KEY TAKEAWAYS
- An interventional phase I trial aimed to assess long-term outcomes in IV-treated patients and establish safety and efficacy for the subcutaneous formulation in a phase 1 trial.
- Subcutaneous ALNUC emerged as a promising option for RRMM with improved safety, durable responses, and MRD negativity, paving the way for further clinical evaluation.
Alnuctamab (ALNUC), a 2+1 T-cell engager (TCE) with bivalent binding to BCMA, exhibited clinical activity in relapsed/refractory multiple myeloma (RRMM) during a phase 1 study.
Intravenous (IV) ALNUC demonstrated a long duration of response (DOR) but was associated with a high incidence (76%) of cytokine release syndrome (CRS). Subcutaneous (SC) dosing mitigated CRS, enabling higher target doses and showing promising antitumor activity.
María-Victoria Mateos and her research team led the study that aimed to report extended follow-up outcomes from IV participants and evaluate the safety and efficacy of SC administration in subjects enrolled in the phase 1 study of ALNUC.
Patients receiving≥3 prior lines of therapy, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapies, were administered intravenous (IV) ALNUC at target doses of 0.15–10 mg, utilizing fixed and step-up dosing. SC ALNUC was administered on Days 1, 4, 8, 15, and 22 of cycle 1 (C1), weekly in C2–3, bi-weekly in C4–6, and every 4 weeks in C7 and beyond, with step-up doses on C1D1 (3 mg) and C1D4 (6 mg), and target doses (≥10 mg) from C1D8 onwards. Primary objectives included assessing safety and tolerability.
About 70 patients received IV ALNUC, yielding an overall response rate (ORR) of 39% (27/70). The median duration of response (DOR) was 33.6 months (95% CI, 10.6–NA), and the median progression-free survival (PFS) was 3.1 months (95% CI, 1.9–5.5).
Among the 73 patients treated with SC ALNUC in dose escalation and expansion, with a target dose ranging from 10 mg to 60 mg, the median age was 64, and 42% were female. These patients had a median of 4 prior regimens, with 93% refractory to the last line of treatment. Additionally, 100% and 63% had been exposed to triple-class and refractory multiple myeloma, respectively, and 66% and 26% had been exposed to penta-drug and refractory multiple myeloma. The median follow-up was 4.3 months (range, 0.5–16.0), and 53% of patients were still on treatment at the data cutoff. In the cohort, cytokine release syndrome (CRS) was reported in 53 (76%) patients, with grade (G) ≥3 observed in 7% of cases.
The G/G3–4 treatment-emergent adverse events(TEAEs) occurred in 99% and 79% of SC patients, with the most common being CRS at (56%/0%), neutropenia at (49%/42%), infections at (47%/10%), for grade 3–4, anemia at 41% (25% for grade 3–4), and thrombocytopenia at 33% (14% for grade 3–4). CRS in SC patients was predominantly limited to grade 1 (44%) or grade 2 (12%). Among SC patients experiencing CRS, 35 received at least one concomitant medication, including tocilizumab (30%) and/or corticosteroids (15%).
The median time to CRS onset was 3 days (range, 1–20), with a median duration of 2 days (range, 1–11). SC ALNUC demonstrated a bioavailability of approximately 61%, and the half-life (t½) was 15 days. Trough concentrations at the 30-mg target dose exceeded predicted efficacy levels by Cycle 2, Day 1. Among 55 efficacy-evaluable patients receiving SC ALNUC, the overall response rate (ORR) was 53% across all doses and 65% at the 30-mg target dose. Of 29 responders with minimal residual disease (MRD)-evaluable, 80% were MRD-negative (10e-5 sensitivity) at either Cycle 2 Day 1 or Cycle 4 Day 1. The median time to response was 1.0 months (95% CI, 0.7–1.3), and 86% of responses were ongoing.
The study demonstrated lasting responses in extensively treated patients with relapsed/refractory multiple myeloma. At the same time, SC ALNUC exhibited a superior safety profile compared to IV ALNUC, featuring manageable low-grade cytokine release syndrome and promising dose-dependent antitumor activity, including a notable proportion of minimal residual disease-negative responders; the phase 1 study continues. The research was sponsored by Celgene.
Clinical Trial: https://clinicaltrials.gov/study/NCT03486067
Mateos MV. ‘’Alnuctamab (ALNUC; BMS-986349; CC-93269), a BCMA × CD3 T-cell engager, in patients (pts) with relapsed/refractory multiple myeloma (RRMM): latest results from a phase 1 first-in-human clinical study.’’Presented at: IMS 20th Annual Meeting and Exposition, Megaron Athens International Conference Centre, Greece.
