What is multiple myeloma?

Multiple Myeloma: Definition and Characteristics

Multiple myeloma (MM) is a malignant neoplasm characterized by the neoplastic proliferation of plasma cell clones that produce monoclonal immunoglobulin, causing bone marrow infiltration and end-organ damage including skeletal destruction, hypercalcemia, renal insufficiency, anemia, and infections. 1

Pathophysiology and Disease Characteristics

• MM is caused by the uncontrolled proliferation of plasma cells that accumulate in the bone marrow, leading to bone destruction and marrow failure 1
• These neoplastic plasma cells produce monoclonal immunoglobulin (M-protein), which can be detected in serum and/or urine 1
• MM accounts for approximately 1.8% of all cancers and more than 15% of all hematologic malignancies in the United States 1
• The median age at diagnosis is approximately 69 years, with the disease most frequently diagnosed among people aged 65 to 74 years 1

Diagnostic Criteria

The International Myeloma Working Group (IMWG) diagnostic criteria for MM include:

• Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma 1, 2

• Evidence of end-organ damage (CRAB criteria) attributed to the plasma cell disorder 1, 2:

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

• Additional MM-defining biomarkers identified by the IMWG include 1:

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

  • 1 focal lesion on MRI (involving bone or bone marrow)

Diagnostic Workup

A comprehensive diagnostic workup for suspected MM should include:

• Laboratory studies 1, 2:

  • Serum and urine protein electrophoresis with immunofixation
  • 24-hour urine collection for protein electrophoresis
  • Nephelometric quantification of IgG, IgA, and IgM immunoglobulins
  • Serum free light chain assay with kappa/lambda ratio
  • Complete blood count with differential
  • Serum calcium, creatinine, and other electrolytes
  • Albumin, LDH, and beta-2 microglobulin (for staging)

• Bone marrow assessment 1, 2:

  • Bone marrow aspiration and/or biopsy to evaluate plasma cell infiltration
  • CD138 staining to accurately determine plasma cell percentage
  • Cytogenetic/FISH studies for risk stratification

• Imaging studies 1:

  • Skeletal survey including spine, pelvis, skull, humeri, and femurs
  • MRI or CT scan for symptomatic bony sites or suspected spinal cord compression
  • PET/CT may be considered but is not routinely recommended

Disease Classification

MM exists on a spectrum of plasma cell disorders:

• Monoclonal Gammopathy of Undetermined Significance (MGUS) 1, 2:

  • Serum monoclonal protein <3 g/dL
  • Clonal bone marrow plasma cells <10%
  • Absence of end-organ damage (CRAB criteria)

• Smoldering Multiple Myeloma (SMM) 1, 2:

  • Serum monoclonal protein (IgG or IgA) ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%
  • Absence of end-organ damage
  • Higher risk of progression than MGUS (10% per year for first 5 years)

• Symptomatic Multiple Myeloma 1:

  • Meets diagnostic criteria for MM with evidence of end-organ damage

Treatment Approach

Treatment is indicated for patients with symptomatic MM (meeting CRAB criteria) 1:

• For elderly patients (non-transplant eligible) 1:

  • Oral combinations of melphalan and prednisone plus novel agents are considered standard of care
  • Recommended regimens include melphalan/prednisone/thalidomide (MPT) or bortezomib/melphalan/prednisone (VMP)

• Novel therapeutic agents that have improved outcomes include 3, 4:

  • Immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide)
  • Proteasome inhibitors (bortezomib, carfilzomib)
  • Monoclonal antibodies (daratumumab)
  • Emerging therapies: bispecific antibodies and CAR-T cell therapy

• Treatment decisions should be based on risk stratification, with high-risk disease requiring more aggressive approaches 1, 5

Disease Complications and Monitoring

• Common complications of MM include 5, 6:

  • Bone pain and pathologic fractures due to skeletal destruction
  • Renal failure from M-protein deposition
  • Hyperviscosity syndrome
  • Recurrent infections due to suppression of uninvolved immunoglobulins
  • Anemia and hypercalcemia

• Regular monitoring is essential to assess treatment response and detect disease progression 2

Important Considerations

• Patients with MGUS or SMM generally do not require immediate treatment but need regular follow-up to monitor for progression 2
• The bone marrow microenvironment plays a critical role in MM pathogenesis and drug resistance mechanisms 6
• Despite significant advances in treatment, MM remains incurable in the majority of patients, highlighting the need for continued research and development of novel therapeutic strategies 7, 4