The primary endpoint analysis from the pivotal trial (LINKER-MM1) investigating linvoseltamab (previously known as REGN5458) demonstrated that the investigational agent doses at 200 mg induced high rates of deep and durable responses in patients with relapsed/refractory (R/R) multiple myeloma (MM).

Multiple myeloma is the second most common blood cancer. Globally, there are over 176,000 new cases diagnosed annually and an estimated 35,000 people were diagnosed in the U.S. It is characterized by the proliferation of cancerous plasma cells (multiple myeloma cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury.

“Multiple myeloma remains an incurable disease, in which patients endure cycles of relapse and remission, resulting in a critical need for innovative medicines,” noted L. Andres Sirulnik, M.D., Ph.D., Senior Vice President, Translational and Clinical Sciences, Hematology at Regeneron.

“Current treatments are able to slow the progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies,” Sirulnik added.

Linvoseltamab is an investigational BCMAxCD3 bispecific antibody designed to bridge B-cell maturation antigen (BCMA) on multiple myeloma cells with CD3-expressing T cells to facilitate T-cell activation and cancer-cell killing.

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Novel treatment
The LINKER-MM1 study, an ongoing, open-label, multi-center Phase 1 / 2 dose-escalation and dose-expansion trial is investigating linvoseltamab in patients with R/R MM. The study enrolled 282 patients, all whom have received at least three prior lines of therapy or are triple refractory. The participating patients were received linvoseltamab using a step-up dosing regimen that was designed to help mitigate cytokine release syndrome (CRS), an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction.

The Phase 1 intravenous dose-escalation portion of the trial, which is now complete, primarily assessed safety, tolerability and dose-limiting toxicities across nine dose levels of linvoseltamab exploring different administration regimens. The Phase 2 dose expansion portion of the trial (LINKER-MM1) is further assessing the safety and anti-tumor activity of linvoseltamab, with a primary objective of ORR. Key secondary objectives include duration of response, PFS, rate of minimal residual disease negative status and overall survival.

Study outcomes
The study demonstrated 71% objective response rate (ORR), with 46% achieving a complete response (CR) or better after 11 months of median follow-up.

“With longer follow-up data on linvoseltamab, we’re seeing deep and durable responses with a complete response rate nearing 50% in a difficult-to-treat patient population who had received a median of 5 prior lines of therapy,” Regeneron’s Sirulnik said.

“Furthermore, in our trial, the regimen had a short monitoring time and a convenient, response-adapted administration schedule that enabled deep responders to go from every two-week to every four-week dosing. This regimen saved time for clinicians and patients, underscoring the potential for linvoseltamab as a patient-centric option in relapsed/refractory (R/R) multiple myeloma,” he added.

Study outcomes
‘At a median duration of follow-up of 11 months, an objective response rate of 71% as assessed by an independent review committee, with 46% achieving a complete response or better, was observed in patients treated with linvoseltamab 200 mg in the Phase 1/2 trial (n=117). After a minimum of 24 weeks of therapy, patients who achieved a very good partial response (VGPR) or better shifted from every two-week to every four-week dosing.

These results build on an earlier data cut, with 8 months of median follow-up, that will be presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition held December 9 to 12, 2023 in San Diego, CA.[1]

Among this group of patients, 27% of patients were over 75 years old, 16% had extramedullary plasmacytomas, 23% had bone marrow plasma cells ≥50%, and 39% had high-risk cytogenetics – representing a patient population with a high disease burden and typically poor prognosis. Additionally, 17% were Black or African American, mirroring rates that are representative of MM in the U.S.

Based on the latest data cut, all patients treated with 200 mg experienced an adverse event (AE), including 85% who experienced Grade ≥3 adverse events (AE). The most commonly occurring AE was cytokine release syndrome (CRS; 46%). Of the CRS cases, the majority (35%) were Grade 1, 10% were Grade 2 and there was one case (1%) of Grade 3 CRS. Adjudicated immune effector cell-associated neurotoxicity syndrome (ICANS) events occurred in 9 patients (8% all Grades); Grade 3 ICANS occurred in 3 patients, and no cases of ≥Grade 4 cases. All grade infections were observed in 73% of patients; 34% were Grade 3 or 4. Deaths due to treatment-emergent AEs on-treatment or within 30 days post last dose occurred in 14 patients (12%), of which 11 (9%) were due to infections.

The development program investigating linvoseltamab, including in earlier stages of the disease is underway. In the U.S., linvoseltamab has been granted Fast Track Designation for multiple myeloma by the FDA. Linvoseltamab is currently under clinical development, and its safety and efficacy have not been fully evaluated by any regulatory authority.

Later this year, Regeneron Pharmaceuticals, the company behind the development of linvoseltamab, plans to submit these results from phase 1 / 2 studies to regulatory authorities, including to submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA).

Clinical trial
Phase 1/2 Study of REGN5458 in Patients With Relapsed or Refractory Multiple Myeloma (LINKER-MM1) – ClinicalTrials.gov Identifier: NCT03761108
A Study to Examine the Effects of Novel Therapy Linvoseltamab in Combination With Other Cancer Treatments for Adult Patients With Multiple Myeloma That is Resistant to Current Standard of Care Treatments – ClinicalTrials.gov Identifier: NCT05137054

References
[1] Jagannath S, Richter J, Dhodapkar MV, Hoffman JE, Lee H, Suvannasankha A, Shah MR, Lentzsch S, Zonder JA, Baz R, Maly JJ, Namburi S, Wu KL, Pianko M, Ye CJ, Silbermann R, Min CK, Vekemans MC, Munder M, Byun JM, Lopez JM, DeVeaux M, Chokshi D, Boyapati A, Hazra A, Rodriguez Lorenc K, Kroog GS, Houvras Y, Bumma N. (4746) Patterns of Response to 200 Mg Linvoseltamab in Patients with Relapsed/Refractory Multiple Myeloma: Longer Follow-Up of the Linker-MM1 Study. Program: Oral and Poster Abstracts. Session: 653. Multiple Myeloma: Prospective Therapeutic Trials: Poster III Hematology Disease Topics & Pathways: Research, clinical trials, Biological therapies, adult, Bispecific Antibody Therapy, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies, Adverse Events, Study Population, Human. Monday, December 11, 2023, 6:00 PM-8:00 PM [Abstract]

Featured image: New Orleans, LA – ASH 2022- Photo courtesy: 2022 – 2023 © ASH/Nick Agro 2022. Used with permission.

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