Understanding Free Light Chains (FLCs)

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Many patients are interested in learning more about the free light chain (FLC) test which is used to help diagnose AL amyloidosis and to follow response to treatment.  Questions about free light chains are common on the NAC patient support forum and are amongst the most common search terms used by people who reach this website. 

Unfortunately interpretation of the FLC results can be really difficult in many patients, even for specialist doctors.  So it’s understandable to find them confusing.  Professor Philip Hawkins, former Director of the National Amyloidosis Centre advises that the most important advice on this subject is to reassure patients not to leap to conclusions when they receive their FLC results!

For those who would like to understand the subject in more detail, the following explanation was developed in response to the concerns that came up frequently on the NAC patient support forum and includes ideas from patients:

Introduction

AL amyloidosis is caused by a ‘clone’ or group of identical abnormal plasma cells which act like little antibody producing factories, churning out abnormal quantities of monoclonal(identical) free light chains (FLCs).  This is known as monoclonal gammopathy.  The abnormal light chains are called ‘free’ light chains because they are not linked to heavy chains within antibodies, like normal light chains.  For further detail on normal antibodies see here.  Free light chains exist freely in the bloodstream until they deposit in the organs as amyloid fibrils which then cause organ damage.

There are two different types of light chain:

• kappa (k) chains
• lambda (l or λ) chains

Under normal circumstances, concentrations of both kappa and lambda light chains are very low in the bloodstream.  In AL amyloidosis, abnormal plasma cells produce a large quantity of one particular type of identical light chain – either kappa chains or lambda chains (known as the involved light chain).  The concentration of the other free light chain (known as the uninvolved light chain) usually remains at or close to normal levels in the blood.

FLC concentration is measured to assess plasma cell response to treatment.  A sensitive blood test can detect abnormal FLC concentrations in about 95% of patients with AL amyloidosis.

The introduction of this test about 15 years ago was a landmark advance in the management of patients with AL amyloidosis.

Blood concentration of FLCs is a sensitive measure of treatment effects on the abnormal plasma cells.

It is often helpful for patients and carers to understand what their FLC results mean.  When AL amyloidosis is first diagnosed, the FLC ratio is checked.  About 95% of patients with AL amyloidosis have an abnormal FLC ratio.  It is important to understand that abnormal FLC ratio alone is not diagnostic of AL amyloidosis.  There may be an abnormal FLC ratio in several related haematological conditions, or sometimes in healthy people with a condition called monoclonal gammopathy of uncertain significance (MGUS).  It is also worth noting that sometimes there may be a raised ratio due to low levels of one type of light chain.  If the person is otherwise healthy with no other findings suggestive of AL amyloidosis or related conditions, then the abnormal ratio in such circumstances may have no medical significance.

About 10-15% of patients with AL amyloidosis have only minimally abnormal FLC.  For these patients FLC cannot be used for accurate monitoring.  A measurable M-protein (also known as paraprotein), defined as >5g/l, is useful for monitoring the haematological response to chemotherapy in this group of patients. 

1-2% of patients with AL amyloidosis lack a measurable serum or urine marker to monitor response at present.  Ongoing studies are evaluating a new method called high sensitivity flow cytometry that may have a role in these patients.

Raised free light chain concentrations are not always due to identical, monoclonal FLCs.  Diseases associated with general stimulation of the immune system, such as infection, inflammation and auto-immune disease, may lead to high concentrations of many different types of FLCs (known as polyclonal FLCs, or polyclonal gammopathy).  Polyclonal gammopathy may also be present in people with chronic kidney disease, due to reduced removal of FLCs from the body by the kidneys.  Some people may have raised concentrations of both monoclonal FLCS and polyclonal FLCs.  This is a particular issue in people with AL amyloidosis who also have chronic kidney disease.  Doctors must take this into account when interpreting their test results. 

