AbstractObjectivesTranslocation t(11;14) is the most common cytogenetic abnormality in patients with systemic AL amyloidosis with prognostic and therapeutic relevance, which has not been clearly defined in the most recent therapeutic era.MethodsWe assessed its prognostic role in 146 newly‐diagnosed patients who received novel agent‐based treatment combinations. Event‐free survival (EFS), a composite endpoint defined by hematological progression, start of a new treatment‐line or death, and overall survival (OS) were the primary endpoints.ResultsHalf of the patients had at least one FISH abnormality; 40% had t(11;14) which was inversely associated with other cytogenetic abnormalities. At 1, 3, and 6‐month landmarks, hematologic response rates were numerically but not statistically higher in the non‐t(11;14) group. Patients with t(11;14) were more frequently switched to second‐line treatment within 12 months (p = .015). At median follow‐up of 31.4 months, t(11;14) was associated with shorter EFS [17.1 (95% CI 3.2–10.6) vs. 27.2 months (95% CI 13.8–40.6), p = .021] and retained its prognostic significance in the multivariate model (HR:1.66, p = .029). The effect on OS was neutral, possibly due to the use of effective salvage therapies.ConclusionsOur data support the use of targeted therapies for patients with t(11;14) to avoid delays in the achievement of deep hematologic responses.