Talquetamab Shows 60% Response Rate in Japanese Myeloma Patients with No Dose-Limiting Toxicity

Multiple myeloma remains a challenging malignancy because nearly all patients eventually relapse, even after modern combination therapies. In Japan, approximately 4,000 deaths per year are attributed to myeloma, and patients who become refractory to all three major drug classes — proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies — face a median overall survival of only 12.4 months with response rates around 30%. Novel mechanisms of action are urgently needed for this triple-class refractory population.

Talquetamab is a first-in-class humanized bispecific antibody that simultaneously binds CD3 on T cells and GPRC5D on malignant plasma cells, redirecting cytotoxic T cells to kill myeloma cells. GPRC5D is highly expressed on plasma cells but has limited expression in normal tissues, making it an attractive target. The global MonumenTAL-1 Phase 1/2 study established two recommended Phase 2 doses — 400 µg/kg weekly (QW) and 800 µg/kg every two weeks (Q2W) — with overall response rates of 74.1% and 71.7%, respectively. This Japanese Phase 1 study was designed to confirm safety, tolerability, and preliminary efficacy specifically in a Japanese patient population.

The study enrolled 15 patients across 6 sites in Japan between May 2021 and a data cutoff of February 9, 2024. Patients were grouped into three cohorts: Cohort 1 received 135 µg/kg QW (n=4), Cohort 2 received 400 µg/kg QW (n=5), and Cohort 3 received 800 µg/kg Q2W (n=6). The population was heavily pretreated, with a median of 5.0 prior lines of therapy (range 2–16), 73.3% having received prior penta-drug therapy, 80% being triple-class refractory, and 20% having previously received BCMA-targeted CAR-T cell therapy. High-risk cytogenetic abnormalities were present in 66.7% of patients.

No dose-limiting toxicities, treatment-related deaths, or AE-related dose reductions or discontinuations were observed across any cohort. The most frequently reported treatment-emergent adverse events were neutropenia (60.0%), lymphopenia (53.3%), and cytokine release syndrome (46.7%), the majority of which were Grade 1 or 2. GPRC5D-related adverse events of clinical interest — dysgeusia, skin toxicity, nail disorder, and dry mouth — were all Grade 2 or lower. Pharmacokinetic analysis confirmed dose-proportional increases in talquetamab exposure consistent with the global data, with no unexpected accumulation or immunogenicity signals.

With a median follow-up of 9.0 months across all cohorts, the overall response rate (ORR; partial response or better) was 60.0% (95% CI: 32.3%–83.7%). Responses were observed in Cohort 1 (135 µg/kg QW: 2/4 patients), Cohort 2 (400 µg/kg QW: 3/5 patients), and Cohort 3 (800 µg/kg Q2W: 4/6 patients). The median time to first response was 1.1 months, and the median duration of response had not been reached at the time of analysis. These results are consistent with those from the global MonumenTAL-1 study, providing confidence that talquetamab's efficacy translates across ethnic populations and supports its regulatory and clinical application in Japan for heavily pretreated RRMM.