Monoclonal gammopathy of undetermined significance (MGUS)

Definition

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic, premalignant clonal plasma cell disorder. An M-protein is detectable in serum or urine without multiple myeloma or a related lymphoplasmacytic neoplasm being present. MGUS is an obligatory precursor of multiple myeloma, Waldenström macroglobulinemia, and AL amyloidosis.

Classification

Diagnostic criteria (IMWG 2014):

• Serum M-protein < 3 g/dL
• clonal bone marrow plasma cells < 10 %
• no end-organ damage attributable to the plasma cell disorder (no CRAB features: hypercalcemia, renal insufficiency, anemia, bone lesions)

Subtypes by isotype:

• Non-IgM MGUS (IgG, IgA, rarely IgD): progression mainly to multiple myeloma
• IgM MGUS: progression mainly to lymphoplasmacytic lymphoma/Waldenström macroglobulinemia
• Light chain MGUS: abnormal free light chain ratio (< 0.26 or > 1.65) without heavy chain

Occurrence & epidemiology

Prevalence increases with age: about 3 % of people aged 50 and older and about 5 % of those aged 70 and older have MGUS; under age 40 it is rare (< 0.3 %). Men are affected more often than women, people of African ancestry two to three times more often. The risk of progression to a malignant disorder is about 1 % per year.

Aetiopathogenesis

A monoclonal plasma cell population emerges from a polyclonal background. About half of MGUS cases show aneuploidy, especially hyperdiploidy; translocations at the immunoglobulin heavy chain locus also occur. Autoimmune disorders and chronic immune stimulation are associated with an increased risk of MGUS. MGUS may also occur together with other diseases.

Clinical features

MGUS usually causes no symptoms and is discovered incidentally on protein electrophoresis. Peripheral neuropathy and increased bone loss with a higher fracture risk may occur. Warning signs of progression include marked fatigue, night sweats, fever, unintentional weight loss, bone pain, organomegaly, lymphadenopathy, bleeding tendency, unexplained anemia, hypercalcemia, or worsening kidney function.

Diagnosis

• Serum protein electrophoresis with immunofixation of serum and urine, quantitative immunoglobulins, and serum free light chains
• Complete blood count, calcium, and creatinine to exclude CRAB features
• Risk factors for progression: abnormal free light chain ratio, non-IgG isotype, and M-protein ≥ 1.5 g/dL; in addition, > 5 % clonal plasma cells and reduction of the uninvolved immunoglobulins
• Bone marrow examination and skeletal imaging at higher risk or with clinical or laboratory abnormalities; dispensable in IgG MGUS with M-protein < 1.5 g/dL and a normal free light chain ratio without warning signs
• With fracture risk, skeletal radiographs and bone densitometry

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Further reading (open access)

1. Fac Rev 2022: Monoclonal gammopathy of undetermined significance (PMC-Volltext)
2. MSD Manual Professional: Monoclonal Gammopathy of Undetermined Significance (MGUS)
3. Clin Exp Med 2026: Monoclonal gammopathies, MGUS, SMM and multiple myeloma (PMC-Volltext)

Cross-references