Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma

• Published in: American journal of hematology Vol. 94; no. 12; pp. 1364 - 1373
• Main Authors: Rustad, Even H., Misund, Kristine, Bernard, Elsa, Coward, Eivind, Yellapantula, Venkata D., Hultcrantz, Malin, Ho, Caleb, Kazandjian, Dickran, Korde, Neha, Mailankody, Sham, Keats, Jonathan J., Akhlaghi, Theresia, Viny, Aaron D., Mayman, David J., Carroll, Kaitlin, Patel, Minal, Famulare, Christopher A., Bruinink, Davine Hofste, Hutt, Kasey, Jacobsen, Austin, Huang, Ying, Miller, Jeffrey E., Maura, Francesco, Papaemmanuil, Elli, Waage, Anders, Arcila, Maria E., Landgren, Ola
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.12.2019; Wiley Subscription Services, Inc
• Subjects: Biomarkers, Tumor; Bone Marrow - pathology; Bone Marrow Cells - metabolism; Clinical Trials as Topic - statistics & numerical data; Clonal Evolution; Clone Cells - pathology; Complementarity Determining Regions - genetics; Complementarity-determining region 3; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Gene Rearrangement, B-Lymphocyte, Light Chain; Genes, Immunoglobulin; Heavy chains; Hematology; High-Throughput Nucleotide Sequencing; Humans; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Light Chains - genetics; Immunoglobulins; Medicin och hälsovetenskap; Minimal residual disease; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Neoplasm, Residual - diagnosis; Neoplasm, Residual - genetics; Next-generation sequencing; RNA, Messenger - genetics; RNA, Neoplasm - genetics; Somatic hypermutation; Somatic Hypermutation, Immunoglobulin; Tumor cells; VDJ Exons
• ISSN: 0361-8609; 1096-8652; 1096-8652
• DOI: 10.1002/ajh.25641

Minimal residual disease (MRD) tracking, by next generation sequencing of immunoglobulin sequences, is moving towards clinical implementation in multiple myeloma. However, there is only sparse information available to address whether clonal sequences remain stable for tracking over time, and to what extent light chain sequences are sufficiently unique for tracking. Here, we analyzed immunoglobulin repertoires from 905 plasma cell myeloma and healthy control samples, focusing on the third complementarity determining region (CDR3). Clonal heavy and/or light chain expression was identified in all patients at baseline, with one or more subclones related to the main clone in 3.2%. In 45 patients with 101 sequential samples, the dominant clonal CDR3 sequences remained identical over time, despite differential clonal evolution by whole exome sequencing in 49% of patients. The low frequency of subclonal CDR3 variants, and absence of evolution over time in active multiple myeloma, indicates that tumor cells at this stage are not under selective pressure to undergo antibody affinity maturation. Next, we establish somatic hypermutation and non‐templated insertions as the most important determinants of light chain clonal uniqueness, identifying a potentially trackable sequence in the majority of patients. Taken together, we show that dominant clonal sequences identified at baseline are reliable biomarkers for long‐term tracking of the malignant clone, including both IGH and the majority of light chain clones.