Chromosome 1 Alterations in Multiple Myeloma: Considerations for Precision Therapy.

Abstract

Multiple myeloma (MM) is an incurable blood malignancy characterized by the clonal expansion of plasma cells and the secretion of monoclonal immunoglobulins. High-risk MM, defined by specific cytogenetic abnormalities, poses significant therapeutic challenges and is associated with inferior survival outcomes compared to standard-risk disease. Although molecularly targeted therapies have shown efficacy in other hematologic malignancies, currently venetoclax is the only targeted therapy approved for MM (t(11;14)). However, chromosome 1q gains, amplifications, and 1p deletions are frequently observed in MM, and have been linked to drug resistance and poor patient prognosis. Accordingly, this review focuses on emerging MM precision therapies capable of targeting dysregulated genes within these regions. It addresses gene therapies, small molecule inhibitors and monoclonal antibodies currently under investigation to antagonize oncogenic drivers including MCL-1, BCL9, F11R, and CKS1B, all of which are implicated in cell survival, proliferation or drug resistance. In conclusion, the link between chromosome 1 abnormalities and high-risk disease in MM patients offers a compelling rationale to identify and explore therapeutic targeting of chromosome 1 gene products as a novel precision medicine approach for a poorly served patient population.