Linvoseltamab Plus Carfilzomib Is Safe, Feasible, and Elicits Durable Responses in R/R Myeloma

Treatment with the combination of linvoseltamab-gcpt (Lynozyfic) and carfilzomib (Kyprolis) was feasible and had an expected safety profile in patients with relapsed/refractory multiple myeloma, according to initial findings from a dose-finding portion of the phase 1b LINKER-MM2 trial (NCT05137054), which were presented at the 22nd Annual International Myeloma Society Meeting and Exposition.1

Among 17 dose-limiting toxicity (DLT)–evaluable patients (100 mg linvoseltamab, n = 10; 150 mg linvoseltamab, n = 3; 200 mg linvoseltamab, n = 4), 1 DLT of grade 4 thrombocytopenia during tumor lysis syndrome was reported. This DLT occurred in a patient treated at the 100-mg dose of linvoseltamab. Notably, this patient had elevated serum free light chain levels. This adverse effect (AE) fully resolved, and treatment was resumed at the same dose.

All safety-evaluable patients (n = 23) experienced at least 1 any-grade treatment-emergent AE (TEAE), and grade 3 or higher TEAEs were reported in 82.6% of patients. Serious TEAEs were reported in 82.6% of patients. TEAEs led to linvoseltamab discontinuation, carfilzomib discontinuation, and death in 8.7%, 26.1%, and 8.7% of patients, respectively.

“The safety profile was generally consistent with expectations [for] the combination based on known toxicities of the drugs,” lead study author Salomon Manier, MD, PhD, said in the poster presentation.

Manier is an associate professor in the Hematology Department at Lille University Hospital in France.

Among patients in the total population, at a median follow-up of 14.8 months (range, 2-29) and a data cutoff date of March 7, 2025, linvoseltamab plus carfilzomib (n = 23) elicited an overall response rate (ORR) of 90%. The rates of stringent complete response (sCR), CR, very good partial response (VGPR), and PR were 48%, 29%, 10%, and 5%, respectively. The 2 patients without responses achieved biochemical CR without resolution of soft tissue plasmacytomas on imaging; 1 of these patients continued to receive treatment.

Among patients in the efficacy analysis set (n = 21), the 6- and 12-month progression-free survival (PFS) rates were 95% (95% CI, 71%-99%) and 83% (95% CI, 55%-94%), respectively. The median time to PR or better was 1.9 months (range, 1-4), and the median time to CR or better was 7.5 months (range, 3.16). Among patients in the efficacy analysis set who achieved a PR or greater (n = 19), the 6- and 12-month duration of response (DOR) rates were 100% (95% CI, 100%-100%) and 87% (95% CI, 56%-97%), respectively.

What Was the Rationale for Investigating Linvoseltamab-Based Combinations in Patients With Relapsed/Refractory Multiple Myeloma?

Linvoseltamab is a human BCMAxCD3 bispecific monoclonal antibody. In July 2025, the FDA approved linvoseltamab for the treatment of adult patients with relapsed/refractory multiple myeloma who have previously received at least 4 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody.2 This regulatory decision was supported by data from the phase 1/2 LINKER-MM1 study (NCT03761108). At a median follow-up of 21.3 months, patients who received linvoseltamab monotherapy at a recommended dose of 200 mg on the trial achieved an ORR of 70% (95% CI, 59%-80%).

“While linvoseltamab is an effective treatment as monotherapy, the combination with other anti-myeloma therapies may provide an additive or even synergistic effect,” Manier explained.1

What Was the Design of the Dose-Finding Linvoseltamab/Carfilzomib Portion of LINKER-MM2?

The ongoing, multicohort LINKER-MM2 study is investigating linvoseltamab in combination with several approved and investigational antimyeloma therapies, including carfilzomib, daratumumab (Darzalex), lenalidomide (Revlimid), bortezomib (Velcade), pomalidomide (Pomalyst), isatuximab-irfc (Sarclisa), fianlimab, cemiplimab-rwlc (Libtayo), nirogacestat (Ogsiveo), and cevostamab (RG6160, BFCR4350A).3 The trial was conducted at 39 sites across the United States, France, Greece, and Spain.1

LINKER-MM2 enrolled patients at least 18 years of age with relapsed/refractory multiple myeloma who had received at least 3 prior lines of therapy, or at least 2 prior lines of therapy if the patient was triple-class exposed or double-class refractory to at least an IMiD and a PI. Patients were allowed to have received prior treatment with carfilzomib if it was previously tolerated and at least 6 months had passed since their last exposure to the agent. Patients with carfilzomib-refractory disease were permitted during the dose-finding portion.

Patients received step-up dosing with intravenous (IV) linvoseltamab on days 1 and 8 of cycle 0, followed by 24 hours of inpatient monitoring after each dose. Following step-up dosing, patients received linvoseltamab at full doses of 100 mg (n = 12), 150 mg (n = 6), or 200 mg (n = 5) weekly, then every 2 weeks from cycle 4 onward. Starting on cycle 1 day 1, patients also received IV carfilzomib at 20 mg/m2 or 56 mg/m2 twice weekly; weekly dosing at 70 mg/m2 was permitted after cycle 2.

DLTs and the incidence and severity of TEAEs served as the primary end points. Key secondary end points included ORR, DOR, and PFS.

What Were the Baseline Characteristics of Patients Enrolled in the Dose-Finding Linvoseltamab/Carfilzomib Portion of LINKER-MM2?

