Skeletal health in the precursor stages of multiple myeloma: fracture risk and bone phenotypes in monoclonal gammopathy of undetermined significance and smouldering myeloma

Multiple myeloma (MM) is a haematological malignancy characterised by clonal plasma cell proliferation principally in the bone marrow. Up to 80% of individuals with MM experience osteolytic bone disease, characterised by an increased risk of pathological fractures and significant bone pain impacting quality of life. MM is preceded by monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM), both of which are usually asymptomatic. Although patients with these precursor conditions do not present with detectable osteolytic bone disease and generally are not commenced on any treatment, there is evidence to suggest an altered skeletal phenotype. Multiple studies have revealed that MGUS patients have an increased risk of fractures, particularly vertebral fractures, associated with a reduced bone mineral density. Ubiquitous changes to bone parameters throughout the skeleton are nevertheless uncommon in MGUS and SMM, with local changes often attributed to plasma cell proximity. Histomorphometric analyses have revealed a distinct bone resorption phenotype in patients with progressing MGUS and SMM compared with those who remain stable, supporting the concept that increased osteoclastic activity precedes disease progression. Therapeutics to reduce bone fracture risk, such as bisphosphonates, are not commonly administered during the MGUS or SMM stages, and there are currently no clinical evidence-based practice or standard-of-care guidelines for monitoring skeletal health. While it is clear that patients with rapidly progressing MGUS and SMM possess a unique bone remodelling phenotype not seen in stable disease, further studies are required to fully characterise the bone histomorphometric changes in these precursor conditions and align them with current diagnostic criteria, to better inform specific bone cell changes that underlie these phenotypes. It is therefore important to consider this skeletal phenotype in the precursor disease stages, particularly the consequences of an increased fracture risk, as well as the skeletal phenotype associated with progression.