Monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS, unknown or uncertain may be substituted for undetermined) or benign monoclonal gammopathy is a condition in which a low or non-quantifiable level of a monoclonal paraprotein is detected in the blood by means of protein electrophoresis. In addition, some patients develop a polyneuropathy (damage to peripheral nerves) or other problems related to the secreted antibody. MGUS is distinct from multiple myeloma, as described below.

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Diagnosis

Patients may be diagnosed with MGUS if they fulfill the following three criteria:^[1]

1. A monoclonal paraprotein band less than 3 g/dl;
2. Plasma cells less than 10% on bone marrow examination; and
3. No evidence of bone lesions, anemia, hypercalcemia, or renal insufficiency related to the paraprotein.

Differential diagnosis

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made:

• Multiple myeloma
• AIDS
• Chronic lymphocytic leukemia
• Non-Hodgkin Lymphoma, particularly Splenic marginal zone lymphoma^[2] and Lymphoplasmocytic lymphoma
• Hepatitis C
• Connective tissue disease such as lupus^[3]
• Immunosuppression following organ tranplantation
• Waldenström macroglobulinemia
• Guillain-Barre syndrome^[4]

Pathology

Pathologically, the lesion in MGUS is in fact very similar to that in multiple myeloma. There is a predominance of clonal plasma cells in the bone marrow with an abnormal immunophenotype (CD38+ CD56+ CD19−) mixed in with cells of a normal phenotype (CD38+ CD56− CD19+);^[5][6] in MGUS, more than 3% of the clonal plasma cells have the normal phenotype, whereas in multiple myeloma, less than 3% of the cells have the normal phenotype.^[7] What causes MGUS to transform into multiple myeloma is as yet unknown.

Prognosis

MGUS may be considered a pre-malignant condition, given the possibility of transformation into multiple myeloma. However, because the condition tends to occur in the elderly, and because the rate of progression is slow, only a small proportion of people with MGUS go on to develop a haematological malignancy. In patients with MGUS, although the actuarial risk of myeloma at 25 years of follow-up is 30%, the actual risk (when competing causes of death are taken into account) is only 11%.^[8]

The annual risk of progressing to multiple myeloma is around 1–2% a year. Kyle et al studied the prevalence of myeloma in a population-wide cohort in Olmsted County, Minnesota. They found that the prevalence of MGUS was 3.2% in people above 50, with a slight male predominance (4.0% vs. 2.7%). Prevalence increased with age: of people over 70 up to 5.3% had MGUS, while in the over-85 age group the prevalence was 7.5%. In the majority of cases (63.5%), the paraprotein level was <1 g/dl, while only a very small group had levels over 2 g/dl.^[9]

In addition to multiple myeloma, MGUS may also progress to Waldenström's macroglobulinemia, primary amyloidosis, B-cell lymphoma, or chronic lymphocytic leukemia.

Annual review

The protein electrophoresis test should be repeated annually, and if there is any concern for a rise in the level of monoclonal protein, then prompt referral to a haematologist is required. The haematologist, when first evaluating a case of MGUS, will usually perform a skeletal survey (X-rays of the proximal skeleton), check the blood for hypercalcemia and deterioration in renal function, check the urine for Bence-Jones protein and perform a bone marrow biopsy. If none of these tests are abnormal, a patient with MGUS is followed up once every 6 months to a year with a blood test (serum protein electrophoresis).

References