Free light chain assay: doing a “good job” in Job's syndrome

In the early 2000s the assay for serum free light chain (sFLC) was developed and first published [1]. This immuno-assay provides a reliable quantitative value utilizing a reaction against specific epitopes present on the light chain, which remains occult when bound to the heavy chain, thereby identifying the presence of monoclonal protein [1,2]. The assay has been widely applied in plasma-cell disorders, mostly multiple myeloma, but has also been employed for cases with monoclonal gammopathy of unknown significance (MGUS) and amyloid light chain (AL) amyloidosis. There is a body of evidence showing its utility in the above disorders [2], which led the International Myeloma Working Group to publish guidelines relating to FLC in 2008 [2]. These guidelines defined its use as a routine test for multiple myeloma and related disorders for screening both at diagnosis and during therapy. It is now agreed that determining immunoglobulin heavy/light chain ratios improves the sensitivity of paraprotein detection and monitoring, identifies residual disease, and correlates with outcome and survival in multiple myeloma [3].

Free light chains are produced in both the bone marrow and lymph nodes, and can be identified not only on mature B-cells as plasma cells, but are also incorporated into immunoglobulin molecules during early B-cell development, where they are already expressed and readily detected on the surface of pre B-cells [4]. These observations have led to a broader application of the FLC immuno-assay in lymphoproliferative disorders, where it can even be used as a possible prognostic marker for some lymphoma subtypes [5,6], acquired immune deficiency syndrome (AIDS)-related lymphoma [7] and chronic lymphocytic leukemia (CLL) [8]. In this respect, when reading the results of the FLC assay it is probably best not only to refer to the absolute levels of each FLC type (kappa or lambda), but rather to report the ratio between them as the critical value to identify pathological and monoclonal conditions.

Recently, several studies have demonstrated that the assay may be relevant in the evaluation of non-clonal or polyclonal disorders. It is interest to note that when Pardanani et al. examined the value of FLC in patients with myeloid malignancies using two independent cohorts of patients with myelodysplastic syndromes (MDS) and primary myelofibrosis (PMF), after exclusion of those with monoclonal FLC, they were able to demonstrate that increased levels of polyclonal FLC could predict survival in these groups [9]. Dispenzieri et al. chose a different approach, analyzing the significance of the sum of kappa and lambda chains and not each light chain on its own. In the latter study involving a cohort of 15 859 people [10], they demonstrated that the total sum of FLC could in fact be used as a surrogate marker for predicting overall survival in the general population [10].

In this issue of Leukemia and Lymphoma, Manasanch et al. chose to investigate a rare orphan disease: Job's syndrome, and analyzed whether polyclonal FLC levels could predict progression to lymphoma in these patients [11]. They compared levels of sFLC in five patients with “lymphoma free” Job's syndrome and in two patients with the syndrome who developed diffuse large B-cell lymphoma (DLBCL), during the course of their disease. Patients with Job's syndrome characteristically have an inherited immunodeficiency disorder, caused by dominant mutations in signal transducer and activator of transcription 3 (STAT3) [12], and similar to other immune deficiency states, also display an increased tendency to develop lymphoproliferative disorders [7]. Although they tested only a small cohort of seven patients with this rare disorder, the investigators showed that there is a different pattern of polyclonal serum FLC associated with lymphomagenesis in these individuals. The established underlying mechanism which generates increased levels of polyclonal serum free light chain appears, in principle, to be related to chronic B-cell activation [13], as evident in the rare patients with Job's syndrome described in this study. This hypothesis explains part of the pathogenesis, perhaps representing merely the “tip of the iceberg,” and may only be applicable to conditions characterized by chronic inflammation and B-cell malignancies. In this respect there still appears to be a missing link in this interesting puzzle requiring further investigation, which, when revealed, may well improve our understanding of why elevations of sFLC occur in aging, as well as sex-related and chronic disorders such as cardiovascular disease [10].

Taking all the above into consideration, it is evident that the assay of sFLC, originating as an additional tool to identify the M-spike, will have broader applications to detect both monoclonal and polyclonal B-cell activation, in malignancy and chronic inflammatory disorders, and could even be used as a surrogate marker in the general population. In addition, it is clearly apparent that there are different ways to interpret assay results, for example reading the absolute value of free kappa or lambda chains, or recording their combined sum or their ratio, all of which seem to be equally valid. Today, it appears that the results obtained using this immuno-assay can in fact reflect the status of the host immune response. The full potential applications of this assay have yet to be fully realized.

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