Monoclonal Gammopathies of Undetermined Significance 

Updated: Sep 07, 2018
Author: Suzanne R Fanning, DO; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Monoclonal gammopathy of undetermined significance (MGUS) is the most common of a spectrum of diseases called plasma cell dyscrasias. The term MGUS denotes the presence of a monoclonal immunoglobulin (Ig), also called an M-protein, in the serum or urine in persons without evidence of multiple myeloma (MM), Waldenström macroglobulinemia (WM), amyloidosis (AL) or other lymphoproliferative disorders.[1]

Immunoglobulin involvement may be IgM, non-IgM (ie, IgA, IgG, or, rarely, IgD or IgE), or light chain.[2] All pose a risk, albeit varying, of progression to a malignant disorder. Typically, IgG and IgA MGUS progress to MM, IgM MGUS progresses to WM or other lymphoproliferative disorders, and light-chain MGUS is the precursor of light-chain MM.[3]

The cause of MGUS is unknown, though the same theories that apply to the pathogenesis of MM may be valid in MGUS. MM is almost always preceded by MGUS.[3]

Distinguishing between MM and MGUS is critical because patients with MGUS are conservatively treated and do not need chemotherapy. In contrast, MM is a uniformly lethal disease that does not need therapy in its initial stages but progresses to an advanced or aggressive stage that requires therapy.

Pathophysiology

The reason for the monoclonal expansion of a single Ig-secreting plasma cell population in what appears to be a nonmalignant manner is unknown in most cases. Most cases involve IgG or IgA monoclonal cell populations. About 15-20% are composed of IgM monoclonal cells.

Kyle et al reported that the cells in IgG and IgA MGUS arise from a mature, somatically mutated, postswitch plasma cell. About 50% of cases have evidence of translocation in the Ig heavy-chain region at 14q32. In contrast, IgM MGUS is described as arising from somatically mutated, postgerminal center B lymphocytes that have not undergone isotype class switching and therefore do not have the 14q32 translocation. These translocations are thought to be important in initiating and sustaining clonal proliferation.[4]

Several studies have confirmed that characteristic genetic abnormalities of multiple myeloma (MM) are present in patients with MGUS.[5, 6, 7] Gene-expression profiling has also led to a group with MGUS-like features. This group of patients had a lower complete remission rate, yet also had a lower-risk clinical course and superior survival.[8]

Nagoshi et al identified a possible secondary genetic change involving MGUS; they found transcriptional dysregulation of the deleted in colorectal carcinoma (DCC) gene in 25% of MGUS cases studied, and in 57% of MM. The DCC gene encodes a tumor suppressor that prevents cell growth; allele loss or decreased expression of DCC has been associated with the progression of solid tumors and hematologic malignancies.[9]

The risk of progression to MM or other lymphoproliferative disorder is present at a constant rate throughout the remainder of a patient's life. This observation suggests that the second event responsible for progression is a random event and not cumulative.

In patients with symptomatic MM, the development of a new monoclonal protein following therapy is associated with better outcomes. A study by Mullikin et al in patients with biclonal gammopathy of undetermined significance found that the rate of progression was similar to that seen in MGUS with one monoclonal protein, suggesting that multiple monoclonal proteins do not clinically impact one another. Of the 393 patients in the study, six progressed to smoldering MM, 11 to MM, three to amyloidosis, and two to Waldenström macroglobulinemia.[10]

Epidemiology

MGUS represents two thirds of all plasma cell dyscrasias. The incidence increases with age. In a study of residents of Olmsted County, Minnesota, MGUS was found in 3.2% of persons 50 years of age or older, 5.3% of those 70 years of age or older, and 7.5% of those 85 years of age or older.[11]

The prevalence of MGUS is higher in HIV-infected patients, although it decreased with the adoption of antiretroviral therapy. In a study of 383 French HIV-infected patients, 359 of whom were on antiretroviral therapy for a median duration of 105 months, there were 12 (3.1%) cases of MGUS, including five IgG kappa cases, 5 IgG lambda cases, one biclonal (2 IgG kappa) case, and one case with three monoclonal immunoglobulins (IgG kappa×2+IgG lambda). In all cases, the monoclonal immunoglobulin levels were low, and the level was below 1 g/l in all cases except two. No factors were found to be predictive of MGUS.[12]

In a prospective cohort study in Vietnam war veterans, the crude prevalence of overall MGUS was 7.1% (34 of 479) in veterans involved in the spraying of Agent Orange, versus 3.1% (15 of 479) in veterans who were not involved in herbicide spray missions. After adjustment for factors including age, race, and body mass index, this translated into a 2.4-fold increased risk for MGUS in exposed veterans (adjusted odds ratio, 2.37; 95% CI, 1.27-4.44; P = 0.007).[13]

