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


Authors: Rustad, E. H.; Misund, K.; Bernard, E.; Coward, E.; Yellapantula, V. D.; Hultcrantz, M.; Ho, C.; Kazandjian, D.; Korde, N.; Mailankody, S.; Keats, J. J.; Akhlaghi, T.; Viny, A. D.; Mayman, D. J.; Carroll, K.; Patel, M.; Famulare, C. A.; op Bruinink, D. H.; Hutt, K.; Jacobsen, A.; Huang, Y.; Miller, J. E.; Maura, F.; Papaemmanuil, E.; Waage, A.; Arcila, M. E.; Landgren, O.
Article Title: Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma
Abstract: 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. © 2019 Wiley Periodicals, Inc.
Keywords: clinical article; controlled study; biological marker; multiple myeloma; somatic hypermutation; immunoglobulin heavy chain; minimal residual disease; tumor cell; immunoglobulin light chain; antibody affinity; clonal evolution; complementarity determining region; next generation sequencing; human; priority journal; article; whole exome sequencing
Journal Title: American Journal of Hematology
Volume: 94
Issue: 12
ISSN: 0361-8609
Publisher: John Wiley & Sons, Inc.  
Date Published: 2019-12-01
Start Page: 1364
End Page: 1373
Language: English
DOI: 10.1002/ajh.25641
PUBMED: 31571261
PROVIDER: scopus
DOI/URL:
Notes: Source: Scopus
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MSK Authors
  1. Maria Eugenia Arcila
    431 Arcila
  2. Minal A Patel
    44 Patel
  3. Carl Ola Landgren
    236 Landgren
  4. Aaron David Viny
    30 Viny
  5. Neha Sanat Korde
    73 Korde
  6. Caleb   Ho
    38 Ho
  7. Even Holth Rustad
    12 Rustad
  8. Francesco Maura
    8 Maura