Io Therapeutics presents today at the American Society for Hematology Annual Meeting, preclinical studies demonstrating combination treatment with BCMA CAR-T cells plus the company's RXR agonist compound IRX4204 has synergistic efficacy against human multiple myeloma
SPRING, Texas, Dec. 06, 2025 (GLOBE NEWSWIRE) -- Io Therapeutics, Inc., a privately held pharmaceutical company headquartered in Spring, Texas; announced today collaborative presentations at the 67th American Society of Hematology Annual Meeting and Exposition, in Orlando, Florida; with scientists from the Duke University School of Medicine in Durham, North Carolina; reporting data from preclinical studies in in vitro and xenograft mouse models demonstrating effectiveness of IRX4204, the company’s retinoid X nuclear receptor (RXR) agonist compound, against human multiple myeloma. IRX4204 had synergistic efficacy against human multiple myeloma in combination with anti-myeloma BCMA CAR-T cells and separately with a standard of care anti-myeloma drug lenalidomide.
The researchers presented two abstracts titled: “RXR Agonist IRX4204 improves BCMA CAR-T functionality by suppressing ferroptosis via CHAC1 downregulation and promoting mitophagy”; and “RXR agonist IRX4204 induces ferroptosis in multiple myeloma via HMOX1/GPX4 axis and enhances lenalidomide efficacy”. Both sets of studies were conducted under the leadership of Professor of Medicine Yubin Kang, M.D, in his laboratory at Duke.
Multiple myeloma remains incurable, and although BCMA CAR-T therapy induces deep responses, most patients eventually relapse due to T-cell exhaustion, limited CAR-T persistence, and metabolic stress in the tumor microenvironment. Activated T-cells are vulnerable to ferroptosis, a form of cell death driven by glutathione depletion, oxidative stress, and CHAC1 activity. Enhancing redox resilience improves CAR-T durability. IRX4204, a selective RXR agonist, protected CAR-T cells from T-cell exhaustion and ferroptotic death, thereby enhancing their persistence and anti-tumor function. Mechanistically, IRX4204 suppresses CHAC1-driven ferroptosis and activates PINK1/PARK2-mediated mitophagy, preserving mitochondrial integrity. In vivo, IRX4204 improved tumor control and prolonged CAR-T persistence in multiple myeloma xenografts.
Further, the studies demonstrated that IRX4204 promotes ferroptosis in human multiple myeloma plasma cells by activating the PPARα/RXRα-HMOX1 axis and suppressing GPX4/SLC7A11-mediated antioxidant defense. This effect synergistically enhances the therapeutic efficacy of IRX4204 with a standard of care anti-myeloma drug lenalidomide, both in vitro and in vivo. In vivo, combination treatment with IRX4204 and lenalidomide significantly reduced tumor growth compared to lenalidomide alone and prolonged median survival without increased systemic toxicity. Tumor analysis confirmed increased HMOX1 and decreased GPX4 expression in combination-treated mice.
Bioinformatic analysis of multiple myeloma patient datasets revealed that high HMOX1 expression in plasma cells correlated with significantly improved overall survival (HR=0.51, p<0.001), while advanced-stage multiple myeloma plasma cells showed progressively lower HMOX1 levels.
Dr. Kang stated: “These studies have multiple important clinical implications. The data identify a druggable ferroptosis pathway in multiple myeloma and provide a mechanistic rationale for combining RXR agonists with established therapies including BCMA CAR-T cells and lenalidomide. Our finding of a strong statistical correlation between HMOX1 expression in patient plasma cells and survival of multiple myeloma patients suggests potential for biomarker-guided therapy selection.”
Martin E. Sanders, M.D., Chief Executive Officer of Io Therapeutics stated “IRX4204 is a clinical stage compound which was invented by Vidyasagar Vuligonda, Ph.D., Chief Science Officer of Io Therapeutics. IRX4204 more potently and more selectively activates RXR than earlier generation RXR agonists. It has demonstrated an excellent chronic dosing safety profile in clinical trials in patients with lung, prostate, and other cancers. The IRX4204 safety profile likely will be suitable for chronic treatment of multiple myeloma in combination with CAR-T cells and lenalidomide. IRX4204 previously showed anti-cancer activity in phase I and II clinical trials in patients with various types of solid tumor malignancies. The new findings that IRX4204 has synergistic efficacy against multiple myeloma with BCMA CAR-T cells, and separately, also with a standard of care anti-myeloma drug lenalidomide, adds to the drug’s scope of potential clinical utilities, and may result in increases of the proportions of multiple myeloma patients achieving cure or long-term maintenance of complete responses of their cancers. The company is planning to evaluate combinations of IRX4204 with CAR-T cells, and with lenalidomide in future clinical trials in multiple myeloma patients.”
More information about Io Therapeutics, Inc., and its product development programs is available on the company’s web site: www.io-therapeutics.com or at info@io-therapeutics.com.
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