In a study of firefighters involved in rescue and/or recovery work at the New York World Trade Center after the September 11, 2001 attack, Landdgren et al reported an age-standardized prevalence rate of MGUS and light-chain MGUS combined of 7.63 per 100 persons (95% CI, 5.45-9.81), which is 1.8-fold higher than rates from a reference population; the rate of light-chain MGUS was more than 3-fold higher than in the same reference population. Of the 781 firefighters studied, 16 had been diagnosed with multiple myeloma (7 of them with light-chain disease), at a median age of 57 years.[14]  

Mortality/Morbidity

Patients with MGUS tend to do well when treated conservatively.[15] Regular surveillance is required to assess for progression to either a lymphoproliferative disorder or to MM.[16] This risk has been quantified at 1% per year.[17]

Race-, Sex-, and Age-related Variances

A retrospective study by the US Department of Veterans Affairs revealed that the age-adjusted prevalence ratio of MGUS in black patients was 3.0 compared with white patients.[18] For a discussion of possible genetic factors in the pathogenesis of MGUS, see Landgren et al.[18, 19]

MGUS occurs more commonly in men than in women, and the prognosis for men was worse than that of women in some studies.

Age-related differences in incidence are as follows:

  • The median age of patients with the disease is 70 years; however, most physicians are observing patients younger than this, possibly because of improved screening rather than an increased incidence of the process

  • The incidence of MGUS is higher in older patients than in younger patients; of patients older than 80 years, the available literature suggests as many as 10-15% may have an M-protein

Prognosis

The annual risk of progression to multiple myeloma (MM), Waldenström macroglobulinemia (WM), amyloidosis (AL), or other lymphoproliferative disorders is approximately 1%. However, the mode and risk of progression vary between IgM MGUS and those with non-IgM MGUS. 

An abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (≥1.5 g per deciliter) are risk factors for progression. In IgM MGUS, Kyle et al reported a risk of progression at 20 years of 55% in patients with both risk factors, compared with 41% in those with one risk factor and 19% in patients with neither risk factor. In patients with non-IgM MGUS, the risk of progression at 20 years was 30% in those with both risk factors, 20% in those iwth one risk factor, and 7% in those with neither risk factor.[17]

Rajkumar et al found that the risk of progression in patients with an abnormal serum free light chain (FLC) ratio (kappa-lambda ratio <  0.26 or > 1.65) is independent of the size and type of the serum M protein, and that the relative risk of progression is related to the extent to which the ratio is abnormal. These authors proposed a risk-stratification model for the progression of MGUS, using the combination of the size and type of the M protein and the serum FLC ratio.[20]

Pelzer et al concluded that light-chain MGUS—defined as an abnormal FLC ratio, increase of involved FLC with complete loss of immunoglobulin heavy chain, and absence of a history of lymphoproliferative disease—is a relatively benign condition, and that the monoclonal protein often diisappears over time. In their longitudinal analysis of 75 German patients with light-chain MGUS, after a median observation time of 11.5 years, none of the cases had progressed to light-chain multiple myeloma or other lymphoproliferative disorders. On serial analysis, light-chain MGUS could not be confirmed in 17 of 31 cases (55%), and disappearance of the monoclonal protein was associated with low concentrations of the involved FLC. Although patients with light-chain MGUS had a 1.5-fold increased risk of cancer, overall survival and renal function were not different than in patients with normal FLC.[21]

In a study of 728 Swedish MGUS patients followed for up to 30 years, 84 patients developed a lymphoid disorder, representing a cumulative risk of 15.4%. The 30-year cumulative risk for myeloid malignancies was less than 2%. The 30-year cumulative risk for MM, which occurred in 53 patients, was 10.6%, with an approximately 0.5% annual risk. The following factors were significantly associated with progression[22] :

  • An abnormal FLC ratio of less than 0.26 or more than 1.65

  • An M-protein concentration of 1.5 g/dL or more

  • Reduction of one or two noninvolved immunoglobulin isotype levels

Venous thromboembolism

The risk of venous thromboembolism (VTE) is increased in patients with MGUS.[23] In a study by Srkalovic et al, 13% of patients with MGUS developed VTE.[24] Univariate correlates of VTE in patients with MGUS included the following:

  • Family or past history of VTE

  • Immobility

  • Low serum albumin level

  • High leukocyte count

Osteoporosis

Using population-based data from Sweden, Kristinsson et al compared the risks of fractures in 5,326 patients with MGUS diagnosed from 1958-2006 with 20,161 matched controls.[25] Patients with MGUS had an increased risk of any fracture at 5 years (hazard ratio [HR] = 1.74) and 10 (HR = 1.61) years. The risk was significantly higher for axial (skull, vertebral/pelvis, and sternum/costae) compared with distal (arm and leg) fractures (P< 0.001).

