A Phase 2 trial of daratumumab monotherapy in newly diagnosed patients with cardiac stage IIIb AL amyloidosis.

Treatment options for patients with immunoglobulin light chain (AL) amyloidosis and advanced cardiac involvement remain limited. The prospective, phase 2 EMN22 trial included previously untreated patients with AL amyloidosis, measurable hematologic disease, and Mayo2004/European cardiac stage IIIB to receive daratumumab monotherapy at the standard dose and schedule for up to two years (28-day cycles); patients with inadequate response after three cycles could additionally receive bortezomib weekly and dexamethasone. The primary endpoint was 6-month overall survival (OS) rate. Of 40 enrolled patients, ten (25.0%) received additional treatment with bortezomib and dexamethasone. The 6-month OS rate was 65.0% (95% CI, 48.2-77.6) and median OS was 10.4 months. The best hematologic response rate (partial response or better) up to six months was 75.0% (very good partial response or better: 47.5%; complete response: 12.5%), the median time to the first and best hematologic response being one week and 2.3 months, respectively. The cardiac response rate at six months was 30.0%. Common serious adverse events were cardiac failure (25.0%), sudden cardiac death (10.0%), and acute kidney injury (7.5%). The patients' quality of life remained stable throughout the trial treatment and observation. In patients with high-risk, advanced (stage IIIB) AL amyloidosis, daratumumab monotherapy was feasible and well-tolerated, achieving rapid hematologic responses and associated with prolonged survival relative to historical cohorts. Cardiac response rates at 6 months were significant, considering the advanced cardiac disease. These findings support daratumumab as the backbone of anti-clonal therapy in advanced cardiac AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT04131309.