Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of monoclonal protein (M protein) in the blood. M protein is produced by plasma cells in bone marrow. Etiology is unknown. Affected patients may experience peripheral neuropathy and are more likely to experience fractures, osteopenia, or osteoporosis. MGUS is clinically asymptomatic and remains benign in 75% of cases, but 25% of cases progress to myeloma or a B-cell disorder (macroglobulinemia, amyloidosis, and lymphoma). Thus, affected patients must be monitored regularly since the condition can become malignant. MGUS occurs in about 5% of the general population over the age of 50 years. The rate is double in those over age 70 years when compared with those aged 50-70 years, and the mean age of diagnosis is in the 70s. Among Black individuals, and among first-degree relatives with multiple myeloma or a related disorder, the prevalence of MGUS is 2-3 times as high as that in the general population. MGUS is often an incidental finding. Associated conditions include Gaucher disease type 1, lymphoid cancer, such as chronic lymphocytic leukemia (CLL) and hairy cell leukemia, chronic viral hepatitis, and certain infections.

Risk factors include obesity, sugar-sweetened beverages, radiation exposure, environmental exposure to pesticides and other carcinogens, chronic inflammation, and immunosuppression.

Several dermatoses are associated with MGUS, including scleromyxedema, primary systemic amyloidosis, and normolipemic plane xanthomas. Additionally, erythema elevatum diutinum, subcorneal pustular dermatosis, scleredema, and acquired angioedema (C1 inhibitor deficiency) may have an underlying monoclonal gammopathy. Schnitzler syndrome and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, multiple myeloma, and skin changes and sclerotic bone changes) are rare syndromes that are seen in the setting of MGUS. The term "monoclonal gammopathy of clinical significance" (MGCS) refers to MGUS that is associated with a serious disorder, such as AL amyloidosis, monoclonal immunoglobulin deposition disease, and cryoglobulinemia.