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Recently , Ronald S . Go , MD , and S . Vincent Rajkumar , MD , wrote about their approach to diagnostic work-up and management of patients with monoclonal gammopathy of undetermined significance ( MGUS ). Below , we summarize their approach . This material was repurposed from “ How I Manage Monoclonal Gammopathy of Undetermined Significance ,” published in the January 11 , 2018 , edition of Blood .
Managing Monoclonal Gammopathy of Undetermined Significance
Understanding MGUS
MGUS is a premalignant , clonal plasma cell disorder characterized by the presence of :
• a monoclonal ( M ) protein
• < 10 % clonal plasma cells in the bone marrow ( BM )
• absence of lymphoplasmacytic malignancy ( LPM )
An MGUS diagnosis is considered a requisite precursor to several LPMs , including multiple myeloma ( MM ), immunoglobulin light-chain ( AL ) amyloidosis , and Waldenström macroglobulinemia ( WM ).
MGUS is of considerable clinical interest , given its high prevalence in the general population ( about 3 % of people ≥50 years old have been diagnosed ), its persistent risk of progression to LPM , its known causal association with several serious non-malignant disorders , and the high frequency with which coincidental associations are detected .
When to Test for MGUS
Symptomatic Patients In general , we test for the presence of monoclonal gammopathy in patients who have clinical symptoms and signs of the presence of MM , AL amyloidosis , or WM ( i . e ., bone pain , unexplained weight loss , hyperviscosity ). However , because LPMs are rare ( approximately 35,000 new diagnoses annually ), the chance of identifying LPM in day-to-day practice is very low . Therefore , when M-protein testing is performed , clinicians typically find an alternative explanation for the clinical presentation . Patients with positive tests are labelled as having an incidental diagnosis of MGUS .
We also look for monoclonal gammopathy if a patient has a non-malignant disease ( such as acquired von Willebrand syndrome , scleromyxedema , or insulin autoimmune syndrome ) known to be a cause of , or associated with , monoclonal gammopathy .
Initial screening for monoclonal gammopathy includes serum protein electrophoresis ( SPEP ), serum immunofixation , and free flightchain ( FLC ). If M-protein is detected , urine protein electrophoresis is ordered . This panel of testing is highly sensitive and will detect an M- protein in virtually all patients with LPMs .
Asymptomatic Patients Practice guidelines do not recommend routine screening for MGUS in the general population because of the lack of proven benefit and the absence of curative or preventive therapy . While this rationale appears to be sound , an estimated 80 percent of MGUS cases are not clinically recognized .
Certain populations also have a higher prevalence of MGUS , including black people , people with occupational exposures to certain pesticides ( including dieldrin , carbon-tetrachloride / carbon disulfide , and chlorothalonil ), immunocompromised patients , and those with first-degree relatives who have MGUS or LPMs .
Until clinical trial results determine whether screening the general population is beneficial , we believe it is reasonable to screen patients at risk for MGUS as described above or who have two or more first-degree relatives with LPMs like MM , AL amyloidosis , or WM .
Diagnostic Criteria for MGUS
Once M-protein is detected , the extent of further evaluation to rule out LPM depends on the pretest probability of the latter and whether clinicians identified an alternative explanation for a patient ’ s presenting symptoms .
To establish an MGUS diagnosis , we generally order the following tests at the time of hematology consult : complete blood count , serum calcium , creatinine , FLC , immunofixation , and 24-hour urine protein electrophoresis . There are three subtypes of MGUS , each with distinct criteria for diagnosis :
• Immunoglobulin M ( IgM ) MGUS must have serum IgM monoclonal protein < 3 gm / dL ; BM lymphoplasmacytic infiltration < 10 %; and no evidence of anemia , constitutional symptoms , hyperviscosity , lymphadenopathy , or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder .
• Non-IgM MGUS must have serum monoclonal protein ( non-IgM type ) < 3 gm / dL , clonal BM plasma cells < 10 %, and absence of end-organ damage such as hypercalcemia , renal insufficiency , anemia , and bone lesions that can be attributed to the plasma cell proliferative disorder .
• Light-chain MGUS must have abnormal FLC ratio (< 0.26 or > 1.65 ), increased level of involved light chain , no immunoglobulin heavy-chain expression on immunofixation , absence of end-organ damage that can be attributed to the plasma cell proliferative disorder , clonal BM plasma cells < 10 %, and urinary monoclonal protein < 500 mg / 24 hours .
Skeletal Imaging and BM Biopsy Although MGUS , by definition , requires BM clonal plasma cells to be less than 10 percent and no evidence of lytic lesions on skeletal imaging , not all patients with suspected MGUS need these tests ( see FIGURE 1 on page 54 for a suggested algorithm for using BM biopsy and skeletal imaging in this setting ).
Both tests can be deferred in patients with low-risk or uncomplicated M-protein test results . Although data on light-chain MGUS are lacking , we do not recommend routine skeletal imaging and BM evaluation in patients who have a low involved or uninvolved FLC ratio and in whom there are no clinical concerns for LPMs .
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