Scientist Allen Institute for Immunology Seattle, Washington, United States
Introduction: Multiple Myeloma is a treatable but ultimately incurable cancer of plasma cells. Plasma cells are differentiated, antigen-experienced effector B cells that secrete antibodies and play an important role in controlling infections. Long-lived plasma cells (LLPCs) reside in the bone marrow and are the source of pathogen-specific antibodies that can be detected in circulation decades after infection. To persist in bone marrow, LLPCs are hypothesized to rely on an array of survival factors and a unique transcriptional program, which has not been fully characterized. Such a transcriptional program may be utilized by myeloma cells to enhance survival and avoid clearance by therapeutic regimens. A comprehensive assessment of the diversity of human plasma cell phenotypes and molecular features in the peripheral blood and bone marrow may enable identification of gene programs enabling plasma cell and myeloma cell longevity, which could be targeted therapeutically.
Methods: We employed mass cytometry to quantify the expression of over 350 surface proteins on human plasma cells from bone marrow, lymph node, tonsil, or peripheral blood samples collected from 21 healthy individuals. Additionally, we applied spectral flow cytometry and CITEseq to peripheral blood samples and bone marrow aspirates of individuals with newly diagnosed and post-treatment Multiple Myeloma to evaluate the phenotypic features of myeloma cells. Based on the results of these cytometry screens, we developed a plasma-cell specific CITEseq panel enabling simultaneous quantification of 150 cell surface molecules and 18000 genes. Using this workflow, we profiled bone marrow plasma cells from individuals with newly diagnosed Multiple Myeloma (n=9), individuals with relapsed myeloma (n=7) and healthy controls (n=11).
Results: Here, we observed that bone marrow plasma cells display highly diverse phenotypes across and within healthy human tissues and donors, including bone marrow. Myeloma cells largely displayed patient-specific phenotypes, but we also observed shared tumor cell signatures across individuals. Longitudinal analysis of samples before, during, and after combination VRD therapies enabled identification of unique molecular features associated with myeloma cell persistence and putative drug resistance.
Conclusions: We identified concurrence between healthy plasma and myeloma cell high-dimensional surface protein and gene expression profiles that may indicate the molecular drivers of myelomagenesis. Collectively, these results demonstrate the diversity of human plasma cells and provide insights into the induction and survival of myeloma cells.
