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Circulating cell-free DNA in the peripheral blood plasma of patients is an informative biomarker for multiple myeloma relapse

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Abstract

Background

Multiple myeloma (MM) is an incurable hematological malignancy. Despite the introduction of several novel drugs, most patients relapse. Biomarkers to identify the early signs of relapse will make it possible to adjust the therapeutic strategy before the disease worsens. Although understanding genetic changes is important for the treatment of MM, currently known biomarkers of relapse, including serum free-light chains and monoclonal paraproteins, are not associated with genetic changes.

Methods

We therefore performed a multicenter study to examine the usefulness of circulating cell-free DNA (cfDNA) present in the peripheral blood (PB) plasma of patients as a biomarker for MM relapse.

Results

We identified several driver mutations by combined analysis of next-generation sequencing and existing databases of candidate oncogenes. Furthermore, relapse was detected more sensitively by monitoring the circulating cfDNA with these driver mutations than by conventional serum free-light chain examination.

Conclusion

These results suggest the potential utility of cfDNA in the PB plasma of patients as a relevant early biomarker for MM relapse.

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References

  1. Kumar SK, Rajkumar V, Kyle RA et al (2017) Multiple myeloma. Nat Rev Dis Primers 3:17046. https://doi.org/10.1038/nrdp.2017.46

    Article  PubMed  Google Scholar 

  2. Kumar SK, Rajkumar SV, Dispenzieri A et al (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111(5):2516–2520. https://doi.org/10.1182/blood-2007-10-116129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Imai Y, Hirano M, Kobayashi M et al (2019) HDAC inhibitors exert anti-myeloma effects through multiple modes of action. Cancers (Basel). https://doi.org/10.3390/cancers11040475

    Article  Google Scholar 

  4. Gulla A, Anderson KC (2020) Multiple myeloma: the (r)evolution of current therapy and a glance into future. Haematologica. https://doi.org/10.3324/haematol.2020.247015

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yasui H, Ishida T, Maruyama R et al (2012) Model of translational cancer research in multiple myeloma. Cancer Sci 103(11):1907–1912. https://doi.org/10.1111/j.1349-7006.2012.02384.x

    Article  CAS  PubMed  Google Scholar 

  6. Hirano M, Imai Y, Kaito Y et al (2021) Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma. J Exp Clin Cancer Res 40(1):110. https://doi.org/10.1186/s13046-021-01909-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rasche L, Chavan SS, Stephens OW et al (2017) Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun 8(1):268. https://doi.org/10.1038/s41467-017-00296-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kumar S, Paiva B, Anderson KC et al (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17(8):e328–e346. https://doi.org/10.1016/S1470-2045(16)30206-6

    Article  PubMed  Google Scholar 

  9. Bolli N, Biancon G, Moarii M et al (2018) Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia 32(12):2604–2616. https://doi.org/10.1038/s41375-018-0037-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Maura F, Bolli N, Angelopoulos N et al (2019) Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nat Commun 10(1):3835. https://doi.org/10.1038/s41467-019-11680-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kubaczkova V, Vrabel D, Sedlarikova L et al (2017) Cell-free DNA - Minimally invasive marker of hematological malignancies. Eur J Haematol 99(4):291–299. https://doi.org/10.1111/ejh.12925

    Article  CAS  PubMed  Google Scholar 

  12. Alix-Panabieres C, Pantel K (2016) Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov 6(5):479–491. https://doi.org/10.1158/2159-8290.CD-15-1483

    Article  CAS  PubMed  Google Scholar 

  13. Kis O, Kaedbey R, Chow S et al (2017) Circulating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates. Nat Commun 8:15086. https://doi.org/10.1038/ncomms15086

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kortüm KM, Mai EK, Hanafiah NH et al (2016) Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood 128(9):1226–1233. https://doi.org/10.1182/blood-2016-02-698092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakamura S, Yokoyama K, Shimizu E et al (2019) Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS. Blood 133(25):2682–2695. https://doi.org/10.1182/blood-2018-10-880690

    Article  CAS  PubMed  Google Scholar 

  16. Xu J, Pfarr N, Endris V et al (2017) Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation. Oncogenesis 6(5):e337. https://doi.org/10.1038/oncsis.2017.36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ding L, Getz G, Wheeler DA et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216):1069–1075. https://doi.org/10.1038/nature07423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zehir A, Benayed R, Shah RH et al (2017) Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23(6):703–713. https://doi.org/10.1038/nm.4333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dufva O, Kankainen M, Kelkka T et al (2018) Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target. Nat Commun 9(1):1567. https://doi.org/10.1038/s41467-018-03987-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Papaemmanuil E, Gerstung M, Bullinger L et al (2016) Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374(23):2209–2221. https://doi.org/10.1056/NEJMoa1516192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Walker BA, Boyle EM, Wardell CP et al (2015) Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol 33(33):3911–3920. https://doi.org/10.1200/JCO.2014.59.1503

