The Relationship Between Serum Free Light Chain Levels and Serum Immunofixation Electrophoresis: Implications for the Definition of “Stringent CR” in Myeloma

Abstract

The serum free light chain (SFLC) assay enables detection of an abnormal protein in patients with plasma cell dyscrasias who secrete no or small quantities of monoclonal protein in the serum. Thus, the SFLC ratio may be abnormal (normal range; 0.26–1.65) in patients who have no M protein on serum immunofixation electrophoresis (SIFE). However, the relationship between the SFLC ratio and abnormal SIFE in patients who do secrete detectable M protein has not been studied.The new international response criteria for myeloma define an entity called stringent complete remission (CR) based on negative SIFE and normal SFLC ratio (with absent clonal plasmacytosis). “CR” is distinguished from “stringent CR” by lack of requirement of normal SFLC ratio in these new criteria. The old criteria did not use SFLC. The new criteria have not been validated prospectively whereas the old criteria have been used in multiple clinical trials.The obvious implication of using normalization of SFLC ratio to define “stringent CR” is that the SFLC ratio is the most sensitive indicator of residual disease. Thus, one would expect to see abnormal SFLC ratio when SIFE is normal but not vice versa. We explored the relationship between SIFE and SFLC ratio in 122 patients with secretory IgG or IgA myeloma. 2648 samples through the continuum of therapy that fulfilled the following criteria were studied: availability of concomitant SFLC and SIFE, and lack of oligoclonal bands on SIFE and UIFE.SIFE showed the original M protein in 2342 samples (88%). SFLC ratio was normal (0.26–1.65) in 1012 (38%). The abnormal ratio was concordant in 1536 and discordant in 100. SFLC ratios were considered concordant if <0.26 for lambda disease and >1.65 for kappa disease, and discordant if <0.26 for kappa disease and >1.65 for lambda disease. Discordant ratios were grouped with normal because they did not reflect an excess of the abnormal light chain associated with the original M protein. If the 95% CI values for SFLC ratio were used (0.3–1.2), 810 (31%) results were normal. With the 95% CI values, the abnormal ratio was concordant in 1702 and discordant in 136.The SFLC ratio was normal in 34% of cases with positive SIFE and abnormal in 66%. On the contrary, the SFLC ratio was normal in 69% of cases with negative SIFE and abnormal in 31%. As the table below shows, the proportion of cases with positive SIFE and normal SFLC ratio was much higher than those with an abnormal SFLC ratio and negative SIFE.SIFESFLC ratioSFLC ratioNormalAbnormalNormal or discordant abnormalConcordant abnormalPositive802 (30%)1540 (58%)874 (33%)1468 (55%)Negative210 (8%)96 (4%)238 (9%)68 (3%)SIFE is currently considered to be the standard indicator of the presence of an M protein. When evaluated against that, the sensitivity of SFLC is 66% and its specificity is 69%. The sensitivity drops to 63% but specificity improves to 77% if discordant abnormal ratios are considered normal.What if either positive SIFE or a concordant abnormal SFLC ratio were considered to indicate residual disease (2410; 91%) and a negative SIFE as well as a normal or discordant abnormal SFLC ratio were required to rule out residual M protein (238; 9%)? In this case, the sensitivity of SIFE is 97% and that of an abnormal concordant SFLC ratio 62%. The assumptions do not allow calculation of specificity.Our data indicate that a normal SFLC ratio cannot rule out the presence of residual disease as conventionally defined by a positive SIFE, and that a normal SFLC ratio is significantly more likely to be seen in the presence of a positive SIFE than is a negative SIFE in the presence of an abnormal SFLC ratio. Additional prospective work is required before SFLC estimation and ratio can be incorporated into assessment of response in myeloma, and to see if the “stringent CR” entity truly defines a more robust disease response than “non-stringent CR.”