Monoclonal gammopathy of unknown significance (MGUS) is not uncommon, affecting about 3% of people ages 50 and older in the general population. Risk for the condition, which is more common in men, climbs with age, reaching 3% for ages 60 to 69, greater than 4% for ages 70 to 79, and six percent for ages 80 and above.
MGUS can be a precursor of multiple myeloma, or a lymphoproliferative disorder such as lymphoplasmacytic lymphoma (Waldenström Macroglobulinemia), marginal zone lymphoma, or chronic lymphocytic leukemia. It is often diagnosed during the workup of chronic kidney disease (CKD) or peripheral neuropathy.
While immunofixation (IFE) is 10-fold more sensitive than protein electrophoresis (PEP), PEP provides quantification of M-protein. Free kappa and lambda light chains levels and ratio are also important parts of the evaluation and cannot be detected by PEP or IFE.
Most MGUS patients will experience no symptoms and will not progress to a disease state; the risk of progression to myeloma, for instance, is about 1 percent a year. Since progression to malignancies usually happens slowly, watchful waiting is often the chosen approach.
Regular long-term follow-up includes history and physical exam, CBC, CMP, serum and urine electrophoresis with immunofixation, and free light chains levels and ratio. Depending on test results and M-protein levels in individual patients, the risk of progression to malignancy can be determined to inform the frequency of follow-up appointments. Three to six months are common starting points.
Common concerning findings include progressive anemia, hypercalcemia, impaired renal function, and bone complications. Patients with underlying lymphoma may develop B symptoms such as persistent fever, night sweats, or progressive lymphadenopathy; patients with Waldenström Macroglobulinemia may develop hyperviscosity syndrome: bleeding diathesis, visual disturbances, and neurologic symptoms.
Sometimes calling a clinical significance can be difficult, as the related problems can be subtle or uncertain. For example, in patients with underlying hypertension and diabetes, the progression of CKD may or may not be associated with MGUS. In addition, rare conditions such as systemic capillary leak syndrome, TEMPI syndrome, or some skin manifestations are underdiagnosed unless an evaluation of M-protein is specifically pursued.
In recent years, a novel concept of monoclonal gammopathy of clinical significance (MGCS) has been developed to provide some guidance. National Comprehensive Cancer Network (NCCN) guidelines also included monoclonal gammopathy of renal significance (MGRS) and monoclonal gammopathy of neurologic significance (MGNS). Recognizing these categories and related findings will help physicians avoid missed cases of MGCS.
For physicians with questions about MGCS, it is encouraged to have a conversation and collaboration with a specialist such as a nephrologist, neurologist, or hematologist. Together, we can make a real difference for these patients.
References:
RA Kyle et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006 Mar 30;354(13):1362-9.
JP Fermand et al. Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications. Blood. 2018 Oct 4;132(14):1478-1485.
Dr. Zhao is a medical oncologist and hematologist with Virginia Oncology Associates, based in their Hampton and Williamsburg offices. virginiacancer.com
