A Phase I Study of a Novel BCMA×CD3 Bispecific Antibody Emb-06 in Relapsed or Refractory Multiple Myeloma

Background: Despite advances in T-cell engager therapies for multiple myeloma, the prevalence of cytokine release syndrome (CRS) and severe neurotoxicity presents clinical challenges. EMB-06 is a novel 2+2 BCMA×CD3 T-cell engaging bispecific antibody developed using EpimAb’s proprietary Fabs-In-Tandem-Immunoglobulin (FIT-Ig®) platform. Unlike existing T-cell engagers, EMB-06 features tetravalent binding domains in cis-configuration and optimized anti-CD3 arms. Preclinical studies have shown that EMB-06 induces minimal cytokine release while maintaining robust anti-tumor activity. Here we report the initial results from an ongoing multicenter, first-in-human, Phase I study of EMB-06 in relapsed or refractory multiple myeloma (RRMM).

Methods: The primary objectives of the Phase 1 dose-escalation study are to assess the safety, tolerability, maximum tolerated dose (MTD), and/or recommended Phase 2 dose (RP2D) of EMB-06. Secondary objectives include assessment of pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary anti-tumor efficacy. Eligible patients with RRMM must have received at least two lines of prior therapies, including proteasome inhibitors (PI), immunomodulatory agents (IMiD), and if accessible, an anti-CD38 antibody. The dose escalation was conducted in accordance with the Bayesian optimal interval (BOIN) design. Efficacy was analyzed in response-evaluable patients, defined as those who received at least one dose of EMB-06 and had at least one post-baseline response evaluation.

Results: As of June 7, 2024, 40 patients had been treated with EMB-06 at doses ranging from 0.2 mg to 300 mg. The median age (range) was 66 years (46-82). Patients had received a median (range) of 3 prior lines of therapy (2-6), and 35 patients (87.5%) were refractory to their most recent therapy. Treatment-related adverse events (TRAEs) were reported in 26 patients (65%), with Grade ≥3 TRAEs in 16 patients (40%). The most common treatment-related adverse events (TRAEs) included neutropenia (30%), ALP increase (27.5%), AST increase (27.5%), white blood cell count decreased (25%), anemia (25%), absolute lymphocyte count decreased (25%), CRS (25%), ALT increase (18%), platelet count decreased (17.5%), upper respiratory tract infections (15%), infective pneumonia (15%). All CRS cases were Grade 1 (20%) or 2 (5%) per ASTCT criteria. No ICANS was observed, and only one patient experienced treatment-related neurological adverse event (Grade 1 paresthesia). One dose-limiting toxicity (DLT) was observed in the 60 mg cohort, presenting as pneumonia, cardiac failure, increased creatinine, and hepatic insufficiency in one patient. Serious TRAEs occurred in 27.5% of patients, predominantly due to infective pneumonia (12.5%). Grade 5 AEs, unrelated to the study drug, occurred in four patients: three due to multiple myeloma progression and one due to heart failure. EMB-06 exhibited a dose-proportional increase in PK exposure across 0.2-300 mg, with a median half-life of 4.4 days. PD activity, including T-cell redistribution and activation with transient low-level cytokine release, was observed at doses ≥0.6 mg. The overall response rate (ORR) was 39% (15/38) among 38 evaluable patients. Among the 12 patients treated with doses ≥120 mg, the ORR was 92%, including 1 stringent complete response (sCR), 3 complete responses (CRs), 5 very good partial responses (VGPRs), and 2 partial responses (PRs). Of the 4 MRD evaluable patients with CR or sCR, 4 (100%) were MRD negative (≤ 10^–5). The median time to response (≥PR) was 1.2 months (range, 1.1-2.1). The median duration of response (DoR) was not reached, with only one patient experiencing progressive disease at a DoR of 22.2 months. Notably, patients experiencing treatment delays of at least 3 months due to adverse events (AEs) still exhibited sustained responses in one patient and deepened responses in two patients (from VGPR to CR and from PR to CR, respectively).

Conclusions: In this analysis of full dose escalation study, EMB-06 demonstrated a differentiated safety profile in RRMM patients, with low rates of CRS and no ICANS, and durable efficacy in heavily pre-treated RRMM patients.