Monoclonal gammopathy of uncertain significance (MGUS) is a relatively common condition that increases in older patients. The definition of monoclonal gammopathy of uncertain significance is somewhat problematic. In essence, it represents the presence of an M spike without an underlying diagnosis of multiple myeloma, Waldenstrom’s macroglobulinemia, or amyloidosis. Formerly known as benign monoclonal gammopathy, it is no longer called this because a significant proportion of patients ultimately will develop one of the aforementioned diseases. In this way, it can be considered one step in the multistep pathway to oncogenesis.

MGUS is defined as having an M spike of IgG less than 3.5 g/dL or IgA less than 2 g/dL or the presence of a small amount of urinary light chain in the urine in 24 h. The plasma cells in the marrow cannot exceed 10%, and there can be no lytic bone lesion or other symptoms related to a lymphoproliferative disorder. Finally, a stable level of monoclonal protein characterizes MGUS. MGUS is common and, like myeloma, shows an increasing incidence with advancing age. As many as 10% to 14% of those over the age of 70 may have a detectable M spike.

The course of monoclonal gammopathy has been well characterized by the Mayo Clinic Group. They followed 241 patients for a median of 19 years and found that only 24% of them had a stable or “benign” monoclonal gammopathy; 22% of them developed myeloma, macroglobulinemia, or amyloidosis, and 51% died of unrelated causes. Only 3% of the patients had a progressive rise of their M protein without the development of an underlying disorder.

The evaluation of a patient who has been found to have an M spike should be aimed at discovering a potential underlying lymphoproliferative disorder. In a report of more than 800 cases of monoclonal protein seen at a referral center during 1988, 64% were related to MGUS, with myeloma, amyloid, lymphoma, Waldenstrom’s macroglobulinemia, and CLL accounting for the remainder. However, it should be remembered that the incidence of MGUS far exceeds the incidence of myeloma in the general population. This referral population is markedly enriched for patients with documented lymphoproliferative disorders.

A complete history and physical examination, routine CBC, electrolytes, and renal function with a serum calcium and uric acid should be obtained. Quantitative immunoglobulin, a 24-h urine for electrophoresis, and total skeletal x-rays may be required to evaluate the significance of a monoclonal gammopathy. A bone marrow aspirate and biopsy or a biopsy of a single soft tissue mass or lytic bone lesion may also be required.

In the absence of identifying an underlying lymphoproliferative disorder, the patient should be diagnosed with MGUS. Follow-up electrophoresis in 3 to 6 months and then yearly should be adequate for those patients who show no progression in their M spike. Patients who have an M protein in the urine should be followed more closely.