International Journal of Hematology

, Volume 108, Issue 6, pp 580–587 | Cite as

Clinical significance of cancer-related fatigue in multiple myeloma patients

  • Kazuhito SuzukiEmail author
  • Nobuyuki Kobayashi
  • Yoji Ogasawara
  • Takaki Shimada
  • Yuichi Yahagi
  • Katsuki Sugiyama
  • Shinobu Takahara
  • Takeshi Saito
  • Jiro Minami
  • Hiroki Yokoyama
  • Yutaro Kamiyama
  • Atsushi Katsube
  • Kazuhiro Kondo
  • Hiroyuki Yanagisawa
  • Keisuke Aiba
  • Shingo Yano
Original Article


Cancer-related fatigue (CRF) is one of the adverse events in multiple myeloma (MM) patients treated with cytotoxic agents, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs) such as bortezomib, lenalidomide, and thalidomide. The aims of our study were to prospectively analyze the clinical significance of CRF, and to evaluate the cumulative incidence of CRF and the survival rates of 16 MM patients who were treated with PIs and IMiDs. Reactivation of salivary human herpes virus (HHV)-6 and HHV-7 was analyzed using real-time quantitative polymerase chain reaction (qPCR). CRF was evaluated using a visual analog scale (VAS). Eleven newly diagnosed multiple myeloma (NDMM) and five relapsed or refractory MM patients were enrolled in this study. The cumulative incidence of CRF was 54.9%. The treatment types were not associated with the CRF incidence. The cumulative incidence of reactivation of HHV-6 and HHV-7 was 73.1% and 45.6%, respectively. However, the reactivation of HHV-6 and HHV-7 was not related to CRF. The overall survival (OS) and progression-free survival (PFS) in NDMM patients with CRF was significantly shorter than in those without CRF. In conclusion, CRF was one of the major symptoms in MM patients, and predicted shorter OS and PFS in NDMM patients.


Multiple myeloma Fatigue Human herpes virus-6 



We thank our attending doctors, dedicated fellows, and nurses at the Jikei University School of Medicine. In addition, we appreciate laboratory technicians of Department of Virology. And we offer special thanks to our MM patients and their families.

Compliance with ethical standards

Conflict of interest

K.K. has submitted a patent application entitled “Methods for Assessing Fatigue Level and Applications Thereof” US patent application publication 2008/0280283 A1. K.K. has stock in Virus Ikagaku Kenkyusho Inc. This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Supported Program for the Strategic Research Foundation at Private Universities (Grant number S1201032); Virus Ikagaku Kenkyusho Inc. The other authors indicated no potential conflicts of interest.


