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Since the first availability of Freelite, many applications for sFLC analysis have become standard practice and indeed, are now recommended in various guidelines for best practice. All guidelines relevant to sFLC analysis are described in Chapter 25 (MM) and Chapter 28 (AL amyloidosis). The main applications for sFLC analysis are described briefly below. The chapters/sections cited in the text contain more detailed discussions plus references.

The sensitivity of sFLC analysis for identifying low levels of monoclonal FLC production indicates that it has a role in the initial screening for plasma cell dyscrasias. Many studies have been performed adding sFLC tests to the (previously) recommended standard of serum and urine electrophoresis assays and reported that extra patients were identified (Chapter 23). Also the efficacy of different screening panels has been assessed using sera from many hundreds of patients with well-characterised plasma cell disorders. The consensus from these studies has been that sFLC analysis plus serum electrophoresis tests comprise a suitable screening algorithm unless AL amyloidosis is suspected, for which the addition of urine electrophoresis will identify a few rare AL amyloidosis patients who are negative by the serum tests. This protocol was recommended in international guidelines published in 2009 [20].

Some of the earliest studies with sFLC assays were performed with sera from LCMM patients. All patients with positive urines were found to have abnormal serum results and it was apparent that sFLC analysis was generally more sensitive for detection of residual disease (Chapter 15). This sensitivity was recognised by the incorporation of a normal sFLC ratio as one of the criteria defining a “stringent complete response” (sCR) in guidelines for response criteria and the uniform reporting of clinical trials (Section 25.3.5) [21]. Guidelines from the International Myeloma Working Group in 2009 [20] recommended that Freelite assays were used for monitoring any “oligosecretory” LCMM patients whose urinary FLC was <200 mg/24 hours and considered unreliable for accurate measurement.

Approximately 3 - 4% of myeloma patients were routinely classified as having nonsecretory disease until it was demonstrated that up to 70% of these patients were actually producing small amounts of FLC that could be identified by sFLC assays (Chapter 16). sFLC analysis was quickly identified as a significant benefit for these patients as it allows their disease to be monitored without recourse to frequent bone-marrow biopsies and permits them to be included in clinical trials. Guideline recommendations for sFLC use encompassed these patients within the definition of oligosecretory disease [20].

The majority of patients with MM produce monoclonal intact immunoglobulin (i.e. IIMM) which is used for monitoring their responses to treatment. However, more than one publication has reported that up to 96% of these patients also produce monoclonal FLCs, detectable by sFLC analysis [21] (Section 17.2). Interestingly, the serum concentrations of FLCs and intact monoclonal immunoglobulins are not correlated (R2<0.1). Monoclonal sFLCs are therefore independent markers of the disease process. This is of potential clinical use particularly when the tumour produces large amounts of FLCs and small amounts of intact monoclonal immunoglobulins. sFLC may be a more sensitive marker of complete response and the designation of sCR is also applied to patients with IIMM . Patients with IIMM may relapse with expression of FLC alone ("FLC escape"). A number of case studies have now been published illustrating how sFLC analysis readily identifies this phenomenon (Section 18.2) so it is advisable to include tests for FLC production when monitoring IIMM patients. One particularly interesting aspect of sFLCs is their short half-life in the blood (κ: 2 - 4 hours; λ: 3 - 6 hours). This is approximately 100 - 200 times shorter than the 21 day half-life of IgG molecules. Hence, responses to treatment can be seen much more rapidly if sFLCs are monitored. This also has been identified in a number of clinical studies (Section 18.3.1).

An additional feature of FLC molecules is that, in contrast to intact immunoglobulins, they are frequently nephrotoxic. Indeed, “myeloma kidney”, which presents as acute kidney injury (AKI), occurs in up to 10% of MM patients (Section 27.1). If renal recovery is not achieved, the life expectancy of these patients is significantly reduced. The benefit of rapid removal of FLCs from these patients has yet to be proven, but it is clear that early diagnosis and treatment of the underlying tumour is essential (Section 27.5) and the International Kidney and Monoclonal Gammopathy Research Group recommended the use of SPE and sFLC analysis to screen for monoclonal disease in all patients presenting with AKI [22].

sFLC assays have made a particular contribution to the diagnosis and management of patients with AL amyloidosis (Chapter 28). This may be unsurprising because it is the FLCs that directly cause the disease whilst the underlying tumours are typically slow-growing and difficult to detect. Characteristically, light chain fibrils form amyloid deposits in various organs and tissues, disrupting their normal function. Concentrations of circulating sFLCs are often insufficient for measurement by serum electrophoretic tests, but sFLC assays provide quantification of the circulating fibril precursors in 75 - 98% of patients (Section 28.2.1). Furthermore, the concentrations of sFLC and their reduction after treatment have been shown to be prognostic in various studies. sFLC analysis is advocated in both national and international guidelines for management of AL amyloidosis (Sections 28.3 and 28.6) [20][23][24][25]. As stated by Dispenzieri et al. [26] from The Mayo Clinic:

“The introduction of the serum immunoglobulin free light chain assay has revolutionized our ability to assess hematological responses in patients with low tumor burden...”

Monoclonal gammopathy of undetermined significance (MGUS) and smouldering myeloma (SMM) are precursor conditions which progress to active disease at rates of approximately 1% and 10% per year, respectively (Chapters 13 and 14). Abnormal sFLC ratios are found in approximately 30% of subjects with MGUS but 80 – 90% of those with SMM. In both conditions, sFLC analysis provides an independent prognostic indication that can help identify those patients who will benefit from more frequent monitoring and those who can be reassured and discharged (low-risk MGUS). Again, these prognostic utilities have been included in guideline recommendations (Chapter 25) [27][28].

In summary, sFLC tests fulfill an important role in the detection, monitoring and prognosis of plasma cell dyscrasias; bringing benefits to a multitude of patients. Their inclusion in multiple guidelines for best clinical practice is witness to this role.

References