Multiple Myeloma (MM) is the second most commonly diagnosed haematological malignancy. The disease is characterised by neoplastic expansion of plasma cells in the bone marrow (BM). Despite continuous medical advancements, a cure remains elusive and relapse is common even after complete remission. Accumulating evidence indicates that survival of malignant plasma cells is influenced by the BM microenvironment. However, the mechanisms that regulate these interactions are not understood. Here, we developed a novel model of myeloma that allows imaging of specific clonal populations in situ using confetti protein tagging. We coupled direct visualisation of myeloma cell behaviour in situ using intravital imaging of BM with molecular profiling using HiDE and Seq (Hi-resolution Imaging of the Direct Environment with scRNA-Seq). We paired analysis of isolated myeloma cells with interrogation of the stromal microenvironment using both sequencing and imaging based spatial transcriptomic approaches performed on sequential tissue sections with clone separation facilitated by confocal imaging.
Our analysis revealed that the BM microenvironment drives clonal selection of pathogenic plasma cells. Furthermore, plasma cell clones have unique cellular behaviour in BM that drives the disease phenotype. In addition, these MM clones expressed unique transcriptional profiles associated with microenvironment dependency. These effects culminate in BM microenvironment remodelling that occurred in a clonal manner leading to changes in specific stroma even when clones were in close proximity. Thus, these results suggest the BM niche could regulate drivers of disease progression and therapy resistance, offering insights for the development of new treatment strategies.