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Monoclonal Gammopathy of Undetermined Significance: Robert A. Kyle, MD


Monoclonal Gammopathy of Undetermined Significance: Robert A. Kyle, MD


The term monoclonal gammopathy of undetermined significance (MGUS) denotes the presence of a monoclonal protein (M-protein) in persons without evidence of multiple myeloma, macroglobulinemia, amyloidosis, or related plasma cell proliferative disorders. MGUS is characterized by a serum M-protein concentration of <3.0 g/dL; fewer than 10% plasma cells in the bone marrow; none or only a small amount of M-protein in the urine; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the plasma cell disorder. MGUS has been found in approximately 3% of persons older than 70 years and in approximately 1% of persons above the age of 50. MGUS occurs more often in African Americans than in whites, and the incidence is lower in the Japanese population.

MGUS is a common finding in the medical practice of all physicians. It is important for both the patient and the physician to determine whether the presence of M-protein will remain benign or will progress to multiple myeloma or related disorders. In a group of 241 patients diagnosed at the Mayo Clinic from 1956 through 1970, 25% of the 241 patients developed multiple myeloma, macroglobulinemia, amyloidosis, or a malignant lymphoproliferative process during a follow-up of 24 to 38 years. The actuarial rate of progression was 17% at 10 years and 33% at 20 years. Two thirds of the patients with progression had multiple myeloma. The interval from the recognition of the M-protein to the diagnosis of multiple myeloma ranged from 2 to 29 years (median 10 years). A “population-based” study was done on 1384 patients with MGUS from southeastern Minnesota diagnosed at the Mayo Clinic from 1960 through 1994. Median age at diagnosis of MGUS was 72 years. Only 2% were under 40 years of age. The heavy-chain type was IgG in 70%, IgA in 12%, and IgM in 15%. A biclonal gammopathy was found in 3%. Reduction of uninvolved (normal or background) immunoglobulins was found in 38% of 840 patients in whom quantitation of immunoglobulins was determined at the time of diagnosis. Ninety-one percent of 418 patients who had immunofixation of the urine had a monoclonal light chain. The patients were followed for a total of 11,009 person-years (median 15 years). In follow-up, 115 patients (8%) developed multiple myeloma, primary amyloidosis, lymphoma with an IgM serum M-protein, macroglobulinemia, plasmacytoma, or chronic lymphocytic leukemia. The cumulative probability of progression to one of these disorders was 10% at 10 years, 21% at 20 years, and 26% at 25 years. Risk of progression was about 1% per year, but patients were at risk for progression even after 25 years or more of stable MGUS. In addition, 32 patients were identified in whom the M-protein value increased to *3 g/dL or the percentage of bone marrow plasma cells increased to *10% but in whom symptomatic multiple myeloma did not develop. The number of patients with progression to a plasma cell disorder (115 patients) was 7.3 times the number expected on the basis of the incidence rates for those conditions in the general population. Risk of developing multiple myeloma was increased 25-fold, macroglobulinemia 46-fold, and primary amyloidosis 8.4-fold. Sixty-five percent of the 115 patients with progression had multiple myeloma. The M-protein disappeared spontaneously in 27 patients (2%). Only six of these 27 patients (0.4% of all patients) had a discrete spike on the densitometer tracing of the initial electrophoresis (median 1.2 g/dL). When multiple myeloma develops, the type of M-protein is always the same as it was in MGUS. Of all the baseline parameters for predicting the progression of MGUS (age; sex; hepatosplenomegaly; hemoglobin; serum creatinine; serum albumin; size of serum M-protein; type of serum M-protein [IgG, IgA, IgM]; presence, type, and amount of monoclonal urinary light chain; number of bone marrow plasma cells; and reduction of uninvolved immunoglobulins), only the concentration and type of M-protein were independent predictors of progression. Presence of a monoclonal urine protein or reduction of one or more uninvolved immunoglobulins were not risk factors for progression. The risk of progression to multiple myeloma or a related disorder 20 years after recognition of the M-protein was 14% for an initial M-protein level of 0.5 g/dL or less, 16% for a level of 1.0 g/dL, 25% for 1.5 g/dL, 41% for 2.0 g/dL, 49% for 2.5 g/dL, and 64% for 3.0 g/dL. Patients with IgM or IgA M-protein had an increased risk of progression when compared with those with IgG M-protein.

MGUS may be associated with disorders other than multiple myeloma, including lymphoproliferative diseases, leukemia, von Willebrand’s disease, connective tissue disorders, neurologic disorders, and a wide variety of other diseases.

Solitary Plasmacytoma

Diagnosis of solitary plasmacytoma of bone is characterized by histologic evidence ofa tumor consisting of monoclonal plasma cells identical to those in multiple myeloma. However, cases of solitary plasmacytoma will not show any lytic lesions on complete skeletal roentgenograms, a bone marrow aspirate will contain no evidence of multiple myeloma, and immunofixation of the serum and concentrated urine should show no M-protein. There are exceptions to the last criterion, but therapy for the solitary lesion usually results in disappearance of the M-protein. Persistence of the M-protein after radiation therapy is associated with an increased risk of progression to multiple myeloma.

In patients with solitary plasmacytoma, uninvolved or background immunoglobulins are usually normal. There should be no evidence of anemia, hypercalcemia, or renal insufficiency related to the plasma cell proliferative process. Magnetic resonance imaging (MRI) of the spine and pelvis is helpful for detecting marrow involvement.

Almost 50% of patients with solitary plasmacytoma are alive at 10 years. The disease-free interval at 10 years ranges from 15% to 25%. Progression, when it occurs, usually does so within 3 to 4 years.

Extramedullary plasmacytoma is a plasma cell tumor that arises outside the bone marrow. The tumor is found in the upper respiratory tract in approximately 80% of cases, especially in the nasal cavity and sinuses, nasopharynx, and larynx. Extramedullary plasmacytomas may also occur in the gastrointestinal tract, central nervous system, urinary bladder, thyroid, breast, testis, parotid gland, or lymph nodes. The diagnosis is based on the finding of a plasma cell tumor in an extramedullary site and the absence of multiple myeloma on bone marrow examination, radiography, and appropriate studies of blood and urine. Treatment consists of tumoricidal irradiation. The plasmacytoma may recur locally, metastasize to original nodes, or, in about 15% of patients, the condition will develop into multiple myeloma.

Selected References

Alexiou C, Kau RJ, Dietzfelbinger H, et al. Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer. 1999;85:2305-2314.

Dimopoulos MA, Moulopoulos LA, Maniatis A, Alexanian R. Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood. 2000;96:2037-2044.

Kyle RA. “Benign” monoclonal gammopathy after 20–35 years of follow-up. Mayo Clin Proc. 1993;68:26-36.

Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564-569.


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