What is Monoclonal Gammopathy of Undetermined Significance (MGUS)?

From the Guidelines

Patients with MGUS should be risk-stratified at diagnosis and followed up based on their risk category, with low-risk patients being followed every 2-3 years or at the time of progression, as recommended by the International Myeloma Working Group 1. The management of Monoclonal Gammopathy of Undetermined Significance (MGUS) involves regular monitoring to assess for progression to more serious conditions like multiple myeloma.

Key Considerations

• The risk of progression to multiple myeloma or related malignancy is approximately 1% per year, as reported in a study published in Leukemia 1.
• Low-risk MGUS is characterized by an M protein <15 g/l, IgG type, and a normal free light chain (FLC) ratio, and these patients can be followed less frequently, either every 2-3 years or at the time of progression 1.
• Patients with intermediate and high-risk MGUS should be followed more closely, with follow-up every 6 months and then annually for life 1.
• Regular monitoring is essential for early detection of any changes, and patients should be aware of symptoms that might indicate progression, including bone pain, unexplained fractures, frequent infections, fatigue, or kidney problems.

Monitoring and Management

• Patients with MGUS should have blood tests every 6-12 months to check protein levels and assess for progression to more serious conditions like multiple myeloma 1.
• A baseline bone marrow examination or skeletal radiography is not routinely indicated for low-risk MGUS patients, but may be required for patients with unexplained anemia, renal insufficiency, hypercalcemia, or bone lesions 1.
• The International Myeloma Working Group recommends risk-stratification of MGUS patients at diagnosis to optimize counseling and follow-up, and to minimize frequent testing for MGUS progression in patients at low risk of progression 1.

From the Research

Definition and Epidemiology of MGUS

• Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum M-protein less than 3 g/dL, less than 10 % clonal plasma cells in the bone marrow, and the absence of myeloma-defining event 2.
• Nearly 5% of adults have MGUS, a precursor malignant condition 3.
• The risk of progression to multiple myeloma (MM) varies greatly for individual patients, but it is uniform and 1 % per year for MGUS 2.

Diagnosis and Management of MGUS

• Management of MGUS centers on differentiating it from more serious conditions to determine additional diagnostic testing, monitoring, and potential therapy 3.
• Guideline-concordant management of MGUS is determined by predicted risk of progression to malignant disease, which depends on subtype of immunoglobulin, M protein concentration, and free light chain ratio 3.
• Patients with low-risk MGUS can safely defer bone marrow biopsy and advanced imaging, and should undergo periodic laboratory monitoring 3.
• Intermediate- and high-risk MGUS should trigger bone marrow biopsy and bone imaging to detect overt MM and shorter monitoring intervals 3.

Relationship between MGUS and Smoldering Multiple Myeloma (SMM)

• SMM is an asymptomatic disorder characterized by the presence of ≥3 g/dL serum M-protein and/or 10-60 % bone marrow plasma cell infiltration with no myeloma-defining event 2.
• SMM is a heterogeneous clinically defined condition in which some patients have MGUS (pre-malignancy), and some have MM (biologic malignancy) 4.
• The risk of progression to MM is higher for SMM patients, with approximately 10 % per year, and is not uniform 2.

Treatment and Risk Stratification

• Patients with newly diagnosed high-risk SMM should be offered therapy with lenalidomide or lenalidomide plus dexamethasone (Rd) for 2 years, or enrollment in clinical trials 4.
• Patients with low-risk SMM should be observed without therapy every 3-4 months 4.
• Biomarkers have become an integrated part of diagnostic criteria for MM requiring therapy, as well as clinical risk stratification of patients with SMM 2.
• Advanced molecular testing may improve on current risk stratification to target monitoring and treatment to those with highest risk of malignant progression and avoid overtreatment of those with low-risk disease 3.