Diagnosis and Management of Monoclonal Gammopathy of Undetermined Significance

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.