A French study found that, in addition to low bone density, patients with MGUS who experienced nontraumatic vertebral fractures were more likely to have a lambda light chain isotype. In this prospective study of 201 patients with incidentally discovered MGUS and no known history of osteoporosis, nontraumatic vertebral fracture was discovered in 8.4% of the patients, with equal distribution between men and women. Patients with lambda light chain had an odds ratio of 4.32 (95% confidence interval 1.80–11.16; P=0.002) for fracture, compared with patients with kappa light chain.[26]

Infection

Kristinsson et al reported that patients with MGUS had a 2-fold increased risk (P < 0.05) of developing any infection.[27] The risk extended to both bacterial and viral infections, and the following specific infections were noted:

  • Pneumonia
  • Osteomyelitis
  • Septicemia
  • Pyelonephritis
  • Cellulitis
  • Endocarditis
  • Meningitis
  • Influenza
  • Herpes zoster

Infection risk was highest in patients with M-protein concentrations over 2.5 g/dL, but was also increased in those with concentrations below 0.5 g/dL. Patients with MGUS who developed infections had no excess risk of progression to related malignancy.

 

Presentation

History and Physical Examination

Monoclonal gammopathy of undetermined significance (MGUS) is usually an unexpected finding during an evaluation for an unrelated disorder. The advances in quantification of an M-spike by immunofixation contribute to the increasing number of patients identified as having MGUS.

No specific abnormalities are detected on physical examination in patients with MGUS. Several syndromes of polyneuropathies are associated with plasma cell dyscrasias, including MGUS. Paraproteinemic neuropathy (PPN) is most commonly observed with IgM gammopathy (48%), followed by IgG (37%), and IgA (15%). [28]

 

 

DDx

Diagnostic Considerations

Monoclonal gammopathy of undetermined significance (MGUS) must be differentiated from multiple myeloma (MM) and smoldering MM (SMM). Criteria for MGUS established by the International Myeloma Working Group[29] and the World Health Organization[30] are as follows:

  • Serum M-protein level < 3 g/dL
  • Bone marrow plasma cells < 10% and low level of plasma cell infiltration in a trephine biopsy specimen
  • No evidence of B-cell proliferative disorder (ie, MM, Waldenström macroglobulinemia, amyloid light-chain amyloidosis)
  • No M-protein or only small amounts of monoclonal light chain in urine
  • No osteolytic lesions, anemia, hypercalcemia, or M-protein–related renal function impairment

Asymptomatic patients who have an M-component higher than 3 g/dL, or more than 10% but less than 20% bone marrow plasma cells, fulfill the criteria for SMM. These patients do not have anemia, renal failure, hypercalcemia, osteolytic bone lesions, or other clinical manifestations related to the monoclonal protein.

In clinical and biologic terms, SMM is closer to MGUS than to overt MM. Recognition of patients with SMM is extremely important because they should not be treated with chemotherapy until progression occurs. No particular laboratory parameter or clinical factor differentiates MGUS or SMM from overt MM. Decreased levels of uninvolved immunoglobulins are not a useful criteria for differentiation because 30-40% of patients with MGUS also have decreased levels of the uninvolved immunoglobulins.

Although Bence-Jones proteinuria suggests MM, finding small amounts of monoclonal light chains in the urine of patients with MGUS is not unusual. Lytic bone lesions on the skeletal survey strongly suggest MM. In patients recently diagnosed with MGUS, serum electrophoresis should be repeated after 3 months to exclude early myeloma, and, if the results are stable, the test should be repeated in 6 months. Patients should be aware that the evolution of MGUS to MM can be abrupt; therefore, they should be reexamined promptly if their clinical condition deteriorates.

