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 Willebrands disease, connective
tissue disorders, neurologic disorders, and a wide variety of other diseases.
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.
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 2035
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.