  1. 1.
    Saligan LN, Olson K, Filler K, Larkin D, Cramp F, Yennurajalingam S, et al. The biology of cancer-related fatigue: a review of the literature. Support Care Cancer. 2015;23:2461–78.CrossRefGoogle Scholar
  2. 2.
    Brown RD, Pope B, Murray A, Esdale W, Sze DM, Gibson J, et al. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7–1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10. Blood. 2001;98:2992–8.CrossRefGoogle Scholar
  3. 3.
    MillsKH CawleyJC. Abnormal monoclonalantibody-defined helper/ suppressor T-cell subpopulations in multiple myeloma: relationship to treatment and clinical stage. Br J Haematol. 1983;53:271–5.CrossRefGoogle Scholar
  4. 4.
    Ogawara H, Handa H, Yamazaki T, Toda T, Yoshida K, Nishimoto N, et al. High Th1/Th2 ratio in patients with multiple myeloma. Leuk Res. 2005;29:135–40.CrossRefGoogle Scholar
  5. 5.
    Dosani T, Carlsten M, Maric I, Landgren O. The cellular immune system in myelomagenesis: NK cells and T cells in the development of MM and their uses in immunotherapies. Blood Cancer J. 2015;5:e306.CrossRefGoogle Scholar
  6. 6.
    Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621–9.CrossRefGoogle Scholar
  7. 7.
    Zerr DM, Corey L, Kim HW, Huang ML, Nguy L, Boeckh M. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis. 2005;40:932–40.CrossRefGoogle Scholar
  8. 8.
    Ogata M, Kikuchi H, Satou T, Kawano R, Ikewaki J, Kohno K, et al. Human herpesvirus 6 DNA in plasma after allogeneic stem cell transplantation: incidence and clinical significance. J Infect Dis. 2006;193:68–79.CrossRefGoogle Scholar
  9. 9.
    Wang LR, Dong LJ, Zhang MJ, Lu DP. The impact of human herpesvirus 6B reactivation on early complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006;12:1031–7.CrossRefGoogle Scholar
  10. 10.
    Zerr DM. Human herpesvirus 6 (HHV-6) disease in the setting of transplantation. Curr Opin Infect Dis. 2012;25:438–44.CrossRefGoogle Scholar
  11. 11.
    Aoki R, Kobayashi N, Suzuki G, Kuratsune H, Shimada K, Oka N, et al. Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue. Biochem Biophys Res Commun. 2016;478:424–30.CrossRefGoogle Scholar
  12. 12.
    Blesch KS, Paice JA, Wickham R, Harte N, Schnoor DK, Purl S, et al. Correlates of fatigue in people with breast or lung cancer. Oncol Nurs Forum. 1991;18:81–7.PubMedGoogle Scholar
  13. 13.
    Gift AG. Visual analogue scales: Measurement of subjective phenomena. Nurs Res. 1989;38:286–8.CrossRefGoogle Scholar
  14. 14.
    Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412–20.CrossRefGoogle Scholar
  15. 15.
    The International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749–57.CrossRefGoogle Scholar
  16. 16.
    Gautheret-Dejean A, Manichanh C, Thien-Ah-Koon F, Fillet AM, Mangeney N, Vidaud M, et al. Development of a real-time polymerase chain reaction assay for the diagnosis of human herpesvirus-6 infection and application to bone marrow transplant patients. J Virol Methods. 2002;100:27–35.CrossRefGoogle Scholar
  17. 17.
    Hara S, Kimura H, Hoshino Y, Tanaka N, Nishikawa K, Ihira M, et al. Detection of herpesvirus DNA in the serum of immunocompetent children. Microbiol Immunol. 2002;46:177–80.CrossRefGoogle Scholar
  18. 18.
    Kanda Y. Investigation of the freely-available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefGoogle Scholar
  19. 19.
    Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21–33.CrossRefGoogle Scholar
  20. 20.
    Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Standtmauer EA, et al. Long-term follow-up on overall survival from MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23:2147–52.CrossRefGoogle Scholar
  21. 21.
    Paiva CE, Paiva BS. Prevalence, predictors, and prognostic impact of fatigue among Brazilian outpatients with advanced cancers. Support Care Cancer. 2013;21:1053–60.CrossRefGoogle Scholar
  22. 22.
    Orre IJ, Murison R, Dahl AA, Ueland T, Aukrust P, Fosså SD. Levels of circulating interleukin-1 receptor antagonist and C-reactive protein in long-term survivors of testicular cancer with chronic cancer-related fatigue. Brain Behav Immun. 2009;23:868–74.CrossRefGoogle Scholar
  23. 23.
    de Raaf PJ, Sleijfer S, Lamers CH, Jager A, Gratama JW, van der Rijt CC. Inflammation and fatigue dimensions in advanced cancer patients and cancer survivors: an explorative study. Cancer. 2012;118:6005–11.CrossRefGoogle Scholar
  24. 24.
    Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clinic Proc. 1975;50:29–40.Google Scholar
  25. 25.
    Riccardi A, Gobbi PG, Ucci G, Bertoloni D, Luoni R, Rutiqliano L, et al. Changing clinical presentation of multiple myeloma. Eur J Cancer. 1991;27:1401–5.CrossRefGoogle Scholar
