Background: New immunotherapy targets in MM are needed as patients (pts) continue to relapse. The orphan receptor GPRC5D is expressed on malignant plasma cells in MM. Talquetamab (JNJ-64407564) is a bispecific IgG4 antibody that redirects T cell killing to MM cells by binding to the novel target, GPRC5D, and CD3. We present updated results of talquetamab at the recommended phase 2 dose (RP2D) from a phase 1 trial in relapsed/refractory MM. Methods: Eligible pts with MM who had relapsed or refractory disease or were intolerant to standard therapies received talquetamab intravenously (IV; range 0.5–180 µg/kg) or subcutaneously (SC; range 5.0–800 µg/kg) weekly or biweekly. Primary objectives were identification of the RP2D (part 1) and talquetamab safety and tolerability at the RP2D (part 2). Adverse events (AEs) were graded by CTCAE v4.03 (cytokine release syndrome [CRS] per Lee 2014). Response was assessed per IMWG criteria. Results: As of Feb 8, 2021, 174 pts received talquetamab, 102 by IV and 72 by SC; in parts 1 and 2, 28 pts were treated at the RP2D, identified as weekly SC 405 µg/kg, with 10.0 and 60.0 µg/kg step-up doses. Pts treated at the RP2D had a median age of 61.5 y (range 46–80) and a median of 5.5 prior lines of therapy (range 2–14; 100%/79% triple-class/penta-drug exposed; 71%/18% triple-class/penta-drug refractory; 86% refractory to last line of therapy; 21% with prior B-cell maturation antigen–directed therapy). No dose-limiting toxicities occurred at the RP2D in part 1. Most common AEs at the RP2D were CRS (79%; grade 3 4%; median time to onset: day after SC injection), neutropenia (64%; grade 3/4 54%), anemia (57%; grade 3/4 29%) and dysgeusia (57%; all grade 1/2); infections were reported in 32% of pts (grade 3/4 4%) and neurotoxicity in 7% (grade 3/4 0). In all, 75% of pts dosed at the RP2D had skin-related AEs (grade 3/4 0), including 18% with nail disorders. The overall response rate at the RP2D in response-evaluable pts (n = 24) was 63%, with 50% reaching very good partial response or better; 9/17 (53%) evaluable triple-class refractory pts and 3/3 (100%) penta-drug refractory pts had a response. Median time to first confirmed response at the RP2D was 1.0 mo (range 0.2–3.8); responses were durable and deepened over time (median follow-up 6.2 mo [range 2.7–9.7+] for responders at the RP2D). At the RP2D, exposure was maintained over the maximum EC₉₀ target level from an ex vivo cytotoxicity assay, and consistent T cell activation was seen. Conclusions: At the RP2D of weekly 405 µg/kg SC, talquetamab showed a high clinical response rate and was well-tolerated in pts with relapsed/refractory MM; based on pharmacokinetic data, other SC dosing strategies are being explored. The promising efficacy, safety profile and convenience of SC dosing support monotherapy development and combination approaches with this novel agent. Clinical trial information: NCT03399799