Monoclonal Gammopathies of Undetermined Significance (MGUS) Differential Diagnoses

Updated: Sep 23, 2021
  • Author: Suzanne R Fanning, DO; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnostic Considerations

Monoclonal gammopathy of undetermined significance (MGUS) must be differentiated from myoclonal gammopathy of renal significance (MGRS), multiple myeloma (MM), and smoldering MM (SMM). Criteria for MGUS established by the International Myeloma Working Group [32] and the World Health Organization [33] are as follows:

  • Serum M-protein level < 3 g/dL
  • Bone marrow plasma cells < 10% and low level of plasma cell infiltration in a trephine biopsy specimen
  • No evidence of B-cell proliferative disorder (ie, MM, Waldenström macroglobulinemia, amyloid light-chain amyloidosis)
  • No M-protein or only small amounts of monoclonal light chain in urine
  • No osteolytic lesions, anemia, hypercalcemia, or M-protein–related renal function impairment

In addition to the hematologic abnormalities, MGRS is associated with a wide spectrum of renal diseases, including AL amyloidosis, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases of MGRS, to identify the exact lesion and determine its severity. [5] Treatment to eradicate the underlying clone is indicated; the proteasome inhibitor bortezomib is the preferred therapy in MGRS but a number of other agents have been used in some settings, including rituximab, cytotoxic chemotherapy, and immunomodulatory agents. [34]

Asymptomatic patients who have an M-component higher than 3 g/dL, or more than 10% but less than 20% bone marrow plasma cells, fulfill the criteria for SMM. These patients do not have anemia, renal failure, hypercalcemia, osteolytic bone lesions, or other clinical manifestations related to the monoclonal protein.

In clinical and biologic terms, SMM is closer to MGUS than to overt MM. Recognition of patients with SMM is extremely important because they should not be treated with chemotherapy until progression occurs. No particular laboratory parameter or clinical factor differentiates MGUS or SMM from overt MM. Decreased levels of uninvolved immunoglobulins are not a useful criteria for differentiation because 30-40% of patients with MGUS also have decreased levels of the uninvolved immunoglobulins.

Although Bence-Jones proteinuria suggests MM, finding small amounts of monoclonal light chains in the urine of patients with MGUS is not unusual. Lytic bone lesions on the skeletal survey strongly suggest MM. In patients recently diagnosed with MGUS, serum electrophoresis should be repeated after 3 months to exclude early myeloma, and, if the results are stable, the test should be repeated in 6 months. Patients should be aware that the evolution of MGUS to MM can be abrupt; therefore, they should be reexamined promptly if their clinical condition deteriorates.

Differential Diagnoses