Differential Diagnoses

 

Workup

Approach Considerations

The workup for monoclonal gammopathies of uncertain significance (MGUS) includes the following:

  • Complete metabolic panel - For example, to evaluate renal function, calcium, uric acid, and lactate dehydrogenase (LDH)[31]

  • Complete blood cell count (CBC) with differential - To evaluate for anemia, thrombocytopenia, and neutropenia

  • Tests for beta2 microglobulin and C-reactive protein - For prognostic information

  • Serum and urine electrophoresis with immunofixation - Diagnostic test of choice

  • Quantitative immunoglobulin measurements - To follow up the progress of the monoclonal gammopathy

  • Measurement of the proliferative rate of the plasma cells or plasma cell labeling index (value is low)

  • Serum electrophoresis

  • Serum free light chain (FLC) assay - Beneficial for prognostic purposes

  • Complete skeletal survey to assess for lytic lesions

  • Unilateral bone marrow aspiration and biopsy - To quantify the percentage of plasma cells and to assess for abnormal cytogenetics[32]

Bone marrow examination is recommended as part of the diagnostic workup for all patients with IgA and IgM M-proteins. In patients with apparent IgG MGUS, bone marrow examination is typically not recommended unless the serum M-protein level is greater than 1.5 g/dL or end-organ damage is evident.[3]

Ng et al reported improved quantification of marrow involvement through the use of CD138 immunostaining of bone marrow trephine specimens.[33] For the importance of immunophenotypic analysis, see Jerez et al.[34]

MGUS is characterized by the following:

  • Serum M-protein value less than 3 g/dL

  • Fewer than 10% plasma cells in the bone marrow

  • No or only small amounts of Bence-Jones protein in the urine

  • Absence of lytic bone lesions

  • No related anemia, hypercalcemia, renal failure, or any related end-organ damage

In patients with recently diagnosed MGUS, serum electrophoresis should be repeated after 3 months to exclude early myeloma. If the results are stable, the test should be repeated in 6 months. Patients should be aware that the evolution of MGUS to multiple myeloma can be abrupt; therefore, they should be reexamined promptly if their clinical condition deteriorates.

 

Treatment

Approach Considerations

No treatment is recommended for patients with MGUS.[29]  Long-term follow-up is generally advised, given the risk of progression to lymphoproliferative malignancy.[35]

If a patient has no other features of a plasma cell dyscrasia and if a serum M-spike is detected, complete assessment of the patient's general medical status is needed. The assessment should include the following:

  • Baseline measurements of serum vitamin B12 and red blood cell folate levels and a hypercoagulation profile

  • Specific workup relative to the gammopathy, with a bone marrow examination, skeletal radiography (including single views of the humeri and femurs and complete spinal with optional lateral views), and a 24-hour urine collection for protein quantitation

If a patient has an IgM M-protein, aspiration and biopsy of the bone marrow and computed tomography (CT) scanning of the abdomen may be useful in detecting Waldenström macroglobulinemia or other lymphoproliferative disorders.

MGUS-associated neuropathies are generally not treated, except in the case of a disabling IgM monoclonal gammopathy or IgG/A MGUS  associated with chronic inflammatory demyelinating neuropathy (CIDP). About 80% of patients with IgG/A MGUS CIDP respond to one of the typical CIDP treatments and some patients stabilize without therapy.[28]

The intensity of follow-up in patients with MGUS is guided by risk stratification. Typically, initial follow-up at 6 months is recommended, with subsequent visits scheduled according to level of risk (see Long-Term Monitoring).[3, 29, 2]  If clinical trials of preventive strategies are available, patients at high risk for progression should be encouraged to participate. 

Serum and urine electrophoresis with immunofixation should be performed if the serum M-protein value increases or if other evidence of evolving multiple myeloma or Waldenström macroglobulinemia is observed.

 

Long-Term Monitoring

Current guidelines suggest lifelong followup in patients with MGUS, so that malignant transformation can be identified early, before the onset of serious complications.[3, 29] Sigurdardottir et al reported significantly better overall survival in patients with MM who had prior knowledge of MGUS than in those without prior knowledge (median survival, 2.8 years versus 2.1 years, respectively; hazard ratio 1.86; 95% confidence index, 1.13-3.04; P = 0.01), suggesting that earlier treatment of MM leads to improved survival.[36]

Followup schedules in patients with MGUS can be based on risk stratification. Various risk prediction models exist, using a variety of risk factors (eg, serum M-protein level ≥1.5 g/dL, non-IgG M-protein, and abnormal free light chain [FLC] ratio; or ≥95% aberrant plasma cells in bone marrow and DNA aneuploidy on flow cytometry).[3, 29]

European Myeloma Network guidelines recommend that followup consist of the following[3] :

  • History and physical examination
  • Serum M-protein electrophoresis
  • Complete blood cell count (CBC)
  • Serum creatinine assay
  • Serum calcium assay

