First-in-Human Phase 1/2 Study of REGN5458 in Heavily Pretreated Patients with Multiple Myeloma

2022 Year in Review - Multiple Myeloma

REGN5458, a BCMAxCD38 bispecific antibody, demonstrated early durable responses with a tolerable safety profile and low rates of CRS in patients with relapsed/refractory multiple myeloma.

Patients with relapsed/refractory multiple myeloma often have limited treatment options in later lines of therapy, despite advances in the treatment landscape. REGN5458 is a BCMAxCD38 bispecific antibody that demonstrated a manageable safety profile with promising efficacy in preliminary data in heavily pretreated patients. At the 2022 European Hematology Association meeting, Zonder and colleagues presented updated safety, overall response, and durability results from the phase 1 portion of an ongoing trial of REGN5458.

The phase 1/2 trial aimed to assess the safety, tolerability, and dose-limiting toxicities with REGN5458, as well as determine the recommended phase 2 dose regimen. Eligible patients were double or triple refractory or intolerant to prior lines of systemic therapy including proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies. Seventy-three patients were treated with REGN5458 in the dose-escalation cohort, and doses ranged from 3 mg to 800 mg. A total of 38.4% of patients were penta-refractory, and patients had a median of 5 prior lines of therapy. The median duration of follow-up was 3 months.

All patients experienced treatment-emergent adverse events (TEAEs), with 42.5% and 32.9% experiencing grade 3 and 4 TEAEs, respectively. The most common all-grade TEAEs were fatigue (45.2%) and cytokine release syndrome (CRS) (38.4%), with the most common grade 3/4 TEAEs being hematologic in 39% of patients. No patients had grade 3 or higher CRS and no patients discontinued treatment due to CRS. Responses were observed across all doses, and 86.5% of responders achieved at least a very good partial response while 43.2% had a complete response (CR) or stringent CR. The response rate was 75% among patients treated with doses between 200 mg and 800 mg.

Overall, REGN5458 demonstrated a tolerable safety profile with low rates of CRS and no new safety signals during the additional follow-up period. Early and durable responses were seen in heavily pretreated patients, including a 75% response rate with doses ranging from 200 mg to 800 mg. The phase 2 portion of this study is ongoing.


  1. Zonder JA, Richter J, Bumma N, et al. S189: early, deep, and durable responses, and low rates of CRS with REGN5458, a BCMAXCD3 bispecific antibody, in a phase 1/2 first-in-human study in patients with relapsed/refractory multiple myeloma. HemaSphere. 2022;6:90-91.

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