Multiple Myeloma
& Free Light Chains

What are free light chains?

Light chains are small proteins produced in two isoforms (kappa, K; and lambda, λ) by plasma cells which are responsible for producing antibodies. Light chains are bound to heavy chains to form an antibody, also called immunoglobulin. Heavy and light chains are produced independently and assembled together within the plasma cell; however, light chains are produced in excess and secreted as free K and free λ light chains (KFLC, λFLC) in the blood (i.e., not bound to a heavy chain as it happens in an intact immunoglobulin).

When do free light chains matter?

When a monoclonal gammopathy (or plasma cell dyscrasia) develops, the majority of plasma cells retain the capability of producing intact immunoglobulins and free light chains. These can be used as biomarkers in multiple myeloma. As the plasma cells grow uncontrollably from one single plasma cell clone, the blood of the patient may have increased levels of a monoclonal protein (M-protein). In the majority of myeloma patients, the M-proteins can be both intact immunoglobulins and free light chains (FLC); however, around 20% of multiple myeloma patients only secrete FLCs or secrete low levels of intact immunoglobulin.

Serum protein electrophoresis (EPG) and capillary zone electrophoresis (CZE) lack the sensitivity to detect low levels of serum FLC (sFLC); in line with this, 1 in 8 patients may be missed if sFLCs are not investigated alongside EPG when ruling out multiple myeloma.¹

For this reason, international² and national³ guidelines recommend including sFLC testing when querying multiple myeloma to maximise the detection of signs indicative of myeloma. Multiple myeloma can be very difficult to diagnose due to the vague nature of its symptoms, and this is reflected in a longer time to diagnosis compared to other blood cancers.⁴ This is why it is pivotal that the correct tests are requested if myeloma is suspected. Through the calculation of serum KFLC / λFLC ratio, it is possible to identify plasma cell clonality and by combining EPG (and immunofixation) and sFLC analysis, >99% of myeloma patients can be correctly diagnosed.¹

EPG and sFLC measurements are also used when monitoring patients with multiple myeloma and they aid clinicians in the assessment of response to therapy.⁵ 

Why is serum free light chain testing recommended over urine testing?

Free light chains are sometimes referred to as Bence-Jones Protein (BJP) when they are identified in urine by the presence of a band in urine protein electrophoresis or immunofixation. However, looking for FLCs in urine can be complicated.

Normal plasma cells produce 0.5-1 g of FLC per day; however, 10-30 g/day can be metabolised by healthy kidneys.⁶ This means that for FLCs to be detected in the urine, the production needs to be higher than the metabolic capacity of the kidney, or the kidney needs to be damaged. Not all myeloma patients will produce high levels of FLC or have impaired kidney function at diagnosis, and FLC might not be present in the urine, potentially leading to delays in diagnosis.

It has been demonstrated that sFLC measurement provides equivalent or better diagnostic sensitivity to urine analysis^{1, 8-11} in myeloma diagnosis.

If FLCs are present in the urine, they were in serum first: with just one blood sample it is possible to test both EPG and sFLC, and complying with the guideline recommendations for ruling out multiple myeloma.

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