AbstractNewly diagnosed AL amyloidosis patients were evaluated to develop a model for early assessment of treatment benefit at 6 months, integrating both hematologic (HR) and organ response (OR) assessment (testing cohort, Mayo: n = 473; validation cohort, Pavia: n = 575). Multiple OR were assessed as follows: All OR (AOR): response in all organs, mixed OR (MOR): response in some organs, no OR (NOR)]. AOR rates at 6 months improved with deepening HR; complete response (CR; 38%, 35%), very good partial response (VGPR; 30%, 26%), and partial response (PR; 16%, 21%), respectively. A composite HR/OR (CHOR) model was developed using incremental scoring based on hazard ratios with scores of 0–3 for HR (0—CR, 1—VGPR, 2—PR, 3—no response) and 0–2 for OR (0—AOR, 1—MOR, 2—NOR). Patients could be divided into two distinct CHOR groups (scores 0–3 and 4–5), with median OS in group 1 and group 2: Not reached vs. 34 months, p < 0.001 [Mayo] and 87 vs. 23 months, p < 0.001 [Pavia]. In conclusion, we developed a model that can assess multiple organs concurrently, and integrate both HR and OR assessments to determine early clinical benefit with treatment, which may be used as a surrogate end-point in trials and to compare outcomes with different therapies.