Monoclonal Gammopathy of Undetermined Significance

Monoclonal gammopathy of undetermined significance (MGUS) is usually detected as an incidental finding when serum protein electrophoresis is ordered. MGUS is defined as an asymptomatic condition with no evidence of end-organ damage due to plasma cell proliferation or monoclonal immunoglobulin deposition. Laboratory diagnostic criteria include a serum monoclonal protein concentration of less than 3 g/dL and fewer than 10% of monoclonal plasma cells in the bone marrow. MGUS is a common disorder with a prevalence of approximately 3% in Caucasians older than 50 years of age, 5% older than 70 years, and 9% older than 85 years. It is two to three times more prevalent in African Americans. Relatives of patients with MGUS have a 4-fold higher risk of developing MGUS. 

The monoclonal immunoglobulins in MGUS are produced by malignant transformation of plasma cells or B lymphocytes. M proteins can be intact immunoglobulins such as IgG, IgA, or IgM. Rarely, they can be IgD or IgE. M proteins can also be kappa or lambda free light chains. 

IgG and IgA MGUS can progress to multiple myeloma or AL amyloidosis. IgM MGUS is more likely to progress to Waldenstrom macroglobulinemia or rarely IgM multiple myeloma. Light chain MGUS typically progresses to AL amyloidosis or light chain multiple myeloma. 

A publication from the Mayo Clinic followed 1384 patients who were diagnosed with MGUS between 1960 and 1994. After a median follow-up period of 34 years, these individuals were assessed for progression to multiple myeloma or another lymphoproliferative disorder.  One hundred forty seven (11%) of these patients progressed to multiple myeloma or another lymphoproliferative disorder. The risk of progression over time is summarized in the following table. 

Thus, the risk of progression from MGUS to multiple myeloma or another lymphoproliferative disorder is approximately 1% per year for at least 35 years. Subgroup analysis revealed that patients with IgM MGUS had a higher risk for progression than patients with non-IgM MGUS. The risk of progression for IgM MGUS was 2% per year after 10 years. Other risk factors for progression included a serum M protein concentration of 1.5 g/dL or greater and an abnormal serum free light chain (FLC) ratio. 

In this cohort of patients, plasma cell disorders accounted for 11% of deaths while other diseases (cardiovascular, cerebrovascular and non-plasma cell cancers) accounted for 87% of deaths. Patients with MGUS had a significantly shorter median survival rate compared with a matched control population (8.1 versus 12.4 years).  At 30 years of follow-up, the overall survival among patients with IgM MGUS was 4% and the survival of patients with non-IgM MGUS was 7%. 

In summary, the risk for progression of MGUS to multiple myeloma or Waldenstrom’s macroglobulinemia is small, but the risk persists indefinitely. Patients need to be followed throughout their lifetime. 

References

Kyle RA, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med. 2018;378:241-249. 

Willrich MA, et al. Laboratory testing for monoclonal gammopathies: Focus on monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Clin Biochem. 2018:38-47.

Liu Y and Parks AL. Diagnosis  and Management of Monoclonal Gammopathy of Undetermined Significance: A Review. JAMA Intern Med. Published online February 17, 2025. doi:10.1001/jamainternmed.2024.8124