Sloot W, Glaser N, Hansen A, Hellmann J, Jaeckel S, Johannes S, Knippel A, Lai V, and Onidi M.
Toxicology and Applied Pharmacology, 2021
Less toxic multiple myeloma treatment shows promise in preclinical testing
Pan-proteasome inhibitors (pan-PIs) used to treat multiple myeloma and other hematological malignancies are known to cause serious side effects including cardiac disorders, peripheral neuropathy, gastrointestinal disturbances, and thrombocytopenia, but new research may offer hope for safer, more targeted treatments in the future. Recent preclinical testing of M3258—the first selective inhibitor of the immunoproteasome subunit LMP7 (Large multifunctional protease 7)—demonstrated a favorable safety profile with toxicity restricted to the lympho-hematopoietic and intestinal systems, but no cardiac, respiratory, or neurobehavioral impairments noted.
To examine the effects of M3258 on the heart, researchers used Axion’s Maestro system to perform bioelectronic assays on spontaneously beating induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) in vitro. The results showed that the selective inhibitor M3258 had no significant effects on the field potentials in the hiPS-CMs—an important marker that can help evaluate the risk of cardiac adverse events such as arrythmia as well as long- and short-QT syndromes. Additional testing revealed no other functional impairments of the cardiovascular system. These promising findings may offer an important safety advantage in the future for people living with multiple myeloma and other blood cancers.
