What is the definition and treatment of multiple myeloma?

Definition and Treatment of Multiple Myeloma

Multiple myeloma is characterized by the neoplastic proliferation of plasma cell clones producing monoclonal immunoglobulin, causing skeletal damage and other complications including hypercalcemia, renal insufficiency, anemia, and infections. 1

Diagnostic Criteria

• Multiple myeloma is diagnosed through the demonstration of clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma, plus evidence of end-organ damage (CRAB criteria) or specific biomarkers 1

• The CRAB criteria include:

  • C: Hypercalcemia (serum calcium >11.5 mg/dL) 1, 2
  • R: Renal insufficiency (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

• The International Myeloma Working Group (IMWG) updated the definition to include biomarkers that define MM even without CRAB features 1:

  • ≥60% clonal plasma cells in the bone marrow 1
  • Involved/uninvolved free light chain ratio ≥100 (with involved FLC level ≥100 mg/L) 1
  • MRI with more than one focal lesion (involving bone or bone marrow) 1

Staging

• The International Staging System (ISS) categorizes MM into three stages based on serum β-2 microglobulin and serum albumin levels 1, 3
• The Revised ISS (R-ISS) incorporates high-risk cytogenetics in addition to the ISS parameters 1
• High-risk MM is defined by the presence of t(4;14), t(14;16), t(14;20), gain 1q, del(17p), or p53 mutation 1

Treatment Approach

Newly Diagnosed Multiple Myeloma

1. Initial Assessment:

   • Determine transplant eligibility based on age, performance status, and comorbidities 1
   • Risk stratification using cytogenetics/FISH studies 2

2. Transplant-Eligible Patients:

   • Induction therapy with triple-drug regimens containing a proteasome inhibitor, immunomodulatory agent, and dexamethasone 1
   • Followed by high-dose chemotherapy with autologous stem cell transplantation 1
   • Maintenance therapy typically with lenalidomide 1

3. Transplant-Ineligible Patients:

   • Combination regimens such as:
     • Daratumumab-lenalidomide-dexamethasone (DRd) - significantly improves progression-free survival and overall survival compared to Rd alone 4
     • Bortezomib-melphalan-prednisone (VMP) 2
     • Melphalan-prednisone-thalidomide (MPT) 2

Relapsed/Refractory Multiple Myeloma

• Treatment options include:

  • Proteasome inhibitors (carfilzomib, bortezomib, ixazomib) 5
  • Immunomodulatory drugs (lenalidomide, pomalidomide) 1
  • Monoclonal antibodies (daratumumab, elotuzumab, isatuximab) 5
  • Various combinations of these agents 5

• Carfilzomib is indicated for relapsed or refractory MM in patients who have received one to three lines of therapy, in combination with:

  • Lenalidomide and dexamethasone
  • Dexamethasone alone
  • Daratumumab and dexamethasone
  • Isatuximab and dexamethasone 5

Supportive Care

• Bone disease management:

  • Bisphosphonates to reduce skeletal-related events 1
  • Surgical decompression for spinal cord compression due to bone fragments 6
  • Local radiotherapy for patients with neurologic impairment 6

• Other supportive measures:

  • High-dose dexamethasone for spinal cord compression to reduce inflammation 6
  • Thromboprophylaxis for patients on immunomodulatory drugs 5
  • Consider antiviral prophylaxis to prevent herpes zoster reactivation 5

Monitoring Response

• Regular assessment of monoclonal protein in serum and urine 2
• Minimal residual disease (MRD) assessment in patients achieving complete response 1
• MRD negativity (absence of tumor plasma cells within 1,000 bone marrow cells) correlates with prolonged progression-free and overall survival 1

Prognosis

• Despite significant improvements in treatment, MM remains incurable in most cases 7
• The 5-year survival rate has increased from 25% in 1975 to 34% in 2003 due to newer treatment options 1
• Factors affecting prognosis include:
  • Cytogenetic abnormalities 1
  • Beta-2 microglobulin levels 3
  • Response to initial therapy 1
  • Achievement of MRD negativity 1

Common Pitfalls and Caveats

• Distinguishing symptomatic MM from smoldering MM or MGUS is critical as treatment approaches differ significantly 1, 2
• Avoid unnecessary bone marrow biopsies and imaging in low-risk MGUS patients 2
• Recognize that renal dysfunction can artificially elevate beta-2 microglobulin levels independent of tumor burden 3
• Be aware that MM can present with varied clinical manifestations beyond the classic CRAB features 8
• Consider clinical trials as the first option for all patients, especially those with high-risk disease 1