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Background: Patients (pts) with relapsed/refractory multiple myeloma (RRMM) are in need of effective treatment options. RG6234 is a T-cell engaging bispecific antibody targeting GPRC5D with a novel 2:1 format. NCT04557150 is an ongoing first-in-human Phase 1 trial. We present initial results from the dose-escalation part using intravenous (IV) administration. Aims: To characterize the safety of RG6234 and to identify a recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetics, pharmacodynamics, and preliminary clinical activity. Methods: Eligible pts with RRMM received RG6234 in escalating weekly step-up doses followed by a q2w regimen at a peak ‘target dose’ for up to 1 year. A mCRM model was used for overdose control. Adverse events (AEs) were graded per CTCAE v5.0 and cytokine release syndrome (CRS) per ASTCT criteria (Lee et al. 2019). Response was assessed by the investigator according to IMWG criteria. All pts provided informed consent. Results: As of January 31, 2022, 41 pts had received RG6234 IV (0.006mg to 10mg). Median age was 63 years (range: 27 to 78) and 61% had R-ISS stage II or III at study entry. High-risk cytogenetics (t(4;14), t(14;16), del(17p), 1q21 gain) were present in 17/29 (58%) evaluable cases. Median number of prior therapies was 5 (range: 2 to 15). Pts were triple-class refractory in 67% of cases and penta-class refractory in 36%. Six pts (14.6%) had prior BCMA-directed therapy. CRS occurred in 85.4% of pts (G1 56.1%, G2 24.4%, G3 2.4%). CRS was generally confined to the first cycle, with a median time to onset of 4.2 hours (range: 0 to 64.2), and 14 pts (34%) requiring tocilizumab. Three pts (7.3%) experienced CNS toxicity related to RG6234 (G1 and G3 headache; G1 confusion). G3/4 neutropenia, thrombocytopenia, and anemia occurred in 9.8%, 19.5%, and 12.2% of pts, respectively. Infections were reported in 46.3% of pts (≥G3 14.6%). One patient died of an E. coli sepsis not considered related to RG6234. AEs probably related to target expression included skin-related AEs in 66% of pts (G3 7.3%), dysgeusia/ageusia (36.6%, all G1/2), dry mouth (36.6%, all G1/2), dysphagia (17.1%, all G1/2), and nail changes (12.2%, all G1/2). No discontinuations due to RG6234-related AEs occurred. The maximum tolerated dose (MTD) was not reached. Within the tested target-dose range, RG6234 serum exposure generally showed a dose-proportional increase, with a preliminary IV terminal T½ of ～5 days (mean value, n=22). At the predicted active-dose range (>0.162mg), RG6234 induced profound and rapid reductions in serum free light chains (FLC) and sBCMA. After the first treatment cycle, 93% of evaluable pts (14/15) had <1% of multiple myeloma cells in bone marrow based on flow cytometry. Overall response rate in 34 efficacy evaluable pts across all doses was 68%, and 50% achieved a VGPR or better response, including 2/6 BCMA pre-treated pts. Responses occurred rapidly, with a median time to first response of 1.3 months (95% CI: 1.1, 1.6). Median follow-up was 3.5 months (range: 0.03 to 11.7). Treatment was ongoing for 58.5% of pts at the time of the data cut. Duration of response was not mature. Response was ongoing in 18/23 (78.3%) responding pts, with a longest duration of response of 10 months. Summary/Conclusion: RG6234, a novel T-cell engaging bispecific antibody targeting GPRC5D, demonstrates compelling clinical activity with manageable safety in heavily pretreated pts with RRMM. Dose escalation via IV and subcutaneous routes continues, and data will be updated.
Riley et al. (Wed,) studied this question.