The immune system produces antibodies (immunoglobulins) to identify and neutralize foreign threats. Each antibody molecule has four protein chains: two heavy chains and two smaller light chains, designated as kappa (\(\kappa\)) and lambda (\(\lambda\)).
Plasma cells, a type of white blood cell, produce these light chains in slight excess, and the unbound portions circulate freely in the blood. An elevated level of one chain, such as a high kappa light chain, causes concern. However, an isolated high number does not automatically signal cancer, but indicates a need for a specialized blood test that assesses the relationship between the two light chain types.
Understanding Free Light Chain Testing
The serum Free Light Chain (FLC) test measures the absolute amounts of unbound kappa and lambda chains circulating in the bloodstream. When plasma cells multiply abnormally, they often produce a high volume of a single type of light chain, which is released into the blood as a monoclonal protein (M-protein).
The most informative result is the calculated kappa-to-lambda ratio, not the individual chain level. In healthy individuals, this ratio typically falls within a narrow normal range, generally between 0.26 and 1.65. This stability occurs because plasma cells normally produce a mixed, or polyclonal, population of antibodies.
A high kappa light chain level is only medically significant if the kappa/lambda ratio is outside this reference range. An abnormal ratio signals a “monoclonal spike,” indicating that a single clone of plasma cells is overproducing one chain type. This imbalance suggests a plasma cell disorder, and the degree of abnormality helps determine the potential severity. Kidney dysfunction can elevate both light chains, but if the ratio remains normal, it is generally not a cause for concern.
The Spectrum of Monoclonal Conditions
The discovery of an abnormal free light chain ratio places a person onto a diagnostic spectrum of plasma cell conditions, ranging from benign to malignant.
Monoclonal Gammopathy of Undetermined Significance (MGUS)
The most common finding is MGUS, a non-cancerous condition. Diagnosis requires a relatively low amount of monoclonal protein in the blood, less than 10% clonal plasma cells in the bone marrow, and no signs of related organ damage. MGUS is considered a pre-malignant disorder, but most people will never develop a more serious condition. The risk of progression to active multiple myeloma is approximately 1% per year, making regular monitoring the standard approach.
Smoldering Multiple Myeloma (SMM)
SMM represents an intermediate stage with a higher burden of abnormal plasma cells. A person is classified as having SMM if they have a higher level of M-protein or if the percentage of clonal plasma cells in the bone marrow is between 10% and 60%. Like MGUS, SMM is asymptomatic and does not cause any end-organ damage. The risk of progression to active myeloma is substantially higher than with MGUS, especially in the first five years. SMM is often described as a biological premalignancy, sitting just before the threshold for active disease.
Active Multiple Myeloma (MM)
Active Multiple Myeloma (MM) is diagnosed when specific criteria are met, indicating the disease has become symptomatic and damaging. Active MM is defined by myeloma-related organ impairment, collectively known as the CRAB criteria:
- High Calcium levels in the blood
- Renal (kidney) dysfunction
- Anemia (low red blood cell count)
- Bone lesions (areas of bone destruction)
Even without CRAB features, active myeloma can be diagnosed if a person meets one of the Myeloma Defining Events (MDEs). These MDEs include having 60% or more clonal plasma cells in the bone marrow or a highly abnormal free light chain ratio greater than 100.
Confirming the Diagnosis
The initial abnormal free light chain result requires an extensive follow-up workup to precisely determine the stage of the plasma cell disorder. The most definitive diagnostic tool is the bone marrow aspiration and biopsy, which is considered the gold standard for confirmation. This procedure allows a physician to physically examine the bone marrow and determine the exact percentage of abnormal, clonal plasma cells present.
Skeletal imaging is also a necessary step to search for the presence of bone lesions, which would fulfill the “B” criterion of the CRAB acronym. While traditional X-rays may be used, more sensitive techniques like whole-body low-dose computed tomography (CT) or positron emission tomography-CT (PET-CT) are often utilized to detect small areas of bone destruction. The presence of even one such lesion can change the diagnosis from a precursor condition to active multiple myeloma.
Further blood and urine tests are performed to evaluate the overall impact of the abnormal protein on the body’s systems. A 24-hour urine protein electrophoresis is crucial to assess the total disease burden and check for light chains being excreted through the kidneys. Blood tests measuring creatinine and calcium levels are also performed to rule out kidney impairment and high blood calcium, which are other components of the CRAB criteria. The combination of these specialized procedures allows for the accurate differentiation between the precursor conditions and the need for immediate treatment.