Bispecific Antibody REGN5459 Shows Activity in Patients With Relapsed or Refractory Multiple Myeloma

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Although the 5-year relative survival rate for multiple myeloma is improving—up from 34.6% in 1998 to 53.9% in 2016—due to the approval of more effective therapies, multiple myeloma remains incurable, and new treatment options are needed, especially in the relapsed/refractory setting.

A small phase I/II study investigating the antitumor activity, safety, and tolerability of REGN5459, a B-cell maturation antigen/CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma reported a response rate of 90.5% among patients treated with higher doses of the agent, of which 61.9% were complete responses or better. In addition, across all dose levels, 53.5% of patients experienced cytokine-release syndrome; most cases (87%) were grade 1. The study was presented by Suvannasankha et al during the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract CT013).

Study Methodology

The study investigators enrolled 43 patients with relapsed or refractory multiple myeloma following three or more prior lines of therapy, including an anti-CD38 antibody, proteasome inhibitor, and immunomodulatory drug. They had exhausted all available treatment options. The patients received REGN5459 until disease progression or intolerable toxicity. The primary objectives of the study were to assess safety, tolerability, dose-limiting toxicities, and to determine the recommended phase II dose (RP2D) of REGN5459 (phase I) and assess the efficacy of REGN5459 (phase II) per overall response rate.

In the phase I portion of the trial, patients were treated with full doses of the therapy ranging from 3 mg to 900 mg; 480 mg was selected as the recommended phase II dose.


In the phase I portion of the trial, one dose-limiting toxicity was reported in a patient receiving the highest dose (900 mg; grade 3 hypoxia). The patient was later found to have primary lung cancer. All of the patients had at least one treatment-emergent adverse event; 74% had grade 3 or higher treatment-emergent adverse events. All-grade treatment-emergent adverse events occurring in ≥ 30% of patients were cytokine-release syndrome (54%), fatigue (44%), neutropenia (37%), anemia (35%), cough (30%), and diarrhea (30%).

Grade 3 or higher treatment-emergent adverse events occurring in ≥ 15% of the patients were neutropenia (37%), anemia (26%), lymphopenia (23%), thrombocytopenia (19%), and hypertension (16%). Grade 1, 2, or 3 cytokine-release syndrome was reported in 47%, 2%, and 5% of patients, respectively; there was no instances of grade 4 or 5 cytokine-release syndrome. No grade 3 cytokine-release syndrome was reported in the phase II portion of the trial.


  • Patients with relapsed or refractory multiple myeloma who received the two highest doses of REGN5459 experienced a 90.5% overall response rate, of which 61.9% were complete responses or better.
  • Across all dose levels, 53.5% of patients experienced cytokine-release syndrome. No cases were grade 4 or 5, and 87% were grade 1. The condition did not lead to treatment discontinuation.

Tocilizumab was used in 19% of the patients and steroids were used in 9% of the patients. One patient developed immune effector cell–associated neurotoxicity syndrome (2%, grade 2). Incidence of serious treatment-emergent adverse events and treatment-emergent adverse events leading to treatment discontinuation was 63% and 16%, respectively. Infections occurred in 61% of patients (37% grade ≥ 3). After the data-cutoff, two deaths due to COVID-19 pneumonia and COVID-19 infection were reported.

The overall response rate was 67% (58% ≥ VGPR [very good partial remission]) for the entire cohort and 100% (85% ≥ VGPR; 15% stringent complete response; 39% complete response) among patients receiving the recommended phase II dose (n = 13). Median follow-up was 7 months (range = 1–26), with the longest response ongoing for 22+ months. Median time to response was 0.8 months. Median duration of response was not reached (95% confidence interval [CI] = 12 months to not evaluable); the 12-month duration of response rate for the recommended phase II dose was 66.7% (95% CI = 5.4–94.5 months). Of the patients with complete response or better with available measurable residual disease (MRD) results (n = 8), 50% were MRD-negative at the 10-5 threshold.

“These initial data show that REGN5459 has acceptable safety/tolerability in [relapsed/refractory multiple myeloma], with most [instances of] cytokine-release syndrome [being] low grade and low incidence of immune effector cell–associated neurotoxicity syndrome. Modulation of CD3 affinity on bispecific antibodies to maximize tumor killing and mitigate cytokine-release syndrome and T-cell exhaustion, warrants further research. Efficacy in this heavily pretreated cohort was encouraging, with an100% overall response rate with the recommended phase II dose,” concluded the study authors.

Promising Therapy for Patients With Relapsed/Refractory Multiple Myeloma

“In comparison to the average lifespan of heavily pretreated patients at this stage, which is 6 to 9 months, that the 1-year progression-free survival may be more than 70% is very promising,” said lead study author Attaya Suvannasankha, MD, Associate Professor of Clinical Medicine in the Division of Hematology and Oncology at Indiana University School of Medicine and a physician-scientist at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center.

Disclosure: Funding for this study was provided by Regeneron Pharmaceuticals. For full disclosures of the study authors, visit

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