Novel Pan-ALDH Inhibitor KS100 Effectively Targets ALDH+/CD138⁻ Stem-like Cells to Overcome Relapse in Multiple Myeloma

Multiple myeloma (MM), a clonal plasma cell disorder is the second most frequent hematological malignancy in the United States. This malignancy is characterized by a series of symptoms such as bone lesions, hypercalcemia, renal failure, and anemia. The current clinical drugs in the market are successful in treating multiple myeloma patients into remission but does not address relapse where a more aggressive phenotype of the cancer remains untreatable. We hypothesize that a small subset of multiple myeloma stem-like cells (MMSLC’s) that overexpress aldehyde dehydrogenases (ALDH ⁺ ) is the cause of the relapse. Overexpression of ALDH bolsters drug resistance via detoxification and stemness via the retinoic acid signaling pathway. The phenotype of MMSLC’s is not yet known for certainty but there are a few well established markers such CD138 negative (CD138 ^neg ) cells that are known to overexpress ALDH. In this study, we target regular MM cells and bortezomib resistant ALDH ⁺ /CD138 ^neg MMSLC’s with a novel, potent, pan-ALDH inhibitor, KS100. Here we report KS100 effectively lowered ALDH expression in regular and bortezomib resistant ALDH ⁺ /CD138 ^neg cells, MM cell viability as well as proteins associated with MMSLC’s. Most importantly we showed that KS100 lowered ALDH ⁺ populations in regular, bortezomib resistant and CD138 ^neg cells via ALDEFLUOR™ assay.