Clinical FAQ
Clinical questions about serum testing for free light chains
Here you will find answers to questions about serum testing for free light chains
- What diseases cause elevation of monoclonal FLC levels in serum?
- Why are serum tests preferable to urine tests?
- How many more MM patients will be detected if sFLC assays are run alongside SPE?
- I currently screen for MM using IFE. Will sFLC assays be of additional benefit?
- Will sFLC concentrations help in understanding tumour kinetics?
- Can you detect plasmacytomas using serum FLC assays?
- How many more MM patients will be detected if I perform sFLC assays together with SPE and IFE?
- How many more MGUS patients will be detected using sFLC assays?
- Can sFLC assays be used to follow-up patients with LCMM?
- How will sFLC tests benefit patients with NSMM?
- Are sFLC measurements helpful in patients with AL amyloidosis?
- What are the normal values for serum FLC?
- Is the absolute value of the FLC or the free κ/λ ratio more important?
- If MM patients are in complete remission, how useful is the sFLC result?
- Why is the serum FLC measure normal when there is a band visible in urine?
- What happens to monoclonal FLC concentrations when patients develop renal impariment?
- Does bone marrow suppression affect FLC concentrations?
- Can sFLC assays be used for transplantation monitoring?
- What diseases cause elevated serum polyclonal FLC concentrations?
What diseases cause elevation of monoclonal FLC levels in serum?
Monoclonal elevations of free κ and λ occur in the same diseases that produce monoclonal gammopathies with intact immunoglobulins. The number of diseases is extensive but clearly MM and AL amyloidosis are important.
Why are serum tests preferable to urine tests?
Since the kidney can metabolise between 10 and 30g of FLCs per day in the proximal tubules, urinary FLC results do not accurately reflect FLC production by the tumour. This results in a poor correlation between serum and uFLC concentrations and makes urine testing unreliable.
How many more MM patients will be detected if sFLC assays are run alongside SPE?
LCMM comprises between 15-18% of all MM. Approximately, half to two thirds of these patients will have abnormalities by SPE. This especially applies to patients who are producing large quantities of FLCs, are in renal failure or have associated hypogammaglobulinaemia. The remaining LCMM patients with normal SPE (5-7%) and 70% of those with NSMM (2%) will be detected by sFLC assays. Most patients with AL
amyloidosis and other rare monoclonal gammopathies will also be detected. In addition, normal individuals with FLC MGUS will be identified. Intact immunoglobulin MGUS occurs in approximately 3% of people aged over 70 and more frequently with increasing age. Therefore, at least 10-15% additional patients with monoclonal gammopathies will be detected using sFLC. The study by Bakshi et al., detected an additional 50% of patients and included B-CLL and other plasma cell dyscrasias.I currently screen for MM using IFE. Will sFLC assays be of additional benefit?
Yes, for two reasons. sFLC analysis will detect monoclonal gammopathies that are missed by IFE. Also, quantification of sFLCs, at the time of clinical presentation provides a base line result for subsequent disease monitoring.
Will sFLC concentrations help in understanding tumour kinetics?
This is an important issue. At present, intact monoclonal immunoglobulins in serum or FLCs in urine are used to monitor the progress of patients. The half-life of IgG is 3-4 weeks, so reductions in tumour mass with chemotherapy may not be reflected in serum monoclonal protein changes for several weeks. The half-life of FLCs is only a few hours - extending to 2-3 days when renal function is impaired. Thus, reductions in tumour mass with chemotherapy can be identified earlier when the patients are being monitored using sFLC tests. Indeed, changes in tumour mass might be assessed between each cycle of chemotherapy allowing subsequent treatments to be specifically tailored to individual patients. Changes in urine and serum levels of FLCs broadly correspond but renal tubular reabsorption prevents accurate assessment of tumour responses from urine measurements.
Approximately 95% of patients with MM, excreting intact immunoglobulins haveabnormal sFLCs. It is likely, because of the short half-life of FLCs, discussed above,that disease monitoring in many of these patients will be better using sFLC levels rather than intact immunoglobulin concentrations.