  26. 26.
    Musto P, Falcone A, D’Arena G, Scalzulli PR, Matera R, Minevini MM, et al. Clinical recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokine and monitoring of erythropoiesis. Eur J Haematol. 1997;58:314–9.CrossRefGoogle Scholar
  27. 27.
    Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585–98.CrossRefGoogle Scholar
  28. 28.
    Okuyama T, Akechi T, Kugaya A, Okamura H, Imoto S, Nakano T, et al. Factors correlated with fatigue in disease-free breast cancer patients: application of the Cancer Fatigue Scale. Support Care Cancer. 2000;8:215–222.CrossRefGoogle Scholar
  29. 29.
    Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer. 1999;85:1186–96.CrossRefGoogle Scholar
  30. 30.
    Fagundes CP, Glaser R, Alfano CM, Bennett JM, Povoski SP, Lipari AM, et al. Fatigue and herpesvirus latency in women newly diagnosed with breast cancer. Brain Behav Immunol. 2012;26:394–400.CrossRefGoogle Scholar
  31. 31.
    Nefzi F, Ben Salem NA, Khelif A, Feki S, Aouni M, Gautheret-Dejean A. Quantitative analysis of human herpesvirus-6 and human cytomegalovirus in blood and saliva from patients with acute leukemia. J Med Virol. 2014;87:451–60.CrossRefGoogle Scholar
  32. 32.
    Gautheret-Dejean A, Aubin JT, Poirel L, Nicolas JC, Rozenbaum W, Agut H. Detection of human Betaherpesvirinae in saliva and urine from immunocompromised and immunocompetent subjects. J Clin Microbiol. 1997;35:1600–3.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Nucci M, Anaisseie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis. 2009;49:1211–25.CrossRefGoogle Scholar
  34. 34.
    San Miguel JF, Sclag R, Khuageva NK, Dimopoulos MA, Shpiberg O, Kropff M, et al. Bortezomib plus melphalan and predonisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–17.CrossRefGoogle Scholar
  35. 35.
    Chanan-Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26:4784–90.CrossRefGoogle Scholar
  36. 36.
    Blanco B, Pérez-Simón JA, Sánchez-Abarca LI, Carvajal-Vergara X, Mateos J, Vidriales B, et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood. 2006;107:3575–83.CrossRefGoogle Scholar
  37. 37.
    Ljungman P, Dahl H, Xu YH, Larsson K, Brytting M, Linde A. Effectiveness of ganciclovir against human herpesvirus-6 excreted in saliva in stem cell transplant recipients. Bone Marrow Transplant. 2007;39:497–9.CrossRefGoogle Scholar
  38. 38.
    Ogata M, Satou T, Kadota J, Saito N, Yoshida T, Okumura H, et al. Human Herpesvirus 6 (HHV-6) Reactivation and HHV-6 Encephalopalitis After Allogeneic Hematopoietic Cell Transplantation: A Multicenter, Prospective Study. Clin Infect Dis. 2013;57:671–81.CrossRefGoogle Scholar
  39. 39.
    Ogata M, Satou T, Kawano R, Yoshikawa T, Ikewaki J, Kohno K, et al. High Incidence of Cytomegalovirus, Human Herpesvirus-6, and Epstein-Barr Virus Reactivation in Patients Receiving Cytotoxic Chemotherapy for Adult T Cell Leukemia. J Med Virol. 2011;83:702–9.CrossRefGoogle Scholar
  40. 40.
    Montoya JG, Kogelnik AM, Bhangoo M, Lunn MR, Flamand L, Merrihew LE, et al. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013;85:2101–9.CrossRefGoogle Scholar
  41. 41.
    Catania G, Bell C, Ottonelli S, Marchetti M, Bryce J, Grossi A, et al. Cancer-related fatigue in Italian cancer patients: validation of the Italian version of the Brief Fatigue Inventory (BFI). Support Care Cancer. 2013;21:413–9.CrossRefGoogle Scholar
  42. 42.
    Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76.CrossRefGoogle Scholar
  43. 43.
    Cocks K, Cohen D, Wisløff F, Sezer O, Lee S, Hippe E, et al. An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. Eur J Cancer. 2007;43:1670–8.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Kazuhito Suzuki
    • 1
    Email author
  • Nobuyuki Kobayashi
    • 2
  • Yoji Ogasawara
    • 3
  • Takaki Shimada
    • 1
  • Yuichi Yahagi
    • 1
  • Katsuki Sugiyama
    • 1
  • Shinobu Takahara
    • 1
  • Takeshi Saito
    • 1
  • Jiro Minami
    • 1
  • Hiroki Yokoyama
    • 1
  • Yutaro Kamiyama
    • 1
  • Atsushi Katsube
    • 1
  • Kazuhiro Kondo
    • 2
  • Hiroyuki Yanagisawa
    • 4
  • Keisuke Aiba
    • 1
  • Shingo Yano
    • 1
  1. 1.Department of Clinical Oncology/HematologyThe Jikei University School of MedicineTokyoJapan
  2. 2.Department of VirologyThe Jikei University School of MedicineTokyoJapan
  3. 3.Central Clinical LaboratoryThe Jikei University HospitalTokyoJapan
  4. 4.Department of Public Health and Enviromental MedicineThe Jikei University School of MedicineTokyoJapan

Personalised recommendations