Applied Evidence

Monoclonal gammopathy of undetermined significance: Using risk stratification to guide follow-up

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Varying combinations of 3 measurable factors determine a patient’s risk of progressing toward multiple myeloma and influence monitoring decisions. This review—and accompanying algorithm—can guide your approach.




› For monoclonal gammopathy of undetermined significance (MGUS) patients at low risk, repeat serum protein electrophoresis (SPE) in 6 months. If no significant elevation of M-protein is found, repeat SPE every 2 to 3 years. A
› For patients with smoldering multiple myeloma, order SPE every 2 to 3 months in the first year following diagnosis; repeat every 4 to 6 months in the following year and every 6 to 12 months thereafter. B

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

CASE › A 54-year-old man’s lab results following a routine annual examination reveal a level of IgM M-protein just under 1.5 g/dL. All other lab values, including free light chain (FLC) ratio and bone marrow exam, are normal. No clinical evidence of a related disorder is found. What is the risk that this patient’s condition could progress toward multiple myeloma, and how would you follow up?

The patient with a monoclonal gammopathy has an abnormal proliferation of monoclonal plasma cells that secrete an immunoglobulin, M-protein. This proliferation occurs most often in the bone marrow but can also be found in extra-medullary body tissue. The condition can begin insidiously, remain stable, or progress to frank malignancy causing bone and end-organ destruction. The major challenge is to separate stable, asymptomatic patients who require no treatment from patients with progressive, symptomatic myeloma who require immediate treatment.

Risk for MGUS progression increases markedly with a serum M-protein concentration ≥1.5 g/dL, a non-IgG isotype, or an abnormal serum FLC ratio (<0.26 or >1.65).

An increased, measurable level of serum monoclonal immunoglobulins or FLCs is called monoclonal gammopathy of undetermined significance (MGUS) when there is <3 g/dL monoclonal protein in the serum, <10% monoclonal plasma cells in the bone marrow, and an absence of beta-cell proliferative disorders, lytic bone lesions, anemia, hypercalcemia, or renal insufficiency (TABLE 1).1,2 Serum and marrow measurements exceeding these values indicate progression of disease to a premalignancy stage. Continued proliferation of plasma cells in the bone marrow results in anemia and bone destruction, while the increase in M-protein leads to end-organ destruction. This final malignant state is multiple myeloma (MM).

Detailed classification of MGUS: A roadmap for monitoring patients

Extensive epidemiologic and clinical studies have refined the classification of MGUS3-5 and related disorders (TABLES 2-4),3 providing physicians with guidance on how to monitor patients. There are 3 kinds of monoclonal gammopathies, each reflecting a particular type of immunoglobulin involvement—non-IgM, IgM, or light chain. Additionally, within each type of gammopathy, patient-specific characteristics determine 3 categories of clinical significance: premalignancy with low risk of progression (1%-2% per year3); premalignancy with high risk of progression (10% per year3); and malignancy.

Non-IgM MGUS with a high risk of progression is designated smoldering multiple myeloma (SMM) (TABLE 2).3 IgM MGUS with a high risk of progression is defined as smoldering Waldenström macroglobulinemia (SWM), with a predisposition to progress to Waldenström macroglobulinemia (WM) and, rarely, to IgM MM (TABLE 3).3

More recently, it has been reported that approximately 20% of the cases of MM belong to a new entity called light-chain MM that features an absence of heavy chain (IgG, IgA, IgM, IgD, or IgE) secretion in serum.6 The premalignant precursor is light-chain MGUS (LC-MGUS). The criteria for LC-MGUS and idiopathic Bence Jones proteinuria are found in TABLE 4.3 Idiopathic Bence Jones proteinuria is equivalent to SMM and SWM due to its higher risk of progression (10%/year)3 to light-chain MM.

Prevalence of MGUS

In general, the prevalence of all types of MGUS increases with age and is affected by race, sex, family history, immunosuppression, and pesticide exposure. The Caucasian American population >50 years exhibits a prevalence of MGUS of approximately 3.2%;7 the African American population exhibits a significantly higher prevalence of 5.9% to 8.4%.7 Native Asians have a lower rate of MM, and, as expected, a lower MGUS prevalence than is seen in the Western population (Thailand ≈2.3%;8 Korea ≈3.3%;9 Japan ≈2.1%;10 China ≈0.8%11). The overall prevalence of the 3 types of MGUS is 4.2% in Caucasians.6

Distinguishing stable from progressive disease

The Mayo Clinic’s risk stratification model12 further specifies risk of disease progression based on 3 indicators: serum M-protein concentration, Ig isotype of M-protein, and serum FLC ratio.

MGUS. A marked increase in risk for disease progression is associated with a serum M-protein concentration ≥1.5 g/dL, a non-IgG isotype, or an abnormal serum FLC ratio (<0.26 or >1.65, reflecting an increase in either the kappa or lambda light chain).12 An MGUS patient exhibiting all 3 of these features has a 58% absolute risk of developing MM after 20 years of follow-up. A patient with 2 of the 3 abnormalities has a 37% risk of progressing to MM, and one who has just one abnormality has a 21% risk. In contrast, an MGUS patient who has an M-protein level <1.5 g/dL, an IgG isotype, and normal FLC range has only a 5% risk of progression to MM in the same 20 years.12

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