Genomic profiling enables personalized strategies to overcome drug resistance in multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. It is a complex and heterogeneous disease that primarily affects older adults and is associated with significant morbidity and mortality. Despite advances in treatment, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, MM remains largely incurable, with most patients experiencing relapse and disease progression. The disease’s biological complexity is driven by a multitude of genetic and molecular alterations, which contribute to its clinical variability and resistance to therapy. The development of drug resistance is a major obstacle in the management of MM, often leading to treatment failure and disease relapse. Resistance mechanisms can be intrinsic, present before therapy initiation, or acquired, emerging during the course of treatment. These mechanisms involve complex molecular pathways, genetic mutations, and interactions within the bone marrow microenvironment that enable malignant plasma cells to evade therapeutic effects. A comprehensive understanding of these resistance pathways is crucial for designing strategies to overcome or prevent resistance, thereby improving patient outcomes. Integrating insights from molecular pathways and genomic profiling into clinical practice holds promise for tailoring personalized therapies that can effectively target resistant disease clones and prolong remission. Additionally, exploring combination therapies that target multiple pathways simultaneously, informed by molecular profiling, holds promise for overcoming intrinsic and acquired resistance. Continued innovation in predictive modeling and functional assays will facilitate the translation of molecular insights into effective, individualized treatment plans.