Single Cell Clonotypic and Transcriptional Evolution of Multiple Myeloma Precursor Disease

Abstract

Multiple myeloma remains an incurable disease and the cellular and molecular evolution of multiple myeloma from precursor disease including monoclonal gammopathy of undetermined significance and smoldering multiple myeloma is incompletely understood. Here, we combined single cell RNA- and B-cell receptor-sequencing in fifty-two patients with myeloma precursors in comparison with myeloma and normal donors. We comprehensively characterized the early genomic drivers of malignant transformation, distinct transcriptional features and divergent clonal expansion in hyperdiploid compared to non-hyperdiploid samples, intra-patient heterogeneity with potential therapeutic implications as well as the distinct evolution patterns from myeloma precursor disease to myeloma. In addition, we describe the unique adaptations of the microenvironment as a response to distinct genomic changes in myeloma cells. These results add to our knowledge about myeloma precursor disease evolution and may inform individual patient progression risk stratification and biomarker identification that could be clinically exploited.

Funding Information: This work was supported in part by The MD Anderson Cancer Center Support Grant (P30 CA016672), Core Grant CA016672 (ATGC) and NIH 1S10OD024977-01 award to the Advanced Technology Genomics Core Facility, the Leukemia and Lymphoma Society Specialized Center of Research (SCOR-12206-17), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Paula and Rodger Riney Foundation’s Riney Family Multiple Myeloma Research Fund at MD Anderson, and the University of Texas MD Anderson Moon Shot Program.

Declaration of Interests: M. Dang reports no conflicts of interest; G. Han reports no conflicts of interest; H. Lee has received consulting fees from Adaptive Biotechnologies, Celgene, Pimera and Takeda and research support from Amgen, Daiichi Sankyo, Janssen and Takeda; K. Patel reports no conflicts of interest; S. Thomas reports no conflicts of interest; D. Hao reports no conflicts of interest; M. Becnel reports no conflicts of interest; D. Weber reports no conflicts of interest; P. Lin reports no conflicts of interest; Z. Berkova reports no conflicts of interest; D. Berrios reports no conflicts of interest; L. Feng reports no conflicts of interest; X. Song reports no conflicts of interest; J. Zhang reports no conflicts of interest; A. Futreal reports no conflicts of interest; Y. Moreno reports no conflicts of interest; D. Symer reports no conflicts of interest;M. Green reports no conflicts of interest; C. Rojas reports no conflicts of interest; M. Kroll reports no conflicts of interest; V. Afshar-Khargan reports no conflicts of interest; L. Ndacayisaba reports no conflicts of interest; P. Kuhn reports no conflicts of interest; S. Neelapu has received research support from Kite/Gilead, Celgene, Cellectis, Poseida, Merck,; Acerta, Karus, and BMS; served as consultant and advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, CellMedica, and Merck; R Orlowski has received consulting fees from Amgen, Inc., Bristol-Myers Squibb, Celgene, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Karyopharm Therapeutics, Molecular Partners, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Sanofi-Aventis, Servier, and Takeda Pharmaceuticals North America, Inc. Clinical research support has come from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc., while laboratory research support has come from Asylia Therapeutics, Inc., BioTheryX, and Heidelberg Pharma; L. Wang reports no conflicts of interest; E. Manasanch has received research support from Sanofi, Quest Diagnostics, Novartis, JW Pharma, Merck, GSK; consultant fees from Takeda, Celgene, Sanofi, Seattle Genetics, BMS, GSK.

Ethics Approval Statement: Approved by the MD Anderson Cancer Center Institutional Review Board (Appendix 1). All the patients and healthy donors signed an informed consent in accordance with the Declaration of Helsinki protocol. All the patients and healthy donors signed an informed consent in accordance with the Declaration of Helsinki protocol.

Keywords: single-cell RNA sequencing (scRNAseq), multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), single-cell B cell receptor sequencing (scBCR-seq), plasma cells (PCs), intra-tumoral heterogeneity (ITH), tumor microenvironment (TME), hyperdiploid (HY), non-hyperdiploid (non-HY)