What is the mechanism of multiple myeloma?

Mechanism of Multiple Myeloma

Multiple myeloma is a neoplastic disease characterized by the proliferation and accumulation of malignant plasma cells in the bone marrow, leading to bone destruction, marrow failure, and production of monoclonal immunoglobulins. 1

Cellular Origin and Pathogenesis

Multiple myeloma develops from neoplastic B-lymphocytes that originate in the follicular germinal center of lymph nodes. These cells undergo the following pathological processes:

• Migration to bone marrow where they interact with stromal cells and extracellular matrix
• Transformation into malignant plasma cells that produce monoclonal immunoglobulin (M-protein or paraprotein)
• Accumulation in bone marrow or, less commonly, in extramedullary tissues 1

Key Molecular and Cytokine Mechanisms

The disease progression involves several critical molecular mechanisms:

• Interleukin-6: The most crucial cytokine in MM growth, providing both proliferative and anti-apoptotic effects
• Osteoclast activation: IL-6 activates osteoclastogenesis while inhibiting osteoblasts, leading to bone loss and osteolytic lesions
• Angiogenesis: Neoplastic plasma cells stimulate bone marrow angiogenesis through:
  • Vascular endothelial growth factor (VEGF) production
  • Fibroblast growth factor (FGF) production 1

Genetic Classification

Multiple myeloma can be classified into two major genetic subtypes:

1. Hyperdiploid (H) Karyotype (40-60% of patients):

   • Characterized by trisomies with 47-75 chromosomes
   • Few or no translocations
   • Generally associated with more indolent disease course 1

2. Non-Hyperdiploid (NH) Karyotype:

   • Characterized by either fewer than 46 chromosomes or IgH translocations
   • Common translocations involve chromosome 14q32 (IgH locus) with partners:
     • 4p16.3 (FGFR3, WHSC1)
     • 11q13 (CCND1)
     • 16q23 (c-maf)
     • 6p25 (IRF7/MUM1)
   • These translocations lead to overexpression of proto-oncogenes due to the strong IgH enhancer
   • Generally associated with more aggressive disease features and shorter survival 1

Disease Progression Factors

Several genetic factors are associated with disease progression:

• Chromosomal deletions: Particularly deletions of chromosomes 13 and 17
• Chromosome 1 abnormalities: 1p deletion and 1q amplification
• Nuclear factor-κB-activating mutations
• Cyclin-dependent pathway deregulation 1

Clinical Manifestations and Complications

The accumulation of malignant plasma cells and their products leads to:

• Bone destruction: The hallmark of multiple myeloma
• Hypercalcemia: Due to increased bone resorption
• Renal insufficiency: From light chain deposition and other mechanisms
• Anemia: Due to bone marrow infiltration
• Increased susceptibility to infections: From immune dysfunction 1

Disease Evolution

Multiple myeloma typically progresses through distinct stages:

1. Early disease: Often evolves from monoclonal gammopathy of undetermined significance (MGUS)
2. Advanced disease: Characterized by focal lesions and increased angiogenesis
3. End-stage disease: Marked by highly proliferative plasmablasts that can cause extramedullary dissemination or plasma cell leukemia 1

Clinical Heterogeneity

The heterogeneity in clinical presentation and outcomes is largely dictated by the underlying genetic features of the tumor cells, with survival ranging from weeks to over 10 years after diagnosis 1.

Understanding these complex mechanisms has led to the development of targeted therapies, including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies that have substantially improved outcomes for patients with multiple myeloma.