Study Testing 187 Samples Shows Differences in the 3 FLC
Assays Can Lead to Clinically Different Results

Multiple myeloma is the second most common hematologic malignancy and is characterized by abnormal proliferation of plasma cells and monoclonal immunoglobulins or free light chains (FLC). Plasma cells make immunoglobulins (antibodies), which are comprised of heavy and light chain proteins. There are two classes of light chains, kappa and lambda, and each plasma cell produces only one kind. Usually, plasma cells make a small excess of unbound (free) light chains that are released into the bloodstream in an approximately 1:1 ratio of κ to λ. However, if the concentration of free light chains (FLC) is higher or lower than normal, it can suggest a monoclonal gammopathy.
The monoclonal gammopathies include multiple myeloma (MM), light chain multiple myeloma (LCMM), Waldenström macroglobulinemia (WM), nonsecretory multiple myeloma (NSMM), smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), primary systemic amyloidosis (AL), and light chain deposition disease (LCDD). These conditions result in a clonal expansion of a single plasma cell, which, in turn, releases a single type of light chain, raising the light chain concentration and skewing the κ/λ ratio.
Being able to accurately measure and track the concentrations and ratio of κ and λ light chains is key for disease diagnosis and progression as well as for the determination and analysis of treatment. In response evaluation, determination of stringent complete response (sCR) is defined by complete response (negative immunofixation in serum and urine; plasma cells in the bone marrow < 5%) with normalized kappa/lambda ratio (κ/λ ratio). Historically, the only available FLC measurements assay was Freelite®, a polyclonal antibody-based agglutination assay. The International Myeloma Working Group (IMWG) has set thresholds for acceptable FLC concentrations and ratios specifically based on the Freelite assay. More recently, two new assays have been developed, one based on monoclonal antibodies and the other, similar to Freelite, based on polyclonal antibodies; two of the tests use agglutination technology, and one uses enzyme-linked immunosorbent assay (ELISA) technology.

In this study, researchers compared intraindividual results of all three assays to determine the FLC (κ, λ, and the κ/λ ratio) for 47 MM patients. They determined that, while each assay has its benefits and drawbacks and all can be used for calculating FLC, the assays are not comparable and should not be used interchangeably as that can lead to misinterpretation in response assessment and overall disease course. Moreover, the thresholds for determining the disease state, which rely on the ratio of the involved FLC (iFLC; the type of FLC present in excess) with the uninvolved FLC (uiFLC; the type of FLC present at the normal level), are not comparable between the three assays. Thus, new threshold values are proposed for each assay.

The study found:

  • Because the results of the iFLC versus uiFLC ratio thresholds were different depending on the test employed, unique thresholds should be defined for each assay. This is especially true in non-MM monoclonal gammopathies where diagnosis and treatment decisions are based solely on the iFLC/uiFLC ratio
  • Although the concordance among tests for kappa FLC was very good, that for lambda FLC was only moderate. Lambda FLC tends to form dimeric and oligomeric complexes, which may interfere with accurate measurements
  • While all three tests were shown to have benefits and drawbacks, this study showed that the three FLC assays should not be used interchangeably when determining patient treatment plan and response
  • This study was based on analysis from a single-center study with a limited number of patients, and further clinical studies are needed to confirm these thresholds in larger cohorts

At a Glance

Unique free light chain assays
Patients with MM or SMM included in the study
Samples tested using the three tests
Source: Schieferdecker, A., Hörber, S., Ums, M., Besemer, B., Bokemeyer, C., Peter, A., & Weisel, K. (2020). Comparison of three different serum-free light-chain assays—implications on diagnostic and therapeutic monitoring of multiple myeloma. Blood Cancer Journal, 10(1).