Updated Safety and Efficacy of REGN5458, a BCMAxCD3 Bispecific Antibody, Treatment for Relapsed/Refractory Multiple Myeloma: A Phase 1/2 First-in-Human Study

Background Multiple myeloma (MM) is a malignant plasma cell disorder. Despite major advancements in diagnosis and treatment, it remains an incurable malignancy. Relapsed disease ultimately becomes refractory to existing treatment options, underscoring the need for new therapeutic classes and targets. B cell maturation antigen (BCMA) is almost exclusively expressed in lymphocytes of B cell origin, and its expression is higher in malignant versus normal plasma cells, making it an ideal target for MM treatment. REGN5458 is a fully human BCMAxCD3 bispecific antibody designed to activate contact-dependent cytolytic killing of BCMA-expressing MM plasma cells by tissue-resident CD3 positive effector T-cells. In preclinical models of MM, REGN5458 demonstrated robust anti-myeloma activity (Di Lillo et al., Blood Advances, 2021). In the first-in-human trial (NCT03761108), REGN5458 induced early, deep, and durable responses with manageable safety profile in patients with relapsed and refractory MM (RRMM; Zonder et al., ASH, 2021). Here we report updated safety and efficacy data from the phase 1-2 study and identify the recommended phase 2 dose (RP2D). Methods Eligibility criteria required patients ≥18 years to be intolerant of, or have MM that progressed either on or after, at least 3 lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory imide (IMiD), and an anti-CD38 antibody, or have disease that is double refractory to a PI and an IMiD, and progressed on or after, an anti-CD38 antibody. The dose-escalation phase followed a modified 3+3 design (4+3) with a 28-day dose-limiting toxicity (DLT) observation period. The Phase 1 portion was comprised of 9 dose-levels. Step-up approach was used to mitigate cytokine release syndrome (CRS). The primary objectives of the escalation phase were to assess the safety, tolerability, and DLTs, and to determine the RP2D of REGN5458 as monotherapy in patients with RRMM. The primary objective of the expansion phase was to assess the objective response rate (ORR) as determined by an Independent Review Committee. Key secondary objectives included duration of response (DOR), progression free survival, rate of minimal residual disease negative status, and overall survival. Results As of January 28, 2022, 167 patients with RRMM across Phase 1 and 2 have received at least one dose of REGN5458. Median age was 64 (range 41-90), 49% of patients were male, patients had a median of 6 prior lines of therapy, and 90% were at least triple class refractory (refractory to a PI, IMiD, and anti-CD38 therapy); prior exposure to BCMA-targeting agents was excluded (except BCMA antibody-drug conjugates). High-risk cytogenetic features were present in 13.6% of patients while 18.6% were stage 3 per revised International Staging System (R-ISS); 40% had bone marrow plasmacytosis >50%. Across both phases, 164 (98.2%) patients experienced treatment-emergent adverse events (TEAEs) for whom 78.4% were Grade (G) 3 or higher TEAEs. The most common hematologic TEAEs were anemia 36.5% (≥G3 29.9%), neutropenia 28.7% (27.5%) and thrombocytopenia 21% (16.2%). The most common non hematologic TEAEs reported (≥ 30%) were CRS 47.9% (G1 36.5%, G2 10.8%, and one patient with G3 0.6% observed in the context of infection) and fatigue 34.1%. Five patients (3%) discontinued REGN5458 due to treatment related adverse events (TRAEs), there were no treatment discontinuations due to CRS. ORR was higher for phase 1 patients treated at ≥200 mg dose levels (N=24) as compared to that for patients treated at doses <200 mg (N=49), 75% versus 40.8%. This observation was consistent across patient subgroups by cytogenetic risk, R-ISS stage, prior therapy, and bone marrow plasmacytosis level. Responses deepened over time with 37.5% of patients with ≥CR. Median DOR has not been reached. Based on the overall benefit/risk profile, the RP2D was determined to be 200mg. Conclusions REGN5458 showed promising efficacy and an acceptable safety profile in patients with heavily pretreated RRMM. Phase 2 portion of the study at the RP2D of 200 mg is recruiting. Preliminary efficacy and updated data at the 200 mg dose will be presented at the meeting.