Multiple myeloma bone disease models with integrated bone marrow adipose tissue for advancing personalized medicine

Multiple myeloma (MM) is an incurable hematological cancer of monoclonal plasma cells, where patients commonly develop osteolytic bone disease. The pathogenesis of myeloma is known to be strongly dependent on the bone marrow (BM) microenvironment, but despite this, successful therapies targeting the niche constituents are lacking. Increased body weight and obesity are associated with poor prognosis and disease outcome, making adipose tissue an important regulatory factor in myeloma. Bone marrow adipose tissue (BMAT) has been recognized as a unique adipose depot, with strong implications in MM bone disease. In this review, we discuss the development of advanced adipose tissue models, including BMAT, and their utility for the design of precise and potentially personalized myeloma therapies. Compared to other adipose models, BMAT models require a complex composition to mimic the BM niche, including BM adipocytes, extracellular matrix, immune cells, bone cells, distinct stem/progenitor cell populations plus myeloma cells. In this sense, BMAT-permissive multicellular 3D models, such as bone and BM organoids, could have significant potential to recapitulate the MM niche. Although advanced 3D models based on induced pluripotent stem cells recreate the mesenchymal–vascular–hematopoietic tissues and BM microenvironment, adult BM recapitulation is still challenging. Incorporating patient-derived cells such as myeloma cells and BM adipocytes into these models will improve the accuracy of determining drug responses, disease progression, and patient-specific therapies, particularly in relapsed and/or refractory MM. Altogether, advanced patient-derived 3D model systems provide a more reliable experimental platform for mechanistic and translational studies across the whole BM and bone ecosystem.