MM-087 Early, Deep, and Durable Responses, and Low Rates of Cytokine Release Syndrome With REGN5458, a BCMAxCD3 Bispecific Antibody, in a Phase 1/2 First-In-Human Study in Patients With Relapsed/Refractory Multiple Myeloma

Context: Despite advances in treatment options, multiple myeloma remains incurable. REGN5458 is a BCMAxCD3 bispecific antibody under investigation in relapsed/refractory multiple myeloma (RRMM): ongoing Phase 1/2 trial (NCT03761108). Objective: To describe updated safety, overall response, and response durability in patients treated with REGN5458 in the Phase 1 part. Design: The Phase 1 part follows a modified 3+3 dose-escalation design (4+3). Patients: Eligible patients with progressive RRMM, who were double- or triple-refractory, or intolerant to prior lines of systemic therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody, were included. Interventions: Sixteen weekly infusions of REGN5458 monotherapy, then every two weeks until disease progression. Main Outcome Measures: Primary objectives were to assess safety, tolerability, and occurrence of dose-limiting toxicities of REGN5458, and to determine a recommended Phase 2 dose regimen. The objective response rate by modified International Myeloma Working Group criteria was a key secondary objective. Results: At data cut-off (September 30, 2021), 73 patients were treated with REGN5458 in the dose-escalation cohort, with full doses ranging from 3–800 mg. The median age at enrollment was 64 years (range, 41–81). As per the Revised International Staging System, stages were 1, 2, or 3 in 15.0%, 57.5%, and 23.3% of patients, respectively. Patients had a median of five prior lines of systemic therapy (range, 2–17), with 89% of patients being triple-refractory. The median duration of follow-up was 3.0 months (range, 0.7–22.1). The most common treatment-emergent adverse events (TEAEs) were fatigue (45.2%), cytokine release syndrome (CRS) (38.4%), pyrexia (35.6%), and nausea (32.9%). There were no Grade ≥3 CRS or Grade ≥3 neurotoxicity events, and no treatment discontinuation due to CRS. Grade 3 and 4 TEAEs were reported in 31 (42.5%) and 24 patients (32.9%), respectively. The most common Grade 3/4 TEAEs were hematologic (39.0%). Responses were observed at all dose levels. Amongst patients treated at the 200–800 mg dose levels, the response rate was 75% (n=18/24). The median duration of response was not reached. Conclusions: REGN5458 shows early, deep, and durable responses with a manageable safety profile in triple or greater-refractory patients with RRMM. This study is funded by Regeneron.