    Article  CAS  PubMed  Google Scholar 

  22. Mithraprabhu S, Khong T, Ramachandran M et al (2017) Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma. Leukemia 31(8):1695–1705. https://doi.org/10.1038/leu.2016.366

    Article  CAS  PubMed  Google Scholar 

  23. Oberle A, Brandt A, Voigtlaender M et al (2017) Monitoring multiple myeloma by next-generation sequencing of V(D)J rearrangements from circulating myeloma cells and cell-free myeloma DNA. Haematologica 102(6):1105–1111. https://doi.org/10.3324/haematol.2016.161414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rustad EH, Coward E, Skytoen ER et al (2017) Monitoring multiple myeloma by quantification of recurrent mutations in serum. Haematologica 102(7):1266–1272. https://doi.org/10.3324/haematol.2016.160564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mithraprabhu S, Morley R, Khong T et al (2019) Monitoring tumour burden and therapeutic response through analysis of circulating tumour DNA and extracellular RNA in multiple myeloma patients. Leukemia 33(8):2022–2033. https://doi.org/10.1038/s41375-019-0469-x

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are very grateful to the patients for their cooperation. This work was partially funded by Celgene Corporation, A Bristol Myers Squibb Company. We would like to thank Editage (www.editage.com) for English language editing. This work was partially funded by Celgene Corporation(Y.I.) and The Japanese Society of Hematology Research Grant(Y.I.).

Author information

Author notes

  1. Hiroshi Yasui and Masayuki Kobayashi contributed equally to this study as first authors

Authors and Affiliations

  1. Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Hiroshi Yasui, Toyotaka Kawamata, Junya Makiyama, Kazuaki Yokoyama, Arinobu Tojo & Yoichi Imai

  2. Division of Molecular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Masayuki Kobayashi, Kanya Kondoh & Arinobu Tojo

  3. Department of Hematology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan

    Masayuki Kobayashi

  4. Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan

    Kota Sato & Tadao Ishida

  5. Department of Hematology, Nippon Medical School, Tokyo, Japan

    Yuta Kaito & Hideto Tamura

  6. Division of Diabetes, Endocrinology and Hematology, Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Mibu, Japan

    Hideto Tamura

  7. Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Japan

    Hiroshi Handa

  8. Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan

    Yutaka Tsukune, Makoto Sasaki & Norio Komatsu

  9. Department of Hematology, Tokyo Women’s Medical University, Tokyo, Japan

    Norina Tanaka & Junji Tanaka

  10. Department of Hematology, Saitama Medical Center, Saitama Medical University, Saitama, Japan

    Masahiro Kizaki

  11. Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Seiya Imoto

Authors
  1. Hiroshi Yasui
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Contributions

Conceptualization: YI; Methodology: YI, MK, KY, SI, AT; Investigation: YI, MK, KK, KY, HY; Resources: TI, KS, HT, HH, YT, MS, NT, JT, MK, TK, JM, KY, HY, AT, YI; Writing—original draft preparation, HY, YI, MK; Writing—review and editing, HY, YI, MK, MK; funding acquisition, YI. All authors have read and approved to the final manuscript.

Corresponding author

Correspondence to Yoichi Imai.

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Conflict of interest

Yoichi Imai received research funding from Celgene Corp., Bristol Myers Squibb K.K.; Hideto Tamura from Celgene Corp., Janssen Pharma K.K., Bristol-Myers Squibb K.K.; Junji Tanaka from Bristol-Myers Squibb K.K. Yoichi Imai received lecture fees from Celgene Corp., Bristol Myers Squibb K.K.; Tadao Ishida from Celgene Corp., Janssen Pharma K.K.; Hideto Tamura from Celgene Corp., Janssen Pharma K.K.; Hiroshi Handa from Celgene Corp., Janssen Pharma KK., Bristol-Myers Squibb K.K.; Junji Tanaka from Janssen Pharma K.K., Bristol-Myers Squibb K.K.; Masahiro Kizaki from Celgene Co., Bristol-Myers Squibb K.K., Janssen Pharma K.K..

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Yasui, H., Kobayashi, M., Sato, K. et al. Circulating cell-free DNA in the peripheral blood plasma of patients is an informative biomarker for multiple myeloma relapse. Int J Clin Oncol 26, 2142–2150 (2021). https://doi.org/10.1007/s10147-021-01991-z

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  • DOI: https://doi.org/10.1007/s10147-021-01991-z

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