Abstract CT146: Safety, tolerability and molecular correlates of the IRF4-targeted antisense oligonucleotide frenlosirsen in patients with relapsed/refractory multiple myeloma: A phase 1a dose escalation trial

Abstract Despite significant advances, multiple myeloma (MM) remains an incurable disease and additional therapeutic strategies are needed. The transcription factor interferon regulatory factor-4 (IRF4) plays a critical role in myeloma pathogenesis and progression, with high expression associated with worse clinical outcomes. Antisense oligonucleotide (ASO)-based inhibition of IRF4 was shown pre-clinically to inhibit malignant plasma cell survival, reduce myeloma progenitor cell burden and impede disease regeneration without adversely affecting normal hematopoietic stem cells. These promising findings led to a first-in-human phase 1a dose escalation trial to assess the safety and tolerability of IRF4-targeted antisense therapy using frenlosirsen (ION251) in patients with relapsed/refractory multiple myeloma (RRMM) (NCT04398485). Eligible patients had RRMM and were intolerant to or not otherwise candidates for currently available therapies. Frenlosirsen was administered via IV infusion in cycle 1 on day 1/4/8/11/15/22 of a 28-day cycle, then weekly starting cycle 2 until unacceptable toxicity, disease progression or intercurrent illness. Dose-escalation was conducted by a conventional 3+3 study design with sequential dose cohorts. The primary endpoints were clinical changes from baseline and evaluation of the maximum tolerated dose. Correlative studies quantified IRF4 mRNA and protein levels in sequential peripheral blood and bone marrow samples as biomarkers of IRF4 inhibition. From 1/2021 to 9/2024, 23 patients were infused with frenlosirsen in 6 dose escalating cohorts: 100mg (n=4), 150mg (n=3), 220 mg (n=6), 320mg (n=5), 460mg (n=4), 660mg (n=1). The median number of prior MM treatment lines was 7. There were no dose limiting toxicities seen up to 660mg and no treatment discontinuation due to drug-related adverse events (AEs). Of 11 treatment emergent AEs, only one (grade 1 pyrexia) was likely related to frenlosirsen. One grade 5 event in the 220mg cohort was due to a fall which was unlikely related to study drug. Best responses were observed in a 460mg patient on therapy for 9 cycles and a 660mg patient for 13 cycles before progression, with evidence of dose-related delays in time to disease progression that were associated with reduced free light chain levels. Biomarker studies quantifying PBMC IRF4 levels demonstrated trends towards reduced IRF4 expression in higher dose cohorts. At studied doses, frenlosirsen targeting IRF4 in RRMM is safe and well tolerated with preliminary evidence of efficacy at higher doses. The trial was closed for non-medical reasons before the highest dose escalation cohorts accrued, yet the excellent safety profile of frenlosirsen and potential for significant clinical benefit support further evaluation in RRMM and other malignancies with aberrant IRF4 activity. Citation Format: Alexander A. Tong, Silvia Vicenzi, Lara C. Avsharian, Joshua D. Hartman, Trung V. Tran, Ashni A. Vora, Robert A. Vescio, Barry A. Paul, Caitlin L. Costello, T. Jesse Kwoh, Leslie A. Crews. Safety, tolerability and molecular correlates of the IRF4-targeted antisense oligonucleotide frenlosirsen in patients with relapsed/refractory multiple myeloma: A phase 1a dose escalation trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT146.