Patients with MM continue to relapse on current therapies, stressing the need for new immunotherapy targets. GPRC5D is an orphan receptor that is expressed on malignant plasma cells in MM. Talquetamab (JNJ-64407564) is a bispecific IgG4 antibody that binds to GPRC5D and CD3, redirecting T cell killing to MM cells. Updated phase 1 results of talquetamab at the recommended phase 2 dose (RP2D) in patients with RRMM are presented.

Eligible patients had RRMM or were intolerant to standard therapies. Patients received talquetamab intravenously (IV; range 0.5–180 μg/kg) or subcutaneously (SC; range 5.0–800 μg/kg) weekly or biweekly. The primary objectives of the study were identification of the RP2D in part 1 and talquetamab safety and tolerability at the RP2D in part 2. Adverse events (AEs) were graded by CTCAE v4.03; cytokine release syndrome (CRS) was graded per Lee 2014 criteria. Response was assessed per IMWG criteria.

As of Feb 8, 2021, 174 patients had received talquetamab, 102 by IV and 72 by SC. Across parts 1 and 2 of the study, 28 patients were treated at the RP2D of weekly SC 405 μg/kg, with 10.0 and 60.0 μg/kg step-up doses. Patients treated at the RP2D had a median age of 61.5 years (range 46–80) and a median of 5.5 prior lines of therapy (range 2–14), with 100%/79% triple-class/penta-drug exposed; 71%/18% triple- class/penta-drug refractory; 86% refractory to last line of therapy; and 21% with prior B- cell maturation antigen–directed therapy. No dose-limiting toxicities at the RP2D occurred in part 1. At the RP2D, most common AEs were CRS (79%; grade 3 4%; median time to onset was 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 patients (grade 3/4 4%) and neurotoxicity in 7% (grade 3/4 none). 75% of patients dosed at the RP2D had skin-related AEs (grade 3/4 none), including 18% with nail disorders. In response-evaluable patients (n = 24), the overall response rate at the RP2D was 63%, with 50% ≥very good partial response; 9/17 (53%) evaluable triple-class refractory patients and 3/3 (100%) penta-drug refractory patients responded. 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 and consistent T cell activation was observed.

The promising efficacy, safety profile, and convenience of SC dosing support monotherapy development and combination approaches with talquetamab. Based on pharmacokinetic data, other SC dosing strategies are being explored.

Talquetamab showed a high clinical response rate and was well-tolerated in patients with RRMM treated at the RP2D of weekly 405 μg/kg SC.