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The risk of infections in multiple myeloma before and after the advent of novel agents: a 12-year survey

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Abstract

Infections represent a major cause of morbidity and mortality in multiple myeloma and are linked to both therapy- and disease-related factors. Although it has been suggested that the rate of infections increased since the introduction of novel agents, controversies still exist. To better assess the risk factors associated with infections in the era of novel agents, we conducted a large retrospective analysis of 479 myeloma patients treated at Jena University Hospital over a period of 12 years. During their disease history, 65% of patients developed at least one infection, and 37% of therapies were associated with at least one infectious episode. The rate of infections was constant over the years, with no increase in infectious complications after the routine implementation of novel agents. Infections were mainly bacterial and strongly associated with high disease burden, relapsed disease, and treatment with high-dose chemotherapy. Varicella zoster virus (VZV) reactivations occurred late during treatment (median time between high-dose chemotherapy and VZV reactivation 6 months, range 0–44 months), and fewer patients developed a VZV reactivation after 2009 (p = 0.001). Infections are still one of the major causes of morbidity in myeloma patients, and prophylactic measures are urgently needed to reduce this potentially lethal complication.

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References

  1. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111:2516–2520. https://doi.org/10.1182/blood-2007-10-116129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, Kapoor P, Dingli D, Hayman SR, Leung N, Lust J, McCurdy A, Russell SJ, Zeldenrust SR, Kyle RA, Rajkumar SV (2014) Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 28:1122–1128. https://doi.org/10.1038/leu.2013.313

    Article  CAS  PubMed  Google Scholar 

  3. Cavo M, Zamagni E, Tosi P et al (2005) Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 106:35–39. https://doi.org/10.1182/blood-2005-02-0522

    Article  CAS  PubMed  Google Scholar 

  4. Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PRE, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA, for the National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group (2012) Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC myeloma IX randomized trial results. Haematologica 97:442–450. https://doi.org/10.3324/haematol.2011.043372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M, GIMEMA Italian Myeloma Network (2010) Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 376:2075–2085. https://doi.org/10.1016/S0140-6736(10)61424-9

    Article  CAS  PubMed  Google Scholar 

  6. Sonneveld P, Schmidt-Wolf IGH, van der Holt B, el Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GMJ, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM (2012) Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol Off J Am Soc Clin Oncol 30:2946–2955. https://doi.org/10.1200/JCO.2011.39.6820

    Article  CAS  Google Scholar 

  7. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD, Multiple Myeloma (009) Study Investigators (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142. https://doi.org/10.1056/NEJMoa070596

    Article  CAS  PubMed  Google Scholar 

  8. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD, Multiple Myeloma (010) Study Investigators (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123–2132. https://doi.org/10.1056/NEJMoa070594

    Article  CAS  PubMed  Google Scholar 

  9. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR, Eastern Cooperative Oncology Group (2010) Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11:29–37. https://doi.org/10.1016/S1470-2045(09)70284-0

    Article  CAS  PubMed  Google Scholar 

  10. San Miguel J, Weisel K, Moreau P et al (2013) Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol 14:1055–1066. https://doi.org/10.1016/S1470-2045(13)70380-2

    Article  CAS  Google Scholar 

  11. Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ, ENDEAVOR Investigators (2016) Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol 17:27–38. https://doi.org/10.1016/S1470-2045(15)00464-7

    Article  CAS  PubMed  Google Scholar 

  12. Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, di Bacco A, Hui AM, van de Velde H, Richardson PG, TOURMALINE-MM1 Study Group (2016) Oral Ixazomib, Lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 374:1621–1634. https://doi.org/10.1056/NEJMoa1516282

    Article  CAS  PubMed  Google Scholar 

  13. Brioli A, Mügge L-O, Hochhaus A, Von Lilienfeld-Toal M (2017) Safety issues and management of toxicities associated with new treatments for multiple myeloma. Expert Rev Hematol 10:193–205. https://doi.org/10.1080/17474086.2017.1284584

    Article  CAS  PubMed  Google Scholar 

  14. Augustson BM, Begum G, Dunn JA, Barth NJ, Davies F, Morgan G, Behrens J, Smith A, Child JA, Drayson MT (2005) Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United Kingdom Medical Research Council trials between 1980 and 2002--Medical Research Council adult Leukaemia working party. J Clin Oncol Off J Am Soc Clin Oncol 23:9219–9226. https://doi.org/10.1200/JCO.2005.03.2086

    Article  Google Scholar 

  15. Blimark C, Holmberg E, Mellqvist U-H, Landgren O, Bjorkholm M, Hultcrantz M, Kjellander C, Turesson I, Kristinsson SY (2015) Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica 100:107–113. https://doi.org/10.3324/haematol.2014.107714

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chanan-Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Neuwirth R, Anderson KC, Richardson PG (2008) Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol Off J Am Soc Clin Oncol 26:4784–4790. https://doi.org/10.1200/JCO.2007.14.9641

    Article  CAS  Google Scholar 

  17. Teh BW, Harrison SJ, Worth LJ, Spelman T, Thursky KA, Slavin MA (2015) Risks, severity and timing of infections in patients with multiple myeloma: a longitudinal cohort study in the era of immunomodulatory drug therapy. Br J Haematol 171:100–108. https://doi.org/10.1111/bjh.13532