FLC ranges

To better understand FLC test results, these are the normal ranges:

Normal values for kappa, lambda and FLC ratio:

  • Kappa light chain concentration range: 3.3-19.4 mg/mL
  • Lambda light chain concentration range: 5.7- 26.3 mg/mL 
  • FLC (kappa/lambda) ratio: 0.26 -1.65

It is normal for there to be small fluctuations in the uninvolved light chain concentration over time, which have no clinical significance at all.  These small fluctuations can have a large effect on the FLC ratio, especially when there is a very high concentration of abnormal free light chains. 

Therefore, changes in FLC ratio may not have clinical significance, even if these changes appear to be quite large. 

Considering a few possible test results can help to clarify this complicated subject:

Kappa could theoretically be 3.3mg/dl with lambda 26.3 mg/dl giving a ratio of 0.125.  Both kappa and lambda concentrations would be in the normal range but the ratio would be significantly abnormal, and the patient could have AL amyloidosis. 

Alternatively kappa could be 19.4 mg/dl with lambda 74.6 mg/dl and the ratio would be normal at 0.26.  Despite the very high lambda concentration, the FLC ratio is within normal range and AL amyloidosis is unlikely.

Monitoring response to treatment

So FLC ratio is useful for diagnosing AL amyloidosis.  However, after that, when monthly FLC tests are used to follow the patient’s response to chemotherapy, the most useful test is the dFLC (difference between involved and uninvolved FLCs), rather than the FLC ratio.  The dFLC is calculated by subtracting the concentration of the normal (uninvolved) light chain type from the concentration of the abnormal (involved) light chain type.

If a patient with AL amyloidosis has amyloid due to abnormal production of kappa chains, dFLC concentration is kappa chain concentration minus lambda chain concentration.

If a patient with AL amyloidosis has amyloid due to abnormal production of lambda chains, dFLC concentration is lambda chain concentration minus kappa chain concentration.

The following table shows how FLC ratio changes can be misleading.  The change in FLC ratio at each time point is quite large, although the involved kappa chain concentration does not change at all and the uninvolved lambda chain concentration only fluctuates slightly within the normal range.  The dFLC accurately reflects that there is no real change over time.

Very high values used here for the involved kappa chains, to illustrate the point.  Many patients with AL amyloidosis have much lower levels of involved FLCs.

Use of the dFLC to monitor treatment is particularly useful in patients with chronic kidney disease in addition to AL amyloidosis.  As mentioned above, kidney disease can lead to reduced clearance of all types of free light chains from the body.  As kidney disease advances, this can lead to a gradual rise in several different types of FLCs (polyclonal gammopathy).  This may hinder the monitoring of the single identical FLC type causing AL amyloidosis (monoclonal gammopathy) by FLC ratios alone.  But monitoring with dFLC measurements is reliable in these patients, as is the method of calculating the percentage of baseline dFLC that remains at the time of each analysis.

Goals of therapy for AL amyloidosis

When treatment is successful, the earliest test which shows improvement is the FLC concentration, as reflected in the dFLC.

FLC concentration drops before there is measurable improvement in the function of affected organs, before patients start to feel better and before there is any visible change in amyloid deposits seen on SAP scans.

The goal of therapy is to achieve either a complete response (CR) or a very good partial response (VGPR).  In the event of a partial response (PR), doctors often consider a change in treatment regime.  Responses are defined as follows:

Complete response (CR): negative serum and urine immunofixation and normal FLC concentration with normal kappa/lambda ratio  

Very good partial response (VGPR): dFLC concentration below 40 mg/L

Partial response (PR): more than 50% reduction in FLC concentration

At the first visit to the NAC, patients are provided with several empty vials for blood samples and padded envelopes addressed to the NAC.  They can go to the GP or the local hospital clinic for the blood to be taken and then send the sample to the NAC in the post.  The FLC concentration is then measured in the NAC laboratories so the NAC doctors can assess the results and make appropriate treatment recommendations.

For more detailed information, a video by the company which makes the FLC assay, The Binding Site is available here: https://www.youtube.com/watch?v=Ye9s6BRgx_Y

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