Linvoseltamab Monotherapy and Linvoseltamab plus Carfilzomib versus Standard of Care in Patients with Relapsed/Refractory Multiple Myeloma

This phase 3 study evaluates the safety and tolerability of condensed step-up dosing for linvoseltamab monotherapy and linvoseltamab plus carfilzomib to determine recommended dose regimens. The primary objectives in the subsequent dual part are to compare the proportion of participants achieving MRD-negative CR at 12 months and to compare progression-free survival (PFS) between the linvoseltamab arms and standard therapy in patients with relapsed/refractory multiple myeloma.

Secondary objectives include:

• Assessment of the incidence of grade ≥2 cytokine release syndrome (CRS) during condensed step-up dosing of linvoseltamab.
• Comparison of overall survival (OS) between treatment arms.
• Evaluation of clinical response rates, including overall response rate (ORR), very good partial response (≥VGPR), and complete response (≥CR).
• Comparison of clinical outcomes such as duration of response (DOR), time to progression (TTP), time to next treatment (TTNT), and PFS2.
• Assessment of MRD-negative CR achievement at any time, sustained MRD negativity, and the duration of MRD-negative CR.
• Comparison of the time to response between treatment arms.
• Evaluation of safety, tolerability, and patient-reported treatment toxicity.
• Analysis of pharmacokinetics (PK) and immunogenicity of linvoseltamab in monotherapy and combination with carfilzomib.
• Measurement of sBCMA concentrations at baseline and over time.
• Comparison of patient-reported health-related quality of life (HRQoL), physical and role functioning, and symptoms.

The study involves 551 participants diagnosed with relapsed refractory multiple myeloma. The study population includes both male and female individuals. The age range of the participants corresponds to specific clinical age codes 3 and 4. Eligible subjects must have received between one and three prior lines of therapy, including lenalidomide and either a protease inhibitor or an anti-CD38 monoclonal antibody. Additionally, participants must demonstrate progressive disease according to International Myeloma Working Group criteria and possess an Eastern Cooperative Oncology Group performance status score of 2 or less. The sponsor did not provide information regarding lifestyle considerations or general health status beyond these parameters.

This Phase 3, open-label, randomized study evaluates the efficacy and safety of linvoseltamab monotherapy or linvoseltamab in combination with carfilzomib compared to standard of care regimens in patients with relapsed/refractory multiple myeloma. The research is divided into two parts. Part 1 focuses on evaluating the safety, tolerability, and treatment emergent adverse events associated with condensed step-up dosing to determine recommended dose levels. Part 2 compares the proportion of participants achieving minimal residual disease-negative complete response at 12 months and evaluates progression-free survival across the study arms. The estimated study duration spans from March 2026 to September 2034. Participant involvement involves a screening process to confirm eligibility based on prior therapy history and disease progression, followed by treatment administration and subsequent monitoring to assess endpoints such as overall survival and quality of life. Early termination may occur based on protocol-defined conditions or safety concerns.

The experimental treatment consists of linvoseltamab, provided as a concentrate for intravenous infusion in doses of 5 mg or 200 mg. This is evaluated in combination with carfilzomib, which is administered as a powder for solution for infusion at doses of 10 mg, 30 mg, or 60 mg via intravenous infusion.

Comparator treatments include daratumumab administered as a subcutaneous injection at 1800 mg, bortezomib as a powder for solution for injection via intravenous injection at 3.5 mg, and pomalidomide provided in hard capsules at doses of 1 mg, 2 mg, 3 mg, or 4 mg for oral administration. Additionally, dexamethasone or dexamethasone phosphate is utilized as a comparator, administered either orally or as a solution for infusion.

Auxiliary medications used during the study include paracetamol in both tablet and solution for infusion forms, aciclovir as an oral tablet, diphenhydramine hydrochloride as an oral tablet or solution for injection, and sulfamethoxazole and trimethoprim as oral tablets.

In this clinical trial for relapsed/refractory multiple myeloma, efficacy assessments are divided into two parts. For Part 1, the study evaluates safety and tolerability through the monitoring of treatment emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs), including their respective occurrences and severities. Additionally, the timing and occurrence of cytokine release syndrome (CRS) of grade ≥2 are assessed.

Part 2 focuses on comparative efficacy between the linvoseltamab arms and standard therapy. The primary efficacy endpoints include the proportion of participants achieving minimal residual disease (MRD)-negative complete response (CR) at 12 months and progression-free survival (PFS) as determined by blinded independent central review (BIRC) per IMWG response criteria. Secondary efficacy parameters include:

• Overall survival (OS)
• Achievement of partial response (PR), very good partial response (VGPR), or stringent complete response (sCR)
• Duration of response (DOR) and time to progression (TTP)
• Time to next treatment (TTNT) and second PFS
• Assessment of MRD-negative CR status at any time, its sustainability, and duration
• Time to reach specific IMWG response categories
• Pharmacokinetic evaluations, including linvoseltamab concentrations in serum and antidrug antibodies (ADAs)
• Serum levels of soluble B-cell maturation antigen (sBCMA)