Aldehyde dehydrogenase inhibition as a strategy to overcome drug-refractory multiple myeloma

Multiple myeloma (MM) remains an incurable hematologic malignancy characterized by inevitable relapse and progressively therapy-resistant disease, despite the widespread use of combination regimens and autologous stem cell transplantation (ASCT). While only ~30% of patients achieve a complete response following initial therapy and ~40-50% with ASCT, the durability of these responses is limited, underscoring the persistence of highly drug-refractory cellular subpopulations. Increasing evidence implicates multiple myeloma stem-like cells (MMSLCs), a CD138⁻/ALDH⁺ phenotype enriched for self-renewal, metabolic plasticity, and intrinsic chemoresistance, as key drivers of relapse. Aldehyde dehydrogenases (ALDHs) promote MM survival by detoxifying cytotoxic aldehydes and sustaining retinoic acid-dependent stemness pathways, making them attractive therapeutic targets. We report the development and characterization of KS100, a novel pan-ALDH inhibitor, which potently eliminates both bulk MM cells and MMSLC populations in treatment-naïve and treatment-resistant models in vitro and in vivo. KS100 significantly reduces clonogenic growth, exhausts the ALDH-high compartment, and synergizes with standard MM therapies, including proteasome inhibitors and IMiDs, even in models with established resistance. These findings demonstrate that ALDH inhibition disrupts a universal resistance mechanism and position KS100 as a promising therapeutic strategy to eradicate stem-like reservoirs and improve long-term disease control in MM.