Monoclonal Gammopathy of Undetermined Significance: A Brief Overview

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder that is often diagnosed incidentally, meaning that it is found when looking for other disorders or during routine medical tests. MGUS is a premalignant, which means having the potential to progress to malignancy (cancer), and asymptomatic condition.¹ To be diagnosed with MGUS, you must meet the following three criteria: serum monoclonal protein (M protein) less than 3mg/dL, clonal bone marrow plasma cells less than 10 percent, and absence of end-organ damage (eg, hypercalcemia, renal insufficiency, anemia, bone lesions) due to the plasma cell disorder.² There are three types of MGUS: non-immunoglobulin M (IgM) MGUS, IgM MGUS, and light-chain MGUS, and their diagnostic criteria (Box 1), and their progression potential differs slightly.^1,3 Since the majority of MGUS cases are non-IgM,¹ the remainder of this article will focus on this type. 

Prevalence

About 2 to 3 percent of adults over the age of 50 years and five percent of those over the age of 70 years have MGUS.¹ MGUS is more prevalent in Black individuals compared to White individuals and in men compared to women. Furthermore, people with first-degree relatives with MGUS or multiple myeloma have a greater risk of developing MGUS, which suggests that there might be a genetic component to this condition.^1,2 

Progression

Non-IgM MGUS can progress to smoldering multiple myeloma or multiple myeloma or related disorders.^1,3 The risk of progression from MGUS to multiple myeloma or a related disorder is one percent per year, which is very low.⁴ However, different clinical features can lead to an increased risk of progression. Researchers have developed a risk stratification guide for MGUS. Patients with low-risk MGUS have serum M protein less than 1.5g/dL, IgG subtype, and normal free light chain (FLC) ratio (0.26–1.65); a light chain is a small subunit that is attached to a heavy chain as part of an antibody, and a FLC is a light chain that is unattached to a heavy chain and is present in the blood. The presence of abnormalities in these factors, which includes M protein of 1.5g/dL or greater, non-IgG subtype, and FLC ratio less than 0.26 or greater than 1.65, increases the risk of disease progression. Patients with low-risk MGUS have a five-percent absolute risk of progression at 20 years; this risk increases to 21 percent for patients with low-intermediate–risk MGUS (any 1 abnormality is present), 37 percent for those with high-intermediate–risk MGUS (any 2 abnormalities are present), and 58 percent for those with high-risk MGUS (all 3 abnormalities are present).⁵ 

Management

Upon diagnosis, patients with MGUS should undergo a complete history and physical, various lab tests (complete blood count [CBC], serum calcium, and creatinine), and a urine protein test.² At 3 to 6 months post-MGUS diagnosis, serum protein electrophoresis should be performed again to rule out multiple myeloma or Waldenström’s macroglobulinemia (a type of lymphoma).²

Patients with low-risk MGUS typically do not need to undergo bone marrow examination since risk of progression is so low. If stable after 3-to-6-month follow-up for serum protein electrophoresis, patients can be followed every 2 to 3 years or if symptoms of a plasma cell malignancy arise. Patients with low-intermediate–risk MGUS or greater should undergo bone marrow examination to rule out plasma cell malignancy; if there is evidence of malignancy, patients should receive further tests to measure lactate dehydrogenase, beta-2 microglobulin, and C-reactive proteins. If the patient is found to have MGUS, they should undergo serum protein electrophoresis and CBC after six months, then annually for life. Patients with MGUS do not receive active treatment unless part of a clinical trial.²

Conclusion

MGUS is an asymptomatic precursor condition to multiple myeloma. Although risk of disease progression is low, patients with MGUS, especially those with high-risk characteristics, should be monitored by a healthcare professional.

Sources

1. Kaseb H, Annamaraju P, Babiker HM. Monoclonal gammopathy of undetermined significance. Updated 10 Jul 2022. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. https://www.ncbi.nlm.nih.gov/books/NBK507880/
2. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24(6):1121–1127. 
3. Rajkumar SV, Kyle RA, Buadi FK. Advances in the diagnosis, classification, risk stratification, and management of monoclonal gammopathy of undetermined significance: implications for recategorizing disease entities in the presence of evolving scientific evidence. Mayo Clin Proc. 2010;85(10):945–948. 
4. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346(8):564–569. 
5. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106(3):812–817.