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Monoclonal gammopathies of undetermined significance

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The monoclonal gammopathies include multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), primary systemic amyloidosis (AL), and Waldenström's macroglobulinemia (WM). At Mayo Clinic, almost 60% of patients with a monoclonal gammopathy have MGUS. MGUS is characterized by the presence of a serum monoclonal protein value <3 g/dL, fewer than 10% plasma cells in the bone marrow, no or a small amount of monoclonal protein in the urine, and absence of lytic bone lesions, anemia, hypercalcemia, or renal insufficiency related to the plasma-cell proliferative process. During long-term follow-up of 241 patients with MGUS seen at Mayo Clinic from 1956 to 1970, MM, WM, AL, or a related disorder developed in 64. To confirm the findings, we conducted a population-based study on MGUS in the 11 counties of southeastern Minnesota from 1960 to 1994. The risk of progression to a malignant plasma-cell disorder was 1% per year.

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MGUS in 1384 patients from Southeastern Minnesota

To confirm the findings of the 241 Mayo Clinic patients from the United States and other countries, which may be subject to referral reference bias, we conducted a population-based study of a group of 1384 patients with MGUS from the 11 counties of southeastern Minnesota evaluated at Mayo Clinic from 1960 to 1994.7 The median age at diagnosis was 72 years (8 years older than the original cohort), and 54% were male. Only 2% were younger than 40 years at diagnosis, and 59% were 70 years or older.

Other series

Of the 64 patients with MGUS in a Swedish study, 11% had some evidence of progression during 20 years of follow-up.11 The actuarial probability of development of malignant disease in 128 patients with MGUS was 8.5% at 5 years and 19.2% at 10 years in another series.12 Malignancy developed in 51 (10%) of 504 patients with MGUS from Iceland after a median follow-up of 6 years.13 More than 5% bone-marrow plasmacytosis, presence of Bence Jones proteinuria, polyclonal immunoglobulin reduction, and

Pathogenesis of progression of MGUS

The events responsible for malignant transformation of MGUS are not well understood. Genetic changes may play a role in the transformation of MGUS to MM.15 Avet-Loiseau et al15 reported that 46% of patients with MGUS had an IgH translocation, t(11;14) being the most common. Fonseca et al16, using cytoplasmic immunoglobulin (cIg) fluorescence in situ hybridization (FISH), reported that 27 of 59 patients with MGUS had IgH translocations, including t(11;14)(q13;q32) in 25%, t(4;14)(p16.3;q32) in

Differentiation of MGUS from MM

Asymptomatic patients who have an M-protein value of more than 3 g/dL or more than 10% bone-marrow plasma cells fulfill the criteria for smoldering MM.24 These patients have no anemia, renal insufficiency, hypercalcemia, lytic bone lesions, or other clinical manifestations related to the plasma-cell proliferative disorder. Consequently, they should not be treated with chemotherapy until progression occurs. Criteria for differentiating MGUS, smoldering multiple myeloma, and MM are listed in Table

Predictors of malignant transformation in MGUS

At the time of recognition of MGUS, one cannot distinguish a patient whose condition will remain stable from one in whom progression to a plasma-cell malignancy will develop. Some parameters are useful for predicting the likelihood of progression from MGUS to MM.

Management of MGUS

Despite the results of sophisticated laboratory tests, MM is differentiated from MGUS on the basis of clinical factors such as symptoms, anemia, hypercalcemia, renal insufficiency, and lytic bone lesions (Table 4). The serum and urine M proteins must be measured periodically and a clinical evaluation conducted to determine whether MM, AL, WM, or a lymphoproliferative disorder has developed.

If a patient has no features of MM or AL and the serum protein level is less than 1.5 g/dL, serum protein

Smoldering (asymptomatic) multiple myeloma

Patients with smoldering multiple myeloma (SMM) have a serum M-protein value ≥3 g/dL or 10% or more plasma cells in the bone marrow. A reduction of uninvolved immunoglobulins in the serum or the presence of a small amount of M protein in the urine is common. Anemia, renal insufficiency, and skeletal lesions are absent. The plasma-cell labeling index is low, and there are few or no circulating myeloma plasma cells in the peripheral blood. Although these patients fulfill the minimal criteria for

Biclonal gammopathies

A biclonal gammopathy is defined as the presence of two different M proteins and occurs in 5–8% of patients with MGUS. Biclonal gammopathy of undetermined significance was noted in 37 (65%) of 57 patients who had a biclonal gammopathy.41

Triclonal gammopathy

In a review of the literature by Grosbois et al42, triclonal gammopathies were associated with a malignant immunoproliferative disorder in 16 patients, occurred in non-hematologic diseases in five, and were of undetermined significance in three.

Idiopathic Bence Jones proteinuria

Patients

Association of monoclonal gammopathies with other diseases

MGUS may be associated with several diseases, as expected in an older population. The association of two diseases depends on the frequency with which each occurs independently. Appropriate epidemiologic and statistical studies, especially with valid control populations, must be done to evaluate these associations. An apparent association may occur because of the difference in the referral population or in other selected patient groups. A more detailed review of the association of monoclonal

Lymphoproliferative disorders

In 1957, Azar et al46 described 13 patients with malignant lymphoma or chronic lymphocytic leukemia who had a serum protein M spike. In 1960, Kyle et al47 described six patients with lymphoma and a serum M spike suggestive of MM. Among 292 patients with a nodular histologic pattern, four (1%) had an M protein, and only one of 218 with Hodgkin's disease had an M protein. In contrast, 44 (7%) of 640 patients with diffuse non-Hodgkin's lymphoma or chronic lymphocytic leukemia had a serum M protein.

