Myeloma bone disease (MBD) is a debilitating condition, with many myeloma patients continuing to experience symptoms such as pain and immobility throughout cancer remission. Currently, there are very few bone-targeted therapies, and those that exist do not successfully support bone repair. The aim of this PhD was to characterise changes in bone health with current therapies and determine whether SD208 (a TGFβ small molecule inhibitor) in combination/sequence with zoledronic acid could optimise bone recovery. The hypothesis therefore, was that MBD has the potential to repair, and that a sequenced approach with bone anabolics (such as SD208) could improve outcomes.
A clinical study was designed to recruit myeloma patients at diagnosis and comprehensively assess bone health throughout first-line treatment. A series of in vivo experiments assessed SD208 in the prevention and repair of MBD in murine xenograft and syngeneic models. Murine bone samples were used to determine changes in the osteocyte lacuno-canalicular network in myeloma.
The clinical study demonstrated that all patients experienced at least partial repair of some osteolytic lesions. Repair was more pronounced than anticipated, likely due to patients receiving proteasome inhibitor containing treatment regimes. In vivo studies suggested proteasome inhibitors improve bone outcomes, particularly in combination with bone-targeted therapies. Sequenced SD208 followed by zoledronic acid resulted in favourable bone outcomes, in keeping with osteoporosis data. Osteocyte numbers were reduced in myeloma, with lacuna-canalicular network disruption and upregulation of peri-lacunar remodelling.
This publication-format thesis presents data across a series of manuscripts (published and draft) that demonstrate the potential of MBD to repair, and the benefit of sequenced bone-targeted treatment. Further investigation of osteocyte network changes in myeloma may expose novel drug targets. In the meantime, this thesis concludes with a draft proposal for a clinical trial to explore whether sequencing existing bone-targeted therapies could improve MBD patient outcomes.
