquetamab is a GPRC5D × CD3–targeting bispecific antibody that redirects T cells to myeloma cells, which have limited GPRC5D expression on normal hematopoietic cells. Daratumumab is an established anti-CD38 monoclonal antibody with both direct on-tumor and immunomodulatory effects. This combination aims to leverage daratumumab's ability to deplete CD38-expressing regulatory T cells, thereby reducing immunosuppression and possibly potentiating the T-cell–mediated apoptosis induced by talquetamab. Preclinical data showed that daratumumab enhanced talquetamab-mediated lysis of myeloma cells.

The study comprised 2 cohorts: cohort 1 received talquetamab at 0.4 mg/kg weekly (n = 14), and cohort 2 received 0.8 mg/kg every 2 weeks (n = 51).^1,2 The primary end point was safety, including the assessment of dose-limiting toxicities. Secondary end points included ORR, duration of response (DOR), time to response, and pharmacodynamics. PFS was an exploratory end point.

The study enrolled a total of 65 patients who were heavily pretreated and had advanced disease. These patients had received a median of 5 prior lines of therapy over a median of 6.6 years since their initial diagnosis.¹

Additional Efficacy Results

The responses achieved were durable, and survival outcomes were promising for this advanced patient population.

At 12 months, the DOR rate was 100% in the once-weekly cohort and 71% in the every 2 weeks cohort. The ORR was lower in the once-weekly cohort at 71.4%, but the median PFS was 23.3 months. Median overall survival was not met in either cohort.

“Switching to a less frequent dosing schedule maintained responses, consistent with talquetamab monotherapy, supporting flexible dosing after achieving a response,” Chari et al wrote.

The treatment combination was effective across multiple clinically relevant subgroups, including patients who had already received other advanced T-cell–redirecting therapies.

• Anti-CD38–naive/sensitive: ORR, 92% (n = 12/13); median PFS, not reached
• Anti-CD38–refractory: ORR, 77% (n = 40/52); median PFS, 18.1 months
• Prior T-cell redirection therapy: ORR, 77% (n = 20/26)
• Prior bispecific antibody: ORR, 75% (n = 12/16); median PFS, 15.0 months
• Prior chimeric antigen receptor T-cell therapy: 82% (n = 9/11); median PFS, not reached

Responses were lower in patients who were pentadrug refractory, had extramedullary plasmacytomas, or had high-risk cytogenetics, although the number of patients in these subgroups was small.

Safety and Tolerability Profile

The safety profile was consistent with the known toxicities of each drug individually, and there was no evidence of overlapping or new safety concerns. Grade 3/4 adverse events occurred in 81.5% of patients. Discontinuations due to adverse events were low, at 9%.

All cytokine release syndrome (CRS) events were grade 1 or 2. They were mostly confined to the initial step-up and first full doses and resolved completely. Tocilizumab was administered to 43% of patients for CRS.

GPRC5D-related events, including oral adverse events (eg, dysgeusia, dry mouth), skin events (eg, rash, dry skin), and nail events, were very common but predominantly low grade. These were manageable and infrequently led to treatment discontinuation.

Infections occurred in 71% of patients, with grade 3/4 infections in 29%. This rate is considered modest compared with that of BCMA-targeting bispecific antibodies. Only 1 patient had a grade 3 or greater opportunistic infection.

Immune effector cell–associated neurotoxicity syndrome (ICANS) was rare, occurring in 5% of patients. All events were grade 1 or 2 and resolved within 1 to 2 days.

These findings support the continued investigation of this combination. The ongoing phase 3 MonumenTAL-3 trial (NCT05455320) is designed to further assess this regimen in patients with at least 1 prior line of therapy.

REFERENCES

1. Chari A, van de Donk NWCJ, Dholaria B, et al. Talquetamab plus daratumumab for the treatment of relapsed or refractory multiple myeloma in the TRIMM-2 study. Blood. Published online September 22, 2025. doi:10.1182/blood.2025029360

2. A study of subcutaneous daratumumab regimens in combination with bispecific T cell redirection antibodies for the treatment of participants with multiple myeloma. ClinicalTrials.gov. Updated November 7, 2025. Accessed November 5, 2025. https://clinicaltrials.gov/study/NCT04108195