The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma

Area of Science:

• Oncology
• Pharmacology

Background:

• Multiple myeloma (MM) treatment requires targeting both cancer cells and the tumor microenvironment.
• The tumor microenvironment supports MM growth, angiogenesis, and bone disease.

Purpose of the Study:

• To investigate the therapeutic efficacy of regorafenib, an oral multikinase inhibitor, in multiple myeloma.
• To evaluate regorafenib's effects on MM cells, the tumor microenvironment, and in preclinical models.

Main Methods:

• In vitro studies using MM cell lines, co-cultures with stromal and endothelial cells.
• Assays for apoptosis, kinase phosphorylation (MEK, ERK, AKT), endothelial cell function, VEGF secretion, and osteoclastogenesis.
• In vivo studies using a xenograft mouse model of human MM.

Main Results:

• Regorafenib induced apoptosis in MM cell lines at sub-clinical concentrations.
• It overcame stromal and endothelial cell-mediated growth advantages and inhibited key signaling pathways.
• Regorafenib suppressed angiogenesis, VEGF secretion, MM cell migration, and osteoclastogenesis.
• Synergistic cytotoxicity was observed with dexamethasone, pomalidomide, and idelalisib.
• Significant delay in tumor growth was observed in a MM xenograft mouse model.

Conclusions:

• Regorafenib exhibits potent anti-myeloma activity by targeting both cancer cells and the tumor microenvironment.
• Its ability to inhibit angiogenesis, osteoclastogenesis, and key signaling pathways supports its therapeutic potential.
• Regorafenib demonstrates efficacy in preclinical models, supporting its further clinical evaluation in MM treatment, alone or in combination therapies.