On May 22, 2025 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported initial results from two cohorts of the Phase 1b LINKER-MM2 trial evaluating linvoseltamab in combination with two different proteasome inhibitors (PI) – carfilzomib or bortezomib – in patients with relapsed/refractory (R/R) multiple myeloma (MM) (Press release, Regeneron, MAY 22, 2025, View Source [SID1234653315]). The trial included patients who had progressed after at least two lines of therapy and were either double-class refractory (immunomodulatory drug [IMiD] and PI) or triple-class exposed (IMiD, PI and anti-CD38 monoclonal antibody). The data will be featured in two oral presentations at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2025 Annual Meeting on Monday, June 2 at 8:00 AM CDT.
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"In clinical trials, treatment with linvoseltamab monotherapy in later-line settings generated impressive response rates, warranting investigation in earlier lines as well as in combination with other cancer therapies," said Salomon Manier, M.D., Ph.D., Professor of Hematology at Lille University Hospital in France. "While early, these compelling results for linvoseltamab combination therapy demonstrated high rates of clinical activity, even amongst those with previous exposure to the proteasome inhibitors evaluated in the cohorts. We look forward to seeing these results mature to see if these benefits can be maintained."
Linvoseltamab combined with carfilzomib showed strong responses in R/R MM
All treated patients (n=23) had previous exposure to PIs and more than half (n=12) were refractory to at least one PI. Moreover, 48% had baseline soft tissue plasmacytomas, and 39% were over 75 years old, representing a patient population with high-risk features. Of the 21 patients evaluable for efficacy, 11 patients received linvoseltamab 100 mg, and five patients each received linvoseltamab 150 mg or 200 mg prior to initiation of carfilzomib.
With a median follow-up of 15 months, efficacy results across all dose levels showed a 90% objective response rate (ORR; 19 of 21 patients), with 76% (16 of 21 patients) achieving a complete response (CR). At 12 months, the estimated probability of maintaining a response was 87% (n=19; 95% confidence interval [CI]: 56% to 97%) and being progression-free was 83% (n=21; 95% CI: 55% to 94%). A registrational, randomized Phase 3 trial investigating this combination against standard-of-care in the same setting is planned.
Among the 23 patients evaluable for safety, the most common treatment emergent adverse events (TEAEs; >50%) of any grade and Grade ≥3 were neutropenia (65% and 56.5%), cytokine release syndrome (CRS; 61% and 0%), diarrhea (52% and 4%) and thrombocytopenia (52% and 30%). Infections occurred in 91% of patients (Grade ≥3: 43.5%, including one fatality). Serious adverse events (SAEs) occurred in 83% of patients. One dose-limiting toxicity (DLT) of Grade 4 thrombocytopenia during tumor lysis syndrome was observed in the 100 mg dose level, and one Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in the 150 mg dose level.
Additional linvoseltamab combination with bortezomib showed promising clinical activity in R/R MM
Among enrolled patients (n=24), 6 received linvoseltamab at 100 mg and 18 at 200 mg before initiating bortezomib. More than half were refractory to PIs, including 58% to carfilzomib and 13% to bortezomib. Of the 20 patients evaluable for efficacy and with a median duration of follow-up of 9 months, results across dose levels showed an 85% ORR (17 of 20 patients), with 50% (10 of 20 patients) achieving a CR.
The most common TEAEs (>50%) of any grade and Grade ≥3 were CRS (58% and 0%), neutropenia (54% and 50%) and thrombocytopenia (54% and 37.5%). Four patients experienced ICANS (one Grade 1 and three Grade 2). Infections occurred in 75% of patients (Grade ≥3: 38%). SAEs occurred in 83% of patients. Two patients died due to adverse events: one due to pneumonia deemed related to treatment and occurring prior to initiation of bortezomib, and another due to COVID-19 deemed unrelated to treatment. One DLT of Grade 3 cytomegalovirus reactivation was observed in the 200 mg dose level.
The uses of linvoseltamab in combination with either carfilzomib or bortezomib in patients with R/R MM are investigational and have not been approved by any regulatory authority.
