Recommended Phase II Doses of Talquetamab in Patients With Relapsed/Refractory Multiple Myeloma From MonumenTAL‐1: Clinical Pharmacology Results

Talquetamab is the first and only GPRC5D × CD3 bispecific antibody approved for relapsed/refractory multiple myeloma (RRMM). In the phase I/II MonumenTAL-1 study, overall response rates (ORRs) were > 66% in patients with RRMM treated with subcutaneous talquetamab at the recommended phase II doses (RP2Ds): 0.4 mg/kg weekly and 0.8 mg/kg every other week. We characterized the pharmacokinetics (PK), pharmacodynamics, immunogenicity, and exposure-response relationships for efficacy and safety following talquetamab administration in phase I and II. In phase I, talquetamab exposure increased in an approximately dose-proportional manner across intravenous and subcutaneous doses and was maintained around or above the 90% maximum effective concentration identified in an ex vivo cytotoxic assay at the RP2Ds. Higher levels of T-cell activation and cytokine induction were observed at the RP2Ds compared with lower doses. Talquetamab demonstrated time-dependent clearance with a half-life of 7.56 days at initial treatment and 12.2 days at steady state. Patients with immunoglobulin G multiple myeloma and International Staging System (ISS) stage II/III exhibited higher clearance of talquetamab, which resulted in lower exposure. Dose adjustment based on myeloma subtype and ISS stage was not required. In exposure-response analyses, a near-flat relationship was demonstrated for ORR, duration of response, and progression-free survival at the exposure range of the RP2Ds. In safety exposure-response analyses, rates of grade 1/2 dysgeusia increased with higher exposures. The incidence of anti-talquetamab antibodies had no apparent impact on the PK, efficacy, or safety of talquetamab. These clinical pharmacology results support the selection of the talquetamab RP2Ds.