A new validated staging system for AL amyloidosis with stage IIIc defining an ultra-poor prognostic in systemic AL amyloidosis in the modern treatment era

Abstract Background: Systemic AL amyloidosis is an incurable disorder caused by misfolded light chain fibrils. Survival is determined by the extent of cardiac involvement and response to therapy. Mayo 2012 (stage I-IV) and European modified Mayo 2004 (stage I-IIIB) prognostic scores were developed in a historic treatment era, prior to widespread bortezomib and daratumumab use. These no longer discriminate those with the poorest outcomes. We presented a new model sub-stratifying IIIB into a high risk, ‘IIIC’ group, incorporating longitudinal strain (LS) to the European modified score (IIIC: LS >-9% + NT-proBNP >8500ng/L + high-sensitivity troponin T [hs-TnT] >50ng/L) in the bortezomib-era (2015-2019) last year (Khwaja et al, ASH 2024). Here, we present an independent external validation of the IIIC model in the modern treatment era. Methods: The ‘IIIC model’ was derived from a large real-world cohort of adults from the UK National Amyloidosis Centre (2015-2019). Performance was externally validated across Europe (Greece, Italy, Netherlands, Switzerland), USA (2015-2024) and UK (2020-2024). Survival estimates were generated from diagnosis to death or last follow-up using the Kaplan-Meier method and groups compared using Cox regression (using Stata v18). Stage IIIB and IIIC were defined as follows IIIB: LS <-9%, NT-proBNP >8500ng/L, hs-TnT >50ng/L and IIIC: LS >-9%, NT-proBNP >8500ng/L, hs-TnT >50ng/L, respectively. Stage I, II and IIIa were defined as previously described in the European modification of Mayo 2004 staging system. Results: 2493 patients were analysed from 2015-2024 (derivation, n=573; validation: Europe, n=374, USA n=458, UK, n=1088). In the derivation cohort, LS ≥-9% and standard cardiac biomarkers (NT-proBNP 332ng/L and 8500ng/L and hs-TnT>50ng/L) were selected as independent prognostic factors in a multivariable model. In the European and UK validation cohort (n=1462), median age at diagnosis was 67 years (range 35-95) with 1014 (69%) cardiac and 869 (60%) renal involvement. Median difference in involved and uninvolved free light chain (dFLC) was 181 mg/L (range 0-24933), NT-proBNP 1911ng/L (range 42-70000), hs-TnT 45ng/L (range 3-1221) and LS -14.7% (range -3- -28). In the US cohort median NT-proBNP was 1764 (range 13-71000) and hs-TnT 44 (6-687). Applying the new model staging, the patient stages were across Europe and UK were stage I: 224 (15%), II: 627 (43%), IIIA: 396 (27%), IIIB: 139 (10%) and IIIC: 76 (5%), respectively. 592 (41%) were treated with first-line daratumumab-based regimens. In the US dataset stage I: 103 (22%), II: 176 (38%), IIIA: 131 (29%), IIIB: 48 (10%) and IIIC: 16 (3%), respectively. 234 (51%) were treated with first-line daratumumab-based regimens. At a median follow-up of 30 months (95% CI 28-32) in the European and UK validation cohort, estimated median overall survival (OS) was not reached and 2-year OS was 74% (95% CI 72-77). Median survival for stages I-II, IIIA, IIIB and IIIC were not reached (NR), 67, 31 and 10 months, respectively (p<0.001). Hazard ratios for stage II, IIIA, IIIB, IIIC were 2.01 (95% CI 1.32-3.07), 3.51 (95% CI 2.31-5.35), 5.67 (95% CI 3.60-8.91) and 11.12 (95% CI 6.93-17.87), respectively (p<0.001). This was confirmed in the US cohort with a median survival for respective stages were NR, NR, NR, 8 and 2 months (p<0.001). External validation in the European and UK cohorts exhibited good predictive performance: 12-month calibration slope was 1.00 (95% CI 0.81-1.20, p=0.98), Harrel's C was 0.90 (95% CI 0.76-1.00), Royston's D 1.07, R2D 0.21 (95% CI 0.15-0.28). In 1462 patients with dataset available, stage IIIC discriminated the poorest outcome despite a greater proportion treated with first-line daratumumab v IIIB in the validation cohort (59% v 40%, p=0.008). 12-month OS for IIIC v IIIB was 44% (95% CI 32-55) v 69% (95% CI 60-76), specificity for 12-month OS 97% v 92% and diagnostic odds ratio 6.62 v 2.36. Conclusions: This study validates the new staging system from stage I-IIIC with robust identification of an ultra-poor prognostic group (Stage IIIC) in a contemporarily treated patient cohort. Despite novel therapies, the OS remains <12 month in the IIIC group and also poor in stage IIIB with median OS 31 months compared to a median of >5 years for all other stages. This staging system can be considered as a new standard of care for risk stratification of AL amyloidosis. Novel approaches are required for patients with advanced risk.