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 iFLC and dFLC were 17 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. CR 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 required. This article is protected by copyright. All rights reserved.