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)[10]. 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)[11][12].

One feature that MM and other plasma cell dyscrasia have in common is the production of monoclonal immunoglobulin proteins that can be detected in the serum, with the exception of a very small percentage of patients whose clonal plasma cells appear to be non-secretory, e.g. in nonsecretory MM (Chapter 16) [15] or POEMS syndrome (Section 34.4) [16]. The monoclonal protein may be intact immunoglobulin: IgG, IgA, IgM, IgD or (very rarely) IgE (Figure 1.1). Immunoglobulin free light chain (FLC) production frequently accompanies the intact immunoglobulin or it can be found in isolation as in light chain MM (LCMM (Chapter 15); rarely isolated immunoglobulin heavy chain may be produced (Section 34.3). Plasma cell tumours are generally “hidden” within the bone marrow and initially give rise to symptoms that are vague and non-specific. Therefore, the presence of monoclonal proteins in the serum is a significant aid, not only for the diagnosis of these disorders but also their clinical management; indicating the response to treatment and persistence of residual disease. The majority of serum tumour markers (for non-plasma cell cancers) are relatively non-specific: the markers are present in healthy individuals but abnormally high concentrations indicate the possibility that a tumour may be present. By contrast, monoclonal immunoglobulins are highly specific tumour markers, the occurrence of a monoclonal immunoglobulin defines the presence of a clone of cells responsible for its production. However, it should be noted that apart from plasma cells, clones of less mature B-lymphocytes may also produce monoclonal immunoglobulin proteins (Chapters 31, 32, and 33) so, in fact, the presence of monoclonal immunoglobulin indicates the existence of a clone of cells of the B-lymphocyte lineage (i.e. a lymphoproliferative disorder).

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)[17][18]. 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).