Multiple myeloma is a B-cell malignancy caused by expansion of plasma cells in the bone marrow. Tumour growth promotes bone resorption and suppresses formation, which leads to development of osteolytic bone lesions, pain, fracture and spinal cord compression. Chemotherapies target the proliferating tumour, however a small population of dormant cells resist treatment and reactivate years later, mediating disease relapse. The development of new drugs that target both dormant and proliferating cells is critical to improve patient outcome. Cabozantinib (Cabo) is a tyrosine kinase inhibitor with activity against cancers that metastasize to bone, including thyroid and breast. However, little is known about the activity of Cabo in myeloma and whether Cabo can target dormant cells. Here, we investigate the activity of Cabo against 5TGM1 myeloma cells in vitro and its effects on dormant and proliferating myeloma cells in vivo.
In vitro, Cabo suppressed proliferation of 5TGM1 myeloma cells in a dose dependent manner (p<0.0001) and induced apoptosis (p<0.0005). In vivo, Cabo treatment (60mg/kg, oral gavage, 5 days/week) beginning 7 days after tumor cell injection reduced myeloma burden in non-osseous sites including spleen and spinal cord (p<0.05, p<0.01, respectively). In contrast, burden was increased in the femur and vertebrae (p<0.005, p<0.0005, respectively). Consistent with this, flow cytometric analysis of myeloma cells labeled with the membrane dye DiD, that labels dormant cells, demonstrated a decrease in DiDhi dormant tumour cells (p<0.05), which is consistent with their activation. Despite increased myeloma burden, Cabo treatment increased cortical and trabecular bone volume (p=0.0005, p=0.0005, respectively). Furthermore, Cabo-treated mice showed no clinical symptoms at endpoint (day 25), while >70% of controls exhibited hind limb paralysis.
These data indicate that Cabo has a differential effect on the myeloma burden in different organs. In the skeleton Cabo can reduce dormant cells and increase tumor burden whilst increasing bone volume.