What is the etiopathogenesis of Multiple Myeloma (MM)?

Etiopathogenesis of Multiple Myeloma (MM)

Multiple myeloma develops through a multistep process involving genetic alterations, epigenetic changes, and complex interactions with the bone marrow microenvironment, progressing from precursor states (MGUS and SMM) to symptomatic disease. 1

Primary Genetic Events in MM Development

• Initial Genetic Events (occur at MGUS stage):

  • Primary IgH translocations involving recurrent chromosomal partners (4p16, 6p21, 11q13, 16q23, 20q11) 1
  • Hyperdiploidy (multiple trisomies of odd-numbered chromosomes) 1
  • Cyclin D dysregulation (very common early event in both hyperdiploidy and translocation pathways) 1

• Risk Factors for MGUS Development:

  • Environmental exposures (obesity, pesticides, radiation)
  • Personal history of autoimmune diseases, inflammatory conditions, infections
  • Genetic predisposition 1

Disease Progression Mechanisms

• Secondary Genetic Events driving progression from MGUS to MM:

  • Chromosomal deletions (particularly del 13q and del 17p13/TP53) 1
  • Chromosome 1 abnormalities (1p deletion and 1q amplification) 1
  • Secondary translocations 1
  • Gene mutations (including NF-κB pathway activating mutations) 1
  • Ras mutations (particularly K-ras mutations) 1

• Clonal Evolution:

  • Progressive replacement of normal/polyclonal plasma cells by clonal plasma cells 1
  • Intraclonal heterogeneity present even at MGUS stage, adding complexity to progression 1
  • Acquisition of additional mutations over time leading to more aggressive disease 1

Microenvironment Interactions

• Bone Marrow Microenvironment Changes:

  • Altered interactions between malignant plasma cells and:
    • Osteoclasts (leading to bone destruction)
    • Endothelial cells (promoting angiogenesis)
    • Immune cells (facilitating immune evasion) 1

• Paracrine Signaling:

  • Interleukin-6 and other cytokines contribute to clonal proliferation 1
  • Abnormal plasma cells produce immunoreceptors stimulated by exogenous molecules and microenvironmental signals 1

Bone Disease Development

• Osteoclast Activation/Osteoblast Inactivation:
  • Leads to characteristic lytic bone lesions in ~80% of MM patients 1
  • Excess bone resorption detectable even at MGUS stage (via bone biopsy and biomarkers like RANK ligand) 1
  • Progressive bone destruction is a hallmark of transition from precursor states to symptomatic MM 1

Molecular Classification

• Genetic Subtypes based on primary events:

  • Hyperdiploid MM (generally better prognosis)
  • Non-hyperdiploid MM with primary translocations:
    • t(11;14) - generally standard risk
    • t(4;14), t(14;16), t(14;20) - high-risk subtypes 1

• Prognostic Genetic Markers:

  • del(17p13) - high-risk feature due to loss of p53 tumor suppressor 1
  • 1q21 gain/amplification - associated with disease progression 1
  • 1p deletion - increases risk of progression 1

Diagnostic Implications

• Bone Marrow Assessment:

  • ≥10% clonal plasma cells is a major criterion for MM diagnosis 1
  • Immunohistochemistry/flow cytometry confirms clonality (kappa or lambda light chain restriction) 1

• Genetic Testing:

  • FISH panel should examine for del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14:20), 1q21 gain/amplification, and 1p deletion 1
  • Helps determine biological subtype and provides prognostic information 1

Progression Rate and Patterns

• MGUS to MM Progression:

  • Occurs at approximately 1% per year 1, 2
  • No reduction in risk even after 25-35 years of follow-up 1
  • Most MGUS patients die from unrelated causes before progression 1

• Progression Patterns:

  • Gradual evolution with steady increase in M-protein in some patients
  • Stable M-protein followed by sudden increase in others 1

Clinical Implications

• The understanding of MM etiopathogenesis has led to risk-stratified approaches to monitoring and management of precursor states 2
• Genetic testing is increasingly incorporated into clinical practice to guide prognosis and treatment selection 1
• Novel therapeutic approaches targeting specific genetic abnormalities and disrupting interactions with the bone marrow microenvironment are emerging 1