Ixazomib treatment has a dual effect on bone remodeling in patients with multiple myeloma: follow-up results from a phase 2 clinical study

Myeloma bone disease (MBD), a common complication in multiple myeloma (MM), causes increased risk of fractures leading to morbidity and impaired quality of life for patients. Proteasome inhibitors, a cancer-targeting therapy for MM, have been shown to have a beneficial off-target bone anabolic effect. However, side effects and toxicities of proteasome inhibitors limits their long-term use, especially in patients in disease remission. Ixazomib is an oral proteasome inhibitor with anti-myeloma effect, but a less severe toxicity profile compared to other approved proteasome inhibitors. To investigate the effect of ixazomib on MBD, we conducted a single-center clinical study where 30 patients with MM in remission received ixazomib, and evaluated bone-specific changes through serum markers, imaging, cell cultures, and bone histomorphometry. We have previously shown that short-term ixazomib treatment (3 months) induces increased trabecular bone volume and formation of enlarged bone structural units (BSU) without changing osteoblast number or activity. Here, we present evidence that long-term (24 months) ixazomib treatment inhibits the activation of new bone remodeling events through attenuation of both bone resorption and formation. The initial gains in percentage of superficial trabecular BSU bone volume remained stable and the proportion of large BSUs containing woven bone decreased, suggesting improved bone mineralization over time. Overall, our results indicate that long-term ixazomib treatment led to prolonged bone formation events during the initial treatment phase, followed by inhibition of new bone resorption and its coupled bone formation, preserving the gained bone and possibly preventing advancement of MBD in patients with MM in remission. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT04028115.