Genetic Evidence against Clonotypic B Lymphocytes as a Reservoir for Plasma Cell Cancers

Abstract Whether multiple myeloma (MM) and light-chain amyloidosis (AL) stem from terminally differentiated plasma cells (PC) or earlier clonotypic B cells remains under debate. Addressing this issue would improve accurate diagnosis and treatment monitoring. We performed single-cell and exome sequencing on highly purified MM and AL samples to define in which B-cell development stage the driver genetic alterations are present. Clonotypic B-cell receptors (BCR) were detected in ≤0.4% of B-cell precursors and mature B cells from patients with MM and AL. Paired single-cell transcriptomes confirmed the immature phenotype of these clonotypic cells. Driver genetic alterations were primarily detected in tumor PCs but very rarely in immature B-cell stages sequenced during treatment. Additional analysis suggested that clonotypic B cells may sporadically result in false-positive minimal residual disease assessments based on next-generation sequencing of BCR. Our results define clonotypic B cells as preneoplastic precursors of malignant PCs that are unlikely to be involved in disease progression. Significance: The cellular origin of MM and light-chain AL remains unknown. Here, we show that these tumors stem from clonotypic B cells, but driver genetic alterations are mainly contained within phenotypically aberrant PCs. These results shed light on the pathogenesis and inform on how to monitor PC neoplasms. See related article by Kim and Ghobrial, p. XX.