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A longitudinal analysis of chromosomal abnormalities in disease progression from MGUS/SMM to newly diagnosed and relapsed multiple myeloma

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Abstract

We analyzed variations in terms of chromosomal abnormalities (CA) by fluorescence in situ hybridization (FISH) analysis on purified bone marrow plasma cells throughout the progression from monoclonal gammopathy of undetermined significance/smoldering multiple myeloma (MGUS/SMM) to newly diagnosed MM/plasma cell leukemia (NDMM/PCL) at diagnosis and from diagnostic samples to progressive disease. High risk was defined by the presence of at least del(17p), t(4;14), and/or t(14;16). 1p/1q detection (in the standard FISH panel from 2012 onward) was not available for all patients. We analyzed 139 MM/PCL diagnostic samples from 144 patients, with a median follow-up of 71 months: high-risk CA at diagnosis (MGUS/SMM or NDMM) was present in 28% of samples, whereas 37–39% showed high-risk CA at relapse. In 115 patients with NDMM who evolved to relapsed/refractory MM, we identified 3 different populations: (1) 31/115 patients (27%) with gain of new CA (del13, del17p, t(4;14), t(14;16) or 1q CA when available); (2) 10/115 (9%) patients with loss of a previously identified CA; and (3) 74 patients with no changes. The CA gain group showed a median overall survival of 66 months vs. 84 months in the third group (HR 0.56, 95% CI 0.34–0.92, p = 0.023). Clonal evolution occurs as disease progresses after different chemotherapy lines. Patients who acquired high-risk CA had the poorest prognosis. Our findings highlight the importance of performing FISH analysis both at diagnosis and at relapse.

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Data availability

After the publication of this article, data collected for this retrospective analysis and related documents will be made available to others upon reasonably justified request, which has to be written and addressed to the attention of the corresponding author Dr. Stefania Oliva at the following e-mail address: stefania.olivamolinet@gmail.com. The corresponding author Dr. Stefania Oliva is responsible to evaluate and eventually accept or refuse every request to disclose data and their related documents, in compliance with the ethical approval conditions, in compliance with applicable laws and regulations, and in conformance with the agreements in place with the involved subjects, the participating institutions, and all the other parties directly or indirectly involved in the participation, conduct, development, management, and evaluation of this analysis.

References

  1. Bolli N, Avet-Loiseau H, Wedge DC, van Loo P, Alexandrov LB, Martincorena I, Dawson KJ, Iorio F, Nik-Zainal S, Bignell GR, Hinton JW, Li Y, Tubio JMC, McLaren S, O' Meara S, Butler AP, Teague JW, Mudie L, Anderson E, Rashid N, Tai YT, Shammas MA, Sperling AS, Fulciniti M, Richardson PG, Parmigiani G, Magrangeas F, Minvielle S, Moreau P, Attal M, Facon T, Futreal PA, Anderson KC, Campbell PJ, Munshi NC (2014) Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 5:2997. https://doi.org/10.1038/ncomms3997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D, Sougnez C, Knoechel B, Gould J, Saksena G, Cibulskis K, McKenna A, Chapman MA, Straussman R, Levy J, Perkins LM, Keats JJ, Schumacher SE, Rosenberg M, Getz G, Golub TR, Anderson KC, Richardson P, Krishnan A, Lonial S, Kaufman J, Siegel DS, Vesole DH, Roy V, Rivera CE, Rajkumar SV, Kumar S, Fonseca R, Ahmann GJ, Bergsagel PL, Stewart AK, Hofmeister CC, Efebera YA, Jagannath S, Chari A, Trudel S, Reece D, Wolf J, Martin T, Zimmerman T, Rosenbaum C, Jakubowiak AJ, Lebovic D, Vij R, Stockerl-Goldstein K (2014) Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 25:91–101. https://doi.org/10.1016/J.CCR.2013.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, Proszek PZ, Johnson DC, Kaiser MF, Melchor L, Aronson LI, Scales M, Pawlyn C, Mirabella F, Jones JR, Brioli A, Mikulasova A, Cairns DA, Gregory WM, Quartilho A, Drayson MT, Russell N, Cook G, Jackson GH, Leleu X, Davies FE, Morgan GJ (2015) Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol 33:3911–3920. https://doi.org/10.1200/JCO.2014.59.1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fonseca R (2003) Many and multiple myeloma(s). Leukemia 17:1943–1944. https://doi.org/10.1038/sj.leu.2403090

  5. Fonseca R, Barlogie B, Bataille R et al (2004) Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 64:1546–1558. https://doi.org/10.1158/0008-5472.can-03-2876

  6. Morgan GJ, Walker BA, Davies FE (2012) The genetic architecture of multiple myeloma. Nat Rev Cancer 12:335–348. https://doi.org/10.1038/nrc3257

