Linvoseltamab is a promising experimental bispecific antibody known as BCMAxCD3. Its purpose is to connect B-cell maturation antigen (BCMA) present on multiple myeloma cells with T cells expressing CD3, with the goal of promoting T-cell activation and enhancing the ability of T cells to eliminate cancer cells.
New findings from the pivotal Phase II study were unveiled at ASCO 2023, involving 104 patients who received a 50 mg dose of linvoseltamab and 117 patients who received the higher 200 mg dose. To mitigate potential side effects, a step-up dosing approach was implemented during the first two weeks in both treatment groups.
- At the recommended dose of 200mg, ORR was 71% and median duration of follow-up was 5.6 months
- According to previous findings, the responses have the potential to intensify as time progresses.
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In the 200 mg treatment group, approximately 13.7% of patients had extramedullary plasmacytomas, and 35.9% exhibited high-risk cytogenetics. About 22.2% of patients had a bone marrow plasma cell percentage of 50% or higher, while this information was unavailable for 24.8% of patients. The median number of previous lines of therapy was 5, and all patients had been exposed to triple-class treatments, with 95.7% also having been exposed to quad-class therapies. Approximately 75.2% of patients had received five different classes of treatment (penta-exposed), and among them, 23.9% were penta-refractory. The majority of patients (73.5%) were refractory to triple-class therapies, and 76.9% were refractory to their most recent line of therapy.
At the 6-month mark, there was an 83.6% likelihood of sustaining a response, which slightly decreased to 79.2% at the 12-month milestone. The median duration of response has not yet been determined. Minimal residual disease (MRD) data, assessed with high sensitivity (10-5) using clonoSEQ and Euroflow, were accessible for 46 patients who achieved either a complete response (CR) or stringent CR across various doses. Among these patients, 54.3% tested negative for MRD, indicating a lower presence of residual disease.
The objective response rate (ORR) remained stable across various subgroup populations, including those considered high-risk. Additionally, the 200 mg dose consistently demonstrated a higher ORR within each subgroup. Among patients aged 75 and older (n=31), the ORR with linvoseltamab was 67.7%. Similarly, individuals with high cytogenetic risk (n=42) achieved an ORR of 61.9% when treated with linvoseltamab.
Patients in the 50 mg treatment group had the option to escalate their dose to 200 mg if they experienced disease progression within 4 to 12 weeks of starting therapy. Among those who escalated (n=8), the majority achieved a very good partial response (VGPR) at a rate of 75%.
In the 50 mg arm, the estimated 6-month progression-free survival (PFS) rate was 54.6%, and the median PFS was 7.9 months. The estimated 3-month PFS rates were 79.6% and 59.4% for the 200 mg and 50 mg linvoseltamab arms, respectively.
Among patients receiving the 200 mg dose, the most common treatment-emergent adverse events (TEAEs) were hematologic in nature. The most frequent Grade 3/4 events included neutropenia (30.8%), anemia (23.9%), thrombocytopenia (13.7%), and lymphopenia (11.1%). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 5.9% of patients across different doses, with most cases appearing during the step-up dosing phase. TEAEs led to treatment discontinuation in 16.2% of patients in the 200 mg arm. Notably, TEAEs leading to death were reported in 7 patients in the 50 mg arm and 6 patients in the 200 mg arm, but these were not considered related to linvoseltamab according to the treating physician.
The most common non-hematologic TEAE in the 200 mg cohort was cytokine release syndrome (CRS), which affected 45.3% of patients. This was followed by cough (33.3%), fatigue (32.5%), and diarrhea (32.5%). The median time to CRS onset was 14.8 hours in the 200 mg arm, with a duration of 16.5 hours. There was one Grade 3 event (0.9%), while the rest were Grade 1 or 2 in severity.
KOL insights
“Early, deep, and durable responses were observed in patients who were mostly triple refractory. At the recommended dose of 200 mg, linvoseltamab is efficacious and showed generally manageable safety in patients with relapsed/refractory multiple myeloma, supporting continued development.” – Expert Opinion.
“Great data on Linvoseltamab. How many BCMA bispecifics can we handle in Multiple Myeloma? Certainly the data holds up to teclistamab and elranatamab; may be better? – Expert Opinion.
“Effective in highly-refractory disease, Clearly better responses and durability at 200mg dose level. Less CRS than other BsAbs? (but hard to know) – Expert Opinion.
Conclusion
Linvoseltamab, when administered at the recommended 200mg dose, demonstrated effective outcomes and generally manageable safety profiles in patients with relapsed/refractory multiple myeloma. These positive findings have further supported the advancement of linvoseltamab's development for multiple myeloma treatment. Notably, linvoseltamab has received Fast Track Designation from the FDA for multiple myeloma. Building upon these encouraging results, a Phase III development program (NCT05730036) investigating linvoseltamab in earlier stages of the disease has been initiated. The data presented at the conference will serve as the foundation for planned submissions to regulatory authorities, including the US FDA, anticipated to occur later this year
