QLS4131, a next-generation GPRC5D×BCMA×CD3 trispecific T-cell engager, in patients with relapsed/refractory multiple myeloma (RRMM): Initial results of a first-in-human Phase Ⅰa study

Abstract Background: Bispecific antibodies targeting B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) are revolutionizing the treatment landscape of multiple myeloma. Trispecific antibody (TsAb) simultaneously targeting BCMA and GPRC5D showed promising potential in addressing tumor heterogeneity and overcoming acquired resistance. QLS4131 is a next-generation T-cell engaging TsAb dual-targeting BCMA and GPRC5D, incorporating‌ a moderate binding affinity GPRC5D nanobody. Thein vivo study of QLS4131 revealed a dose-dependent suppression of tumor growth, induction of tumor regression, and superior antitumor efficacy. Here we report the initial results of the ongoing first-in-human Phase Ⅰa study (NCT06500507) evaluating the safety and efficacy of QLS4131 in the treatment of RRMM. Methods: The Phase Ⅰa dose-escalation phase enrolled patients with measurable RRMM who had disease progression after currently available therapies or were intolerable to them. Escalation included intravenous (IV) dosages from 0.06 µg/kg to 30 µg/kg given at QW and subcutaneous (SC) dosages from 30 µg/kg to 600 µg/kg given at Q2W. Patients received 1 or 2 step-up doses (SUD) prior to the first target dose from 3 µg/kg dose level to attenuate cytokine release syndrome (CRS). SUD of higher dosages will be determined by Safety Monitoring Committee (SMC) according to PK data and safety data. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events v5.0. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT guidelines. Response was evaluated per International Myeloma Working Group criteria. The primary endpoints of Phase Ia included dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, and safety. Results: As of 15th Jul, 2025, 17 patients received QLS4131 treatment at doses ranging from 0.06 to 30 µg/kg (IV, QW). Besides, another 3 enrolled patients received QLS4131 treatment at 30 µg/kg (SC, Q2W). Median age was 59.0 (range, 48–75), 41.2% male, 41.2% currently diagnosed as IgG subtype, 64.7% revised-ISS (R-ISS) stage Ⅱ/Ⅲ, 41.2% extramedullary disease (EMD), and 47.1% high risk cytogenetics (t(4;14), t(14;16), del(17p)). Median prior treatment lines was 3.0 (range, 1–8), 64.7% had ≥ 3 lines of prior therapies, and 35% had prior stem cell transplantation. QLS4131 exhibited an overall manageable tolerability. No DLT occurred and MTD was not reached. The most common TRAEs were cytopenias and CRS. The overall incidence of CRS was 80% (47.1% Grade 1, 29.4% Grade 2), with median onset at 21.08 h (range, 0.02–71.83) and duration of 0.42 day (range, 0.05–19.01). There were no occurrence of immune effector cell-associated neurotoxicity syndrome (ICANS). Eight patients had non-rash skin AEs, and 5 patients had nail AEs, all of which were mild (all Grade 1). Response was observed at doses ≥ 1 µg/kg cohorts. In 15 response-evaluable patients who received IV QLS4131, the overall objective response rate was 60% (≥VGPR 40%), with 100% ≥VGPR in 30 µg /kg cohort. In the 2 patients who failed from prior BCMA-targeted CAR-T/CAR-NK therapy in the 10 μg/kg IV cohort, one achieved stringent complete response (sCR) and the other partial response (PR). Conclusions: Preliminary dose-escalation data of QLS4131 in patients with RRMM demonstrated tolerable toxicity with no DLT observed, and relatively lower incidence of GPRC5D-related AEs compared with published data from competitors (eg. JNJ-79635322). Primary efficacy data showed positive response observed even at low-dose levels. This trial is still ongoing and the DLT, MTD, and RP2D are to be determined.