  7. Nowell PC (1976) The clonal evolution of tumor cell populations. Science (80- ) 194:23–28. https://doi.org/10.1126/science.959840

    Article  CAS  Google Scholar 

  8. Burrell RA, McGranahan N, Bartek J, Swanton C (2013) The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501:338–345. https://doi.org/10.1038/nature12625

  9. Corre J, Munshi N, Avet-Loiseau H (2015) Genetics of multiple myeloma: another heterogeneity level? Blood 125:1870–1876. https://doi.org/10.1182/blood-2014-10-567370

  10. Robiou Du Pont S, Cleynen A, Fontan C et al (2017) Genomics of multiple myeloma. J Clin Oncol 35:963–967. https://doi.org/10.1200/jco.2016.70.6705

  11. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, Morgan G, van Ness B, Chesi M, Minvielle S, Neri A, Barlogie B, Kuehl WM, Liebisch P, Davies F, Chen-Kiang S, Durie BG, Carrasco R, Sezer O, Reiman T, Pilarski L, Avet-Loiseau H, International Myeloma Working Group (2009) International myeloma working group molecular classification of multiple myeloma: spotlight review. Leukemia 23:2210–2221. https://doi.org/10.1038/leu.2009.174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR, Dispenzieri A, Fonseca R, Sher T, Kyle RA, Lin Y, Russell SJ, Kumar S, Bergsagel PL, Zeldenrust SR, Leung N, Drake MT, Kapoor P, Ansell SM, Witzig TE, Lust JA, Dalton RJ, Gertz MA, Stewart AK, Rajkumar SV, Chanan-Khan A, Lacy MQ, Mayo Clinic (2013) Management of newly diagnosed symptomatic multiple myeloma: updated Mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc 88:360–376. https://doi.org/10.1016/j.mayocp.2013.01.019

    Article  PubMed  Google Scholar 

  13. Avet-Loiseau H, Attal M, Campion L, Caillot D, Hulin C, Marit G, Stoppa AM, Voillat L, Wetterwald M, Pegourie B, Voog E, Tiab M, Banos A, Jaubert J, Bouscary D, Macro M, Kolb B, Traulle C, Mathiot C, Magrangeas F, Minvielle S, Facon T, Moreau P (2012) Long-term analysis of the ifm 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. J Clin Oncol 30:1949–1952. https://doi.org/10.1200/JCO.2011.36.5726

    Article  PubMed  Google Scholar 

  14. Zandecki M, Laï JL, Geneviève F et al (1997) Several cytogenetic subclones may be identified within plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. Blood 90:3682–3690

    Article  CAS  Google Scholar 

  15. López-Corral L, Gutiérrez NC, Vidriales MB et al (2011) The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin Cancer Res 17:1692–1700. https://doi.org/10.1158/1078-0432.CCR-10-1066

    Article  CAS  PubMed  Google Scholar 

  16. Drach J, Angerler J, Schuster J, Rothermundt C, Thalhammer R, Haas OA, Jäger U, Fiegl M, Geissler K, Ludwig H, Huber H (1995) Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance. Blood 86:3915–3921

    Article  CAS  Google Scholar 

  17. Zhao S, Choi M, Heuck C, Mane S, Barlogie B, Lifton RP, Dhodapkar MV (2014) Serial exome analysis of disease progression in premalignant gammopathies. Leukemia 28:1548–1552. https://doi.org/10.1038/leu.2014.59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF, Mirabella F, Lopez-Corral L, Humphray S, Murray L, Ross M, Bentley D, Gutiérrez NC, Garcia-Sanz R, San Miguel J, Davies FE, Gonzalez D, Morgan GJ (2014) Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 28:384–390. https://doi.org/10.1038/leu.2013.199

    Article  PubMed  Google Scholar 

  19. Mikulasova A, Wardell CP, Murison A, Boyle EM, Jackson GH, Smetana J, Kufova Z, Pour L, Sandecka V, Almasi M, Vsianska P, Gregora E, Kuglik P, Hajek R, Davies FE, Morgan GJ, Walker BA (2017) The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma. Haematologica 102:1617–1625. https://doi.org/10.3324/haematol.2017.163766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dutta AK, Fink JL, Grady JP, Morgan GJ, Mullighan CG, To LB, Hewett DR, Zannettino ACW (2019) Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability. Leukemia 33:457–468. https://doi.org/10.1038/s41375-018-0206-x

