Bortezomib in combination with standard-of-care for late active antibody-mediated rejection with de novo donor-specific antibodies after kidney transplantation: a multicenter randomized trial.

Bortezomib has been proposed as a treatment for antibody-mediated rejection (AMR) after kidney transplantation; however, its efficacy remains uncertain. We conducted a multicenter, randomized, open-label trial in France between February 2015 and July 2019 in adult kidney transplant recipients with late active AMR associated with de novo donor-specific antibodies (dnDSA). Sixty of the planned 100 patients were randomized 1:1 to receive standard-of-care consisting of corticosteroids, plasmapheresis, and intravenous immunoglobulin, either alone or with bortezomib administered as two cycles of four infusions. The primary endpoint was a composite of a >50% reduction in immunodominant DSA mean fluorescence intensity and stabilization or improvement of microvascular inflammation and transplant glomerulopathy on graft biopsy at 12 months. This endpoint was achieved in 40.0% of patients receiving bortezomib and 33.3% receiving standard-of-care alone in the intention-to-treat analysis (RR = 1.20, 95% CI 0.61-2.34; p = 0.59), and in 50.0% and 42.1%, respectively, in the per-protocol analysis (RR = 1.19, 95% CI 0.60-2.36; p = 0.62). Neither component differed between groups. Serious adverse events occurred in 23 patients (76.7%) receiving bortezomib and 14 patients (46.7%) receiving standard-of-care alone (p = 0.017). Adding bortezomib did not demonstrate a significant efficacy benefit and was associated with a higher incidence of serious adverse events (ClinicalTrials.gov number: NCT02201576).