Targeted therapy of multiple myeloma

Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Non-targeted drugs, while effective, can also harm normal healthy cells, leading to adverse effects such as gastrointestinal problems (nausea, vomiting, diarrhea, and constipation) myelosuppression (reduction in white blood cells and platelets), alopecia, anemia, liver and kidney impairment, and an increased risk of infections. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI۳K/AKT/ mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. For example, Afuresertib, AZD۶۲۴۴, Atiprimod, BHQ۸۸۰/DKK۱, and Carfilzomib are the inhibitors of Akt, MEK, STAT۳, Wnt, and NF-kB, respectively. Immunotherapy is the treatment of disease by inducing, enhancing, or suppressing an immune response. Drugs of targeted immunotherapy such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. These drugs target various antigens on MM cells and induce death in these cells through various mechanisms. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. This review highlights the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes.

کلیدواژه ها:

Multiple myeloma ، Signaling pathways ، Targeted therapy ، Immunotherapies