AbstractWe performed an international retrospective cohort study to investigate the prognostic impact of cytogenetic abnormalities by fluorescence in situ hybridization in 283 patients with light chain (AL) amyloidosis treated with frontline daratumumab–bortezomib-cyclophosphamide-dexamethasone (Dara-VCD) or Dara-VD. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) (hereafter, +1q), hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The end points of interest were rate of hematologic complete response (heme-CR), very good partial response (VGPR) or better, and hematologic event-free survival (heme-EFS). The incidence of abnormalities was as follows: t(11;14), 53.4%; deletion (13q), 28.9%; +1q, 22.3%; hyperdiploidy, 19.4%; HR translocations, 6.6%; and deletion(17p), 4.5%. The heme-CR rate by cytogenetic subgroups were as follows: t(11;14) vs no t(11;14), 45.2% vs 41.8%; del(13q) vs no del(13q), 46.8% vs 42.8%; +1q vs no +1q, 30.2% vs 47.9%; hyperdiploidy vs no hyperdiploidy, 39.5% vs 44.9%; HR translocations vs none, 45.5% vs 43.1%; and del(17p) vs no del(17p), 50.0% vs 42.9%, respectively. Similarly, +1q was the only subgroup with a significantly lower VGPR or better rate (64.2% vs 79.0%). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months, and the 2-year overall survival (OS) was 80.98%. The presence of +1q was significantly associated with worse heme-EFS on multivariate analysis. Notably, there was no adverse prognostic impact of t(11;14) on heme-EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab era. Clinical trials testing novel frontline immunotherapies should be enriched in +1q to further improve outcomes in this subgroup.