Refining amyloid complete hematological response: Quantitative serum free light chains superior to ratio

Abstract

Response assessment in light chain (AL) amyloidosis is based on serum and urine monoclonal protein studies. Newly diagnosed patients (n = 373) who achieved very good partial response or complete response (CR) to first line therapy were assessed for the survival impact of each of the monoclonal protein studies. At end of therapy (EOT), negative serum/urine immunofixation (IFE) was achieved in 61% of patients, 72% achieved normal serum free light chain ratio (sFLCR), and the median involved free light chain (iFLC) and difference between involved to uninvolved light chain (dFLC) were 17 mg/L and 5 mg/L, respectively. Overall, 46% of patients achieved a CR at EOT. At EOT, iFLC ≤20 mg/L and dFLC ≤10 mg/L were additive in survival discrimination to negative serum/urine IFE and were independent predictors of overall survival. In contrast, normalization of sFLCR did not add survival discrimination to serum/urine IFE and was not independent predictor of survival. We propose a new definition for hematological CR to include serum/urine IFE negativity plus iFLC ≤20 mg/L or dFLC ≤10 mg/L, instead of the current definition of serum/urine IFE negativity and normal sFLCR. Complete response using dFLC ≤10 mg/L had the best performance in those with significant renal dysfunction and by light chain isotype, making it the preferred partner to IFE. Validation of these results in a multicenter cohort is warranted.

Management of AL amyloidosis in 2020

“…Early and profound reductions of the amyloid LC are associated with the greatest chance of organ improvement, and prolongation of progression-free (PFS) and overall (OS) survival. [17][18][19] Changes in biomarkers can be used to assess response to therapy according to validated criteria (Table 3). 12,17,20,21 The optimal end point of therapy is still a matter of debate.…”

“…Novel definitions of deep HR are being investigated. 18,19 The relatively low sensitivity and imprecision of available FLC assays demand novel technologies, such as mass spectrometry (MS)-based detection of monoclonal components 22 and assessment of MRD 23 that await validation in AL amyloidosis.…”

Characterization and prognostic implication of delayed complete response in AL amyloidosis

“…We and others recently re‐assessed the definition of the conventional hematological CR definition 14‐16 . In these studies, both the immunofixation component of the CR definition as well as its light chain component (whether quantitative measure or the light chain ratio) were found to be important from survival standpoint 14‐16 . However, the quantitative light chain component (expressed as iFLC < 20 mg/L or dFLC < 10 mg/L) directly impacts the organ dysfunction and arguably needs to be achieved early to positively affect survival.…”

“…However, as shown in this study, CR may still not be achieved at EOT by the conventional definition, but outcome remains favorable if CR is eventually achieved in a delayed fashion. We and others recently re‐assessed the definition of the conventional hematological CR definition 14‐16 . In these studies, both the immunofixation component of the CR definition as well as its light chain component (whether quantitative measure or the light chain ratio) were found to be important from survival standpoint 14‐16 .…”

Immunoglobulin light chain amyloidosis

“…An additional serologic parameter of a very low dFLC level (<10 mg/L) for optimization of deep response assessment is being considered. Other forms of MRD measurements are assessed by new generation multiparametric flow cytometry, but are limited to highly specialized centers and are currently under investigation [39].…”