Time to Redefine Risk-Stratification and Response Criteria in Immunoglobulin Light Chain Amyloidosis?

Immunoglobulin light chain (AL) amyloidosis results from clonal plasma cell (PC)-derived immunoglobulin light chain -mediated end-organ dysfunction, the extent and severity of which predicts survival. Anti-PC therapies reduce clonal light chain burden, which usually results in improvement of organ function, and consequently overall survival. Response assessment is critical to gauge therapeutic efficacy, to report clinical trial outcomes, and to switch therapy in those without response. Response in AL amyloidosis is 2-fold: hematologic response and organ response (OR). Depth of hematologic response is graded on the basis of serum free light chain (sFLC) parameters, but assessment of OR is binary. The role of normal sFLC ratio or complete remission as a treatment end point has been challenged, thus highlighting the need to quantify involved FLC and residual PC beyond the normal sFLC ratio to possibly account for the ongoing organ damage seen in some patients with complete remission. Mass spectrometry and urinary exosome represent ultrasensitive strategies to estimate involved FLC below the detection threshold of current sFLC assays. The role of new sFLC parameters and minimal residual disease as potential prognostic parameters has been recognized. Brain natriuretic peptide (BNP) and 24-hour proteinuria:estimated glomerular filtration rate ratio were identified to overcome certain limitations of N-terminal-Pro-BNP, 24-hour proteinuria, and estimated glomerular filtration rate for cardiac and renal response assessment, respectively. Use of monoclonal antibodies targeting PC and amyloid deposits has expanded the therapeutic armamentarium of AL amyloidosis, and given their excellent efficacy, early ORs are reported. This review provides insights into recent advances in the risk-stratification and response assessment of patients with AL amyloidosis in light of the changing therapeutic paradigms. Incorporation of these advancements into formal consensus guidelines would require further validation.