What is the pathophysiology of multiple myeloma?

Pathophysiology of Multiple Myeloma

Multiple myeloma is characterized by the neoplastic proliferation of plasma cell clones that produce monoclonal immunoglobulin, causing bone marrow infiltration, skeletal damage, and related complications including hypercalcemia, renal insufficiency, anemia, and increased susceptibility to infections. 1

Core Pathophysiological Features

Cellular Origin and Clonal Proliferation

• Multiple myeloma originates from post-germinal center B-cells that have undergone somatic hypermutation and differentiated into plasma cells
• These malignant plasma cells accumulate in the bone marrow, leading to:
  • Displacement of normal hematopoietic cells
  • Bone destruction
  • Marrow failure 1

Genetic and Molecular Basis

Multiple myeloma can be classified into two major genetic subtypes:

1. Hyperdiploid Myeloma (40-50% of cases) 1

   • Characterized by trisomies of odd-numbered chromosomes
   • Generally associated with more indolent disease course
   • Better prognosis than non-hyperdiploid variants

2. Non-Hyperdiploid Myeloma (40-50% of cases) 1

   • Primarily characterized by IgH translocations
   • Main translocations include:
     • t(11;14)(q13;q32)
     • t(4;14)(p16;q32)
     • t(14;16)(q32;q23)
   • Generally associated with more aggressive disease features

Disease Progression Factors

• Genetic progression factors include:
  • Deletions of chromosomes 13 and 17
  • Abnormalities of chromosome 1 (1p deletion and 1q amplification)
  • Nuclear factor-κB-activating mutations
  • Deregulation of cyclin-dependent pathway regulators 1

Pathophysiological Consequences

1. Bone Disease

• Malignant plasma cells disrupt the balance between osteoblasts and osteoclasts
• Increased osteoclast activity and decreased osteoblast function lead to:
  • Lytic bone lesions
  • Pathologic fractures
  • Bone pain
  • Hypercalcemia 1

2. Hematologic Complications

• Bone marrow infiltration by malignant plasma cells results in:
  • Anemia (normochromic, normocytic)
  • Thrombocytopenia
  • Leukopenia 1

3. Renal Dysfunction

• Caused by multiple mechanisms:
  • Cast nephropathy from excess light chains
  • Hypercalcemia
  • Amyloidosis
  • Direct tubular toxicity from light chains
  • Dehydration 1

4. Immune Dysfunction

• Suppression of normal immunoglobulin production
• Functional defects in various immune cells
• Increased susceptibility to bacterial and viral infections 1

Disease Evolution and Progression

Multiple myeloma typically evolves through a multi-step process:

1. Monoclonal Gammopathy of Undetermined Significance (MGUS)

   • Pre-malignant asymptomatic stage
   • <10% clonal plasma cells in bone marrow
   • Serum monoclonal protein <3 g/dL
   • No end-organ damage
   • Progresses to MM at a rate of approximately 1% per year 1

2. Smoldering Multiple Myeloma (SMM)

   • Intermediate asymptomatic stage
   • ≥10% clonal plasma cells in bone marrow and/or ≥3 g/dL monoclonal protein
   • No end-organ damage
   • Progresses to symptomatic MM at a rate of 10% per year for the first 5 years 1

3. Symptomatic Multiple Myeloma

   • ≥10% clonal plasma cells in bone marrow or biopsy-proven plasmacytoma
   • Evidence of end-organ damage (CRAB criteria)
   • Requires immediate treatment 1

Diagnostic Criteria (CRAB)

The CRAB criteria define end-organ damage in multiple myeloma:

• C: Hypercalcemia (serum calcium >11.5 mg/dL)
• R: Renal insufficiency (creatinine >2 mg/dL or creatinine clearance <40 mL/min)
• A: Anemia (hemoglobin <10 g/dL or 2 g/dL below normal)
• B: Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures) 1

Additionally, the International Myeloma Working Group has identified biomarkers that define multiple myeloma even in the absence of CRAB features:

• ≥60% clonal plasma cells in bone marrow
• Involved/uninvolved serum free light chain ratio ≥100

• 1 focal lesion on MRI (≥5 mm in size) 1

Clinical Implications

The complex pathophysiology of multiple myeloma explains:

• The heterogeneous clinical presentation
• Variable response to treatment
• Differences in prognosis among patients
• The eventual development of treatment resistance in most cases 2

Understanding the underlying biological mechanisms has led to the development of targeted therapies directed at specific pathways involved in myeloma cell growth, survival, and interactions with the bone marrow microenvironment.