Novel Bispecific Antibody, REGN5458, Demonstrates Positive Responses, Safety Profile in R/R Multiple Myeloma

Naresh Bumma, MD

Updated results from the ongoing phase 1/2 dose escalation and expansion study LINKER-MM1 (NCT03761108) show early, deep, and durable responses and low rates of cytokine release syndrome (CRS) in patients with relapsed/refractory (R/R) multiple myeloma who were treated with REGN5458, a B-cell maturation antigen (BCMA) and CD3 bispecific antibody.¹

In the phase 1 portion of the study, patients who were a minimum of triple-class refractory had an overall response rate (ORR) of 75%, with 58% of responders achieving a very good partial response (VGPR) rate or better at higher doses, according to Naresh Bumma, MD, a hematologist at the Ohio State University Comprehensive Cancer Center, during a presentation of the data at the 19th Annual International Myeloma Society Meeting. Bumma said 38% of patients experienced CRS, with the majority being grade 1, and occurring within the first 2 weeks with resolution occurring within 1 day.

The 4 plus 3 study design evaluated 73 patients who had R/R multiple myeloma and were treated with 3 or more prior lines of therapy including an immunomodulatory imide and proteasome inhibitor, and who had progressed on or after an anti-CD38 antibody. The study included 9 different dose levels that ranged from 3 mg to 800 mg with a step-up dose given on week 1 and 2 and a full dose administered once daily from week 3 to week 16. After week 16, a full dose was administered once every 2 weeks.

Primary objectives of the trial were safety, tolerability, and dose-limiting toxicities (DLTs). Investigators also determined the recommended phase 2 dose regimen. Secondary objectives were ORR, duration of response (DOR), progression-free survival, minimal residual disease (MRD) status, and overall survival.

Median age of patients was 64 years (range, 41-81) and 21% (15/73) were 75 years or older. Forty-seven percent were male and the majority (70%) had an ECOG performance status of 1. Patients had a median of 5 prior lines of therapy (range, 2-17), with 89% being triple-refractory, 70% being quad-refractory, and 38% being penta-refractory. Ninety percent of patients were refractory to their last line of therapy.

“Looking at the safety data, almost all patients had some sort of adverse reaction but the most common hematologic adverse reaction was anemia with all-grade being 32% and a grade 3 or more being 23%,” Bumma said.

The most common non-hematologic treatment-emergent adverse events were fatigue (45%), CRS (38%), and pyrexia (36%). Two patients experienced dose-limiting toxicities at dose level 4 (24 mg) and dose level 6 (96 mg) and the maximum-tolerated dose was not reached. Further safety data indicated 3 patients (4%) reported grade 2 immune cell–associated neurologic syndrome (ICANS) but no grade 3 ICANS.

Bumma said there were 5 deaths (7%) and these were attributed to sepsis (n = 3), COVID-19 (n = 1), and pneumonia (n =1). The investigators reported that these events were not related to study treatment.

Regarding CRS, 38% (28/73) reported this adverse event and the median time to first CRS onset was 10.1 hours (range, 6-47). The median duration was 14.7 hours (range, 0-96). For supportive care, 43% of patients received tocilizumab (Actemra) and 21% received steroids.

“No relationship was observed between CRS and dose level or CRS and response,” Bumma said.

Responses were observed for all dose levels and there was a trend for higher response rates at higher doses. At the data cut-off of September 30, 2021, investigators reported that the ORR was 29% in the 3-12 mg dose level (n = 24), 48% in the 24-96 mg dose level (n = 25), and 75% in the 200-800 mg dose level (n = 24). There was an 86% VGPR rate or better and 43% complete response (CR) rate or better among all responders.

Ten patients achieved a CR and stringent CR with available MRD data that were assessed using next-generation flow cytometry. Of those 10, 4 patients were negative MRD at 10-5, according to investigators.

Bumma said responses occurred early, were durable, and deepened over time. The median time to response was less than 1 month and 70% of responses occurred within the first 2 months. The estimated median DOR was not reached, with the longest responses ongoing for over 19 months at the latest data cut-off. The probability of responders being in response at 8 months was 90.2% (95% CI, 72.6%-96.7%).

“REGN5458 demonstrated promising efficacy and acceptable safety profile in patients with heavily pretreated R/R multiple myeloma and these results support further development as monotherapy,” Bumma said. “The phase 2 portion is currently recruiting.”

_REFERENCE

_{Zonder JA, Richter J, Bumma N, et al. 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 (RRMM). Presented at: 19th Annual International Myeloma Society Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-056.}