How I Treat In Brief: Managing Monoclonal Gammopathy of Undetermined Significance

This month, Ronald S. Go, MD, and S. Vincent Rajkumar, MD, discuss the management of patients with monoclonal gammopathy of undetermined significance (MGUS).

This material was repurposed from “How I Manage Monoclonal Gammopathy of Undetermined Significance,” published in the January 11, 2018, edition of Blood.

  • The discovery of MGUS is most often incidental and made by nonhematologists.
  • There is international consensus on the criteria for diagnosis of the three subtypes of MGUS (IgM MGUS, non-IgM MGUS, and lightchain MGUS).
  • Despite the high prevalence of MGUS, there is limited evidence to inform best clinical practice for initial evaluation and subsequent follow-up care.
  • MGUS is considered an obligate precursor to several LPMs, so longterm follow-up is generally recommended.
  • The potential harms associated with an MGUS diagnosis include psychological distress and the cost of follow-up.

Understanding MGUS 

MGUS is a premalignant, clonal plasma cell disorder characterized by the presence of:

  • a monoclonal (M) protein
  • <10% clonal plasma cells in the bone marrow (BM)
  • absence of lymphoplasmacytic malignancy (LPM)

An MGUS diagnosis is considered a requisite precursor to several LPMs, including multiple myeloma (MM), immunoglobulin light-chain (AL) amyloidosis, and Waldenström macroglobulinemia (WM).

MGUS is of considerable clinical interest, given its high prevalence in the general population (about 3% of people ≥50 years old have been diagnosed), its persistent risk of progression to LPM, its known causal association with several serious non-malignant disorders, and the high frequency with which coincidental associations are detected.

When to Test for MGUS 

Symptomatic Patients

In general, we test for the presence of monoclonal gammopathy in patients who have clinical symptoms and signs of the presence of MM, AL amyloidosis, or WM (i.e., bone pain, unexplained weight loss, hyperviscosity). However, because LPMs are rare (approximately 35,000 new diagnoses annually), the chance of identifying LPM in day-to-day practice is very low. Therefore, when M-protein testing is performed, clinicians typically find an alternative explanation for the clinical presentation. Patients with positive tests are labelled as having an incidental diagnosis of MGUS.

We also look for monoclonal gammopathy if a patient has a non-malignant disease (such as acquired von Willebrand syndrome, scleromyxedema, or insulin autoimmune syndrome) known to be a cause of, or associated with, monoclonal gammopathy.

Initial screening for monoclonal gammopathy includes serum protein electrophoresis (SPEP), serum immunofixation, and free flightchain (FLC). If M-protein is detected, urine protein electrophoresis is ordered. This panel of testing is highly sensitive and will detect an M protein in virtually all patients with LPMs.

Asymptomatic Patients

Practice guidelines do not recommend routine screening for MGUS in the general population because of the lack of proven benefit and the absence of curative or preventive therapy. While this rationale appears to be sound, an estimated 80 percent of MGUS cases are not clinically recognized.

Certain populations also have a higher prevalence of MGUS, including black people, people with occupational exposures to certain pesticides (including dieldrin, carbon-tetrachloride/carbon disulfide, and chlorothalonil), immunocompromised patients, and those with first-degree relatives who have MGUS or LPMs.

Until clinical trial results determine whether screening the general population is beneficial, we believe it is reasonable to screen patients at risk for MGUS as described above or who have two or more first-degree relatives with LPMs like MM, AL amyloidosis, or WM.

Diagnostic Criteria for MGUS 

Once M-protein is detected, the extent of further evaluation to rule out LPM depends on the pretest probability of the latter and whether clinicians identified an alternative explanation for a patient’s presenting symptoms.

To establish an MGUS diagnosis, we generally order the following tests at the time of hematology consult: complete blood count, serum calcium, creatinine, FLC, immunofixation, and 24-hour urine protein electrophoresis.

There are three subtypes of MGUS, each with distinct criteria for diagnosis:

  • Immunoglobulin M (IgM) MGUS must have serum IgM monoclonal protein <3 gm/dL; BM lymphoplasmacytic infiltration <10%; and no evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
  • Non-IgM MGUS must have serum monoclonal protein (non-IgM type) <3 gm/dL, clonal BM plasma cells <10%, and absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions that can be attributed to the plasma cell proliferative disorder.
  • Light-chain MGUS must have abnormal FLC ratio (<0.26 or >1.65), increased level of involved light chain, no immunoglobulin heavy-chain expression on immunofixation, absence of end-organ damage that can be attributed to the plasma cell proliferative disorder, clonal BM plasma cells <10%, and urinary monoclonal protein <500 mg/24 hours.

