PreclinicalActivityoftheOralProteasomeInhibitorMLN9708 in Myeloma Bone Disease

Purpose: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolicandantiresorptiveeffectsinthemyelomasettingandincomparisonwithbortezomibinpreclinical models. Experimental Design:Theinvitroeffectof MLN2238wastested on osteoclastsandosteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow–disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities. Results:ClinicallyachievableconcentrationsofMLN2238markedlyinhibitedinvitroosteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-kB ligand)induced NF-kB activation, F-actin ring disruption, and diminished expression of aVb3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/b-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow–disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities). Conclusion: Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708,itisconceivablethatthisproteasomeinhibitormayachievebonebeneficialeffectsinadditionto its antimyeloma activity in patients with myeloma. Clin Cancer Res; 20(6); 1542–54. � 2014 AACR.