Patients had a median age of 70 years (range, 53-83), and 39.1% of patients were at least 75 years of age. In total, 47.8% of patients were male, 69.6% of patients were White, and 56.5% of patients had an ECOG performance status of 0. Revised ISS stages included I (60.9%), II (34.8%), and III (4.3%). The median sBCMA level was 216.0 ng/mL (range, 85.5-1350.0), and 21.7% of patients had levels of at least 400 ng/mL. A total of 47.8% of patients had baseline soft tissue plasmacytomas, and 17.4% of patients had high-risk cytogenetics.

Patients had received a median of 3 prior lines of therapy (range, 2-6). All patients had prior exposure to at least 1 PI, including bortezomib (95.7%) and carfilzomib (8.7%). All patients had prior exposure to at least 1 IMiD, and 91.3% of patients had prior exposure to at least 1 anti-CD38 antibody. Most patients (52.2%) were refractory to at least 1 PI, including bortezomib (43.5%) and carfilzomib (4.3%). In total, 78.3% and 87.0% of patients were refractory to at least 1 IMiD and at least 1 anti-CD38 antibody, respectively. A total of 91.3%, 65.2%, and 8.7% of patients were triple-exposed, quadra-exposed, or penta-exposed, respectively. Additionally, 43.5% and 26.1% of patients, respectively, were triple- and quadra-refractory to prior lines of therapy; no patients were penta-refractory. Furthermore, 91.3% of patients were refractory to their last line of therapy.

What Additional Safety Data Were Seen With Linvoseltamab Plus Carfilzomib in LINKER-MM2?

In the total patient population, the mean duration of exposure to linvoseltamab was 56.9 weeks (standard deviation [SD], 39.25), and the mean duration of exposure to carfilzomib was 37.5 weeks (SD, 28.92). Broken down by linvoseltamab dose level, the mean durations of exposure to linvoseltamab and carfilzomib, respectively, were as follows:

• 100 mg: 74.4 weeks (SD, 44.10); 46.8 weeks (SD, 32.43)
• 150 mg: 50.4 weeks (SD, 21.53); 37.9 weeks (SD, 26.52)
• 200 mg: 22.5 weeks (SD, 8.95); 16.4 weeks (SD, 9.28)

Broken down by linvoseltamab dose level, serious TEAEs, TEAEs leading to linvoseltamab discontinuation, and TEAEs leading to death, respectively occurred in:

• 100 mg: 91.7%, 0%, 25.0%, and 16.7% of patients
• 150 mg: 50.0%, 16.7%, 16.7%, and 0% of patients
• 200 mg: 100%, 20.0%, 40.0%, and 0% of patients

In the total population, the most common hematologic, nonhematologic, and non-infection TEAEs included neutropenia (any-grade, 65.2%; grade ≥ 3, 56.5%), thrombocytopenia (52.2%; 30.4%), anemia (39.1%; 21.7%), cytokine release syndrome (CRS; 60.9%; 0%), diarrhea (52.2%; 4.3%), asthenia (47.8%; 17.4%), nausea (34.8%; 0%), pyrexia (34.8%; 4.3%), vomiting (34.8%; 0%), peripheral edema (21.7%; 4.3%), and hypogammaglobulinemia (21.7%; 4.3%). Any-grade and grade 3 or higher infections occurred in 91.3% and 43.5% of patients, respectively. The most common infections were cytomegalovirus infection (any-grade, 34.8%; grade ≥ 3, 4.3%), COVID-19 (26.1%; 4.3%), and upper respiratory tract infection (21.7%; 0%). One fatal infection (grade ≥ 3 septic shock following E. coli infection in a patient treated at the 100-mg linvoseltamab dose) occurred.

Most cases of CRS occurred prior to carfilzomib initiation. Additionally, 1 patient treated at the 150-mg linvoseltamab dose had overlapping grade 1 immune effector cell–associated neurotoxicity syndrome and grade 2 CRS during cycle 1; this resolved within 1 day of onset. Furthermore, 5 patients experienced cardiac TEAEs, 2 of whom had grade 3 or higher cardiac TEAEs.

What Additional Efficacy Findings Were Seen With Linvoseltamab Plus Carfilzomib in LINKER-MM2?

Broken down by linvoseltamab dose level, the respective ORRs and rates of sCR, CR, VGPR, and PR were as follows:

• 100 mg: 91% (95% CI, 59%-100%); 64%; 27%; 0%; 0% (median follow-up, 22.3 months [range, 3-29])
• 150 mg: 100% (95% CI, 48%-100%); 60%; 40%; 0%; 0% (median follow-up, 13.2 months [range, 2.15])
• 200 mg: 80% (95% CI, 28%-100%); 0%; 20%; 40%; 20% (median follow-up, 5.6 months [range, 5-8])

Among 7 minimal residual disease (MRD)–evaluable patients, 5 were MRD negative at a sensitivity of 10–5.

“These encouraging results are being validated in an expansion cohort, and a phase 3 study testing the combination of linvoseltamab and carfilzomib vs standard of care is planned,” Manier concluded.

Disclosures: Manier reported receiving consulting fees from AbbVie, Adaptive Biotechnology, Amgen, Celgene/Bristol Myers Squibb, GSK, Janssen, Novartis, Regeneron Pharmaceuticals, Inc., Roche, Sanofi, and Takeda.

References

1. Manier S, Ocio EM, Martínez-Chamorro, et al. Linvoseltamab (LINVO) + carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): initial results from the LINKER-MM2 trial. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract PA-064.
2. FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. FDA. July 2, 2025. Accessed July 2, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-linvoseltamab-gcpt-relapsed-or-refractory-multiple-myeloma
3. 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. Updated August 28, 2025. Accessed September 18, 2025. https://www.clinicaltrials.gov/study/NCT05137054