M-protein levels were significantly higher in patients with IgG M-proteins than in those with IgA M-proteins ( P<0.001, Mann-Whitney U-test). Furthermore, a significant proportion of those patients presented with M-protein levels of <10 g/L the threshold for accurate assessment of response to therapy. A sizable proportion of these patients with symptomatic multiple myeloma presented with M-protein levels 30 g/L). Data are shown for patients with IgG (n=1,894, left panel) and IgA (n=757, right panel) multiple myeloma at first diagnosis. Five percent of IgG patients and 11% of IgA patients presented with an M-protein level <10 g/L, which is below the threshold recommended for accurate assessment of M-protein response to therapy.ĭistribution of M-protein levels in IgG and IgA myeloma patients at entry into the Myeloma IX and Myeloma XI clinical trials. In this large cohort of newly diagnosed myeloma patients who required anti-myeloma therapy 33% of IgG patients and 43% of IgA patients had M-proteins <30 g/L. A cutoff of 30 g/L is used to separate MGUS from smoldering (asymptomatic) myeloma. IgG patients had significantly higher M-protein levels (median 37 g/L, range 0.80–129 g/L) compared to IgA patients (median 34.5 g/L, range 0.2–109 g/L) ( P<0.001) likely reflecting the longer serum half-life of IgG. The distribution of M-protein levels for myeloma patients with an IgG or IgA M-protein (accounting for 84% of all myeloma patients) are shown in Figure 1. Central laboratory serum FLC ratios and M-protein concentrations in 3,177 newly diagnosed myeloma patients from UK clinical trials 12, 13 and 711 MGUS cases were analyzed. We examined the use of different M-protein level thresholds combined with different serum FLC ratio ranges to distinguish myeloma from MGUS without loss of sensitivity for identifying patients who need urgent referral for myeloma diagnosis and assessment. It would be useful to have evidence-based guidelines on laboratory reporting of M-protein levels and serum FLC ratios that would enable primary care and other specialty doctors to decide which patients to refer urgently to hematology for suspected myeloma. There is a lack of guidance for non-hematologists in interpretation of abnormal test results in this setting. This is a significant problem in the UK where patients are frequently referred unnecessarily as urgent suspected cases of cancer and contributes to gross inefficiency within healthcare systems that are struggling with capacity. 11 Particularly in primary care and other specialties there may be unnecessary rapid referrals to hematologists, inappropriate testing (imaging or bone marrow biopsies), and associated anxiety in patients. 8– 10 MGUS is not usually clinically significant and not the cause of the patients presenting illness but requires differentiation from myeloma and this can be difficult. Myeloma arises in an age range in which these conditions are common and there is a need to define serum FLC ratio reference ranges better in these groups of patients. 7 In clinical practice the majority of M-proteins and abnormal serum FLC ratios derive from MGUS plasma cell clones or are small abnormalities in the ratio caused by conditions unrelated to neoplastic plasma cells, including kidney disease, inflammation and infection. 6 However, ordering these tests is tempered because they also reveal the 100 times more common condition monoclonal gammopathy of undetermined significance (MGUS). Absence of an M-protein and abnormal serum FLC ratio is only found in the rare non-secretory myeloma, and therefore with close to 100% sensitivity for diagnosis of myeloma, encouraging widespread use of these simple blood tests may reduce delays in myeloma diagnosis. 4, 5Ĭritical to the diagnosis of myeloma is testing serum for the presence of an M-protein (paraprotein) plus serum and/or urine testing for monoclonal free light chains (FLC). Myeloma is rare in primary care consultations and the symptoms are nonspecific, common and of low predictive value (odds ratios ≤3). 3 Myeloma is suspected when patients present with one or more features of myeloma-related end-organ damage including anemia, skeletal disease, renal impairment and immunodeficiency but any of these are more likely caused by much commoner diseases. 2 Population data from England show that a third of 22,249 newly diagnosed myeloma patients presented as emergencies and had the worst 12-month survival at just 61%. 1 Myeloma is one of the worst cancers for delays in diagnosis and half of patients saw their primary physician three or more times before referral to a hematologist. In Western Europe in 2016 there were 35,000 new cases of and 22,000 deaths from multiple myeloma.
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