Monoclonal Gammopathy of Undetermined Significance (MGUS) Overview

Monoclonal gammopathy of undetermined significance (MGUS) occurs when plasma cells in the bone marrow produce an abnormal antibody known as monoclonal protein (M protein). Although MGUS is generally considered benign, it can sometimes be a precursor to a more serious condition, such as multiple myeloma, light chain amyloidosis, Waldenstrom macroglobulinemia, or lymphoma. It has also been linked to osteoporosis and fractures, blood clots, kidney issues and peripheral neuropathy.

Some patients have a more advanced plasma cell disorder with a larger amount of abnormal plasma cells in the bone marrow, called smoldering multiple myeloma (SMM). Like MGUS, SMM does not cause noticeable symptoms; however, it carries a higher likelihood of evolving into active multiple myeloma. A rare and aggressive blood cancer, multiple myeloma can cause low blood cell counts, weakened bones, kidney damage and impaired immune function.

Monoclonal gammopathy of undetermined significance is relatively common in older adults, affecting approximately 3% of those over 50 years and 5% of those over 70 years. The iSTOPMM prospective study noted that 5% and 0.5% of individuals over 40 years had MGUS and SMM, respectively.   

What causes monoclonal gammopathy of undetermined significance?

The exact cause of MGUS is unknown. While researchers suspect that certain infections, immune system disorders and environmental factors may play a role in its development, no definitive links have been established to date.

What are the risk factors for monoclonal gammopathy of undetermined significance?

Known risk factors for MGUS include:

• Advanced age – Monoclonal gammopathy of undetermined significance is most prevalent in individuals older than 50, and the risk increases with age.
• Gender – For unknown reasons, MGUS disproportionately affects men.
• Race and ethnicity – Monoclonal gammopathy of undetermined significance and multiple myeloma are diagnosed more frequently in people of African descent than those of European or Asian descent.
• Immune system disorders – Certain autoimmune conditions, such as rheumatoid arthritis and lupus, and chronic infections, such as hepatitis and Epstein-Barr virus (EBV), may contribute to MGUS development.
• Family history – A family history of monoclonal gammopathy of undetermined significance or related plasma cell disorders may increase the risk.
• Exposure to toxins – Long-term exposure to pesticides, herbicides or other environmental toxins has been associated with an elevated risk of MGUS.

What are the symptoms of monoclonal gammopathy of undetermined significance?

Most individuals with MGUS do not experience symptoms. Often, the condition is detected incidentally through routine blood testing. These conditions are diagnosed when a monoclonal gammopathy is associated with specific renal, dermatologic, neurologic or thrombotic disorders.

How is monoclonal gammopathy of undetermined significance diagnosed?

MGUS is typically diagnosed through a combination of blood and urine tests, which are minimally invasive and highly accurate. The diagnostic process may include:

• Serum protein electrophoresis (SPEP) or immunofixation electrophoresis (IFE) – SPEP and IFE can identify and measure M proteins in a blood sample.
• Serum free light chain assay (sFLC) – sFLC measures the levels of two types of plasma-produced proteins (free light chains) in a blood sample.
• Urine protein electrophoresis (UPEP) – UPEP is a 24-hour urine test that can detect M proteins in the urine.
• Complete blood count (CBC) – A CBC can provide important clues about the patient’s overall health and help the physician rule out other conditions.
• Bone marrow biopsy (if needed) – In some cases, a bone marrow biopsy may be performed to assess plasma cell levels and rule out multiple myeloma and other plasma cell disorders.

How is monoclonal gammopathy of undetermined significance treated?

Usually, MGUS does not require immediate treatment, mainly because it is a benign condition with no symptoms. Instead, management focuses on “watchful waiting” to detect any signs of progression to multiple myeloma or other plasma cell disorders. This may include:

• Observation and monitoring – Patients with MGUS are typically advised to undergo periodic blood and urine tests to track M protein levels and look for changes in kidney function, bone health and blood cell counts.
• Addressing risk factors – Although there is no direct treatment for MGUS, managing any underlying conditions, such as diabetes, high blood pressure and vitamin D deficiency, can help maintain overall health.
• Bone health management – Since MGUS is linked to an increased risk of bone loss, a physician may suggest calcium and vitamin D supplementation, or possibly medications such as bisphosphonates, if bone density is a concern.

How can multiple myeloma and other complications of monoclonal gammopathy of undetermined significance be prevented?

According to a recent study published online in the JCO™ Clinical Cancer Informatics, screening individuals with a high lifetime risk of developing MGUS can reduce the prevalence of multiple myeloma and improve outcomes. Researchers at Moffitt Cancer Center, in collaboration with scientists from Dana-Farber Cancer Institute, Harvard University, the University of Manchester and the University of Iowa, conducted a series of computational modeling experiments to evaluate optimal screening strategies for different populations. The study aimed to identify the most effective time to initiate screening, the ideal screening frequency and the specific individuals who would benefit most. The researchers discovered that certain screening strategies could effectively reduce the risk of MGUS progression. For instance, the prevalence of multiple myeloma could be reduced by 19% in individuals who begin screening at age 55 and have follow-up screening every six years.

In sum, screening for monoclonal gammopathy of undetermined significance has the potential to significantly reduce the incidence of multiple myeloma, provided that safe and effective interventions are identified. Early and regular monitoring, ideally beginning as soon as any risk factors are recognized, may be beneficial. Biannual follow-ups should be prioritized for high-risk individuals, particularly those with a family history of multiple myeloma or a high likelihood of MGUS progression.

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