Preface to 6th edition

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Preface to 6th edition 2010

Since those early days of serum free light chain (FLC) tests, eleven years ago, there has been huge progress in understanding their clinical importance. There are now nearly one thousand publications analysing their measurement; there have been six international conferences and now a sixth edition of ‘Serum Free Light Chain Analysis.’ I had imagined, maybe even wished, that the rate of new indications would slow down. This would permit a clear focus on implementing the current clinical uses on a widespread basis. But, it seems that this is not to be because there are a range of new and important applications.

First, there are novel observations regarding monoclonal free light chains. It has recently been shown that FLC MGUS is a precursor abnormality for light chain multiple myeloma. This completes the story of pre-malignant markers in the disease and presumably similar observations will apply to other monoclonal gammopathies. Additionally, the diagnostic importance of monoclonal serum FLCs has been validated in several large studies and its use is fully established, alongside SPE, for identifying monoclonal proteins. This reduces serum and urine IFE to the secondary role of typing monoclonal proteins, except under exceptional circumstances such as when AL amyloidosis is suspected. Also, serum FLC tests should replace urine tests in new cases of acute and chronic renal failure as soon as light chain diseases are suspected. Flowing from these observations has been the application of ‘high cut-off’ dialysers for treating light chain cast nephropathy. Patients with this type of acute renal failure have benefitted from rapid removal of toxic light chains by dialysis, when combined with novel chemotherapeutics such as Velcade. Reported renal recovery rates are now approaching 80%.

Second, there are novel observations regarding polyclonal FLCs. Since these molecules are produced by all B-cells, concentrations increase with any inflammatory process and, it seems, in a diagnostically sensitive manner. Publications attest to this in, systemic rheumatic diseases, chronic liver diseases, HIV infections, acute and chronic infections, to name but a few. Furthermore, increases resulting from intense B-cell stimulation such as in Sjogren’s syndrome, HIV and hepatitis C infections, predict malignant transformation to lymphomas. In addition, patients with Hodgkin lymphoma have raised polyclonal FLCs in a prognostically dependant manner for, as yet, unexplained reasons. Serum polyclonal FLC concentrations, moreover, increase when their metabolism is impaired. Hence, serum FLCs are very sensitive markers of impaired glomerular filtration, in fact considerably more sensitive than creatinine clearance or urine albumin/creatinine ratios. Early observations also indicate that polyclonal FLCs are sensitive markers of liver damage. Impaired hepatic function, particularly by ongoing hepatic inflammation appears to cause marked increases in FLCs in relation to organ destruction. Even in cardiovascular disease, where C-reactive protein (CRP) tests have proven diagnostic utility, polyclonal FLCs appear to have additional clinical sensitivity. These many preliminary observations suggest that serum FLC analysis may be helpful in a multitude of inflammatory conditions.

Third, there is the application of protein ratios to monoclonal intact immunoglobulin measurements – so called Hevylite tests. Historically, IgG, IgA and IgM tests have comprised either monoclonal measurements by SPE or total immunoglobulins by immunochemical tests. Neither of these measurements takes into account the suppression of the un-involved immunoglobulins – which underpins the clinical value of serum FLC analysis. Studies of Hevylite ratios have now been completed in a variety of clinical situations. In multiple myeloma, they are more accurate for the diagnosis of some patients with IgA disease, they are more sensitive than IFE when monitoring clinical changes and, in particular, are of prognostic significance. This latter observation relates largely to suppression of the un-involved immunoglobulin of the same isotype as the tumour. Similar observations have been made in MGUS. These and other results lead to a host of interesting questions. What is the underlying mechanism of the suppression? Does it apply to other monoclonal gammopathies? Are there immunoglobulin-specific niches in the bone marrow? Should Hevylite tests be used alongside IFE because of their prognostic value? Do Hevylite tests predict transformation of smouldering myeloma to multiple myeloma?

So that myself and others might keep abreast of these new developments, it seemed appropriate to write a sixth edition of The Book. But, to prevent a pleasure from becoming an obsession, many people have helped with the text, particularly Richard Hughes. My new role as ‘editor in chief,’ allows more reflection with less direct input. A big thank you to all those who have helped make the writing process easier.

AR Bradwell, August 2010