Tremblay S, Driscoll JJ, Rike-Shields A, et al. - Researchers here examined the safety, toxicity, and preliminary efficacy of carfilzomib, a second-generation proteasome inhibitor, in highly HLA-sensitized kidney transplant candidates. Escalating doses of carfilzomib were provided to renal transplant candidates followed by plasmapheresis (group A) or an identical regimen with additional plasmapheresis once weekly before carfilzomib dosing. Carfilzomib was administered to 13 participants and was well tolerated with most adverse events classified as low grade. carfilzomib alone led to substantial reduction in HLA antibodies; median maximal immunodominant antibody reduction was 72.8% (69.8% for group A, P = .031, 80.1% for group B). The rebound occurred rapidly and antibody levels returned to baseline between days 81 and 141 following depletion. In bone marrow studies, depletion of nearly 69.2% of plasma cells was observed following carfilzomib monotherapy. These findings suggest that with an acceptable safety and toxicity profile, carfilzomib monotherapy–based desensitization leads to significant bone marrow plasma cell depletion and anti-HLA antibody reduction.