Increased Bone Volume by Ixazomib in Multiple Myeloma: 3-Month Results from an Open Label Phase 2 Study

Abstract

Multiple myeloma (MM) is an incurable bone marrow cancer characterized by the development of osteolytic lesions due to the myeloma-induced increase in osteoclastogenesis and decrease in osteoblastic activity. The standard treatment of MM often involves proteasome inhibitors (PIs), which can also have a beneficial off-target bone anabolic effect. However, long-term treatment with PIs is unadvised due to their high side-effect burden and inconvenient route of administration. Ixazomib is a new-generation, oral PI that is generally well tolerated; however, its bone effect remains unknown. Here, we describe the 3-month results of a single-center phase II clinical trial investigating the effect of ixazomib treatment on bone formation and bone microstructure. Thirty patients with MM in stable disease not receiving antimyeloma treatment for ≥3 months and presenting ≥2 osteolytic lesions received monthly ixazomib treatment cycles. Serum and plasma samples were collected at baseline and monthly thereafter. Sodium 18 F-Fluoride positron emission tomography (NaF-PET) whole-body scans and trephine iliac crest bone biopsies were collected before and after three treatment cycles. The serum levels of bone remodeling biomarkers suggested an early ixazomib-induced decrease in bone resorption. NaF-PET scans indicated unchanged bone formation ratios; however, histological analyses of bone biopsies revealed a significant increase in bone volume per total volume after treatment. Further analyses of bone biopsies showed unchanged osteoclast number and COLL1A1 High -expressing osteoblasts on bone surfaces. Next, we analyzed the superficial bone structural units (BSUs), which represent each recent microscopic bone remodeling event. Osteopontin staining revealed that following treatment, significantly more BSUs were enlarged (>200,000 μm 2 ), and the distribution frequency of their shape was significantly different from baseline. Overall, our data suggest that ixazomib induces overflow remodeling-based bone formation by decreasing the level of bone resorption and promoting longer bone formation events, making it a potentially valuable candidate for future maintenance treatment.

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

“…The effect of ixazomib on myeloma bone disease is currently being investigated in a clinical trial on patients with MM in remission (clinaltrials.gov NCT04028115, accessed on 1 November 2023). Recently published preliminary results from this trial [136] revealed a drug-mediated increase in trabecular bone volume mediated by decreased osteoclast activity and longer bone formation events in bone biopsies taken after just 3 months of treatment [136]. Daratumumab, a CD38 antibody that is extensively used to treat MM, has also demonstrated positive effects on bone formation.…”

Ixazomib-Thalidomide-Dexamethasone Induction Followed by Ixazomib or Placebo Maintenance in Nontransplant Eligible Newly Diagnosed Multiple Myeloma Patients: Long-term Results of HOVON-126/NMSG 21.13

“…Third, it can be hypothesized that continuous ixazomib treatment has influenced the bone marrow microenvironment by inhibiting osteoclasts while maintaining/stimulating the proliferation of osteoblasts. [8][9][10] Notably, osteoblasts are known to trigger apoptosis and cell cycle arrest in plasma cells. 11 Whether the indirect effects of ixazomib, through its impact on osteoblasts, contribute to the improvement in OS remains to be substantiated; and the fact why such an impact would be less in subsequent lines of therapy, as PIs were more often used in patients not having received ixazomib maintenance in first line.…”