Genetic evidence against clonotypic B-lymphocytes as reservoir of plasma-cell cancers

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% B-cell precursors and mature B cells from MM and AL patients. Paired single-cell transcriptomes confirmed the immature phenotype of these clonotypic cells. Driver genetic alterations were primarily detected in tumor PC 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 pre-neoplastic precursors of malignant PC that are unlikely to be involved in disease progression.