High-risk multiple myeloma is an aggressive disease in which plasma cells grow uncontrollably. It is typically resistant to treatment and the prognosis for patients is poor. However, the genes that contribute to this behavior are not fully understood. Using single-cell transcriptomics, researchers led by Robert Orlowski, M.D., Ph.D., identified that CLPP, a protein in mitochondria, is overexpressed in high-risk cases and may also enable progression from earlier precursor cases to more advanced disease. Inhibiting CLPP genetically or through treatment with inobrodib reduced cancer cell growth, increased cell death and weakened the mitochondria of cancer cells in lab models.
Additionally, combining CLPP inhibition with different therapies targeting cell metabolism or other mechanisms of protein breakdown worked more efficiently. These findings suggest that CLPP plays a key role in aggressive multiple myeloma, highlighting its potential as a therapeutic target.