Skeletal Imaging and BM Biopsy

Although MGUS, by definition, requires BM clonal plasma cells to be less than 10 percent and no evidence of lytic lesions on skeletal imaging, not all patients with suspected MGUS need these tests (see FIGURE 1 for a suggested algorithm for using BM biopsy and skeletal imaging in this setting).

Both tests can be deferred in patients with low-risk or uncomplicated M-protein test results. Although data on light-chain MGUS are lacking, we do not recommend routine skeletal imaging and BM evaluation in patients who have a low involved or uninvolved FLC ratio and in whom there are no clinical concerns for LPMs.

For all other patients with MGUS, we perform BM biopsy and skeletal imaging at the time of diagnosis.

Follow-Up After Diagnosis 

The purpose of follow-up is to detect early progression of MGUS into LPM, with the expectation that timely treatment will minimize major complications and prolong survival. Despite a lack of prospective data from randomized trials, clinical practice guidelines recommend annual follow-up for most patients with MGUS, given the seriousness of LPM complications and the relative ease of testing for M-proteins.

We recommend that all patients be reassessed with complete blood count, SPEP, FLC, calcium, and creatinine testing six months after MGUS diagnosis to determine clinical stability and detect rapidly evolving LPM. (See FIGURE 2 for a suggested algorithm for follow-up.)

After initial follow-up, patients with low-risk MGUS need further evaluation only if concerning symptoms or LPMs develop (including anemia, cardiomyopathy, hypercalcemia, or neuropathy); all other patients should have an annual follow-up. Patients with a life expectancy of less than 5 years or those older than 80 years may not need this follow-up.

Progression After MGUS Diagnosis 

A rising M-protein or serum FLC level should raise concern about disease progression, but these elevations are seen in only about 50 percent of patients with MGUS prior to progression. Even when a change occurs, its significance is challenging to interpret if it is not accompanied by symptoms or alterations in other laboratory parameters, such as hemoglobin, calcium, or creatinine.

In addition to changes in M-protein level, progression should be considered in the presence of any of the following unexplained signs and symptoms: anemia, cardiomyopathy (restrictive), diarrhea, fracture, hepatomegaly, hypercalcemia, hyperviscosity (in the setting of IgM M-protein), intestinal pseudo-obstruction, lytic lesion, macroglossia, nephrotic syndrome, neuropathy (autonomic, sensory, or motor), purpura, and renal insufficiency.

Any concern for progression should prompt additional testing, such as imaging studies or BM or tissue biopsy. Current diagnostic criteria for MM allow a diagnosis to be made prior to end-organ damage and enable the use of advanced imaging for early detection of bone disease.

Harms of MGUS Diagnosis 

The potential harms associated with an MGUS diagnosis are rarely a topic of doctor’s office conversation or even academic debate. However, paying more attention to the psychologic distress conferred by an MGUS diagnosis is warranted, as it is similar to the distress associated with diagnosis of a malignancy.

Overdiagnosis of LPMs is also inevitable, but the harms of overtreatment and surveillance have yet to be studied in MGUS.

The cost of MGUS follow-up – estimated to be more than $100 million annually in the U.S. – is substantial and cannot be ignored. Tests should be performed only in patients in whom there is clear suspicion of certain LPMs or conditions known to be associated with M-protein.

Future Directions 

We expect that the number of Americans living with a diagnosis of MGUS will rise from approximately 500,000 to well over one million in the next 30 years, yet there is surprisingly limited evidence to inform best clinical practice for the extent of initial evaluation and subsequent followup care.

To fill this gap, we need studies in populations that are at the highest risk of developing MGUS and a better understanding of biomarkers that predict the risk of transformation to malignant disease.

While the hematology community awaits this type of research, we should harness the power of machine-learning methods to analyze existing big data accumulated from patients with MGUS to collect more information about how and in whom MGUS evolves to malignant disease. Further evidence will help reduce patient anxiety and define optimal followup and preventive strategies.

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