*Purpose: Ixazomib is a second-generation oral proteasome inhibitor, FDA approved for the treatment of refractory multiple myeloma. The purpose of the study was (1) to examine the safety and efficacy of ixazomib and (2) to address the role of HLA and non-HLA antibodies, T and B cell phenotypes, and circulating cytokines in immune monitoring of sensitized kidney transplant candidates.

*Methods: IXADES (IXAzomib for DESensitization) was a pilot exploratory, proof of concept, open-label, single-center phase II clinical trial (NCT03213158) in which highly sensitized (cPRA > 80%) kidney transplant candidates, active on the waitlist for > 24 months were treated with 12 monthly cycles of Ixazomib 3 mg + dexamethasone 20 mg.

*Results: Ten subjects were enrolled in the trial. Of these, 6 completed the study: 2 subjects were lost to follow-up, 1 subject became ineligible for transplantation due to frailty, and 1 subject was removed by the investigator because of substance abuse. Overall, the study drug was well tolerated with 0 grade 4, 3 grade 3, 11 grade 2, and 43 grade 1 adverse events, which were primarily infections (5), paresthesia (3), nausea/vomiting/diarrhea (5). No significant change in CBC or left ventricular ejection fraction was noted. Ancillary studies demonstrated a statistically significant decline in circulating BAFF, TRAIL, CD3+ and CD4+ T cells, and mature (CD3-CD19+CD20+CD27+CD38-) and memory (CD3-CD19+CD20+CD27+CD38-) B cells, combined with a reduction of bone marrow lymphocytes. While most subjects demonstrated a statistically significant decline in circulating HLA class I and II antibodies, the decline was not consistent across all specificities. Surprisingly, HLA-A, DR, and DQ antibodies increased in 2 subjects. There was no significant change in AT1-R and ETA-R circulating antibodies, bone marrow plasma cells, plasmablasts, or B cells. Interestingly, significant positive correlations were observed between bone marrow TRAIL expression and bone marrow B cells and plasmablasts. Positive correlations were also observed between bone marrow Blimp-1+ cells and circulating memory cells. Negative correlations were observed between bone marrow Blimp-1+ cells and bone marrow B cells.

*Conclusions: Ixazomib alone or in combination with other immunosuppressive agents may offer a simple, safe, and effective approach to desensitization strategies in kidney transplantation.

« Back to 2022 American Transplant Congress