Linvoseltamab, an investigational bispecific antibody, has shown promising results in patients with relapsed/refractory (R/R) multiple myeloma (MM). Data from the Phase 1/2 LINKER-MM1 trial, presented at the American Association for Cancer Research (AACR) Annual Meeting 2024, demonstrated a high objective response rate and durable responses in a heavily pre-treated patient population. The FDA is expected to make a decision on approval by August 22, 2024.
Mechanism of Action
Linvoseltamab is designed to bridge B-cell maturation antigen (BCMA) on multiple myeloma cells with CD3-expressing T cells. This interaction facilitates T-cell activation and subsequent killing of the cancer cells.
Clinical Trial Results
The LINKER-MM1 trial evaluated linvoseltamab in patients with R/R MM. Key findings from the 117 patients included in the analysis, with a median follow-up of 11 months, are:
- Objective Response Rate (ORR): 71% as determined by an independent review committee.
- Complete Response (CR) or better: 46% of patients achieved a CR or better.
- Very Good Partial Response (VGPR) or better: 62% of patients achieved a VGPR or better.
- Time to Response: Median time to response was 1 month (range: <1-6 months).
- Duration of Response (DoR): Median DoR was not reached. The estimated probability of maintaining a response at 12 months was 78%.
- Progression-Free Survival (PFS): Median PFS was not reached. The estimated probability of being progression-free at 12 months was 69%.
- Overall Survival (OS): Median OS was not reached. The estimated probability of survival at 12 months was 75%.
- MRD Negativity: Among patients who had a CR or better and were minimum residual disease (MRD) evaluable, 93% (25 of 27 patients) were MRD negative at 10-5.
Response-Adapted Regimen
The trial incorporated a response-adapted regimen, allowing patients who achieved a VGPR or better and completed at least 24 weeks of therapy to transition to every four-week dosing. In the dose expansion portion of the trial (n=105), 90% (56 of 62) of patients who had at least 24 weeks of therapy at data cutoff achieved a VGPR or better and were able to transition to every four-week dosing. Notably, 48% (14 of 29) of patients who transitioned to the extended dosing regimen prior to achieving a CR subsequently experienced a deepening of response to CR or better.
Subgroup Analysis
High ORRs were observed across various prespecified subgroups, including high-risk and high-disease burden populations:
- 85% among Black or African American patients (17 of 20 patients)
- 71% among those aged 75 years or older (22 of 31 patients)
- 67% among those with high cytogenetic risk (31 of 46 patients)
- 62% among those with International Staging System stage III disease (13 of 21 patients)
- 53% among those with extramedullary plasmacytomas (10 of 19 patients)
Safety Profile
The most common treatment-emergent adverse event (TEAE) was cytokine release syndrome (CRS), observed in 46% of patients (35% Grade 1, 10% Grade 2, and 1% Grade 3). Adjudicated immune effector cell-associated neurotoxicity syndrome (ICANS) events of any grade occurred in 8% of patients, including three cases that were Grade 3. Infections occurred in 73% of patients, with their frequency and severity decreasing after 6 months; 34% were Grade 3 or 4. The most common Grade 3 or 4 TEAEs (≥20%) were neutropenia (40%) and anaemia (31%). Six deaths occurred on treatment or within 30 days of the last treatment dose due to TEAEs; five were due to infection, and one was due to renal failure.
Regulatory Status and Future Directions
Linvoseltamab has been granted Fast Track Designation and was accepted for Priority Review by the FDA for the treatment of R/R MM, with a target action date of August 22, 2024. It is also under review by the EMA. A Phase 3 confirmatory trial (LINKER-MM3) is currently underway.
Sundar Jagannath, M.D., Director of the Multiple Myeloma Center of Excellence at Tisch Cancer Center at Mount Sinai in New York City and a trial investigator, stated, “In clinical trials, linvoseltamab treatment led to responses that occurred early, were durable and deepened over time – all critical efficacy measures for this heavily pre-treated patient population. Further, among patients who had at least 24 weeks of treatment, the majority achieved a very good partial response, enabling them to transition from every two-week to every four-week dosing.”
