Daratumumab Monotherapy versus Bortezomib-Based Regimens in frail patients with Biopsy-Proven Renal AL Amyloidosis

BACKGROUND: Bortezomib-based regimens have long represented the standard option for systemic AL amyloidosis, whereas daratumumab has recently emerged as a promising alternative. We compared two consecutive single-center cohorts of frail, non-transplant-eligible patients treated with either bortezomib-based therapy or daratumumab monotherapy, assessing clinical and renal outcomes. METHODS: Thirty-one patients with renal AL amyloidosis were included: 17 received bortezomib-based regimens (historical cohort) and 14 received daratumumab monotherapy (prospective cohort). All had biopsy-confirmed renal amyloid deposition and were transplan-ineligible. Hematologic and organ responses followed International Society of Amyloidosis criteria. RESULTS: Baseline characteristics were similar between cohorts. Hematologic response rates were 57.1% with bortezomib versus 92.8% with daratumumab (p = 0.03), with complete responses in 28.6% and 57.1%, respectively. Renal response occurred in 35% of bortezomib-treated patients versus 71.4% with daratumumab (p = 0.04). Proteinuria declined by 76% in bortezomib responders and 72% in daratumumab responders, with stable creatinine in both groups. Among patients achieving dual hematologic and renal responses, 12-month survival was 100% in the daratumumab cohort versus 71% in the historical group. At last follow-up, renal survival was 67% versus 86%, and overall survival 47% versus 79% (p = 0.08). Major infections occurred in 18% and 14%, respectively. Repeat biopsies showed stabilization or regression of amyloid in 62% of daratumumab-treated versus 20% of historical cases. CONCLUSIONS: In frail, ASCT-ineligible patients with biopsy-proven renal AL amyloidosis, daratumumab monotherapy yielded higher hematologic and renal response rates compared with bortezomib-based regimens. These findings support early anti-CD38 therapy as a potential strategy to improve renal preservation and survival, warranting confirmation in multicenter trials.