Hematologic response criteria in light chain (AL) amyloidosis require the difference in involved and uninvolved free light chains (dFLC) to be at least 5 mg/dl. We describe the clinical presentation and outcomes of newly diagnosed amyloidosis patients with dFLC o5 mg/dl (non-evaluable dFLC; 14%, n = 165) compared with patients with dFLC ≥5 mg/dl (evaluable dFLC; 86%, n = 975). Patients with non-evaluable dFLC had less cardiac involvement (40% vs 80%, P<0.001), less liver involvement (11% vs 17%, P = 0.04) and a trend toward less gastrointestinal involvement (18% vs 25%, P = 0.08). However, significantly higher renal involvement (72% vs 56%, P = 0.0002) was observed in the non-evaluable dFLC cohort. Differences in treatment patterns were observed, with 51% of treated patients undergoing upfront stem cell transplantation in the non-evaluable cohort compared with 28% in the evaluable dFLC group (P<0.001). Progression-free survival (61 vs 13 months, P<0.001) and overall survival (OS; 101 vs 29 months, P<0.001) were significantly longer in the non-evaluable dFLC cohort. Normalization of involved light chain levels and decrease in dFLC o1 mg/dl (baseline at least 2 mg/dl) were predictive of OS and associated with better dialysis-free survival and may be used for response assessment in patients with non-evaluable FLC levels.