The bispecific antibody REGN5459 appears safe and can produce durable responses in patients with relapsed or refractory multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2023.

REGN5459 binds to BCMA on MM cells and to CD3 on T cells, an interaction that causes T-cell activation and clearance of plasma cells, explained study presenter Attaya Suvannasankha, MD, of Indiana University in Indianapolis.

She and her colleagues found that REGN5459 produced responses lasting more than 26 months in MM patients who had exhausted all available treatment options. REGN5459 also caused cytokine release syndrome (CRS) in a majority of patients, but all CRS events were grade 1 or 2.

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These results come from a phase 1/2, first in-human trial of REGN5459 in 43 patients with relapsed/refractory MM ( Identifier: NCT04083534). The patients had received a median of 5 prior lines of therapy (range, 2-9), and 86% had received an autologous stem cell transplant. The median age at baseline was 67 (range, 26-85) years, 51.2% of patients were women, and 79.1% were White. 

Patients received REGN5459 at doses of 3-60 mg or 120-900 mg weekly. Step-up dosing was used to mitigate the risk of CRS. All patients also received 20 mg of dexamethasone as premedication, which was tapered after the full dose was reached. 

The maximum-tolerated dose was not reached, but the phase 2 dose was 480 mg. There was 1 dose-limiting toxicity (grade 3 hypoxia) at the 900 mg dose level. In addition, 16.3% of patients discontinued treatment due to treatment-emergent adverse events (TEAEs).

All patients experienced a TEAE. The most common hematologic TEAEs were neutropenia (39.5%) and anemia (34.9%), and the most common non-hematologic TEAE was CRS (53.5%). One patient developed grade 3 immune effector cell-associated neurotoxicity syndrome.

The rate of CRS increased as the dose of REGN5459 increased, from 23.1% at 3-60 mg to 33.3% at 120-240 mg and 81.0% at 480-900 mg. However, most cases of CRS (n=20) were grade 1. There was 1 case of grade 2 CRS and 2 cases of grade 3 CRS.

The objective response rate (ORR) was 65.1%. Patients achieved stringent complete responses (32.6%), complete responses (18.6%), very good partial responses (7.0%), and partial responses (7.0%). Among evaluable patients with a complete response or greater, 79.0% were negative for minimal residual disease. 

The ORRs increased as the dose of REGN5459 increased, from 23.1% with 3-60 mg to 66.7% with 120-240 mg and 90.5% with 480-900 mg. 

The median time to response was 0.8 months. At a median follow-up of 9 months, the median duration of response was not reached. The probability of maintaining a response at 12 months was 78.1%. The longest responses had lasted 26 months or longer at the data cutoff.

“REGN5459 shows early and durable response in patients with relapsed or refractory multiple myeloma who are heavily pretreated,” Dr Suvannasankha said. “The agent is efficacious and shows a manageable side effect profile. Further development of this agent is under consideration.”

Disclosures: This research was supported by Regeneron Pharmaceuticals. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 


Suvannasankha A, Kapoor P, Pianko MJ, et al. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMAxCD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma. AACR 2023. April 14-19, 2023. Abstract CT013.