Amyloidogenic serum free light chains (sFLC) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry-based free light chain assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival and organ response rates. Serum samples were analysed using FLC-MS at diagnosis and at 6-, and 12months post-treatment. The impact of FLC-MS negativity over standard haematological responses on survival and organ response was assessed. 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC-isotype identified by FLC-MS. At 6- and 12-months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional haematological complete response (CR) at 6- and 12months, 42 (26.4%) and 64 (39%) were FLC-MS negative. At 12 months, median overall survival for CR+ + FLC-MS negative was not reached vs. 108 months in CR+FLC-MS positive (p=0.024). At 12 months, 70% of FLC-MS negative (vs. 50% FLC-MS positive) patients achieved a cardiac response (p=0.015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional haematological CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.