Questionable role of free light chain assay ratio to determine stringent complete remission in multiple myeloma patients

To the editor:

We read with interest the Brief Report by Fernandez de Larrera investigating the role of abnormal serum free light chain ration in patients with complete remission.¹  The qualitative assay for free light chain has been reported to be sensitive and specific for detecting and monitoring diseases caused by monoclonal gammopathies, such as multiple myeloma.²  More recently, the International Myeloma Working Group proposed uniform response criteria including a new definition of stringent complete remission (sCR). The definition of sCR requires absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence and normalization of free light chain ratio in serum.³  More recently, the International Myeloma Working Group also published guidelines for serum free light chain analysis in multiple myeloma and related disorders.⁴  Here, it was recommended to be performed in all patients who achieved a complete remission with negative immunofixation a serum-free light chain assay to determine a “stringent CR.” However, the authors also pointed out that there were no data yet to document that a complete response, with or without a free light chain ratio criterion, is prognostic for progression-free survival or overall survival.

In a small study monitoring sequential serum-free light chain assay in 26 patients with negative immunofixation, we observed that normalization of the free light chain ratio preceded the occurrence of immunofixation negativity by approximately 3 months, which is probably due to the shorter serum half-life in comparison with intact immunoglobulin.⁵ 

Here, we evaluate the value of free light chain assay to determine sCR by monitoring 52 patients with multiple myeloma who achieved complete remission between January 2003 and December 2008 according European Group for Blood and Marrow Transplantation criteria⁶  with negative immunofixation in serum and urine for the original monoclonal myeloma protein. Free light chain measurements were performed with the commercially available Freelite Kit (Binding Site). Because of the aforementioned shorter half-life of free light chain assay ratio,⁵  patients were included only if the complete remission remained stable for at least 3 months. The comparison between immunofixation and free light chain ratio was performed at least 6 weeks after immunofixation becomes negative for the first time. The patients had intact immunoglobulin (n = 47) or light chain immunoglobulin (n = 5) at time of diagnosis. The remission status was determined either after allogeneic (n = 45) or autologous (n = 3) stem cell transplantation or after conventional bortezomib- or lenalidomide-containing chemotherapy (n = 4).

These 52 patients achieved complete remission according to the European Group for Blood and Marrow Transplantation criteria with negative immunofixation for at least 3 months. Fifty-one of 52 patients (98%) had a normal free light chain κ/λ ratio. In contrast to the study of de Larrea, none of the patient with oligoclonal bands in immunofixation (n = 13) had abnormal free light chain κ/λ ratio. However, in a subgroup of patients (n = 10) who relapsed during follow-up from complete remission sequential monitoring of immunofixation and free light assay was performed as recently described.⁵  In 9 of 10 patients a free light chain ratio became abnormal at a median of 90 days before immunofixation became positive. These results confirm that the free light chain assay ratio is, due to its shorter half-life, a useful marker for faster detection of remission or progression in myeloma patients, but these results do not support additional value of free light chain ratio to determine the depth of remission in immunofixation-negative patients. More sensitive methods such as imunophenotyping analysis by fluorescence-activated cell sorting or molecular primer should be used to determine depth of complete remission because these methods have shown relevant clinical impact.^7-9