Anti-CD3/B-Cell Maturation Antigen Bispecific Antibody CM336 in Relapsed/Refractory Multiple Myeloma: An Open-Label, Phase I/II Study

Introduction: Multiple myeloma is an incurable malignancy characterized with high relapse rates. Therapeutic options to improve clinical outcomes remain limited for patients with relapsed/refractory multiple myeloma (RRMM). CM336 is a novel bispecific antibody targeting both CD3 and B-cell maturation antigen (BCMA), redirecting T cells to BCMA-expressing myeloma cells. Here, we report the dose-escalation results of CM336 from a first-in-human, open-label, phase I/II study (NCT05299424).

Methods: This study included a dose-escalation and a dose-expansion part. For dose escalation, eligible subjects (18 years or older) were diagnosed with RRMM (per International Myeloma Working Group criteria), had a measurable disease, and had exposed to at least one proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. Subjects received CM336 at doses ranging from 0.04 to 160 mg using an accelerated titration design for the first 3 cohorts, followed by a "3+3" design. CM336 was administrated subcutaneously weekly, with a step-up dosing scheme for 40 mg and higher doses.

Results: As of June 30, 2024, 25 subjects received CM336 (median age, 63 years [range 41-76]; 72% female) in the dose-escalation part. Subjects had received a median of 4 (range 2-15) prior lines of therapy, with all being triple-class exposed and 20% with extramedullary plasmacytoma. The median CM336 exposure duration was 4.8 months (range 0.03-12). Maximum tolerated dose was not reached. The most common treatment-emergent adverse events (TEAEs) included cytokine release syndrome (CRS) (any grade: 68%; grade ≥3: only one subject), anaemia (68%; 32%), lymphocyte count decreased (64%; 56%), neutrophil count decreased (56%; 44%), pneumonia (44%; 32%), and pyrexia (44%; 0). All CRS events were resolved completely, and no immune effector cell associated neurotoxicity syndrome (ICANS) events were reported. At a median follow-up of 8.0 months, the confirmed overall response rate (ORR) was 60.9% (14/23; 95% CI, 38.5%-80.3%). Notably, for subjects in the 80 mg and 160mg cohorts who received at least one target dose (n=8), the ORR was 100%. Of the 10 subjects (43.5%) with a confirmed stringent complete response (sCR), 9 were evaluable for minimal residual disease (MRD), and the MRD negativity rate (at a threshold of 10−5 cells) was 88.9% (8/9). The median time to response was 1.4 months (range 0.7-3.8). The median duration of response and median progression-free survival were not reached. All subjects in remission have not experienced disease progression yet.

Conclusions: Treatment with CM336 was well tolerated with preliminary promising anti-myeloma efficacy. CM336 is expected to improve the prognosis of subjects with RRMM. With longer follow-up, additional efficacy/safety data will be presented.