ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS) is defined as a serum M protein level of less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of end-organ damage. The prevalence of MGUS is 3.2% in the white population but is approximately twice that high in the black population. MGUS may progress to multiple myeloma, AL amyloidosis, Waldenström macroglobulinemia, or lymphoma. The risk of progression is approximately 1% per year, but the risk continues even after more than 25 years of observation. Risk factors for progression include the size of the serum M protein, the type of serum M protein, the number of plasma cells in the bone marrow, and the serum free light chain ratio. Smoldering (asymptomatic) multiple myeloma (SMM) is characterized by the presence of an M protein level of 3 g/dL or higher and/or 10% or more monoclonal plasma cells in the bone marrow but no evidence of end-organ damage. The overall risk of progression to a malignant condition is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% to 2% per year for the following 10 years. Patients with both MGUS and SMM must be followed up for their lifetime.
Monoclonal Gammopathy of Undetermined Significance
The term “monoclonal gammopathy of undetermined significance” (MGUS) was introduced over three decades ago. MGUS is defined as a serum M (monoclonal) protein < 3 g/dL, < 10% clonal plasma cells in the bone marrow, and most importantly, the absence of end-organ damage that can be attributed to the plasma cell proliferative disorder. End-organ damage is characterized by CRAB features (hypercalcemia, renal insufficiency, anemia, bone lesions) related to the plasma cell proliferative disorder.
Recognition of a monoclonal gammopathy
If myeloma or a related disorder is suspected, a patient can be screened effectively for an M protein using serum protein electrophoresis, serum immunofixation, and the free light chain (FLC) assay. Agarose gel electrophoresis is the preferred method for detection of an M protein. If a localized band or spike or suspicion of either is found, immunofixation is needed to confirm the presence of an M protein and to determine its heavy chain and light chain type.
All patients who present with back pain, anemia, renal insufficiency, hypercalcemia, age-inappropriate osteopenia, or osteolytic lesions must be screened for the presence of an M protein. Utilizing only serum protein electrophoresis, serum immunofixation, and the FLC assay, 426 of 428 patients with MGUS, smoldering multiple myeloma (SMM), multiple myeloma (MM), AL amyloidosis, or solitary plasmacytoma were identified. Electrophoresis and immunofixation of an aliquot from a 24-hour urine specimen were unnecessary for screening, but these must be done if a serum M protein is found. In a recent study, 94% of 1,877 patients with a monoclonal plasma cell proliferative disorder were identified with only two tests—serum protein electrophoresis and the FLC assay. These two tests identified 100% of patients with MM or Waldenström macroglobulinemia (WM), 99.5% of those with SMM, 96% of patients with AL amyloidosis, and 89% of patients with MGUS. The clinician should screen for an M protein if there is only a low clinical suspicion of MM, WM, AL amyloidosis, or a related disorder. Berenson et al recommend screening for MGUS in all patients with age-inappropriate osteoporosis or osteopenia.
Prevalence of MGUS
Approximately 1.5% of persons older than 50 years and 3% of the population more than 70 years of age in Sweden, the United States, and western France have an M protein without evidence of MM or a related disorder.[6-8] In Olmsted County, Minnesota, a population-based study reported serum samples from 21,463 (77%) of the 28,038 enumerated residents who were 50 years of age or older. MGUS was found in 694 (3.2%) of this population (Table 1). The prevalence was 5.3% in persons 70 years of age or older and 8.9% in men older than 85 years. Age-adjusted rates were higher in men than in women (4.0% vs 2.7%) (Figure 1). The size of the M protein was < 1.5 g/dL in 80% of those with MGUS and ≥ 2 g/dL in only 4.5%. Reduced concentration of uninvolved immunoglobulins was present in 28% of the 447 patients tested.
The Olmsted County study involved a predominantly white population. However, the prevalence of MGUS is approximately twice as high in African-Americans as in whites. In one study in North Carolina, 8.6% of 916 African-American patients had an M protein compared with 3.6% of white patients. The prevalence of MGUS in African-Americans was 3.0-fold higher than in whites in a report of 4 million African-American and white male veterans admitted to Veterans Affairs hospitals. The age-adjusted prevalence of MGUS was 5.8% in 917 black men aged 50 to 74 years from Ghana. Interestingly, the prevalence did not increase with advancing age. In contrast, the prevalence of MGUS is lower in Japanese patients. In a study of 52,802 persons in Nagasaki City, Japan, 2.4% of patients 50 years of age or older and 4.4% of those ≥ 80 years of age had MGUS.
Prevalence of light-chain MGUS
Light-chain MGUS is defined as the presence of an abnormal free light chain ratio with no heavy chain expression plus an increased concentration of the involved light chain. In our southeastern Minnesota cohort in whom 18,353 persons were tested, 146 had light chain MGUS; the prevalence of light-chain MGUS was 0.8%.
Etiology and risk factors
The cause of MGUS is not known. There is a genetic element in some patients. In a study of 911 relatives of 97 MGUS probands and 232 MM probands, the prevalence of MGUS in first-degree relatives was 6.9% in those 50 to 59 years of age, 14.6% in those 70 to 79 years of age, and 21% in persons ≥ 80 years of age. The risk of MGUS in relatives of patients with MM was increased two-fold, while the risk in relatives of patients with MGUS was increased 3.3-fold. This suggests a shared environmental and/or genetic effect.
