What are the characteristics of multiple myeloma?

Characteristics of Multiple Myeloma

Multiple myeloma is characterized by clonal plasma cell proliferation in bone marrow leading to end-organ damage (CRAB criteria: hypercalcemia, renal insufficiency, anemia, and bone lesions), with production of monoclonal immunoglobulins detectable in serum or urine. 1, 2

Epidemiology and Pathophysiology

• Accounts for 1% of all cancers and approximately 10% of hematological malignancies
• 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

Multiple myeloma evolves through a multi-step process:

1. Monoclonal Gammopathy of Undetermined Significance (MGUS) - a pre-malignant condition progressing to MM at a rate of 1% per year
2. Smoldering Multiple Myeloma (SMM) - an intermediate asymptomatic stage progressing to MM at a rate of 10% per year over the first 5 years, 3% per year over the next 5 years, and 1.5% per year thereafter 1, 2

Genetic Classification

Multiple myeloma can be classified into two major genetic subtypes:

• Hyperdiploid Myeloma (40-50% of cases): characterized by trisomies of odd-numbered chromosomes, generally associated with more indolent disease and better prognosis
• Non-Hyperdiploid Myeloma (40-50% of cases): characterized by IgH translocations, generally associated with more aggressive disease 2

Diagnostic Criteria

The diagnosis of symptomatic multiple myeloma requires:

1. ≥10% clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma
2. Evidence of end-organ damage (CRAB criteria) attributed to the plasma cell disorder 1, 2

CRAB Criteria

• C: Hypercalcemia (serum calcium >11.5 mg/dl)
• R: Renal insufficiency (serum creatinine >1.73 μmol/l or >2 mg/dl or creatinine clearance <40 ml/min)
• A: Anemia (normochromic, normocytic with hemoglobin value ≥2 g/dl below lower limit of normal or <10 g/dl)
• B: Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures) 1

Diagnostic Workup

The comprehensive diagnostic evaluation includes:

1. Blood Tests:

   • Complete blood count (anemia present in 73% of patients) 3
   • Serum creatinine and calcium levels
   • Serum protein electrophoresis with immunofixation
   • Quantification of immunoglobulins (IgG, IgA, IgM)
   • Serum free light chain measurement

2. Urine Tests:

   • 24-hour urine collection for protein electrophoresis

3. Bone Marrow Assessment:

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

4. Imaging Studies:

   • Skeletal survey (79% have osteolytic bone disease at presentation) 3
   • Whole-body low-dose CT (more sensitive than conventional radiography for detecting lytic lesions) 1
   • MRI or CT for symptomatic bony sites
   • MRI recommended when spinal cord compression is suspected 1, 2

Clinical Manifestations

The clinical presentation of multiple myeloma includes:

• Bone disease (79% of patients): bone pain, pathologic fractures, lytic lesions
• Anemia (73% of patients): fatigue, weakness
• Renal impairment (19% of patients): acute kidney injury, chronic kidney disease
• Hypercalcemia: confusion, dehydration, constipation, nausea
• Recurrent infections: due to immunodeficiency
• Neurological symptoms: spinal cord compression, peripheral neuropathy 3

Pathophysiological Mechanisms

• Bone disease: Malignant plasma cells disrupt the balance between osteoblasts and osteoclasts, leading to increased osteoclast activity and decreased osteoblast function
• Anemia: Results from bone marrow infiltration by malignant plasma cells
• Renal insufficiency: Caused by multiple mechanisms including cast nephropathy from excess light chains, hypercalcemia, and direct tubular toxicity
• Immunodeficiency: Associated with suppression of normal immunoglobulin production and functional defects in immune cells 2

Treatment Approaches

Treatment should be initiated in all patients with active myeloma fulfilling the CRAB criteria or those symptomatic due to the underlying disease. Standard treatment options include:

• For elderly patients (non-transplant setting):

  • Melphalan/prednisone/thalidomide (MPT)
  • Bortezomib/melphalan/prednisone (VMP)
  • Bendamustine plus prednisone (for patients with clinical neuropathy) 1

• For eligible patients:

  • Induction therapy with a proteasome inhibitor (bortezomib), an immunomodulatory agent (lenalidomide), and dexamethasone
  • Followed by autologous stem cell transplantation
  • Maintenance therapy with lenalidomide 3

• For bone disease:

  • Bisphosphonates (zoledronic acid or pamidronate) for patients with adequate renal function and bone disease 1

Prognosis

• Median survival after diagnosis: approximately 3 years due to frequent relapses 4
• Revised International Staging System Stage I: 82% 5-year survival rate 3
• Despite improvements in treatment, MM remains incurable for the majority of patients 5

The management of multiple myeloma has significantly improved with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to better outcomes and increased survival rates, but early diagnosis and appropriate treatment remain critical for optimal management of this complex malignancy.