REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Madduri Deepu , Rosko Ashley , Brayer Jason , Zonder Jeffrey , Bensinger William I. , Li Jingjin , Xu Linzhi , Adriaens Lieve , Chokshi Dhruti , Zhang Weijiang , Boyapati Anita , Sharma Manish , Seebach Frank , Sirulnik L. Andres , Weinreich David M. , Yancopoulos George D. , Dhodapkar Madhav V. , Lentzsch Suzanne , Cooper Dennis , Jagannath Sundar 
Published: November 2020

Background
Multiple myeloma (MM) is characterized by expression of the cell surface protein B-cell maturation antigen (BCMA), a validated target for therapeutic intervention. REGN5458 is a BCMA x CD3 bispecific antibody (Ab) that binds to both BCMA and CD3, thereby targeting MM cells with T-cell effector function via BCMA. Previously, we presented data showing REGN5458 has an acceptable safety profile with evidence of clinical efficacy in heavily pre-treated patients with RRMM. Here we describe the updated safety and response durability in a Phase 1 trial of REGN5458 monotherapy in patients with RRMM (NCT03761108).
Methods
The primary objectives of the Phase 1 portion of the study are to determine the safety, tolerability, and occurrence of dose-limiting toxicities (DLTs) of REGN5458. Key secondary objectives include assessment of objective response rate (ORR), duration of response (DOR), minimum residual disease (MRD) status, pharmacokinetics (PK), and pharmacodynamics. Enrollment into the Phase 1 portion follows a standard 4+3 dose escalation design. Enrolled patients must have progressive MM after ≥3 prior lines of systemic therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 Ab. Treatment consists of weekly doses of REGN5458, followed by a maintenance phase administered every 2 weeks. Response assessments are according to modified International Myeloma Working Group criteria. MRD is assessed by flow cytometry.
Results
As of the June 15, 2020 data cut-off, 45 patients were treated with REGN5458. The median age at enrollment was 64.0 years (range, 41−81), of which 14 (31.1%) patients were &gt;70 years. As per Revised International Staging System, 60.0% and 22.2% of patients were stage 2 and 3, respectively. Patients had a median of 5.0 (range, 2−17) prior lines of systemic therapy; 32 patients (71.1%) received a prior autologous stem cell transplant. All patients were refractory to an anti-CD38 Ab; 6.7% were triple-refractory, 33.3% were quad-refractory, and 53.3% were penta-refractory. REGN5458 was escalated in cohorts from 3−96 mg over six dose levels. The median duration of follow-up was 2.37 months (range, 0.7−12.3).
The most common treatment-related adverse events (TRAEs) include cytokine release syndrome (CRS; 37.8%), fatigue (17.8%), nausea (17.8%), and myalgias (13.3%). CRS occurred primarily during the initial doses and was Grade (Gr) 1 in 88.2% of patients. No patients had Gr &gt;3 CRS. Infusion-related reactions occurred in 6.7% of patients. Infection-related adverse events (AEs) occurred in 46.7% of patients (Gr ≥3 20%). Gr &gt;3 treatment-related neurological events occurred in one patient (Gr 3 syncope 130 days after first infusion). Four patients discontinued due to AE with one patient having a TRAE (also DLT) of Gr 4 acute kidney injury. One patient had a DLT due to transient Gr 3 liver transaminases associated with CRS. Upon recovery, the patient continued study drug and has achieved ongoing partial remission. Gr &gt;3 TRAEs occurred in 28.9% of patients, with the most common being anemia (8.9%) and lymphopenia (6.7%). Serious TRAEs occurred in 22.2% of patients, with the most common due to CRS (11.1%). Gr 5 AEs (all unrelated to study drug) occurred in three patients: two sepsis and one COVID-19.
ORR was 35.6% across all dose levels (60% in highest dose level), with 81.3% of responders achieving at least a very good partial response; 31.3% had a complete response (CR) or stringent CR. A total of 43.8% of responders had a DOR &gt;4 months and 18.8% had a DOR &gt;8 months. The ORR in patients with extramedullary plasmacytomas was 16.7%.
Additional efficacy, PK, and biomarker data will be available at the time of presentation.
Conclusions
In this updated analysis of the first-in-human study, REGN5458 continues to show an acceptable safety profile and durable efficacy in heavily pre-treated patients with RRMM. Enrollment in the Phase 1 dose escalation portion is ongoing, and the Phase 2 portion of the study is recruiting.

Disclosures
Madduri: Janssen: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Brayer:Janssen: Consultancy; Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau. Zonder:Prothena: Consultancy; BMS: Consultancy, Research Funding; Caelum: Consultancy; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Other: Personal fees; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Research Funding. Bensinger:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Li:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Xu:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Adriaens:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Dosing regime that mitigates cytokine release syndrome for therapeutic antibodies (status: pending). Chokshi:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Boyapati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sharma:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Seebach:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sirulnik:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Weinreich:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Dhodapkar:Amgen: Membership on an entity's Board of Directors or advisory committees, Other; Kite: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Membership on an entity's Board of Directors or advisory committees, Other; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other. Lentzsch:Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celularity: Consultancy, Other; Janssen: Consultancy; Karyopharm: Research Funding; Magenta: Current equity holder in private company. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy.

OffLabel Disclosure:
The data described in the abstract will report on use of REGN5458 in a first-in-human trial in patients with multiple myeloma.