Updated results of a first-in-human, Phase Ⅰa/Ⅰb study of QLS32015 (GPRC5D×CD3) in patients (pts) with relapsed/refractory multiple myeloma (RRMM)

Abstract Background: QLS32015 is a novel cis-link G-protein-coupled receptor class 5 member D (GPRC5D)×CD3 bispecific antibody, utilizing high-affinity GPRC5D and low-affinity CD3 arms to enhance T-cell-tumor bridging and reduce off-target T-cell activation. QLS32015 mediated potent cytotoxicity against cells expressing high or low level of GPRC5D. We previously reported initial safety and efficacy of QLS32015 in 13 RRMM pts (ASH 2024, Blood 2024;144 (Suppl 1):1990). Here, we present updated analyses in safety and efficacy from the dose-escalation/expansion phase Ⅰa/Ⅰb in 62 pts. Methods Eligible pts received QLS32015 (subcutaneously) in escalating weekly 2 step-up doses followed corresponding target doses for up to 2 years. Escalating doses (2/6/18 μg/kg QW and 54/100 μg/kg Q2W) were evaluated sequentially in phase Ⅰa. Three dose levels were selected for dose-expansion. The primary endpoints were the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommend phase 2 dose (RP2D) and safety in phase Ia, and IMWG objective response rate (ORR) in phase Ib. Results As of Jun 20, 2025, 62 pts received QLS32015 (2–100 μg/kg). Median age was 61.0 years (range, 43–78), 54.8% of pts were diagnosed as IgG and 21.0% as light-chain subtypes. Among them, 40.3% had extramedullary disease (EMD), and 62.9% were revised-International Staging System stage II/III. Median lines of prior therapy was 3.0 (range, 1–8); 82.2% pts had ≥3 lines of therapy; 77.4% of pts were triple-class-exposed; 40.3% had one autologous stem cell transplant; and 25.8% had prior B-cell maturation antigen (BCMA)-targeted therapies. DLT occurred in only 1 pt at 54 μg/kg Q2W dose level. MTD was not reached. TRAEs of any grade (Gr) occurred in 58 (93.5%) pts. The most common TRAEs were hematological toxicities (88.7%) and cytokine release syndrome (CRS, 77.4%). The majority of CRS were Gr 1 (75.8%) or Gr 2 (12.9%), mainly in the first cycle, with a median onset time of 47.8 h (range, 4.4–603.8) and median duration of 2.0 days. No immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. Mild to moderate skin and nail toxicity (predominantly Gr 1/2) was noticed, with skin-related TRAEs in 53.2% of pts and nail changes in 32.3%. Notably, only 1 pts experienced a Gr ≥3 skin-related TRAE. The most common infections were upper respiratory tract infections and pneumonia (Gr ≥3 19.4%). Within the study dose range, QLS32015 demonstrated dose-proportional increases in serum exposure from the first dose, with a PopPK-estimated half-life of 19.8 days. At doses of ≥54 μg/kg Q2W, the Ctrough exceeded the EC90 derived from efficacy tests in vitro. The dose-expansion to optimize dosing was conducted at dose levels of 36 g/kg Q2W, 54 g/kg Q2W, and 54 g/kg Q4W. RP2D was determined as 54 ug/kg Q2W integrated with safety data and PK parameters. Its long half-life supports Q4W or less frequent dosing strategies. As of cutoff date, median follow-up was 4.63 months (95% CI 3.42–6.05). Response was noticed from dose level of 6 μg/kg Q2W. In 52 efficacy-evaluable pts, ORR was 78.8% (95% CI 65.3–89.0). At RP2D (n=30), ORR was 86.7% (95% CI 69.3–96.2), with 70.0% ≥very good partial response (VGPR), 33.3% ≥complete response (CR), and 23.3% CR-minimal residual disease-negative. At RP2D, median time to response was 1.30 months (IQR, 0.92–1.51), and duration of response was not reached. Robust therapeutic efficacy was also observed in pts with poorer prognosis in the RP2D cohort, in particular, with ORR of 100% in pts with high-risk cytogenetics, 88.9% in pts with prior BCMA-targeted therapy, and 75.0% in pts with EMD. Median progression-free survival (PFS) at RP2D was not reached, with the 12-month PFS rate of 86.7% (95% CI 51.5–97.0). The median overall survival was not reached. In exposure-response analysis, RP2D derived better efficacy without increase in safety risk. Deep response rates (both ≥VGPR and ≥CR) escalated with cumulative exposure (all p<0.05), while no exposure-related increase in incidence of Gr ≥2 CRS, Gr ≥3 thrombocytopenia/neutropenia, or Gr ≥3/4 TRAEs (all p > 0.05). Conclusions QLS32015 showed manageable safety profile, with low incidence of GPRC5D-associated TRAEs and no occurrence of ICANS event. Notably, QLS32015 at RP2D exhibited remarkable preliminary efficacy in pts with high risk cytogenetics, prior BCMA-targeted therapy, or EMD. The long half-time of 19.8 days supports extended dosing intervals of QLS32015 with convenience and compliance.