Monoclonal gammopathy of undetermined significance: A primary care guide

WHEN SHOULD WE LOOK FOR AN M PROTEIN?

An M protein is typically an incidental finding when a patient is being assessed for any of a number of presenting symptoms or conditions. A large retrospective study⁹ found that screening for MGUS was mostly performed by internal medicine physicians. The indications for testing were anemia, bone-related issues, elevated creatinine, elevated erythrocyte sedimentation rate, and neuropathy.

Routine screening for an M protein in the absence of clinical suspicion is not recommended, given the low risk of malignant progression, lack of effect on patient outcomes, the accompanying emotional burden, and lack of treatment options.^5,10 Evaluation for monoclonal gammopathy may be considered as part of the workup of associated clinical symptoms and signs and laboratory and imaging findings (Table 2).^2,10,11

A low anion gap is not a major indicator of an M protein unless in a high concentration, in which case other manifestations would be present, such as renal failure, which would guide the diagnosis. Polyclonal hypergammaglobulinemia as a cause of low anion gap is far more common than MGUS.

HOW SHOULD WE SCREEN FOR AN M PROTEIN?

Serum protein electrophoresis is an initial test used to identify an M protein and has a key role in quantifying it (Figure 2). An M protein appears as a narrow spike on the agarose gel and should be distinguished from the broad band seen in polyclonal gammopathies associated with cirrhosis and chronic infectious and inflammatory conditions, among others.¹² A major disadvantage of serum protein electrophoresis is that it cannot detect an M protein in very low concentrations or determine its identity.

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Figure 2

Serum protein electrophoresis from a patient with monoclonal gammopathy of undetermined significance (right) shows an abnormal band of gamma globulin (labeled M) that is not present in a normal study (left).

Serum immunofixation is more sensitive than serum protein electrophoresis and should always be ordered in conjunction with it, mostly to ensure detecting tiny amounts of M protein and to identify the type of its heavy chain and light-chain components.¹³

The serum free light-chain assay is also considered an essential part of the screening process to detect light-chain MGUS and light-chain myeloma. As many as 16% of myeloma patients secrete only light chains, which may not be identified on serum immunofixation.^{3,6,7,10,14,15} In general, a low kappa-lambda ratio (< 0.26) indicates the overproduction of lambda light chains, and a high ratio (> 1.65) indicates the overproduction of kappa light chains.

The serum free light-chain assay helps detect abnormal secretion of monoclonal light chains before they appear in the urine once the kidney tubules become saturated and unable to reabsorb them.

Of note, the free light-chain ratio can be abnormal (< 0.26 or > 1.65) in chronic kidney disease. Thus, it may be challenging to discern whether an abnormal light-chain ratio is related to impaired light-chain clearance by the kidneys or to MGUS. In general, kappa light chains are more elevated than lambda light chains in chronic kidney disease, but the ratio should not be considerably skewed. A kappa-lambda ratio below 0.37 or above 3 is rarely seen in chronic kidney disease and should prompt workup for MGUS.¹⁶

Tests in combination. The sensitivity of screening for M proteins ranges from 82% with serum protein electrophoresis alone to 93% with the addition of serum immunofixation and to 98% with the serum free light-chain assay.¹⁵ The latter can replace urine protein electrophoresis and immunofixation when screening for M protein, given its higher sensitivity.^15,17 An important caveat is that urine dipstick testing does not detect urine light chains.

Once an M protein is found, immunoglobulin quantification, a complete blood cell count, and serum creatinine and calcium measurements are also recommended to look for anemia, renal failure, and hypercalcemia, which can be associated with symptomatic myeloma.^{3,5,6,18–22}

Table 3 lists the initial laboratory tests required in patients with MGUS.

WHAT IS THE DIFFERENTIAL DIAGNOSIS OF MONOCLONAL GAMMOPATHIES?

MGUS should be differentiated from other plasma-cell and lymphoproliferative disorders that feature an M protein and would otherwise require treatment (Table 4). The differential diagnosis includes smoldering multiple myeloma, symptomatic multiple myeloma, Waldenström macroglobulinemia, lightchain amyloidosis, low-grade B-cell lymphoproliferative disorders, a variety of monoclonal protein-related kidney disorders, and plasmacytomas.^10,14

HOW ARE PATIENTS WITH MGUS RISK-STRATIFIED AND FOLLOWED?