The International Myeloma Working Group (IMWG) recommends followup serum protein electrophoresis for patients with MGUS 6 months after diagnosis, with subsequent followup depending on risk. The IMWG considers patients with IgG MGUS who have an M-protein level below 1.5 g/dL and a normal FLC ratio to be at low risk; if findings at 6 months are stable, subsequent follow-up can be every 2 to 3 years thereafter or when symptoms suggestive of a plasma cell malignancy arise. For patients with intermediate and high-risk MGUS, the IMWG recommends annual follow-up.[29]

With IgM MGUS, which poses a high risk for malignant progression, some experts recommend more intensive follow-up, with twice-annual visits that include clinical assessment, CBC, comprehensive metabolic panel, serum protein electrophoresis, serum FLC assay, and quantitative immunoglobulin serum electrophoresis.[37]

The European Myeloma Network advises that for low-risk MGUS, follow-up at 6 months and every 1–2 years thereafter can be justified. Alternatively, follow-up for low-risk MGUS may be limited to performing laboratory studies or bone marrow analysis when patients develop symptoms suggestive of MM or related diseases. In patients who are elderly or have significant morbidity with a short life expectancy, it may be reasonable to forgo follow-up.[3]

 

 

 

Medication

Medication Summary

No treatment is recommended for patients with uncomplicated monoclonal gammopathy of undetermined significance (MGUS). However, polyneuropathy in IgM monoclonal gammopathy can be a disabling disorder. A prospective open-label trial by Niermeijer et al in 17 patients with IgM MGUS polyneuropathy found that treatment with rituximab (a chimeric anti-CD-20 monoclonal antibody) therapy was associated with improvement on three impairment measures and the presence of CD20 B-cell depletion in the bone marrow of all patients, and no serious adverse events.[38]

Niermeijer et al also reported that the response percentage rate with rituximab was comparable to that seen with intermittent cyclophosphamide/prednisone or fludarabine therapy, but with fewer side effects, and suggested that the presence of anti-MAG antibodies and a disease duration shorter than 10 years may predict treatment response.[38]

 

Questions & Answers

Overview

What is monoclonal gammopathy of undetermined significance (MGUS)?

What is the pathophysiology of monoclonal gammopathy of undetermined significance (MGUS)?

What are the genetic abnormalities in monoclonal gammopathy of undetermined significance (MGUS)?

What is the risk of progression to multiple myeloma (MM) from monoclonal gammopathy of undetermined significance (MGUS)?

What is the prevalence of monoclonal gammopathy of undetermined significance (MGUS)?

What is the mortality and morbidity associated with monoclonal gammopathy of undetermined significance (MGUS)?

What are the race-related differences in the incidence of monoclonal gammopathy of undetermined significance (MGUS)?

Is monoclonal gammopathy of undetermined significance (MGUS) more common in men or women?

What are the age-related differences in the incidence of monoclonal gammopathy of undetermined significance (MGUS)?

What is the prognosis of monoclonal gammopathy of undetermined significance (MGUS)?

Which factors are associated with the progression of monoclonal gammopathy of undetermined significance (MGUS) to myeloid malignancy?

What is the risk of venous thromboembolism (VTE) in patients with monoclonal gammopathy of undetermined significance (MGUS)?

What is the risk of osteoporosis in patients with monoclonal gammopathy of undetermined significance (MGUS)?

What is the risk of infection in patients with monoclonal gammopathy of undetermined significance (MGUS)?

Presentation

What are the clinical history and physical exam findings in monoclonal gammopathy of undetermined significance (MGUS)?

DDX

What are the diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS)?

What are the diagnostic considerations in monoclonal gammopathy of undetermined significance (MGUS)?

What are the differential diagnoses for Monoclonal Gammopathies of Undetermined Significance?

Workup

What is included in the workup of monoclonal gammopathy of undetermined significance (MGUS)?

What is the role of bone marrow exam in the workup of monoclonal gammopathy of undetermined significance (MGUS)?

What are the characteristic lab findings in monoclonal gammopathy of undetermined significance (MGUS)?

What lab testing is indicated in the surveillance of monoclonal gammopathy of undetermined significance (MGUS)?

Treatment

How is monoclonal gammopathy of undetermined significance (MGUS) managed?

What are the approach considerations in the treatment of monoclonal gammopathy of undetermined significance (MGUS)?

What is involved in the long-term monitoring of monoclonal gammopathy of undetermined significance (MGUS)?

What are the recommendations for long-term monitoring of monoclonal gammopathy of undetermined significance (MGUS)?

What is the recommended follow-up for patients with monoclonal gammopathy of undetermined significance (MGUS) at risk for malignant progression?

Medications

What is the role of drug treatment for monoclonal gammopathy of undetermined significance (MGUS)?