This phase 1, first-in-human study evaluates patients with relapsed/refractory multiple myeloma (RRMM) who are heavily pretreated with REGN5458. Results of this updated analysis are consistent with those of previous findings showing an acceptable safety profile and deep and durable responses. The phase 2 portion of the study is further progressing.
REGN5458 is a bispecific antibody designed to bind to B-cell maturation antigen (BCMA) on multiple myeloma cells and the CD3 receptor on T-lymphocytes, thereby bridging them together and promoting immunologically mediated cancer cell death. In a phase 1 trial in patients with RRMM, data showing an acceptable safety profile and preliminary clinical efficacy were presented previously. Updated safety and response durability data are now available. Primary objectives are to assess the safety, tolerability, and occurrence of dose-limiting toxicities (DLTs) of REGN5458; key secondary objectives include evaluation of overall response rate (ORR), duration of response (DOR), minimal residual disease status, pharmacokinetics, and pharmacodynamics.
Enrolled in the study were patients with multiple myeloma with progressive disease after ≥3 lines of systemic therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. Patients were treated with REGN5458 weekly followed by maintenance every 2 weeks. A typical 4+3 dose-escalation design was followed in this study.
The current updated analysis includes 45 patients who received REGN5458. Median age was 64.0 years, and 31.1% (N = 14) of patients were aged >70 years. Based on the Revised International Staging System, 60.0% and 22.2% of patients were stages II and III, respectively. Patients received a median of 5.0 prior lines of systemic therapy; 6.7% were triple refractory, 33.3% were quad refractory, 53.3% were penta refractory, and all patients were refractory to an anti-CD38 antibody. A prior autologous stem-cell transplantation was received by the majority of patients (71.1%; N = 32). Dose escalation from 3 mg to 96 mg over 6 dose levels was performed in cohorts; median duration of follow-up was 2.37 months.
Treatment-related adverse events (TRAEs) were experienced by 37.8% of patients with cytokine release syndrome (CRS), 17.8% with fatigue, 17.8% with nausea, and 13.3% with myalgia. Most CRS events were grade 1 (88.2%) and were mostly observed with the initial doses; no grade ≥3 events were observed. One patient experienced a DLT due to transient grade 3 liver transaminases associated with CRS. However, the patient recovered and achieved partial remission. A total of 6.7% of patients experienced infusion-related reactions and 46.7% of patients experienced infection-related adverse events (grade ≥3: 20%). One patient experienced a treatment-related neurologic event (grade 3 syncope 130 days after first infusion). In 4 patients, discontinuation due to adverse events occurred; 1 patient had both a TRAE and a DLT of grade 4 acute kidney injury. A total of 28.9% of patients and 22.2% of patients experienced grade >3 and serious TRAEs, respectively. The most common grade 3 TRAEs were anemia and lymphopenia (8.9% and 6.7%, respectively), and the most common serious TRAEs were caused by CRS (11.1%). Grade 5 adverse events were experienced by 3 patients (sepsis: 2; COVID-19: 1) unrelated to study drug.
Across all dose levels, ORR was 35.6%, 81.3% of patients achieve a very good partial response or better, and 31.3% of patients achieved a complete response or stringent complete response. At the highest dose level, ORR was 60%. In patients with extramedullary plasmacytomas, a lower ORR was observed at 16.7%. Regarding duration, 43.8% and 18.8% of patients had DORs >4 and >8 months, respectively.
In heavily pretreated patients with RRMM, updated analysis results of a phase 1, first-in-human study of REGN5458 are consistent with previous findings that show an acceptable safety profile and deep and durable responses. Continued assessment is warranted and ongoing. Enrollment is occurring for the phase 1 dose-escalation portion and recruitment for the phase 2 portion is ongoing.
Abstract 291. ASH 2020. December 5, 2020. REGN5458, a BCMA × CD3 bispecific monoclonal antibody, induces deep and durable responses in patients with relapsed/refractory multiple myeloma (RRMM).