Multiple myeloma is a haematological cancer characterised by proliferation of clonal plasma cells in the bone marrow. Myeloma is proceeded by precursor stages known as monoclonal gammopathy of undetermined significance (MGUS) and smouldering myeloma (SMM). Up to 90% of patients with myeloma experience osteolytic bone disease with increased osteoclastic bone resorption and reduced osteoblast bone formation. MGUS and SMM patients do not have detectable osteolytic lesions. We know that complex interactions exist between the myeloma tumour cells and the resident cells of the bone marrow microenvironment particularly the mesenchymal stromal (MSC) lineage cells. Our research aims to understand the role of the bone marrow microenvironment in myeloma progression to identify new treatment targets and to discover biomarkers of disease progression.
Using in vitro assays, we have demonstrated impairments in osteogenic but not adipogenic capacity in MSCs isolated from MGUS and myeloma trephine biopsies. In addition, these MSCs display a senescent phenotype, which is associated with their ability to support myeloma cell proliferation through production of factors such as Gremlin-1. We have also identified bone microenvironment changes that are prognostic of risk of myeloma development. Increased MSC senescence and production of proliferative factors such as Gremlin-1 are associated with risk of progression to myeloma in MGUS patients. We have also investigated CTX-1 (C-terminal telopeptide 1, β-Crosslaps), a serum marker of osteoclast activity and discovered it to be a prognostic marker for risk of progression in SMM. We are currently using single cell and spatial approaches to further unravel these complex cellular interactions in the bone marrow microenvironment to discover what drives progression along with novel proteomic approaches to discover biomarkers of progression.
These projects are all undertaken with a strong involvement and engagement with consumers through the Myeloma Research Laboratory and Myeloma Australia as well as clinicians and myeloma nurses. These interactions are critical in helping shape the projects to ensure that we are addressing issues identified by consumers and clinicians. This will increase the likelihood of translation of the results and overall lead to positive impacts for those impacted by myeloma.