Diagnostic Criteria for Monoclonal Gammopathy of Undetermined Significance (MGUS)
MGUS is diagnosed when all three of the following criteria are met: serum monoclonal protein < 3 g/dL, clonal bone marrow plasma cells < 10%, and absence of end-organ damage (CRAB criteria) attributable to a plasma cell proliferative disorder. 1
Types of MGUS
Non-IgM MGUS
- Serum monoclonal protein < 3 g/dL
- Clonal bone marrow plasma cells < 10%
- Absence of CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions)
IgM MGUS
- Serum monoclonal protein < 3 g/dL
- Clonal bone marrow lymphoplasmacytic cells < 10%
- Absence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly
Light Chain MGUS
- Abnormal free light chain (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%
- Absence of CRAB criteria
Diagnostic Workup
Essential Tests
- Serum protein electrophoresis with immunofixation
- Serum free light chain assay
- Complete blood count
- Serum calcium and creatinine
- Urinalysis with 24-hour urine protein electrophoresis if proteinuria is present
Risk Stratification
Risk factors for progression to multiple myeloma or related disorders:
- Serum M protein level ≥ 1.5 g/dL
- Non-IgG isotype (IgA or IgM)
- Abnormal free light chain ratio
Risk groups:
- Low risk (no risk factors): 2% lifetime risk of progression
- Low-intermediate risk (1 factor): 10% risk at 20 years
- High-intermediate risk (2 factors): 18% risk at 20 years
- High risk (all 3 factors): 27% risk at 20 years 1
Differential Diagnosis
MGUS must be differentiated from:
Smoldering Multiple Myeloma (SMM)
- Serum M protein ≥ 3 g/dL and/or
- Clonal bone marrow plasma cells ≥ 10%
- Absence of CRAB criteria
Multiple Myeloma
- Clonal bone marrow plasma cells ≥ 10% or biopsy-proven plasmacytoma
- Presence of CRAB criteria:
- Hypercalcemia: serum calcium > 11.5 mg/dL
- Renal insufficiency: serum creatinine > 2 mg/dL or creatinine clearance < 40 mL/min
- Anemia: hemoglobin < 10 g/dL or > 2 g/dL below lower limit of normal
- Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures
Management Recommendations
Low-risk MGUS
- Baseline bone marrow examination and skeletal radiography not routinely indicated if clinical evaluation and blood tests suggest MGUS
- Follow-up with serum protein electrophoresis at 6 months
- If stable, follow-up every 2-3 years or when symptoms suggestive of plasma cell malignancy arise 1
Intermediate and High-risk MGUS
- Baseline bone marrow aspirate and biopsy recommended
- Cytogenetics and FISH should be performed
- Follow-up with serum protein electrophoresis and complete blood count at 6 months, then annually for life 1
Important Considerations
- The risk of progression to multiple myeloma or related disorders is approximately 1% per year and continues indefinitely, even after 25+ years of observation 2
- No treatment is indicated for MGUS unless part of a clinical trial
- Patients must contact their physician if there is any change in their clinical condition
- MGUS may progress to multiple myeloma, AL amyloidosis, Waldenström macroglobulinemia, or lymphoma 2
Common Pitfalls
- Failing to distinguish between MGUS and smoldering myeloma (progression risk 1% vs. 10% per year)
- Not performing appropriate risk stratification, which can lead to inadequate follow-up
- Overlooking the need for lifelong monitoring, as the risk of progression continues indefinitely
- Missing the diagnosis of monoclonal gammopathy of clinical significance (MGCS), where patients have symptoms related to the monoclonal protein despite not meeting criteria for multiple myeloma 3