Ongoing Phase 3 LINKER-MM3 Trial Assesses Safety and Efficacy of Linvoseltamab Monotherapy in Patients With RRMM

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The monotherapy is compared with the combination regimen of elotuzumab plus pomalidomide and dexamethasone in adult patients with relapsed or refractory multiple myeloma.

Burgundy ribbon for multiple myeloma awareness -- Image credit: Jo Panuwat D | stock.adobe.com

Image credit: Jo Panuwat D | stock.adobe.com

About the Trial

Trial Name: A Trial to Learn How Well Linvoseltamab Works Compared to the Combination of Elotuzumab, Pomalidomide and Dexamethasone for Adult Participants With Relapsed/​Refractory Multiple Myeloma (LINKER-MM3)

ClinicalTrials.gov ID: NCT05730036

Sponsor: Regeneron Pharmaceuticals

Completion Date (Estimated): December 26, 2032

In the multiple myeloma space, frontline treatment often consists of a combination of 2 to 4 active drugs, including an immunomodulatory drug, a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb). Relapse continues to be a persistent and significant problem when treating multiple myeloma, and there is currently no single algorithm or regimen to treat patients with relapsed or refractory multiple myeloma (RRMM).1

Currently, pomalidomide-based regimens are available as treatment in the RRMM setting, and the combinations that avoid the re-use of anti-CD38 mAbs are of greater importance following the positioning of these mAbs in frontline therapy. Additionally, elotuzumab (Empliciti; Bristol Myers Squibb and AbbVie) in combination with pomalidomide (Pomalyst; Bristol Myers Squibb) and dexamethasone (EPd, Darzalex; Janssen Biotech) is a recognized anti-CD38 mAb-free combination; however, approximately half of patients responded to this regimen and the efficacy in patients with RRMM who were previously exposed to anti-CD38 mAbs has not yet been assessed. With this knowledge, investigators looked to expand the available treatment options with drugs that have new mechanisms in patients with multiple myeloma, and more specifically, RRMM.1

Further, the FDA accepted for priority review the biologics license application (BLA) for linvoseltamab (REGN5458; Regeron Pharmaceuticals) to treat adult patients with RRMM whose disease progressed after at least 3 prior therapies. The BLA came after data from the phase 1/2 LINKER-MM1 trial (NCT03761108) and was accepted in February 2024; the FDA is targeting August 22, 2024, as an action date for decision.2

Linvoseltamab is an investigational bispecific antibody that is designed to bridge B-cell maturation antigen on MM cells with CD3-expressing T cells to accelerate T-cell activation and the killing of cancer cells. In the phase 1/2 trial, it was administered with an initial step-up dosing regimen, and was then followed by a full dose. The phase 1 section of the trial assessed safety, tolerability, and dose-limiting toxicities across 9 different levels of linvoseltamab and administration regimens, then the phase 2 dose expansion portion assessed safety and anti-tumor activity of the bispecific antibody.2

Currently, an open-label, randomized phase 3 clinical trial, LINKER-MM3 (NCT05730036), is assessing the safety and efficacy of linvoseltamab monotherapy compared with the EPd combination therapy in patients with RRMM who are 18 years or older. All eligible patients have received at least 1 and up to 4 prior lines of therapy, including lenalidomide and a PI, and have progressed either while on or following the last therapy. Additionally, the investigators note that prior treatment with an anti-CD38 mAb is acceptable for enrollment eligibility. Further, all patients had to have measurable disease according to 2016 International Myeloma Working Group (IMWG); no prior treatment with elotuzumab, pomalidomide, or B-cell maturation antigen-directed immunotherapies; and adequate bone marrow reserves and hepatic, renal, and cardiac function.1,3

A total of 286 enrolled patients are randomly assigned to receive either an intravenous (IV) infusion of linvoseltamab or the combination EPd therapy, with elotuzumab administered via an IV infusion, pomalidomide capsules administered orally, and either dexamethasone tablets or capsules administered orally, or via an IV infusion. Both regimens will be administered in 28-day cycles and will continue to be given until disease progression, intolerance, or another defined reason leading to drug discontinuation.1,3

According to the investigators, the trial’s primary end point is progression-free survival as per IMWG criteria up to approximately 5 years, and key secondary end points are objective response rate, minimal residual disease negative status, and overall survival, which will also be assessed up to 5 years. Additionally, change in pain following treatment will be assessed at week 12, and the incidence and severity of treatment-emergent adverse events will also be assessed up to 5 years.1,3

The trial is currently ongoing to determine the utility of linvoseltamab monotherapy as an alternative treatment to the EPd combination therapy in patients with RRMM.1,3

References

1. Weisel K, Hungria V, Quach H, et al. PB2133: TRIAL IN PROGRESS: LINKER-MM3, A PHASE 3, OPEN-LABEL, RANDOMIZED STUDY OF LINVOSELTAMAB VERSUS ELOTUZUMAB, POMALIDOMIDE, AND DEXAMETHASONE (EPD) IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM). Hemasphere. 2023;7(Suppl ):e465366a. Published 2023 Aug 8. doi:10.1097/01.HS9.0000975296.46536.6a
2. McGovern, G. FDA Accepts Priority Review for Linvoseltamab to Treat Adult Patients With R/R MM. Pharmacy Times. February 22, 2024. Accessed June 26, 2024. https://www.pharmacytimes.com/view/fda-accepts-priority-review-for-linvoseltamab-to-treat-adult-patients-with-r-r-mm
3. A Trial to Learn How Well Linvoseltamab Works Compared to the Combination of Elotuzumab, Pomalidomide and Dexamethasone for Adult Participants With Relapsed/​Refractory Multiple Myeloma (LINKER-MM3). ClinicalTrials.gov identifier: NCT05730036. Updated June 7, 2024. Accessed June 26, 2024. https://clinicaltrials.gov/study/NCT05730036
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