Multiple myeloma (MM) is a hematological disease that remains largely incurable. The introduction of proteasome inhibitors (PIs) at the turn of the century led to prolonged survival of patients, though most will inevitably develop resistance over successive treatments. It is of great clinical interest, then, to resensitize MM cells to PIs. This review discusses some of the most well-established resistance pathways, such as alterations in the proteostasis network and the bone marrow microenvironment. Novel targets are highlighted and placed in the context of potential treatment strategies where applicable.

Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells, leading to organ damage and symptoms summarized by the acronym CRAB (calcium elevation, renal insufficiency, anemia, and bone lesions). The disease can also present with extramedullary involvement, which signifies a more aggressive course and may affect various organs such as the skin, liver, kidneys, and central nervous system. MM progresses from precursor stages like monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which differ in their risk of progression to active disease. Genetic alterations—including chromosomal translocations, deletions, amplifications, and point mutations—are central to pathogenesis and may influence prognosis and therapeutic response in MM. This review explores the genetic changes that drive MM progression, their prognostic implications, and the role of advanced diagnostic technologies in improving risk stratification and guiding personalized treatment. In particular, we examine key genetic alterations such as t(4;14), del(17p), and cellular myelocytomatosis oncogene (c-MYC) amplification, and their influence on treatment outcomes. The review also highlights recent advancements in diagnostic techniques, including next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR), which are transforming MM management through more precise and targeted therapeutic strategies. The integration of these diagnostic tools promises to enhance personalized treatment approaches, leading to improved outcomes and survival by tailoring therapies to each patient's genetic profile.