RG6234, a GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Intravenous (IV) and First Subcutaneous (SC) Results from a Phase I Dose-Escalation Study

Background: Despite advances in treatment, almost all pts with newly diagnosed multiple myeloma (MM) eventually relapse and progression-free survival decreases with each subsequent line of therapy. New treatments that target novel antigens and/or have novel mechanisms of action (MOAs) are needed. GPRC5D is a G-protein coupled receptor that is overexpressed on malignant plasma cells. Expression on normal tissue is limited to skin (hair follicles and eccrine glands) and testis (seminiferous tubules). In a Phase I study (NCT04557150), RG6234, a GPRC5DxCD3 T-cell engaging bispecific antibody with a novel 2:1 configuration, was highly active in pts with RRMM and had a safety profile consistent with its MOA and target distribution when given IV (Hasselbalch Riley et al. EHA 2022). We report updated IV and first SC results. Methods: All pts had RRMM for which no established therapy was available, appropriate or tolerable and had received ≥1 prior IMiD and ≥1 prior PI. Prior CAR T-cells, antibody-drug conjugates and bispecific antibodies were allowed. RG6234 was initiated with step-up dosing, reaching the target dose 2 weeks after the initial step dose, and was given for up to 1 year unless disease progression or unacceptable toxicity occurred. All pts who received RG6234 in the dose-escalation phase of the study were included in the analysis (IV dose range: 6-10000µg; SC dose range: 30-7200µg). Results: At data cut-off (June 8, 2022), 51 pts had been enrolled into the IV cohorts (median age: 62 years; min-max: 27-78) and 54 into the SC cohorts (64 years; 46-79). Median number of prior lines was 5 (min-max: 2-15) and 4 (2-14), respectively. Many pts were triple-class refractory (IV: 63.3%; SC: 73.1%), some were penta-class refractory (IV: 30.6%; SC: 42.3%), and some had received prior anti-BCMA therapies (IV: 19.6%; SC: 20.4%). High-risk cytogenetics (t(4;14), t(14:16), del(17p)) were common (IV: 46.7% of 30 evaluable pts; SC: 50.0% of 28). Across all tested doses, cytokine release syndrome (CRS) was the most common adverse event (AE; IV: 82.4% of pts; SC: 77.8%). Grade (Gr) ≥3 CRS was uncommon (IV: 2.0%; SC: 1.9%) and most events were confined to Cycle 1. CRS management often involved tocilizumab (IV: 39.2% of pts; SC: 25.9%) and corticosteroids (IV: 52.9%; SC: 25.9%). ICANS-like AEs were infrequent and mostly mild (any Gr: 9 pts [8.6%]; Gr ≥3: 2 pts [1.9%]). AEs related to on-target, off-tumor effects included dermal and epidermal conditions (IV: 72.5%; Gr 3: 11.8%; SC: 81.5%; Gr 3: 14.8%), hair and nail changes (IV: 17.6% [all Gr 1-2]; SC: 22.2% [all Gr 1-2]), and AEs affecting the gastrointestinal mucosal epithelium or tongue (IV: 70.6% [all Gr 1-2]; SC: 74.1%; Gr 3: 5.6%). Gr ≥3 hematologic AEs were infrequent (anemia: IV 13.7%, SC 5.2%; thrombocytopenia: IV 13.8%, SC 18.5%; neutropenia: IV 11.8%, SC 16.7%). Infections were common (IV: 56.9%; Gr ≥3: 19.6%; SC: 37.0%; Gr ≥3: 24.1%). RG6234-related AEs leading to treatment discontinuation occurred in 2 pts (3.9%) in the IV group and 2 pts (3.7%) in the SC group. One RG6234-related Gr 5 (fatal) AE (1.9%) of acute respiratory failure was reported in the SC group. Median follow-up among efficacy evaluable pts in the IV group (7.1 months; min-max: 0.5-16.8; n=49 pts) was longer than in the SC group (3.9 months; min-max: 1.1-10.5; n=48 pts). Overall response rates were 71.4% and 60.4%, respectively (Figure). Responses were observed in 10/18 pts (55.6%) overall who had received prior anti-BCMA therapies and 18/28 pts (64.2%) who had high-risk cytogenetics. Median time to first response in the IV and SC cohorts was 1.4 months (95% CI: 1.2-1.8) and 1.6 months (1.2-2.1), respectively. Duration of response (DoR) data were immature at cut-off. Responses were ongoing in 24/35 pts (68.6%) in the IV cohorts and in 26/29 (89.7%) in the SC cohorts, with a maximum DoR of 12.9 months and 8.8 months, respectively. Biomarker data demonstrated rapid T-cell activation and T cell-mediated anti-MM activity irrespective of administration route (Dekhtiarenko et al. ASH 2022). Anti-drug antibody incidence was low (IV: 7.8%; SC: 1.8%), and impacted RG6234 PK and efficacy in one pt (1.0%) only. Conclusions: RG6234 is highly active in pts with heavily pretreated RRMM when administered IV or SC. AEs are consistent with its MOA and target distribution. Evaluation and optimization of IV and SC dosing is ongoing. Updated data will be presented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal