Changes in serum-free light chain rather than intact monoclonal immunoglobulin levels predicts outcome following therapy in primary amyloidosis

Abstract

Current response criteria for light-chain amyloidosis (AL) relegate FLC response to a subsidiary status relative to serum M-protein response. Given that light chains form the substrate for amyloid fibril formation, we hypothesized that changes in FLC might better predict outcome compared to changes in intact immunoglobulin levels. Two patient cohorts were studied, 347 patients who underwent an autologous stem-cell transplant (SCT) and 96 patients treated with melphalan/dexamethasone. We identified the lowest value following therapy for intact serum M-protein and the difference between involved and uninvolved FLC (FLC-diff). We first examined the relative contribution of M-protein and FLC-diff on the overall survival (OS), and found that FLC reduction, rather than M-protein reduction, significantly impacted OS. The median OS was not reached among those with a 50% decrease in FLC-diff compared to 20 months for the remainder. On regression analysis, a 90% reduction in FLC-diff following SCT best predicted being alive at 3 or 5 years. The median OS among those with a 90% decrease was not reached compared to 37.4 months for the rest P < 0.001. The current study supports the notion that FLC response is a more useful measure of hematological response than M-protein response. It also highlights the importance of achieving at least a 90% reduction in the FLC-diff to improve the outcome of patients with light-chain AL.

Figure 1

Panel A shows the relationship between a 50% decrease in the FLC-diff and the overall survival (OS) from transplant among patients who survived at least 100 days posttransplant and who had a baseline FLC-diff > = 10 mg/dL. The median OS from SCT was not reached among those with a 50% decrease in FLC-diff (n = 120) compared to 20 months (95% CI; 3, 22) for the remaining patients (n = 5). Panel B shows the relationship between a 90% decrease in the FLC-diff and the OS from transplant among patients who survived at least 100 days posttransplant and who had a baseline FLC-diff > = 10 mg/dL. The median OS among those with a 90% decrease in FLC-diff (n = 77) was not reached compared to 37.4 months (95% CI; 32, 58) for the remaining patients (n = 48), P < 0.001. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Panel A shows the relationship between a 50% decrease in the FLC-diff and the overall survival (OS) from start of therapy among patients who received at least three cycles of therapy with melphalan and dexamethasone and who had a baseline FLC-diff > = 10 mg/dL. The median OS was not reached for those with > = 50% decrease in FLC-diff compared to 12.2 months (95% CI; 3, 49) for the rest, P < 0.001. Panel B shows relationship between a 90% decrease in the FLC-diff and the OS from start of therapy among patients who received at least three cycles of therapy with melphalan and dexamethasone and who had a baseline FLC-diff > = 10 mg/dL. The median OS for those attaining a 90% decrease in FLC-diff was not reached compared to 15.3 months (95% CI; 11, 49) for the remaining patients, P < 0.001. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]