Talquetamab: Mechanism of Action, Clinical, and Translational Science

Talquetamab is a first-in-class, T-cell-redirecting bispecific antibody targeting GPRC5D, a novel antigen highly expressed on malignant plasma cells with limited expression in normal tissues. Despite advances in treatment, multiple myeloma (MM) remains incurable, and talquetamab offers a promising therapeutic option for patients with relapsed/refractory MM. By binding to both GPRC5D on myeloma cells and CD3 on T cells, talquetamab induces T-cell activation and subsequent lysis of GPRC5D-expressing cells. The recommended subcutaneous (SC) dosing regimens of talquetamab monotherapy 0.4 mg/kg QW (preceded by step-up doses of 0.01 and 0.06 mg/kg) or 0.8 mg/kg Q2W (preceded by step-up doses of 0.01, 0.06, and 0.4 mg/kg) were selected based on the totality of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Exposure-response analyses for efficacy and safety further supported the dose selection. In clinical studies, talquetamab demonstrated robust and durable responses in heavily pretreated RRMM patients, with a favorable benefit-risk profile. Common adverse events included cytokine release syndrome, hematologic toxicities, oral adverse events (dysgeusia etc.), and infections, with hematological toxicities being the most common grade 3-4 events. During talquetamab treatment, 35.8% (130/363) of participants developed anti-drug antibodies, including 18.2% (66/363) with neutralizing antibodies, across both recommended doses, and no clinically meaningful impact of immunogenicity on talquetamab pharmacokinetics, efficacy, or safety was observed. Talquetamab has received accelerated approval (US) and conditional marketing authorization (EU) with further ongoing investigation as monotherapy or in combination regimens across various MM treatment settings.