Efficacy, safety, pharmacokinetic (PK), and pharmacodynamic (PD) support for talquetamab (tal) QW and Q2W dosing in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Analyses from MonumenTAL-1.

8041 Background: Tal is a first-in-class bispecific antibody targeting the novel antigen G protein–coupled receptor family C group 5 member D. In MonumenTAL-1 (NCT03399799/NCT04634552), tal demonstrated an overall response rate (ORR) of > 70%, with clinically manageable safety in pts with RRMM. We summarize efficacy, safety, PD, and PK results supporting the recommended phase 2 doses (RP2Ds) of tal: 0.4 mg/kg QW and 0.8 mg/kg Q2W SC. Methods: In MonumenTAL-1, pts received IV (0.5–180 µg/kg) or SC (5–1600 µg/kg) tal doses in phase 1 and at the RP2Ds in phase 2, preceded by step-up doses. Blood samples were collected for the measurement of tal serum concentration and anti-tal antibodies (ADAs). Covariate effects on PK and efficacy were characterized. Efficacy and safety exposure–relationships (E–R) were evaluated using predicted PK metrics, ORR, and key treatment-emergent adverse events (TEAEs), including neurotoxicity, infections, cytopenia, ageusia, dysgeusia, weight loss, and cytokine release syndrome (CRS). Results: PK exposure was approximately dose proportional across IV and SC doses, with a SC bioavailability of 61.9%. At the RP2Ds, the mean concentration–time profiles were comparable and maintained at or above the concentration associated with the 90% maximal drug effect identified in an ex vivo cytotoxicity assay. The incidence of ADAs was 29% (QW) and 20% (Q2W). Presence of ADAs had no apparent impact on PK, safety (CRS, systemic administration–related reaction, or injection site reaction), or efficacy (ORR). At the RP2Ds, PD changes indicative of the proposed mechanism of action, such as T-cell activation, induction of cytokines, and T-cell redistribution, were comparable. Body weight, myeloma subtype, and International Staging System stage were identified as covariates for tal PK; however, there was no clinically relevant impact of age, sex, race, or mild/moderate hepatic or renal impairment on PK. Across SC doses in phase 1, ORR increased with exposure and reached a plateau at or above the RP2Ds, supporting the selected RP2Ds. Baseline myeloma subtype and extramedullary plasmacytoma status were identified as prognostic factors for ORR at the RP2Ds. There were no observed E–R for key TEAEs, including grade ≥3 infections or cytopenia, grade ≥2 weight loss, or grade 2 ageusia. No E–R for grade ≥1/≥2 CRS and peak tal exposure for any step-up doses, irrespective of tocilizumab administration, was observed. Dysgeusia rates were comparable between the 2 RP2Ds. Conclusions: Efficacy, safety, PK, and PD analyses support the selection of tal 0.4 mg/kg QW and 0.8 mg/kg Q2W SC regimens as RP2Ds. The RP2Ds provided comparable PK, PD, efficacy, and safety profiles. Covariates for PK exposure had no impact on E–R, and dose adjustment was not warranted. Clinical trial information: NCT03399799 , NCT04634552 .