What is multiple myeloma?

Multiple Myeloma: Definition and Characteristics

Multiple myeloma is a hematologic malignancy characterized by clonal plasma cell proliferation in the bone marrow leading to end-organ damage, with production of monoclonal immunoglobulins detectable in serum or urine. 1

Pathophysiology

Multiple myeloma originates from post-germinal center B-cells that have undergone somatic hypermutation and differentiated into plasma cells. These malignant plasma cells:

• Displace normal hematopoietic cells in bone marrow
• Cause bone destruction through disruption of osteoblast/osteoclast balance
• Lead to marrow failure 1
• Produce monoclonal immunoglobulins (M-proteins)
• Suppress normal immunoglobulin production

The disease typically evolves through a multi-step process:

1. Monoclonal Gammopathy of Undetermined Significance (MGUS)
2. Smoldering Multiple Myeloma (SMM)
3. Symptomatic Multiple Myeloma 1

Diagnostic Criteria

The diagnosis of symptomatic multiple myeloma requires:

• ≥10% clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma
• Evidence of end-organ damage (CRAB criteria) attributed to the plasma cell disorder 1

CRAB Criteria:

• C: Hypercalcemia (serum calcium >11 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, osteoporosis with compression fractures) 1

Additional biomarkers that define multiple myeloma even without CRAB features include:

• ≥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

Genetic Classification

Multiple myeloma can be classified into two major genetic subtypes:

1. Hyperdiploid Myeloma:

   • Characterized by trisomies of odd-numbered chromosomes
   • Generally associated with more indolent disease and better prognosis 1

2. Non-Hyperdiploid Myeloma:

   • Primarily characterized by IgH translocations
   • Generally associated with more aggressive disease features 1

Clinical Manifestations

The clinical presentation of multiple myeloma results from:

• Bone involvement: Pain, pathologic fractures, and hypercalcemia due to increased osteoclast activity and decreased osteoblast function 1
• Bone marrow infiltration: Anemia, thrombocytopenia, and leukopenia 1
• Renal dysfunction: Due to cast nephropathy, hypercalcemia, amyloidosis, direct tubular toxicity from light chains, and dehydration 1
• Immunodeficiency: Increased susceptibility to bacterial and viral infections due to suppression of normal immunoglobulin production and functional defects in immune cells 1

Diagnostic Evaluation

A comprehensive diagnostic workup includes:

• Blood tests:

  • Complete blood count
  • Serum creatinine and calcium levels
  • Serum protein electrophoresis with immunofixation
  • Quantification of immunoglobulins 1

• Imaging studies:

  • Whole-body low-dose CT (more sensitive than conventional radiography)
  • MRI for symptomatic bony sites or suspected spinal cord compression 1

• Bone marrow assessment:

  • Bone marrow aspiration and/or biopsy
  • Cytogenetic/FISH studies
  • Immunophenotypic and molecular investigations 1

• Urine analysis:

  • 24-hour urine for total protein
  • Urine protein electrophoresis 1

Epidemiology

• Incidence in Europe: 4.5-6.0/100,000/year
• Median age at diagnosis: 65-70 years
• Mortality rate: 4.1/100,000/year 1
• Second most common hematologic cancer 2

Treatment Approach

Treatment is indicated for all patients with active myeloma fulfilling the CRAB criteria or those symptomatic due to the underlying disease. Standard treatment options include:

• For elderly patients: melphalan/prednisone/thalidomide (MPT) or bortezomib/melphalan/prednisone (VMP)
• For eligible patients: induction therapy with a proteasome inhibitor, an immunomodulatory agent, and dexamethasone, followed by autologous stem cell transplantation, and maintenance therapy with lenalidomide 1
• Bisphosphonates for patients with adequate renal function and bone disease 1

Despite significant advances in treatment, multiple myeloma remains incurable in most cases, with a survival time range of 5-7 years for newly diagnosed patients. 2