What are the diagnostic criteria for Monoclonal Gammopathy of Undetermined Significance (MGUS)?

Diagnostic Criteria for Monoclonal Gammopathy of Undetermined Significance (MGUS)

MGUS is diagnosed when all three criteria are met: serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of end-organ damage attributable to the plasma cell proliferative disorder. 1

Essential Diagnostic Tests

Laboratory Evaluation

• Serum tests:

  • Serum protein electrophoresis (SPEP) to detect and quantify M-protein
  • Immunofixation to identify the type of M-protein (IgG, IgA, IgM)
  • Quantification of immunoglobulins (IgG, IgA, IgM)
  • Serum free light chain (FLC) assay with κ:λ ratio 1

• Urine tests:

  • 24-hour urine protein electrophoresis
  • Urine immunofixation 1

Bone Marrow Assessment

• Bone marrow aspiration and biopsy to evaluate plasma cell percentage and morphology
• Must show <10% clonal plasma cells 1
• For IgG MGUS with M-protein ≤15 g/L without symptoms, bone marrow examination may be deferred until evidence of progression 1
• Bone marrow examination should be performed for all IgA and IgM M-proteins 1

Imaging Studies

• Not routinely recommended for patients with IgG M-protein ≤15 g/L or IgA M-protein ≤10 g/L without bone pain 1
• Consider skeletal survey for non-IgM MGUS with higher M-protein levels
• CT scan of chest, abdomen, and pelvis for IgM MGUS 1
• Low-dose whole-body CT may be a good alternative to conventional X-rays 1

Types of MGUS

Non-IgM MGUS

• Serum monoclonal protein <3 g/dL
• Clonal bone marrow plasma cells <10%
• No end-organ damage (CRAB: hypercalcemia, renal insufficiency, anemia, bone lesions) 1

IgM MGUS

• Serum IgM monoclonal protein <3 g/dL
• Bone marrow lymphoplasmacytic infiltration <10%
• No anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly 1

Light Chain MGUS

• Abnormal FLC ratio (<0.26 or >1.65)
• Increased level of involved light chain
• No immunoglobulin heavy chain expression on immunofixation
• Clonal bone marrow plasma cells <10%
• No end-organ damage 1

Differential Diagnosis

MGUS must be differentiated from:

1. Smoldering Multiple Myeloma (SMM):

   • Serum M-protein (IgG or IgA) ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%
   • No end-organ damage 1

2. Multiple Myeloma:

   • Clonal bone marrow plasma cells ≥10%
   • Presence of serum/urine M-protein
   • Evidence of end-organ damage (CRAB criteria) 1, 2

3. Waldenström Macroglobulinemia:

   • IgM monoclonal gammopathy
   • ≥10% bone marrow lymphoplasmacytic infiltration
   • Evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly 1

Risk Stratification

Risk factors for progression to malignancy include:

• Size of serum M-protein
• Type of M-protein
• Abnormal serum free light chain ratio
• Percentage of bone marrow plasma cells 3

Common Pitfalls and Caveats

1. Renal disease assessment: In patients with significant proteinuria or renal insufficiency, kidney biopsy may be indicated to rule out monoclonal gammopathy of renal significance (MGRS) 1

2. Bone health evaluation: Consider dual-energy X-ray absorptiometry (DXA) to evaluate for osteoporosis, especially with other risk factors 1

3. Follow-up requirements: Lifelong follow-up is generally advised since there is no decline in risk of progression (approximately 1% per year) 1, 3

4. Serum free light chain assay interpretation: Renal impairment can alter the normal FLC ratio range (0.26-1.65 can rise to 0.34-3.10 in severe renal impairment) 1

5. Stability assessment: An important criterion for MGUS is stability of the monoclonal protein over time 4

By following these diagnostic criteria and conducting appropriate testing, clinicians can accurately diagnose MGUS and distinguish it from more serious plasma cell disorders that require immediate treatment.