Highlight
- Talquetamab, a bispecific antibody targeting GPRC5D, combined with daratumumab, shows enhanced efficacy in relapsed/refractory multiple myeloma (RRMM).
- The phase 1b TRIMM-2 trial reported overall response rates of up to 82.4% with manageable safety in heavily pretreated patients.
- Median progression-free survival exceeded 20 months, indicating durable disease control.
- The combination leverages daratumumab’s immunomodulatory effects to create an environment conducive to talquetamab activity.
Study Background and Disease Burden
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells primarily within the bone marrow. Despite advances in therapy including proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies such as daratumumab, a substantial subset of patients eventually develops relapsed or refractory disease. Triple-class refractory MM, resistant to proteasome inhibitors, IMiDs, and anti-CD38 antibodies, poses a significant unmet clinical need given limited treatment options and poor prognosis. Emerging immunotherapies targeting novel antigens have generated interest in improving outcomes in this heavily pretreated population. Talquetamab is a bispecific antibody directed against GPRC5D, a novel target overexpressed on malignant plasma cells but with limited expression on normal tissue, thus providing a promising therapeutic avenue. The combination of talquetamab with daratumumab, an anti-CD38 monoclonal antibody with known immunomodulatory effects, has the potential to induce deeper and more durable responses through complementary mechanisms of action.
Study Design
The TRIMM-2 study (ClinicalTrials.gov ID: NCT04108195) is a phase 1b open-label trial evaluating the safety, efficacy, and pharmacodynamics of talquetamab in combination with daratumumab in patients with relapsed/refractory multiple myeloma. Eligible patients had received at least three prior lines of therapy or were double refractory to a proteasome inhibitor and an IMiD. Of note, 61.5% were triple-class refractory while 24.6% had prior bispecific antibody exposure. Participants were assigned to two cohorts based on dosing schedule: weekly subcutaneous talquetamab 0.4 mg/kg (QW cohort) or every other week at 0.8 mg/kg (Q2W cohort), both combined with daratumumab 1800 mg per approved administration schedule. The primary endpoint was safety, while secondary endpoints included overall response rate (ORR) and duration of response (DoR). Progression-free survival (PFS) was designated as an exploratory endpoint. Median follow-up duration was 18.6 months.
Key Findings
A total of 65 patients were treated (QW, n=14; Q2W, n=51) with a median of five prior therapy lines, reflecting a heavily pretreated cohort. Among safety outcomes, the most common adverse events were oral and skin-related events, cytokine release syndrome (CRS), and infections. Grade 3 or 4 adverse events were observed in 81.5% of patients, including dose-limiting toxicities in two individuals in the Q2W cohort (grade 3 stomatitis/oral mucositis and maculopapular rash). Importantly, no new safety signals beyond the known profiles of each monotherapy agent emerged.
Efficacy outcomes demonstrated promising activity: ORR was 71.4% in the weekly cohort and 82.4% in the biweekly cohort. Median PFS was 23.3 months (QW) and 21.2 months (Q2W), indicating durable disease control in a challenging population. Although the study was not powered for direct comparison between cohorts, this suggests flexibility in dosing regimens without compromising efficacy.
Pharmacodynamic analyses suggested that daratumumab’s immunomodulatory action—especially its ability to reduce immunosuppressive cell populations such as regulatory T cells—creates a microenvironment conducive to effective talquetamab engagement of malignant plasma cells. This mechanistic synergy may explain the enhanced therapeutic benefit observed with this combination.
Expert Commentary
The TRIMM-2 study provides compelling early clinical evidence supporting the combination of talquetamab and daratumumab in relapsed/refractory multiple myeloma. The durable responses and overall tolerability observed are encouraging, especially given the challenging nature of this patient population, many of whom have exhausted standard therapies. The bispecific antibody talquetamab targets a novel antigen, GPRC5D, distinct from traditional targets, addressing an important resistance mechanism.
Combination with daratumumab may potentiate anti-myeloma immunity not only by direct cytotoxic effects but also by modulating the suppressive tumor microenvironment. This highlights a trend in multiple myeloma treatment toward rational combinations of immunotherapies that harness multiple facets of immune engagement.
However, limitations include the relatively small sample size and the non-randomized, phase 1b design, which precludes definitive efficacy comparisons. Longer follow-up and randomized studies will be required to confirm these findings and define optimal dosing schedules. Additionally, attention to managing oral and skin toxicities will be crucial in clinical practice.
Conclusion
Talquetamab plus daratumumab presents a promising new combination immunotherapy for patients with relapsed/refractory multiple myeloma, including those with triple-class refractory disease. The TRIMM-2 trial results demonstrate a favorable balance between efficacy and safety, with durable responses exceeding 20 months of median progression-free survival. These findings support further development of this regimen in larger randomized studies to establish its role in the evolving therapeutic landscape of multiple myeloma.
Funding and ClinicalTrials.gov
The TRIMM-2 trial was conducted with support as detailed in the original publication. The study is registered under ClinicalTrials.gov identifier NCT04108195.
References
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. 2025 Sep 22:blood.2025029360. doi: 10.1182/blood.2025029360. Epub ahead of print. PMID: 40983036.