    Article  CAS  PubMed  Google Scholar 

  21. Bolli N, Maura F, Minvielle S, Gloznik D, Szalat R, Fullam A, Martincorena I, Dawson KJ, Samur MK, Zamora J, Tarpey P, Davies H, Fulciniti M, Shammas MA, Tai YT, Magrangeas F, Moreau P, Corradini P, Anderson K, Alexandrov L, Wedge DC, Avet-Loiseau H, Campbell P, Munshi N (2018) Genomic patterns of progression in smoldering multiple myeloma. Nat Commun 9:3363. https://doi.org/10.1038/s41467-018-05058-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ledergor G, Weiner A, Zada M, Wang SY, Cohen YC, Gatt ME, Snir N, Magen H, Koren-Michowitz M, Herzog-Tzarfati K, Keren-Shaul H, Bornstein C, Rotkopf R, Yofe I, David E, Yellapantula V, Kay S, Salai M, Ben Yehuda D, Nagler A, Shvidel L, Orr-Urtreger A, Halpern KB, Itzkovitz S, Landgren O, San-Miguel J, Paiva B, Keats JJ, Papaemmanuil E, Avivi I, Barbash GI, Tanay A, Amit I (2018) Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma. Nat Med 24:1867–1876. https://doi.org/10.1038/s41591-018-0269-2

    Article  CAS  PubMed  Google Scholar 

  23. Mailankody S, Kazandjian D, Korde N, Roschewski M, Manasanch E, Bhutani M, Tageja N, Kwok M, Zhang Y, Zingone A, Lamy L, Costello R, Morrison C, Hultcrantz M, Christofferson A, Washington M, Boateng M, Steinberg SM, Stetler-Stevenson M, Figg WD, Papaemmanuil E, Wilson WH, Keats JJ, Landgren O (2017) Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma. Blood Adv 1:1911–1918. https://doi.org/10.1182/bloodadvances.2017005934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gerber B, Manzoni M, Spina V, Bruscaggin A, Lionetti M, Fabris S, Barbieri M, Ciceri G, Pompa A, Forestieri G, Lerch E, Servida P, Bertoni F, Zucca E, Ghielmini M, Cortelezzi A, Cavalli F, Stussi G, Baldini L, Rossi D, Neri A (2018) Circulating tumor DNA as a liquid biopsy in plasma cell dyscrasias. Haematologica 103:e245–e248. https://doi.org/10.3324/haematol.2017.184358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Corre J, Cleynen A, Robiou du Pont S, Buisson L, Bolli N, Attal M, Munshi N, Avet-Loiseau H (2018) Multiple myeloma clonal evolution in homogeneously treated patients. Leukemia 32:2636–2647. https://doi.org/10.1038/s41375-018-0153-6

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bergsagel PL, Zhan F, Sawyer J et al (2005) Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 106:296–303. https://doi.org/10.1182/blood-2005-01-0034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hébraud B, Caillot D, Corre J et al (2013) The translocation t(4;14) can be present only in minor subclones in multiple myeloma. Clin Cancer Res 19:4634–4637. https://doi.org/10.1158/1078-0432.CCR-12-3866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank all the patients involved in this analysis, the nurses Manuela Grasso and Luca Merlone, the statistician Stefano Spada, the data manager Marco Poggiu, and Ugo Panzani from the Torino site.

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Authors and Affiliations

  1. Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, via Genova 3, 10126, Torino, Italy

    Stefania Oliva, Marina Ruggeri, Simona Caltagirone, Rossella Troia, Daniela Oddolo, Mattia D’Agostino, Milena Gilestro, Roberto Mina, Elona Saraci, Elisa Genuardi, Sara Bringhen, Mario Boccadoro & Paola Omedé

  2. Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy

    Lorenzo De Paoli & Gloria Margiotta Casaluci

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  1. Stefania Oliva
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Contributions

SO and PO conceived and designed the work that led to the submission.

All the authors acquired the data and interpreted the results.

SO drafted the first version of the manuscript.

All the authors revised the manuscript and approved the final version.

All the authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Stefania Oliva.

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Conflict of interest

SO has received honoraria from Amgen, Celgene, and Janssen and has served on the advisory boards for Adaptive Biotechnologies, Janssen, Amgen, and Takeda. MD has received honoraria for lectures from Sanofi and GSK and has served on the advisory boards for GSK. RM has received honoraria from Sanofi, Celgene, Takeda, and Janssen; has served on the advisory boards for Sanofi, Takeda, and Janssen; and has received consultancy fees from Janssen. SB has received honoraria from Celgene, Amgen, Janssen, and Bristol-Myers Squibb; has served on the advisory boards for Celgene, Amgen, Janssen, and Karyopharm; and has received consultancy fees from Janssen and Takeda. MB has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GSK; and has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma. PO has served on the advisory boards for Janssen. The other authors declare no competing financial interests.

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All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Patients gave written informed consent before bone marrow aspiration and before starting therapy.

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Oliva, S., De Paoli, L., Ruggeri, M. et al. A longitudinal analysis of chromosomal abnormalities in disease progression from MGUS/SMM to newly diagnosed and relapsed multiple myeloma. Ann Hematol 100, 437–443 (2021). https://doi.org/10.1007/s00277-020-04384-w

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