Multiple myeloma (MM) is a disease with many faces. It usually presents in old age but may occur in youth. Bone pain and fractures are characteristic, but soft tissue involvement by plasmacytomas may also occur. Some patients may die within weeks of presentation, while others "smoulder" for years. Patients may develop renal failure, acute and chronic infections or AL amyloidosis, and many will require stem cell transplantation or intensive chemotherapy. Consequently, many specialists, including haematologists, nephrologists, immunologists, orthopaedic surgeons and chemical pathologists, become involved in disease management. Furthermore, the prevalence of MM is increasing due to a slowly rising incidence and a longer life expectancy (Section 12.2). Other plasma cell dyscrasias encompass a similar, if not greater, diversity of outcomes. Monoclonal gammopathy of undetermined significance (MGUS) can be found in approximately 3% of the (Caucasian) population over the age of 50 years but of this 3%, the vast majority will die of unrelated causes (Chapter 13). By contrast, for patients with plasma cell leukaemia or AL amyloidosis with cardiac involvement, median survival is close to 12 months (Chapters 22 and 28).
Monoclonal immunoglobulin proteins (specifically FLC) have been linked to MM since they were first reported by Dr Henry Bence Jones over 150 years ago (Chapter 2). Notwithstanding their substantial history and great utility, measurement of these tumour markers, particularly FLC, remained problematic for many years. Principally, this was a consequence of attempting to measure FLC concentrations in urine. An important function of the kidneys is to prevent the loss of FLCs and other small protein molecules into the urine. FLCs are rapidly cleared through the renal glomeruli with half-lives of 2 - 6 hours before being metabolised in the proximal tubules of the nephrons with reabsorption of the constituent amino acids. Under normal circumstances, little protein escapes to the urine so serum FLC (sFLC) concentrations have to increase many-fold before absorption mechanisms are overwhelmed (Chapter 26). Hence, urinalysis is an unreliable method for detecting changes in monoclonal FLC production.
An alternative strategy is to measure FLCs in serum. Experimental assays from the 1970s onwards revealed the potential for serum FLC (sFLC) measurement, but the assay technology was never sufficiently practical or accurate enough for general use (Section 2.3). Why, therefore, have adequate serum immunoassays not been produced before? It is now apparent that the overriding barrier was the difficulty in developing satisfactory antibodies for use in the assays. To function correctly, these antibodies must not only be of high affinity to allow measurement of low concentrations of sFLCs, but must also be highly specific. Concentrations of sFLC are several orders of magnitude lower than those of light chains bound to intact immunoglobulins, so even minor antibody cross-reactivity produces unacceptable results. Only recently have suitable antibodies been developed that bind exclusively to the hidden epitopes of FLC molecules (Chapter 5). These antibodies have facilitated the development of Freelite® sFLC assays that are specific, sensitive and quantitative.
Serum concentrations of FLCs are dependent upon the balance between production by plasma cells (and their progenitors) and renal clearance (Chapter 3). When there is increased polyclonal immunoglobulin production and/or renal impairment, both κ and λ FLC concentrations can increase 30-40 fold. However, the relative concentrations of κ to λ (i.e. the κ/λ ratio) remain unchanged, or only slightly increase (Section 6.3). By contrast, tumours produce a monoclonal excess of only one of the light chain types, often with bone marrow suppression of the alternate light chain, so that κ/λ ratios become highly abnormal. Accurate measurement of κ/λ ratios underpins the utility of sFLC immunoassays and provides a numerical indicator of clonality. This same concept is the basis for the immunoglobulin heavy/light chain (Hevylite®, HLC) assays, which have more recently been developed and allow accurate measurement of the different light chain types of intact immunoglobulin, such that κ/λ ratios can be determined (eg. the IgGκ/IgGλ ratio) (Chapter 9). The availability of Freelite assays, after 2001, provoked a “renaissance” of interest in FLC studies and a dramatic rise in publications. Although HLC assays do not provide the same “step change” that sFLC assays did (with the move from urine to serum measurement) they should also stimulate further research, notably through insight into HLC pair suppression (e.g. the suppression of IgGλ by an IgGκ tumour) and the existence of different bone marrow “niches” Sections 13.2.2 and 18.4.4).