Io Therapeutics reported today at the American Society of Hematology Annual Meeting (ASH 2025) that its retinoid X receptor (RXR) agonist compound IRX4204 exhibited strong synergistic efficacy against human multiple myeloma in preclinical models when combined with either BCMA-targeted CAR-T cells or the standard-of-care drug Lenalidomide.
In in vitro and xenograft mouse studies led in collaboration with Duke University School of Medicine, IRX4204 was shown to enhance CAR-T cell function by protecting them from ferroptosis—a form of cell death triggered by oxidative stress—via downregulation of CHAC1 and activation of mitochondrial recycling (mitophagy). This resulted in improved CAR-T persistence and enhanced tumour control in treated mice.
Separately, IRX4204 induced ferroptosis in myeloma plasma cells via modulation of the PPARα/RXRα–HMOX1/GPX4 pathway, thereby increasing sensitivity to Lenalidomide. The combination led to a significant reduction in tumour growth and extended survival in mouse models, without increasing systemic toxicity.
According to Io Therapeutics, these findings reveal a “druggable ferroptosis pathway” in multiple myeloma and offer a mechanistic rationale for combining RXR agonists with existing therapies to improve patient outcomes. The company says it plans to advance IRX4204 combinations with CAR-T cells and Lenalidomide into clinical trials.