Leukemia

In a series of 100 patients with chronic lymphocytic leukemia and monoclonal gammopathy, the type of serum M protein was IgG in 51, IgM in 38, IgA in one, and monoclonal light chains only in 10.50 Monoclonal gammopathies also have been reported in hairy-cell leukemia, chronic myelocytic leukemia, T-cell leukemia, and acute leukemia.

Other hematologic diseases

Acquired von Willebrand's disease is uncommon, but it may be associated with a monoclonal gammopathy. In a group of seven patients with MGUS and acquired von Willebrand's syndrome, the infusion of intravenous gamma globulin had a longer lasting effect than did an infusion of von Willebrand's factor concentrate.51 Patients with monoclonal gammopathy and lupus anti-coagulant activity have been evaluated. Monoclonal gammopathies also have been reported with pernicious anemia, refractory anemia,

Connective tissue disorders

Rheumatoid arthritis has been noted in patients with monoclonal gammopathies. Lupus erythematosus, ankylosing spondylitis, polymyositis, discoid lupus erythematosus, and scleroderma all have been reported with monoclonal gammopathies. Polymyalgia rheumatica has been described with monoclonal gammopathy but, because both conditions occur more commonly in an older population, the relationship is questionable. Inclusion body myositis also has been associated with an M protein.

Peripheral neuropathy

Kelly et al52 found 28 cases (10%) of monoclonal gammopathy in a series of 279 patients with a sensorimotor peripheral neuropathy of unknown cause (MGUS in 16, AL in seven, MM in three, WM in one, and γ heavy-chain disease in one). The incidence of an M protein in peripheral neuropathy is variable and depends on patient selection, the vigor with which the presence of an M protein is sought, and whether peripheral neuropathy is diagnosed on the basis of clinical features or electrophysiologic

POEMS syndrome

POEMS syndrome is characterized by a chronic progressive sensorimotor polyneuropathy with predominantly motor involvement.62 Single or multiple osteosclerotic lesions are prominent features. In addition, hyperpigmentation, hypertrichosis, gynecomastia, testicular atrophy, hepatosplenomegaly, and lymphadenopathy may occur. Thrombocytosis or polycythemia may be present and mistakenly diagnosed as a myeloproliferative process. Papilledema may occur. Almost all patients have an M protein of the λ

Dermatologic diseases

Lichen myxedematosus (papular mucinosis, scleromyxedema) is an uncommon disease characterized by papules, macules, and plaques infiltrating the skin. It is frequently associated with a cathodal IgG λ protein.64 Pyoderma gangrenosum, an ulcerative disease of the skin, has been associated with monoclonal gammopathy. In a series of 67 patients, eight (12%) had a monoclonal gammopathy.65 Seven of the eight patients had an IgA M protein. IgG monoclonal gammopathy was recognized in 16 (73%) of 22

Liver disease

Although polyclonal increases in immunoglobulin are expected in liver disease, an M protein was reported in 11 of 31 patients with chronic active hepatitis. There is an association of hepatitis C virus (HCV) and monoclonal gammopathy. In a series of patients with chronic liver disease, M protein was found in 11% of 239 HCV-positive patients, and an M protein was present in only 1% of 98 HCV-negative patients.

Endocrine disorders

Monoclonal gammopathy has been reported in patients with hyperparathyroidism. We reviewed the records of 911 patients at Mayo Clinic who had hyperparathyroidism and were 50 years or older and in whom immunoelectrophoresis was performed. Of these 911 patients, nine (1%) had MGUS, which is similar to the prevalence in a normal population.68 However, 20 of 101 patients with hyperparathyroidism had an M protein, compared with only two of 127 controls.69 Thus, the association of hyperparathyroidism

Immunosuppression

Transplant procedures are frequently associated with monoclonal gammopathies. In a series of 201 liver-transplant patients, 28% had a monoclonal gammopathy.70 Allogeneic bone-marrow transplantation was associated with an M protein in 12 of 47 patients; cytomegalovirus infection was present in 11 of the 12 patients. Zent et al71 reported the presence of abnormal protein bands in 10% of 550 patients receiving an autologous stem-cell transplant for MM. Of 182 patients with a kidney transplant, 30%

M proteins with antibody activity

M proteins have shown unusual specificities to various antigens, such as actin, von Willebrand's factor, thyroglobulin, insulin, riboflavin, dextran, anti-streptolysin O, anti-nuclear activity, double-stranded DNA, apolipoprotein, thyroxin, cephalin, lactate dehydrogenase, and several antibiotics.74

The binding of calcium by an M protein may produce hypercalcemia without pathologic consequences because the ionized calcium is normal.75 M proteins may also bind to copper, transferrin, or serum

Miscellaneous conditions

Various other diseases have been reported as having an association with MGUS. Gelfand et al76 described a patient who had angioedema and acquired deficiency of C1 esterase inhibitor and reviewed the records of 14 other patients reported in the literature. In another report, 12 of 19 patients with acquired angioedema type 2 had MGUS.77 In a review of the literature, all 21 patients with systemic capillary leak syndrome had an M protein. All but one of the proteins were IgG.78

The association of

Summary

Monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), primary systemic amyloidosis (AL), and Waldenström's macroglobulinemia (WM) constitute the monoclonal gammopathies. During long-term follow-up of 241 patients with MGUS seen at Mayo Clinic between 1956 and 1970, MM, WM, AL, or a related disorder developed in 64. To confirm the findings of the 241 Mayo Clinic patients from the United States and other countries, we subsequently conducted a population-based study on

Acknowledgements

This was supported in part by a research grant, CA 62242, from the National Cancer Institute.

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