Therapeutic inhibition of myeloperoxidase with AZD5904 attenuates disease progression in mouse models of early stage and relapsed multiple myeloma.

Despite advances in therapeutic strategies for multiple myeloma (MM), long-term outcomes remain poor, largely due to inevitable relapse and acquired drug resistance. Reciprocal interactions between malignant MM plasma cells (PC) and the bone marrow microenvironment (BMME) drive disease progression, immune evasion, and therapeutic resistance, positioning the BM niche as a focus for targeted therapeutics. Myeloperoxidase (MPO) has recently emerged as a key regulator of MM progression via modification of the BMME. Here, we evaluate the efficacy of AZD5904, an orally bioavailable, irreversible MPO inhibitor, in preclinical models of MM. Initiation of MPO inhibition with AZD5904 during the early stages of MM tumor development significantly reduced tumor burden in the KaLwRij/5TGM1 and Vk*Myc murine models, however, had no effect when initiated in established disease. Furthermore, AZD5904 modulated immune responses by decreasing PD1+ T cells in vivo and restoring CD8+ T-cell cytotoxicity in vitro. While combining AZD5904 with the frontline agent bortezomib did not provide additional benefit in limiting disease progression, adjuvant AZD5904 following bortezomib treatment markedly delayed 5TGM1 tumor relapse. These findings suggest that while MPO inhibition may not enhance efficacy of bortezomib induction therapy, it holds promise as a maintenance strategy to improve long-term outcomes in MM. Collectively, our data support further investigation of AZD5904 as a novel maintenance therapy targeting the BM microenvironment, with potential to enhance and sustain the effectiveness of existing, standard of care regimens.