Radiation exposure may also be a factor. MGUS developed in 1,082 of 52,525 Nagasaki atomic bomb survivors. The prevalence of MGUS was 2.7% in persons within 1.5 km of the explosion (a 1.4-fold increase compared with those beyond 3.0 km). Persons younger than 20 years of age at the time of the bombing had increased prevalence of MGUS, but no difference was seen in older patients.
The risk of MM in agricultural workers has been higher in a number of case control studies. This increased risk has been attributed to insecticides, herbicides, and fungicides, as well as other environmental agents. In a report of 555 men from a well-characterized prospective cohort of persons applying restricted-use pesticides, 6.8% of those > 50 years of age had MGUS compared with 3.7% in 9,469 men from Olmsted County, Minnesota. The age-adjusted prevalence of MGUS was 1.9-fold greater among the male pesticide workers.
In a report of 1,000 black women and 996 white women of similar age, 3.9% of the black women had MGUS, while 2.1% of the white women had MGUS. Multivariate analysis revealed that obesity (odds ratio [OR] = 1.8), black race (OR = 1.8) and increasing age (OR = 2.5) were independently associated with an excess risk of MGUS.
Clinical course and prognosis
MGUS is a common finding in medical practice. It is asymptomatic and is found unexpectedly during laboratory testing of an apparently normal person, or it may be found during the evaluation of an unrelated disorder. It is important to determine whether the M protein will remain stable or progress to MM or a related plasma cell proliferative disorder.
Progression of MGUS
In a referral population. In a referral population of 241 patients seen at the Mayo Clinic, the actuarial risk of progression was 17% at 10 years, 34% at 20 years, and 39% at 25 years; a rate of approximately 1.5% per year (Figure 2). More than two-thirds of the 64 patients whose condition progressed developed MM. The interval from recognition of MGUS to the diagnosis of MM ranged from 1 to 32 years (median, 10.6 years). The diagnosis of MM was made 20 years after recognition of MGUS in 10 patients. WM developed in 7 patients, AL amyloidosis in 8, and a malignant lymphoproliferative disorder in 5 patients (Table 2). Death occurred without progression to symptomatic MM or a related disorder in 138 patients (57%) (Table 3).
In a southeastern Minnesota population-based study. In order to eliminate the bias that occurs with referral populations, we conducted a population-based study of 1,384 patients with MGUS from the 11 counties of southeastern Minnesota who were evaluated from 1960 to 1994. The median age at diagnosis of MGUS was 72 years (in contrast to 64 years for the cohort of 241 referred patients). These patients were observed for a total of 11,009 person-years (median, 15.4 years; range, 0 to 35 years). MM, AL amyloidosis, lymphoma with IgM serum protein, WM, plasmacytoma, or chronic lymphocytic leukemia (CLL) developed in 115 patients (8%) during follow-up (Table 4). At 10 years, 10% had progressed; at 20 years, 21% had progressed; and at 25 years, 26% had progressed – approximately 1% per year (Figure 3). Patients were at risk for progression even after 25 years of follow-up. The 115 patients with progression to a plasma cell disorder was 7.3 times the number expected on the basis of the incidence rates in the general population. It must be emphasized that patients are at risk for progression of MGUS even after more than 25 years of observation.
In other series. Similar findings have been reported in a Swedish study of 64 patients with MGUS. In another group, 13 of 128 patients with MGUS developed a malignant disease during a median follow-up of 66 months. In another study, 6.8% of 335 patients with MGUS progressed during a median follow-up of 70 months. In a group of 1,324 patients with MGUS in North Jutland, Denmark, malignancy caused death in 97 patients, compared with 4.9 deaths expected. In the Danish Cancer Registry, 64 new cases of malignancy were found among 1,229 patients with MGUS (5 expected; relative risk [RR], 12.9). In a series of 504 Icelandic patients with MGUS, a related malignancy developed in 51 (10%) after a median follow-up of 6 years.
Kristinsson et al reported hazard ratios for venous thrombosis of 3.4, 2.1, and 2.1 one, five, and ten years after MGUS diagnosis in a group of 5,326 MGUS patients and 20,161 matched controls from Sweden. Cohen et al reported a venous thromboembolic rate of 2.2 per 100 person-years in 166 patients with MGUS. This was not significantly differently than the 1.4 per 100 person-years in 465 control patients. The authors suggested that the increased venous thromboembolic rate reported with MGUS may have been due mainly to underlying conditions that led to testing for a monoclonal protein rather than to MGUS itself.
In a population-based study from Sweden, 5,326 MGUS patients were compared to 20,161 matched controls. The risk of fracture was increased in the MGUS patients (hazard ratio [HR], 1.74), and at 10-year follow-up, the risk of vertebral/pelvic fractures had increased (hazard ratio, 2.37).
Mode of detection of progression
From our southeastern Minnesota cohort, we identified 116 patients with MGUS with satisfactory follow-up who subsequently progressed to MM. Serial follow-up with laboratory testing led to the diagnosis of MM in 16%, while the diagnosis was made only after a serious MM-related complication in 45%. Workup of less serious symptoms led to the diagnosis in 25%, while evaluation of an unrelated medical condition resulted in the diagnosis of MM in 11%. This study suggests that routine follow-up of MGUS does not detect MM in the majority of patients.