First in Human (FIH) Study of REGN5458 in Patients With Relapsed or Refractory Multiple Myeloma LINKER-MM1

What's the purpose of this trial?

The primary objectives of the study are:

  • In the phase 1 portion of the study: To assess the safety, tolerability, and dose-limiting toxicities (DLTs) and to determine a recommended phase 2 dose regimen (RP2DR) of REGN5458 as monotherapy in patients with relapsed or refractory multiple myeloma (MM).
  • In the phase 2 portion of the study: To assess the anti-tumor activity of REGN5458 as measured by objective response rate (ORR) and as determined by an Independent Review Committee (IRC)

This trial is currently open and accepting patients.

What will happen during the trial?

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

Key Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
  • Confirmed diagnosis of active Multiple Myeloma (MM) by International Myeloma Working Group (IMWG) diagnostic criteria
  • Patients must have myeloma that is response-evaluable according to the 2016 IMWG response criteria.
  • Phase 1 Dose Escalation: Patients with MM who have exhausted all therapeutic options that are expected to provide meaningful clinical benefit, either through disease relapse, treatment refractory disease or intolerance of the therapy and including either:
    1. Progression on or after at least 3 lines of therapy, or intolerance of therapy, including a proteasome inhibitor, an Immunomodulatory agent (IMiD), and an anti-CD38 antibody, OR
    2. Progression on or after an anti-CD38 antibody and have disease that is "double refractory" to a proteasome inhibitor and an IMiD, or intolerance of therapy. The anti-CD38 antibody may have been administered alone or in combination with another agent such as a proteasome inhibitor. Refractory disease is defined as lack of response or relapse within 60 days of last treatment.
  • Phase 2: Patients must be triple-refractory, defined as being refractory to prior treatment with at least 1 anti-CD38 antibody, a proteasome inhibitor, and an IMiD. In addition, patients must be penta-exposed (ie, having prior exposure to 2 PIs, 2 IMiDs [lenalidomide and pomalidomide], and 1 anti-CD38 monoclonal antibody). Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or less than 25% response to therapy.

Key Exclusion Criteria:

  • Diagnosis of plasma cell leukemia, primary systemic light-chain amyloidosis, (excluding myeloma-associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Patients with known MM brain lesions or meningeal involvement
  • Prior treatment with BCMA-directed immunotherapies, including BCMA bispecific antibodies and BiTEs, and BCMA CAR T cells. Note: BCMA antibody-drug conjugates are not excluded
  • History of allogeneic stem cell transplantation at any time, or autologous stem cell transplantation within 12 weeks of the start of study treatment

Note: Other protocol defined inclusion / exclusion criteria apply

Additional Trial Information

Phase 1/2

Enrollment: 291 patients (estimated)

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Published Results

REGN5458 Elicits Early, Sustainable Responses in Heavily Pretreated Multiple Myeloma

June 13, 2022

The overall response rate (ORR) was 51% among all enrolled patients (n = 73). Among all responders, 86% achieved a very good partial response (VGPR) or better and 43% achieved a complete response (CR) or better.

All-grade treatment-emergent adverse effects (TEAEs) occurred in 100% of patients (grade 3, 42%; grade 4, 33%).

Hematologic TEAEs occurring in at least 20% of patients included anemia (all grade, 32%; grade 3, 23%), lymphopenia (all grade, 23%; grade 3, 10%; grade 4, 10%), neutropenia (all grade, 23%; grade 3, 7%; grade 4, 15%), and thrombocytopenia (all grade, 21%; grade 3, 8%; grade 4, 5%).

Nonhematologic TEAEs occurring in at least 20% of patients included fatigue (all grade, 45%; grade 3, 3%), CRS (all grade, 38%), pyrexia (all grade, 36%; grade 3, 4%), nausea (all grade, 33%), dyspnea (all grade, 26%), diarrhea (all grade, 25%; grade 3, 3%), back pain (all grade, 25%; grade 3, 5%), vomiting (all grade, 25%), pneumonia (all grade, 23%, grade 3, 11%), chills (all grade, 22%; grade 3, 1%), cough (all grade 22%), and headache (all grade, 21%; grade 3, 3%).

Three patients (4%) experienced grade 2 immune effector cell–associated neurotoxicity syndrome (ICANS); notably, no grade 3 ICANS events were reported.

Five (7%) grade 5 AEs occurred due to sepsis (n = 3), COVID-19 (n = 1), and pneumonia (n = 1); all deaths were determined to be unrelated to study treatment.

Across the study population, 38% of patients developed CRS. Most CRS events were grade 1 (n = 25), and only 3 patients (4%) experienced grade 2 CRS; no grade 3 or greater CRS events occurred.

Early, Deep, and Durable Responses, and Low Rates of Cytokine Release Syndrome with REGN5458, a BCMAxCD3 Bispecific Monoclonal Antibody, in a Phase 1/2 First-in-Human Study in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

December 11, 2021

As of data cut-off (June 10, 2021), 68 pts were treated with REGN5458 in the dose escalation cohort with full doses ranging from 3–400 mg. The median age at enrollment was 64 years (range, 41‒81) and 20.6% pts were ≥75 years. As per Revised International Staging System, stage was 1, 2 or 3 in 14.7%, 60.3% and 23.5% of pts respectively. Pts had a median of 5 prior lines of systemic therapy (range, 2–17) with the majority of pts (51.5%) being penta-refractory (see Table). The median duration of follow-up was 2.4 months (range, 0.1–20.8).

