Talquetamab, a T-Cell–Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma

abstract

Background

G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed on malignant plasma cells. Talquetumab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells.

method

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In a phase I study, we evaluated talquetamab administered intravenously weekly or weekly (at doses of 0.5 to 180 μg per kilogram of body weight) or subcutaneously weekly, weekly, or monthly (5 to 1600 μg per kilogram) in patients. Those with heavily pretreated relapsed or refractory multiple myeloma that progressed with established therapy (a median of six prior therapies) or who could not receive these therapies without unacceptable side effects. Primary endpoints—frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities—were evaluated to select recommended doses for a phase 2 study.

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result

At the data-cut-off date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At two subcutaneous doses (405 μg per kilogram weekly) recommended for phase 2 studies [30 patients] and 800 μg per kilogram per week [44 patients]), the most common adverse events were cytokine release syndrome (in 77% and 80% of patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (63% and 57%); All but one cytokine release syndrome event were grade 1 or 2. A dose-limiting toxicity of grade 3 rash was reported in a patient receiving talquetumab at the 800-μg dose level. At a median follow-up of 11.7 months (patients who received talquetumab at the 405-μg dose level) and 4.2 months (those who received it at the 800-μg dose level), the percentage of patients with a response was 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively.

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Conclusion

Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were initially low-grade. Talquetumab elicited substantial responses in patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumentAL-1 ClinicalTrials.gov number, NCT03399799.)

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Talquetumab, a bispecific antibody for multiple myeloma
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