Research has helped to refine the diagnostic workup and recognize subsets of patients with MGUS at different risks of progression to myeloma and related disorders. Factors predicting progression are^1,6,7,26,27:

• The amount of the M protein

• The type of M protein (IgG vs non-IgG)

• An abnormal free light-chain ratio. Based on these predictors, MGUS can be classified into 4 risk categories: low, low-intermediate, high-intermediate, and high (Table 5).

Half of patients with MGUS fall into the low-risk category, which is defined by IgG-type serum M protein in a concentration less than 1.5 g/dL and a normal serum free light-chain ratio (kappa-lambda 0.26–1.65).^5,27 The absolute risk of progression at 20 years is only 5% for patients with low-risk MGUS, compared with 58% in patients with high-risk MGUS (positive for all 3 risk factors).⁵

The presence of less than 10% plasma cells in the bone marrow is required to satisfy the definition of MGUS, but bone marrow biopsy can be omitted for patients with low-risk MGUS, given the slim chance of finding a significant percentage of clonal plasma cells in the marrow and the inherently low risk of progression.^5,10 Skeletal surveys are often deferred for low-risk MGUS, but we obtain them in all our patients to ensure the absence of plasmacytomas, which need to be treated (typically with radiotherapy). Importantly, patients with unexplained bone pain (mostly in long bones, ribs, and spine, whereas joints are not typically involved) and a normal skeletal survey should undergo advanced imaging (whole-body magnetic resonance imaging or whole-body positron emission tomography and computed tomography) to detect bone lesions otherwise missed on plain radiography.^28,29

Most of the recommendations regarding follow-up are based on expert opinion, given the lack of randomized data. Most experts agree that all patients should be reevaluated 6 months after an M protein is detected, with laboratory surveillance tests (complete blood cell count, serum creatinine, serum calcium level, serum protein electrophoresis, and serum free light chains). Low-risk patients with a stable M protein level can be followed every 2 to 3 years.

Suspect malignant progression if the serum M protein level increases by 50% or more (with an absolute increase of ≥ 0.5 g/dL); the serum M protein level is 3 g/dL or higher; the serum free light-chain ratio is more than 100; or the patient has unexplained anemia, elevated creatinine, bone pain, fracture, or hypercalcemia.

Patients at intermediate or high risk should be followed annually after the initial 6-month visit.^5,7,10

A recent study highlighted the importance of risk stratification in reducing the costs associated with an overzealous diagnostic workup of patients with low-risk MGUS.³⁰ These savings are in addition to a reduction in patient anticipation and anxiety that universally occur before invasive procedures.

THE ROLE OF THE PRIMARY CARE PROVIDER AND THE HEMATOLOGIST

Once an M protein is identified, a comprehensive history, physical examination, and laboratory tests (serum protein electrophoresis to quantify the protein, serum immunofixation, serum free light chains, complete blood cell count, calcium, and creatinine) should be done, taking into consideration the differential diagnosis of monoclonal gammopathies discussed above. After MGUS is confirmed, the patient should be risk-stratified to determine the need for bone marrow biopsy and to predict the risk of progression to more serious conditions.

Referral to a hematologist is warranted for patients with intermediate- and high-risk MGUS, patients with abnormal serum free light-chain ratios, and those who show evidence of malignant progression. Patients with intermediate-and high-risk MGUS could be referred for bone marrow biopsy before assessment by a hematologist. The primary care provider may continue to follow patients with low-risk MGUS who do not display clinical or laboratory evidence of myeloma or related disorders.

When light-chain amyloidosis, Waldenström macroglobulinemia, or another M protein-related disorder is suspected, referral to subspecialists is advised to better define the correlation between the M protein and the pa tient’s symptoms and signs (Table 6).

The importance of educating patients to report any new worrisome symptom (eg, fatigue, neuropathy, weight loss, night sweats, bone pain) cannot be over-emphasized, as some patients may progress to myeloma or other disorders between follow-up visits.