First-in-Human, Phase Ia, Dose Escalation, Monotherapy Study of QLS32015, a Novel GPRC5D×CD3 T-Cell Engaging Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Qiu Lu-Gui , An Gang , Fang Baijun , Huang Xiaobing , Xu Yan , Liu Yuzhang , Che Feifei , Yang Xinai , Duan Xianlin , Shao Peng , Kang Xiaoyan 
Published: December 2024

Background:
G-protein-coupled receptor class 5 member D (GPRC5D) is a cell-surface protein expressed at high levels on multiple Myeloma (MM) cells. Concurrent binding to GPRC5D on tumor cells and CD3 subunit within the T-cell receptor (TCR) on T cells results in immunological synapse formation and T-cell activation which directs tumor cell killing. QLS32015 is a novel humanized IgG1 GPRC5D×CD3 T-cell engaging bispecific antibody. The ongoing phase Ia study was conducted to evaluate the safety, tolerability, recommended phase 2 dose (RP2D) of subcutaneous QLS32015 monotherapy in RRMM patients.
Methods:
This is a first-in-human, open-label, dose-escalation/expansion, phase I trial (NCT05920876). In the phase Ia dose-escalation stage, eligible patients were aged ≥18 years old, who were diagnosed as multiple myeloma (MM) according to the International Myeloma Working Group (IMWG) criteria, and had progressed from or were intolerable to established therapies. The dose of QLS32105 were set from 2 to 800 (2, 6, 18, 54, 100, 200, 400, 800) g/kg (subcutaneously; QW, every 3 weeks a cycle, for doses 2-18 g/kg; or Q2W, every 4 weeks a cycle, for doses ≥ 54 g/kg). Adopting an accelerated titration design (ATD), dose of QLS32015 within the first 3 dose groups were escalated in one-subject cohort until one subject experienced Grade &gt;2 toxicity related with QLS32105. In dose level ≥ 6 g/kg group, the step-up priming dosing strategy (2 g/kg on the 3rd day before C1D1 for 6 g/kg group; 2 g/kg on the 7th day before C1D1 and 6 g/kg on the 3rd day before C1D1 for ≥ 18 g/kg groups) was applied, thereafter, the target doses were administrated. The duration from initiation of priming phase to the end of the first cycle was defined as the dose-limiting toxicity (DLT) observation period. From that point or after completion of ATD phase, Bayesian optimal interval (BOIN) design was adopted in the rest doses for dose escalation and determination of maximum tolerated dose (MTD). The primary endpoints of the Ia stage included DLT, MTD, RP2D, and safety.
Results:
As of 31th May, 2024, 11 patients were enrolled from 3 sites, with median age of 61.0 years (range, 48-72), 45.5% male, 100% ethnic Han Chinese, 100% ECOG performance score ≤ 1, 45.5% with the International Staging System (ISS) stage I/II; 63.6% with revised-ISS (R-ISS) stage I/II, 45.5% with extramedullary lesions, and 36.4% with ≥30% bone marrow plasma cells. Patients had a median of 3.0 (range, 1-8) prior lines of therapy; 63.6% were triple-class-exposed RRMM; 54.5% had one autologous stem cell transplant (ASCT); and 18.2% had been treated with B-cell maturation antigen (BCMA)-CART. There was 1 patient treated with QLS32015 at 2 g/kg, 3 at 6 g/kg, 4 at 18 g/kg, and 3 at 54 g/kg. No DLT was observed and the MTD was not reached. Treatment-related adverse events (TRAEs) were reported in 11 (100%) patients, with grade ≥3 occurring in 11 (100%) patients. The most common TRAEs were cytokine release syndrome (CRS) (100%), lymphocyte count decreased (90.9%), platelet count decreased (90.9%), anemia (90.9%), and white blood cell count decreased (90.9%). All CRS was grade 1 or 2 and the median duration time was 2.0 days (range, 0.1-19.8). No patient reported the occurrence of immune effector cell-associated neurotoxicity syndrome (ICANS). There was no occurrence of TRAE leading to discontinuation or death. After a median follow-up of 2.9 months (range, 1-8), 8 out of 11 patients had been evaluated for response, with 3 patients being not yet to have their first efficacy evaluation. The IMWG objective response rate was 75.0% (6/8), with 1 (12.5%) patient assessed as very good partial response (VGPR) in the 18 g/kg group, 5 (62.5%) partial response (PR) (2 PR in the 6 g/kg group and 3 PR in the18 g/kg group). There were 1 (12.5%) sable disease (SD) in the 6 g/kg group and 1 (12.5%) progressive disease (PD) in the 2 g/kg group. The median duration of response, median progression-free survival, and median overall survival had not been reached.
Conclusions:
QLS32015 showed tolerable safety profile and encouraging response rate in patients with RRMM. Current dose escalation using BOIN design was ongoing. DLT, MTD, and RP2D were to be determined. Updated safety and efficacy results will be presented.