GPRC5D, an orphan G protein–coupled receptor, has been identified in bone marrow cells in patients with multiple myeloma (MM). Talquetamab, a first-in-class bispecific antibody (monoclonal antibody that can simultaneously bind to 2 different types of antigen), binds to both GPRC5D on MM cells and CD3 on T-lymphocytes to induce immunologically mediated killing of MM cells. The initial results from an ongoing phase 1 dose-escalation study are presented here.
Patients were eligible for this study if they had measurable MM that either progressed or for which other established therapies were not viable. The primary objectives were to assess the safety of talquetamab and to identify a dose for phase 2 investigation. Secondary objectives were to assess the preliminary efficacy, pharmacokinetics, and pharmacodynamics. Escalating doses of talquetamab (both intravenous [IV] and subcutaneous [SC]) ± step-up doses were assessed.
The median age was 64 years, and 30% of patients were aged ≥70 years. Patients received IV talquetamab (0.5-180 μg/kg; n = 102) or SC talquetamab (5-800 μg/kg; n = 55). Twenty-two percent of patients had ISS stage 3 disease upon entering the study. Patients had received a median of 6 prior therapies. The majority of patients in the trial were refractory to prior therapies; 87% were refractory to the last line of therapy received and 82% were triple-class refractory. Twenty-seven percent of patients (n = 17) had received B-cell maturation antigen–directed therapy.
Anemia, cytokine release syndrome (CRS), neutropenia, and lymphopenia were the most frequent all-grade adverse events (AEs), occurring in 48%, 54%, 47%, and 40% of patients, respectively. The most common grade 3/4 AEs were lymphopenia, anemia, and neutropenia, occurring in 36%, 27%, and 31% of patients, respectively. Most CRS AEs were grade 1/2, with the exception of 5 patients in the IV group (grade 3). CRS generally occurred in the first cycle and appeared within 1 to 2 days of dosing. Six percent of patients (n = 9) experienced treatment-related neurotoxicity. Thirty-eight percent of patients experienced infections (8%), which were grade 3/4. Infusion-related reactions and injection-site reactions were experienced by <20% of patients and were grade 1/2. Dose-limiting toxicities were observed in 3 patients: clinically asymptomatic grade 4 increased lipase in the setting of a pancreatic plasmacytoma with 7.5 μg/kg IV talquetamab, and grade 3 maculopapular rash with 135 μg/kg SC talquetamab (n = 2). The maximum tolerated dose for talquetamab has not been identified.
Weekly IV dosing is supported by the half-life of talquetamab. Increases in T-cell activation and plasma cytokine levels were similar with IV and SC dosing. Step-up dosing was effective at modulating cytokine production while maintaining T-cell activation.
The overall response rate (ORR) was 67% (12/18) for talquetamab IV 20 μg/kg to 180 μg/kg. The ORR was 66% (21/32) for talquetamab SC 135 μg/kg to 405 μg/kg. Responses began at doses as low as 1.0 μg/kg and were rapid (median, 1 month) and durable.
Results from this phase 1 first-in-human study of talquetamab showed encouraging clinical activity with manageable toxicity in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). The study is ongoing to identify a dose for the phase 2 investigation.
Abstract 290. ASH 2020. December 5, 2020. A phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody, in patients with relapsed and/or refractory multiple myeloma (RRMM).