    Article  CAS  PubMed  Google Scholar 

  18. Rajkumar SV, Harousseau J-L, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade J, Richardson P, Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, Palumbo A, Zonder J, Ludwig H, Vesole D, Sezer O, Munshi NC, San Miguel J, on behalf of the International Myeloma Workshop Consensus Panel 1 (2011) Consensus recommendations for the uniform reporting of clinical trials: report of the international myeloma workshop consensus panel 1. Blood 117:4691–4695. https://doi.org/10.1182/blood-2010-10-299487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nucci M, Anaissie E (2009) Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis Off Publ Infect Dis Soc Am 49:1211–1225. https://doi.org/10.1086/605664

    Article  CAS  Google Scholar 

  20. König C, Kleber M, Reinhardt H, Knop S, Wäsch R, Engelhardt M (2014) Incidence, risk factors, and implemented prophylaxis of varicella zoster virus infection, including complicated varicella zoster virus and herpes simplex virus infections, in lenalidomide-treated multiple myeloma patients. Ann Hematol 93:479–484. https://doi.org/10.1007/s00277-013-1951-6

    Article  CAS  PubMed  Google Scholar 

  21. Sørrig R, Klausen TW, Salomo M, Vangsted A, Gimsing P (2018) Risk factors for blood stream infections in multiple myeloma: a population-based study of 1154 patients in Denmark. Eur J Haematol 101:21–27. https://doi.org/10.1111/ejh.13066

    Article  PubMed  Google Scholar 

  22. Sandherr M, Hentrich M, von Lilienfeld-Toal M, Massenkeil G, Neumann S, Penack O, Biehl L, Cornely OA (2015) Antiviral prophylaxis in patients with solid tumours and haematological malignancies--update of the guidelines of the infectious diseases working party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). Ann Hematol 94:1441–1450. https://doi.org/10.1007/s00277-015-2447-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

AB is a fellow of the Else-Kröner Forschungskolleg Antiage Jena, supported by funding from the Foundation “Else Kröner-Fresenius-Stiftung”; MvLT is supported by the German Federal Ministry of Education and Health (BMBF) Germany (InfectoGnostic Research Campus, (13GW0096D)); AS is supported by the Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), at the Jena University Hospital funded by the BMBF (01EO1502). AS also received funding by BMBF grant 01ZZ1803C.

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Author notes

  1. Annamaria Brioli and Maximilian Klaus contributed equally to this work.

Authors and Affiliations

  1. Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany

    Annamaria Brioli, Maximilian Klaus, Sebastian Scholl, Thomas Ernst, Inken Hilgendorf, Olaposi Yomade, Kristina Schilling, Andreas Hochhaus & Marie von Lilienfeld-Toal

  2. Research Program “Else Kröner-Forschungskolleg AntiAge”, Universitätsklinikum Jena, Jena, Germany

    Annamaria Brioli

  3. HELIOS Klinikum, 4. Medizinische Klinik, Abt. Hämatologie und internistische Onkologie, Hämostaseologie, Erfurt, Germany

    Herbert Sayer

  4. Integriertes Forschungs-und Behandlungszentrum (IFB) Sepsis und Sepsisfolgen, Center for Sepsis Control and Care (CSCC), Universitätsklinikum Jena, Jena, Germany

    André Scherag

  5. Institut für Medizinische Statistik, Informatik und Datenwissenschaften, Universitätsklinikum Jena, Jena, Germany

    André Scherag

  6. Heinrich-Braun-Klinikum, Klinik für Innere Medizin III, Abt. Hämatologie, Onkologie und palliative Medizin, Zwickau, Germany

    Lars-Olof Mügge

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  1. Annamaria Brioli
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Contributions

AB performed analysis and wrote the paper, MK collected data and performed analysis, AS performed analysis, MvLT designed the research and wrote the paper, SS, IH, TE, HS, OY, KS, LOM, AH provided patients data and important intellectual input. All authors reviewed and gave the final approval to the paper.

Corresponding author

Correspondence to Marie von Lilienfeld-Toal.

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Ethical approval and informed consent

The present study was conducted after approval by the institutional review board at Jena University Hospital in Germany. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. As data analyzed were pseudonimized data normally collected during clinical practice, the responsible ethic committee was of the opinion that no extra informed consent was needed for the present research.

Conflict of interest

AB: Honoraria: Celgene, Takeda, Travel support: Janssen, Celgene, Takeda, Research support: Celgene; IH: Research support: Medac, Novartis, Travel support: Medac, Novartis, Gilead; LOM: Research support: Celgene, Honoraria: Celgene, Janssen, Novartis, Amgen, Bristol Myers Squibb; MvLT: Honoraria: Janssen, Celgene, Novartis, Takeda, Travel support: Janssen, Celgene, Novartis, Takeda, Research support: Janssen, Celgene, Novartis, Takeda; the other authors have no relevant conflict of interest to disclose.

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Brioli, A., Klaus, M., Sayer, H. et al. The risk of infections in multiple myeloma before and after the advent of novel agents: a 12-year survey. Ann Hematol 98, 713–722 (2019). https://doi.org/10.1007/s00277-019-03621-1

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