Treatment-emergent adverse events (TEAE) were reported in 66 pts (97.1%), and Grade (Gr) ≥3 TEAEs in 52 (76.5%) pts. The most frequent TEAEs were fatigue in 29 pts (42.6%), Gr 1/2 in 26 pts (38.2%), Gr 3 in 3 pts (4.4%); cytokine release syndrome (CRS) in 26 pts (38.2%), CRS was Gr 1 in 23 pts (33.8%) and Gr 2 in 3 pts (4.4%). No pt had Gr ≥3 CRS or discontinued treatment due to CRS. There were no Gr ≥3 neurotoxicity events. Nausea was reported in 22 pts (32.4%). The severity of nausea was Gr 1 in 23.5% of pts and Gr 2 in 8.8% of pts.

Treatment-related adverse events (TRAE) were reported in 56 patients (82.4%). The most frequent hematologic TRAE was neutropenia in 11 pts (16.2%), with Gr ≥3 severity in 9 of these pts (13.2%). The most frequent non-hematologic TRAEs were CRS (38.2%) and fatigue (20.6%). The safety profile was consistent across all dose levels, and there was no correlation between CRS and the full dose of REGN5458.

Responses were observed at all dose levels. Amongst pts treated at the 96 and 200 mg dose levels, the response rate was 73.3% (11/15). Across all dose levels, 92.6% (n=25) of all responders achieved at least a very good partial response and 48.1% (n=13) of responders had a complete response (CR) or stringent CR. Pts without extramedullary plasmacytomas (EMP) responded more frequently than those with EMP. The Kaplan–Meier estimated median DOR was not reached and the probability of DOR ≥8 months was 92.1% (95% confidence interval: 72.1, 98.0), with responses ongoing up to 19 months at the latest data cut-off.

Disease response was not impacted by level of BCMA expression in the core biopsy, as assessed by immunohistochemistry.

BCMA/CD3 Bispecific Antibody REGN5458 Elicits Early, Deep Responses in Relapsed/Refractory Myeloma

December 05, 2020

Results indicated that 95% (n = 18) of 19 patients who responded to treatment experienced a very good partial response (VGPR) or better and 42% achieved a complete response (CR) or a stringent CR (sCR).

At a median follow-up of 2.6 months, patients who received the agent at a dose of 3 mg, 6 mg, or 12 mg (n = 24; dosing levels [DL] 1-3) experienced an overall response rate (ORR) of 29.2%; 20.9% of these responders experienced a CR or sCR, while 4.2% had VGPR or better and 4.2% achieved a partial response (PR).

The ORR was higher among those who received REGN5458 at a dose of 24 mg or 48 mg (n = 17; DL 4-5), at 41.2%, with 11.8% of patients collectively experiencing a CR (11.8%)/sCR (5.9%) and 23.5% of patients achieving a VGPR. Patients who received 96 mg (n = 8; DL 6), the highest dose of the antibody evaluated on the trial, experienced the highest ORR, at 62.5%; all of these patients had a VGPR.

First Clinical Data for REGN5458 (BCMAxCD3) Show Positive Preliminary Results in Multiple Myeloma

December 08, 2019

Results were presented today at the American Society of Hematology (ASH) Annual Meeting from the first two dose groups (3 mg and 6 mg weekly doses).

  • Patients had a median of seven lines of prior systemic therapy, and all had failed CD38 antibody treatment.
  • Responses were observed in 4 of 7 (57%) patients, including 3 of 4 (75%) in the 6 mg dose group.
  • In the 6 mg dose group, 2 patients (50%) were also minimal residual disease (MRD) negative, meaning that no cancer cells were detectable in their bone marrow.

Trial Locations

All Trial Locations

View all clinical trial locations sorted by state.


Sylvester Comprehensive Cancer Center University of Miami Health System

Miami, FL

Open and Accepting

Moffitt Cancer Center Magnolia Campus

Tampa, FL

Open and Accepting


Winship Cancer Institute of Emory University

Atlanta, GA

Open and Accepting


IU Simon Cancer Center Indiana University

Indianapolis, IN

Open and Accepting


Norton Cancer Institute (St. Matthews) St. Matthews Campus

Louisville, KY

Open and Accepting


University of Michigan Comprehensive Cancer Center

Ann Arbor, MI

Open and Accepting

Barbara Ann Karmanos Cancer Institute Wayne State University

Detroit, MI

Open and Accepting

New Jersey

Rutgers Cancer Institute of New Jersey Rutgers, The State University of New Jersey

New Brunswick, NJ

Open and Accepting

New York

Mount Sinai Hospital Tisch Cancer Institute

New York, NY

Open and Accepting



Oregon Health and Science University (OHSU) Knight Cancer Institute

Portland, OR

Open and Accepting


MD Anderson Cancer Center The University of Texas

Houston, TX

Open and Accepting


Swedish Medical Center (Ballard Campus)

Seattle, WA

Open and Accepting

Trial Links

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