Multiple Myeloma pathophysiology in adults
Multiple myeloma is a complex hematologic malignancy characterized by the uncontrolled proliferation of plasma cells within the bone marrow. These abnormal plasma cells, which are mature B lymphocytes specialized in antibody production, begin to multiply excessively, disrupting normal blood cell production and leading to a cascade of physiological disturbances. Understanding the pathophysiology of multiple myeloma in adults involves exploring the cellular, molecular, and microenvironmental interactions that contribute to disease development and progression.
The origin of multiple myeloma lies in genetic alterations within plasma cells. These changes often involve chromosomal translocations, such as t(11;14), t(4;14), or deletions like del(13q), which activate oncogenes or deactivate tumor suppressor genes. These genetic anomalies promote plasma cell survival and proliferation. Initially, a single malignant plasma cell undergoes clonal expansion, forming a monoclonal population identifiable by the production of a unique monoclonal immunoglobulin, commonly called M protein.
Within the bone marrow niche, malignant plasma cells interact intricately with stromal cells, immune cells, and the extracellular matrix. These interactions foster a supportive microenvironment that sustains tumor growth. Growth factors such as interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) are secreted by stromal cells and malignant plasma cells themselves, promoting proliferation, survival, and angiogenesis. IL-6, in particular, plays a central role as a potent growth factor for myeloma cells, activating signaling pathways like JAK/STAT, MAPK, and PI3K/Akt, which enhance cell survival and resistance to apoptosis.
The abnormal plasma cells also produce excess monoclonal immunoglobulin and light chains, which circulate in the blood and can deposit in tissues, causing end-organ damage—most notably in the kidneys, leading to conditions such as myeloma cast nephropathy. These monoclonal proteins contribute to hyperviscosity, anemia, and increased susceptibility to infections by impairing normal immune function.
Bone destruction is another hallmark of multiple myeloma’s pathophysiology. Malignant plasma cells secrete factors that stimulate osteoclast activity, such as RANKL and macrophage inflammatory protein-1α (MIP-1α), leading to increased bone resorption. Simultaneously, they suppress osteoblast function, impairing bone formation. This imbalance results in lytic lesions, osteoporosis, and pathological fractures, significantly impacting patient morbidity.
Furthermore, multiple myeloma induces immune suppression by impairing normal immune cell function, including T-cell exhaustion and defective dendritic cell activity. This immune dysregulation facilitates disease progression and complicates treatment responses.
In summary, multiple myeloma arises from genetic mutations in plasma cells that promote their malignant transformation and expansion within the bone marrow. The disease’s progression is driven by interactions within the bone marrow microenvironment, leading to increased proliferation, bone destruction, immunosuppression, and the production of pathogenic monoclonal proteins. Advances in understanding these mechanisms continue to inform targeted therapies aimed at disrupting these pathogenic pathways, offering hope for improved management and patient outcomes.