Can you detect plasmacytomas using serum FLC assays?
A small study showed that yes, most plasmacytomas produce FLC in sufficient quantities to be detectable by serum FLC assay. Although FLC levels are generally low most of the plasmacytomas are detectable by an abnormal FLC ratio.
How many more MM patients will be detected if I perform sFLC assays together with SPE and IFE?
FLC serum assays are more sensitive for FLC detection than both SPE and IFE so approximately 5% extra patients with low concentration monoclonal FLCs will be detected. Some of these patients will have LCMM, NSMM or AL amyloidosis. Many of these patients also have FLCs in the urine but some do not. If monoclonal FLCs are detected in the serum then there is little value in performing additional urine tests.
However, there are rare patients that have normal sFLC concentrations but have detectable FLCs in concentrated urine by IFE. These include patients with AL amyloidosis but not patients with LCMM.How many more MGUS patients will be detected using sFLC assays?
MGUS have historically comprised intact immunoglobulins and these are detected using SPE. FLC only MGUS have been observed in the urine but only rarely. FLC MGUS have recently been detected in serum using FLC immunoassays at a frequency of approximately 20% of intact immunoglobulin MGUS (3% of samples from individuals over 70 years of age). Since MGUS comprises 60-80% of monoclonal gammopathies, many new FLC MGUS patients will be detected. These may be the precursor of LCMM and AL amyloidosis and are a focus of considerable clinical interest.
Can sFLC assays be used to follow-up patients with LCMM?
Yes, serum is preferable to urine for monitoring patients for several reasons. Serum samples are easier to collect than 24-hour urine samples and serum is a more reliable fluid for assessing changes in production of FLCs. Also, normal serum concentrations of FLCs are less variable than urine concentrations so abnormal results are more easily assessed. Since serum is more sensitive for detection of FLCs than urine, sFLCs are more effective for assessing minimal residual disease.
How will sFLC tests benefit patients with NSMM?
By definition, these patients have no detectable monoclonal proteins in their serum and urine by conventional electrophoresis tests and have to be monitored by marrow biopsies or bone scans. sFLC tests are clearly useful in these patients and more accurate than bone marrow biopsies that can miss patchy tumour deposits. sFLC concentrations assess FLC production by the whole bone marrow (and extramedullary sites) so are probably a better reflection of overall tumour activity than isolated bone marrow aspirations. sFLC tests will lead to a reduced number of bone marrow biopsies in most of these patients. However, as for all tumours, a tissue diagnosis, obtained by biopsy, is essential to establish the initial diagnosis, even if the FLC test results are grossly abnormal.
Are sFLC measurements helpful in patients with AL amyloidosis?
AL amyloidosis is a difficult disease to diagnose because existing serum and urine tests are not sufficiently sensitive to identify all patients. sFLC measurements not only identify more patients than electrophoresis tests of serum and urine but also they are important for monitoring disease progress. The short serum half-life of FLCs makes them a mandatory test for evaluating responses to treatment and identifying relapse.
What are the normal values for serum FLC?
Publications from Birmingham University and The Mayo Clinic have shown similar results. The data from The Mayo Clinic contains results from older people and indicates that serum FLC concentrations increase in normal individuals aged >70 years due to deteriorating glomerular filtration. Results from patients should be compared with the age-matched, normal range data. However, all laboratories should make some assessment of normal ranges in their own laboratories since there will be minor variations resulting from differences in race, age, exposure to infections, etc. Normal ranges are usually established by reference to standards (comprising purified proteins) that have been agreed by International committees. Freelite is a unique test and since there is no international agreement at present no definitive statement on the accuracy of the normal ranges can be made. In time, agreed reference materials will be manufactured, International agreement established, and the normal ranges will then be adjusted to take into account any recommendations.
Is the absolute value of the FLC or the free κ/λ ratio more important?
