RG6234 Shows Promise as Monotherapy in Heavily Pretreated Multiple Myeloma

A first-in-human study (NCT04557150) involving patients with relapsed or refractory multiple myeloma who previously received an immunomodulatory agent and a proteasome inhibitor demonstrated feasibility of bispecific antibody RG6234 to induce high rates of durable responses.

In a cohort of heavily pretreated patients who had received a median of 5 (range, 2-15) prior lines of therapy, the overall response rate in 42 efficacy evaluable patients was 71.4%, which included a very good partial response or better rate of 52.4%. Partial response was reached in 19.0% of patients, VGPR was achieved in 28.6%, and complete response (CR) as well as stringent CR were each noted in 11.9% of patients.

Expression of GPRC5d is greater on malignant vs plasma cells, with its presence in normal tissue limited to cells of the skin, hair follicles, eccrine glands, and the testis. RG6234 displays high-affinity binding to GPRC5D on plasma cells and CD3 on T cells, resulting in T-cell–directed lysis of plasma cells.

The open-label multicenter study of RG6234 was conducted using both dose-escalation (Part I) and dose-expansion (Part II) phases. Initial data from part I of the trial was reported at the 2022 European Hematology Association Congress.

Patients were included in the study if they had no treatment options of established, available therapy; an ECOG performance status of 0 or 1; and a life expectancy of at least 12 weeks. Patients with recent treatment involving monoclonal antibodies, radioimmunoconjugates, or antibody-drug conjugates; immune-mediated adverse effects (AEs) that were considered treatment related with a prior immunotherapeutic; or stem cell transplant within 100 days prior to the start of treatment were excluded. Prior experience with CAR T-cell therapy antibody-drug conjugates, and bispecific antibodies was allowed.

A step-up dosing strategy was employed in 51 patients, with patients receiving the agent on days 1, 8, and 15 of the first 28-day cycles followed by day 1 of each subsequent 14-day cycle thereafter. One patient was administered 6 μg on day 1, 18 μg on day 8, and 18 μg on day 15. The final dosing cohort of 6 patients received 18 μg on day 1, 162 μg on day 8, and 7200 μg on day 15, with every 3-week infusions thereafter. Patients were treated with corticosteroid premedication in cycle 1 to moderate the effects of cytokine release syndrome (CRS).

The primary end point is safety and tolerability as well as finding the maximum tolerated dose and the recommended phase 2 dose (RP2D). Dose escalation via intravenous and subcutaneous routes will continue to find the RP2D. Secondary end points include pharmacokinetics and pharmacodynamics, immunogenicity, and clinical activity.

Patients had a median age of 62 years (range, 27-78), 28 (54.9%) were men, and 7 (13.7%) had extramedullary disease. High-risk cytogenetics were present in 46.7% of those assessed (14 out of 30), with 1q21 gain being the only feature detected in 23.3% (7 out of 30). In 48 patients with information regarding prior therapies, 30 (62.5%) were triple-class refractory, 15 (31.3%) were penta-class refractory, 39 (81.3%) had experience with prior anti-CD38 treatment, and 10 (20.8%) had received a BCMA-targeted therapy.

Almost all patients (96.1%) experienced AEs, 45.1% of whom had grade 3 and 17.6% had grade 4 events. Serious AEs occurred in 64.7% of patients, and fatal grade 5 AEs occurred in 2 patients (3.9%) which were determined to not be related to RG6234. AEs leading to dose reductions and drug discontinuation occurred in 7.8% and 5.9%, respectively. CRS was the most common all-grade AE followed by dysgeusia, infection, and dry mouth. Overall, AEs were consistent with the drug class by target (GPRC5D) and mechanism of action.

Looking at CRS, overall incidence was 78.4% and was comprised of grade 1 (49.0%), grade 2 (27.5%), or grade 3 (2.0%) events. No events of CRS led to treatment discontinuation. Median time to CRS onset was 5 hours (range, 0 -64) from the last dose of treatment and the median duration was 2 days (range, 1-8). Management of CRS was done by way of corticosteroids (52.9%), tocilizumab (Actemra; 37.3%), or single vasopressor (2.0%). The investigators noted that step-up dosing mitigated the risk of severe CRS.

Immune effector cell–associated neurotoxicity syndrome of any grade only occurred in 3 patients (5.9%), manifesting as headache in 2 and confusion in 1; only 1 patient with headache experienced grade 3 toxicity. Any-grade hematologic AEs included anemia (27.5%), thrombocytopenia (25.4%), and neutropenia (23.6%).

Reference

Hasselbalch Riley C, Hutchings M, Yoon SS, et al. RG6234, a novel GPRC5D T-cell engaging bispecific antibody, induces rapid responses in patients with relapsed/refractory multiple myeloma: preliminary results from a first-in-human trial. Presented at: 2022 European Hematology Association Congress; June 9-12, 2022; Vienna, Austria. Abstract S180. https://bit.ly/3NaPgKL