Diagnosis

Multiple myeloma

Etiology

Cause [peb]

• Unknown

• Spontaneous mutation in the promoter genes or oncogenes NRAS, KRAS, and BRAF

Pathophysiology [peb]

1. Monoclonal gammopathy of undetermined significance (MGUS):

   • Monoclonal immunoglobulins in the blood or urine without end-organ damage

   • Plasma cell proliferation --> overproduction of monoclonal IgG, IgA, light chains

   • Risk of progression to multiple myeloma

2. MGUS --> Multiple myeloma:

   • Genetic alterations --> increased expression of promoter genes --> resistance to apoptosis --> higher plasma cell proliferation and population >10% of the bone marrow

3. Myeloma cells --> activation of osteoclasts and suppression of osteoblasts

4. Osteolytic lesions in the vertebrae, ribs, skull, pelvis, femur, clavicle and scapula

Risk factors [peb]

• Obesity

• Alcohol

• Insecticides, organic solvents, agent orange

• Radiation exposure

Complications [peb]

• Renal failure

• Hyperviscosity (stroke, myocardial infartcion, venous thromboembolism)

• Pancytopenia: Anemia, thrombocytopenia, and leukopenia

• Neuropathy

• Infection

• Skeletal lesions: pathological fractures, spinal cord compression

• Hypercalcemia

Epidemiology

Incidence per 100.000 [eia][2h5][6aa]

Approach

• Blood test: Hb, WBC, Trc, SR, CRP, BUN, creatinine, uric acid, calcium, LDH, beta-2 microglobulin

• Urine:

  • 24-hour proteinuria

  • Urine protein electrophoresis, Bence Jones protein (lambda light chains)

  • Urine immunofixation electrophoresis

• Serum protein electrophoresis:

  • Serum immunoglobulins

  • Serum protein electrophoresis

  • Serum immunofixation electrophoresis

  • Serum-free light chain assay

• Blood smear

• Bone marrow aspirate and biopsy:

  • Immunohistochemistry and/or flow cytometry,

  • Cytogenetics

• Plasma cell FISH

• Bone biopsy

• X-ray

• MRI

• Whole body PET-CT

Diagnostic criteria (International Myeloma Working Group 2014) [peb]

1. Clonal bone marrow plasma cells > 10% on bone marrow biopsy

   • Or if a biopsy-proven plasmacytoma

2. And one of the following criteria for end-organ damage:

   • Serum calcium level >2.75 mmol/L (>11 mg/dL)

   • Renal insufficiency (creatinine > 2 mg/dL [> 177 umol/L] or clearance < 40 mL/min)

   • Anemia (Hb <10 g/dL)

   • One or more osteolytic bone lesions

   • Bone marrow plasma cells equal to 60%

   • Involved/uninvolved serum free light chain ratio ≥ 100

   • Abnormal MRI with more than one focal lesion >5 mm

Treatment

Treatment is dependant on subtype: [q5a][peb]

1. Monoclonal gammopathy of undetermined significance (MGUS): 2-3% of the elderly

   • Premalignant state

   • Bone marrow plasma cell concentration < 10%

   • No end-organ damage

   • Active surveillance or watchful waiting

2. Solitary plasmacytoma (lesion made up of clonal plasma cells)

   • Normal bone marrow

   • No end-organ damage

   • Treatment: Radiation therapy or surgery if structural instability

3. Smoldering multiple myeloma (SMM)

   • Monoclonal protein is greater than or equal to 3 g/dl

   • Clonal bone marrow plasma cells between 10% to 59%

   • No end-organ damage

   • Treatment: Active surveillance or watchful waiting

4. Symptomatic MM

   • Supportive treatment: Hypercalcemia, renal dysfunction, spinal cord compression

   • Young patients --> Transplantation

   • Elderly patients --> Triplet regime:

     • lenalidomide/dexamethasone/Bortezomib or Carfilzomib

     • Bortezomib/cyclophosphamide/dexamethasone (if kidney failure)

     • Carfilzomib/cyclophosphamide/dexamethasone (peripheral neuropathy)

Differential diagnoses

Amyloidosis, Breast cancer, Leukemia, Lung cancer, Lymphoma, Macroglobulinemia, Metastatic bone tumors, Polyneuropathy, Prostate cancer, Renal cell carcinoma, Renal failure, Thyroid cancer