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Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant plasma-cell proliferative disorder that is present in approximately 5% of the general population over the age of 50 years.1-4 This disorder is important not only because it is the precursor to plasma-cell cancers, including multiple myeloma, solitary plasmacytoma, and Waldenström’s macroglobulinemia, but also because it is causally related to numerous serious nonmalignant disorders, collectively referred to as monoclonal gammopathy of clinical significance (MGCS).5 MGUS is characterized by a limited yet monoclonal proliferation of plasma cells secreting abnormal levels of immunoglobulins (antibodies) that are identical to each other, with the same amino acid sequence, referred to as monoclonal (M) proteins.6 These secreted M proteins are best appreciated as fully functioning human antibodies present in high concentrations that fortunately lack affinity to self-antigens (autoantibody characteristics) in most persons. As a result, MGUS remains asymptomatic in the absence of malignant transformation in most people. However, there is potential for serious harm if the M protein has or develops affinity for one or more organs in the body, resulting in MGCS.
Importance: Nearly 5% of adults have the precursor malignant condition monoclonal gammopathy of unknown significance (MGUS). Management centers on differentiating MGUS from more serious conditions to determine additional diagnostic testing, monitoring, and potential therapy.
Observations: MGUS is defined by the absence of end-organ damage or symptoms, a small amount of monoclonal immunoglobulin (M protein), and low volume of plasma cells. MGUS must be distinguished from overt malignant diseases like multiple myeloma (MM), immunoglobulin light-chain (AL) amyloidosis, and monoclonal gammopathy of clinical significance (MGCS), all of which cause organ damage or symptoms. Although testing for M proteins is often prompted by clinical findings (eg, osteoporosis or autoimmune disease), recent evidence from screened populations suggests that previous MGUS disease associations were likely overestimated and that testing for M proteins should be reserved for when malignant disease or MGCS is suspected. Risk of progression to malignant disease ranges from 0.5% to 1%, meaning most patients have indolent disease. Guideline-concordant management of MGUS is determined by predicted risk of progression to malignant disease, which depends on subtype of immunoglobulin, M protein concentration, and free light chain ratio. Patients with low-risk MGUS can safely defer bone marrow biopsy and advanced imaging, and should undergo periodic laboratory monitoring. Intermediate- and high-risk MGUS should trigger bone marrow biopsy and bone imaging to detect overt MM and shorter monitoring intervals. Advanced molecular testing may improve on current risk stratification to target monitoring and treatment to those with highest risk of malignant progression and avoid overtreatment of those with low-risk disease. Management will also be informed by results of several clinical trials to clarify the risks and benefits of screening, optimal monitoring strategy, predictors of progression, and potential preventive or curative therapies.
Conclusions and relevance: Evidence-based management of MGUS currently rests on separating clinically indolent from high-risk precursor disease. Research using novel detection methods, incorporating molecular testing into risk stratification, and evaluating screening, monitoring, and therapeutic or lifestyle interventions has the potential to improve outcomes.
