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1.3.4. New guidelines

Chapter 1

New guidelines, pertinent to the use of sFLC analysis, have also been published in recent years (Chapters 25 and 28). The revised British guidelines for management of MM [41] now recommend that sFLC assays are used to assess response in all LCMM patients and in the management of patients with renal failure. In addition, an update to the International Myeloma Working Group criteria for MM diagnosis was published by Rajkumar et al. [42]. This included new definitions of light chain MGUS (identified by an abnormal sFLC ratio) and defined sFLC ratios >100 as a biomarker of malignancy for MM diagnosis. This latter definition is of particular importance because a proportion of patients previously classified as having smouldering MM are now re-defined as having MM, justifying treatment. New guidelines for the conduct and reporting of clinical trials in AL amyloidosis have also been published, including updated definitions of haematological response based upon sFLC analysis [23].

The 2016 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment [905] contains a section on HLC analysis: Kumar et al. recognise the usefulness of the assays in oligosecretory disease patients (Section 18.4.2) and monitoring patients with β-migrating IgA monoclonal proteins in order to overcome limitations associated with electrophoresis (Section 18.4.1). They also state that HLC analysis may have a role in minimal residual disease assessment as it not only allows detection of persistent secretory clones of plasma cells but is also an indicator of immune system normalisation (Section 18.4.3).

Questions

  1. What accounts for immunoglobulin light chain heterogeneity?
  2. What are the normal serum half-lives of IgG and FLCs?
  3. Do urine FLC concentrations always increase alongside rising sFLC concentrations?
  4. Why does the IgG half-life vary with concentration?

Answers

  1. Light chain heterogeneity arises from genetic recombination, isotypic, allotypic and idiotypic variation and somatic hypermutation of the variable regions after antigen exposure (Sections 3.1 and 3.2)
  2. IgG is approximately 21 days and FLCs 2 - 6 hours (Section 3.4).
  3. No. If there is significant renal impairment, urine FLC excretion falls (Section 3.4).
  4. FcRn receptors saturate at high IgG concentrations so the half-life shortens (Section 3.4). At low IgG concentrations, the half-life lengthens because FcRn receptor recycling is maximal (Section 3.4).
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