Serum FLC abnormalities should be established by assessing both the concentrations of the clonal free light chain, the alternate free light chain and the free κ/λ ratio. This is optimally performed using a κ/λ log plot for each patient’s result which is then compared with normal range and disease group data. This elegantly identifies monoclonal FLC diseases from polyclonal FLC abnormalities and individuals in the normal range. Since renal function is frequently affected in myeloma patients, the alternate light chain concentrations are often elevated but the κ/λ ratio may still be highly abnormal. If the patient has bone marrow suppression, the individual FLC concentrations might be low, in which case the κ/λ ratio may be more helpful. This is typical of patients undergoing chemotherapy and in patients with nonsecretory myeloma and primary amyloidosis with bone marrow suppression. Clinical judgement should be used in these cases. If either the FLC concentrations or the κ/λ ratios are outside the normal range then the cause should be investigated. Consideration should be given to assessment of renal function and causes of increased immunoglobulin production such as autoimmune diseases, chronic infections and some malignant tumours.
If MM patients are in complete remission, how useful is the sFLC result?
FLC results are more useful than existing SPE or IFE because they are more sensitive and, therefore, more likely to detect residual disease. Also, sFLC concentrations are more likely to be elevated than uFLC levels when patients are in remission. Thus, some patients apparently in full remission by existing tests might have abnormal FLC concentrations and their clinical status will need to be revised. Some patients who
relapse between monitoring periods may be more easily identified using sFLC assays rather than SPE or IFE.Why is the serum FLC measure normal when there is a band visible in urine?
This is rare but can occur for three reasons. If there is a very minor level of production of monoclonal FLC that does not lead to any serum FLC abnormality it is possible it may be detectable as a weak band on an IFE of a highly concentrated urine. Arguably such a minor band would be irrelevant. Other urinary proteins (eg transferrin) may be found at the same point on a gel as a free light chain band. Bands from IFE of urine samples are often diffuse and poorly defined, occasionally an unusually strong (or weak) batch of kappa or lambda antibody used in IFE can lead to uneven staining and give the appearance of monoclonality.
What happens to monoclonal FLC concentrations when patients develop renal impariment?
As patients develop renal impairment the concentrations of κ and λ polyclonal serum FLCs increase. This is associated with an increase in the monoclonal FLC but the κ/λ ratio will also increase slightly because of the relative reduction in clearance of κ molecules (Chapter 11.2). However, changes in the κ/λ ratio are a better guide to changes in clinical status when glomerular filtration rates are changing than the
concentrations of the monoclonal FLC. Changes in the concentrations of creatinine or cystatin C should be assessed, under these circumstances, in order to provide an independent assessment of renal function and a correction factor for the κ/λ ratios.Does bone marrow suppression affect FLC concentrations?
Bone marrow suppression, either because of bone marrow replacement by tumour or resulting from chemotherapy, leads to a reduction in the concentrations of polyclonal FLCs. Typically, at the time of diagnosis, the alternate FLC is suppressed and there is a grossly distorted κ/λ ratio. κ/λ ratios play an important role in assessing changing FLC concentrations in these patients and may even be useful when the concentrations of the monoclonal FLCs are below normal levels.
Can sFLC assays be used for transplantation monitoring?
Yes, sFLC assays are useful for monitoring post transplantation progress in AL amyloidosis and MM and may indicate early relapse and early responses.
What diseases cause elevated serum polyclonal FLC concentrations?
Serum polyclonal FLC concentrations increase if there is increased production orreduced glomerular filtration of κand λproteins. Increased production results from anydisease that stimulates B-cell proliferation such as infections, autoimmune diseases,various tumours etc. For example, in active SLE, total immunoglobulin productionincreases 3-4 fold with a corresponding increase in sFLC concentrations.
Reduced glomerular filtration of FLCs occurs in renal damage because almost allFLC removal is via the glomerular pores and the proximal renal tubules. In renal failure,sFLC concentrations may rise 10-20 fold but in all cases both free κand λare elevated,so the free κ/λratio remains normal. In many diseases, particularly SLE, increases inpolyclonal FLC concentrations are due to a combination of increased FLC productionand reduced renal filtration.
In situations of increased polyclonal FLC production or reduced filtration, there maybe moderate distortions of κ/λratios (e.g., 3-4 standard deviations from the normalrange). These patients are borderline abnormal and should be investigated appropriately.
