In WM, accurate determination of serum IgM is considered crucial both at diagnosis and to monitor response to therapy . However, there are limitations to the routine laboratory methods used for IgM quantification.
Nephelometric total IgM assays may be unreliable due to an overestimation of IgM polymers, leading to a poor correlation with serum protein electrophoresis (SPE) . Other disadvantages include the inability to distinguish between polyclonal IgM and disease-associated monoclonal IgM, especially at low monoclonal protein concentrations, when total IgM measurements may contain a significant proportion of polyclonal IgM. Nephelometric antisera may also react variably with monoclonal IgM from different patients .Chapter 4) . Other limitations of SPE include: inaccurate quantitation when the concentration of monoclonal IgM is low; cases of ‘sticky IgM’ (in which insoluble aggregates form that precipitate in the loading site); the presence of IgM multimers (which create ‘overlapping peaks’); and comigration of monoclonal IgM in the β-region alongside other serum proteins (Figure 32.1). In addition, the presence of cryoglobulins affects IgM measurements by all methods .
Immunoglobulin heavy/light chain immunoassays (Hevylite, HLC), may provide some benefits. HLC assays quantify the different light chain types of each immunoglobulin class (i.e. IgMκ and IgMλ), and the molecules are measured in pairs to produce HLC ratios (i.e. IgMκ/IgMλ, Chapter 11) . HLC analysis also allows the concentration of the uninvolved HLC-pair to be measured (e.g. IgMλ in an IgMκ patient). When the concentration of the HLC-pair is below the normal reference interval, this is termed “HLC-pair suppression” (Section 11.2.2). In a WM patient with monoclonal IgMκ (for example), nephelometric measurement of IgMκ may provide a measure closer to the concentration of the monoclonal immunoglobulin than a total IgM assay. In addition, measurement of the HLC ratio, which is influenced by HLC pair suppression, has been found to be a sensitive marker of tumour activity in other diseases.
However, if a WM patient's tumour produces measurable quantities of monoclonal sFLCs, monitoring these concentrations could avoid most of the limitations encountered with monoclonal IgM quantitation (above).