Linvoseltamab is approved in the European Union as Lynozyfic for adults to treat R/R MM that has progressed after at least three prior therapies (including a PI, an IMiD and an anti-CD38 monoclonal antibody) and that has demonstrated progression on the last therapy. For complete product information, please see the Summary of Product Characteristics that can be found on www.ema.europa.eu. In the U.S., the FDA accepted for review the Biologics License Application for linvoseltamab in adults with R/R MM with a target action date of July 10, 2025.
About Multiple Myeloma
As the second most common blood cancer, there are over 187,000 new cases of MM diagnosed globally every year, with more than 36,000 diagnosed and 12,000 deaths anticipated in the U.S. in 2025. In the U.S., there are approximately 8,000 people who have MM that has progressed after three lines of therapy. The disease is characterized by the proliferation of cancerous plasma cells (MM cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury. Despite treatment advances, MM is not curable and while current treatments are able to slow progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies.
About LINKER-MM2
LINKER-MM2 is a Phase 1b, open-label clinical trial evaluating linvoseltamab in combination with other cancer treatments in patients with R/R MM. Combination treatments include standard-of-care and novel therapies such as IMiD, PIs, anti-CD38 antibodies, checkpoint inhibitors, and a gamma secretase inhibitor. The primary endpoints are incidence of DLTs (dose-finding portion only) and incidence and severity of TEAEs. Secondary endpoints include ORR, DoR and progression-free survival.
In the carfilzomib cohort, linvoseltamab is administered first with an initial step-up dosing regimen followed by at least two full doses (100, 150 or 200 mg) before initiation of carfilzomib (56 mg/m²). In the bortezomib cohort, the same initial step-up process is followed but linvoseltamab is administered with at least one full dose (100 or 200 mg) before initiation of bortezomib (1.3 mg/m²).
About the Linvoseltamab Clinical Development Program
Linvoseltamab is an investigational 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.
Linvoseltamab is being investigated in a broad clinical development program exploring its use as a monotherapy as well as in combination regimens across different lines of therapy in MM, including earlier lines of treatment, as well as plasma cell precursor disorders.
In addition to LINKER-MM2, trials include:
LINKER-MM1: Phase 1/2 dose-escalation and dose-expansion trial evaluating the safety, tolerability, dose-limiting toxicities and anti-tumor activity of linvoseltamab monotherapy in R/R MM
LINKER-MM3: Phase 3 confirmatory trial evaluating linvoseltamab monotherapy compared to the combination of elotuzumab, pomalidomide and dexamethasone in R/R MM
Phase 1 trial evaluating linvoseltamab in combination with a Regeneron CD38xCD28 costimulatory bispecific in R/R MM
LINKER-MM4: Phase 1/2 trial evaluating linvoseltamab monotherapy in newly diagnosed MM
LINKER-SMM1: Phase 2 trial evaluating linvoseltamab monotherapy in high-risk smoldering MM
LINKER-MGUS1: Phase 2 dose-ranging trial evaluating linvoseltamab monotherapy in high-risk monoclonal gammopathy of unknown significance and non-high-risk SMM
LINKER-AL2: Phase 1/2 trial evaluating linvoseltamab monotherapy in R/R systemic light chain amyloidosis
For more information on Regeneron’s clinical trials in blood cancer, visit the clinical trials website, or contact via [email protected] or 844-734-6643.
About Regeneron in Hematology
At Regeneron, we’re applying more than three decades of biology expertise with our proprietary VelociSuite technologies to develop medicines for patients with diverse blood cancers and rare blood disorders.
Our blood cancer research is focused on bispecific antibodies that are being investigated both as monotherapies and in various combinations and emerging therapeutic modalities. Together, they provide us with unique combinatorial flexibility to develop customized and potentially synergistic cancer treatments.
Our research and collaborations to develop potential treatments for rare blood disorders include explorations in antibody medicine, gene editing and gene-knockout technologies, and investigational RNA-approaches focused on depleting abnormal proteins or blocking disease-causing cellular signaling.