International Journal of Hematology

, Volume 106, Issue 4, pp 541–551 | Cite as

Safety and efficacy of daratumumab in Japanese patients with relapsed or refractory multiple myeloma: a multicenter, phase 1, dose-escalation study

  • Shinsuke Iida
  • Kenshi Suzuki
  • Shigeru Kusumoto
  • Masaki Ri
  • Nobuhiro Tsukada
  • Yu Abe
  • Masayuki Aoki
  • Mitsuo Inagaki
Original Article


Safety, efficacy, and pharmacokinetics (PK) of daratumumab as a monotherapy were investigated in Japanese patients with relapsed/refractory multiple myeloma (MM). This multicenter, dose-escalation study included patients (age ≥20 years) with ≥2 prior therapies. Daratumumab was administered intravenously: 8 mg/kg (n = 4) and 16 mg/kg (n = 5). The primary endpoint was safety. Secondary endpoints included objective response, overall response rate (ORR), progression-free survival (PFS), PK, and immunogenicity. Daratumumab was well-tolerated. Eight patients experienced Grade ≥3 adverse event (AE). Four serious AEs were observed in three patients; no AEs leading to death. Infusion-related reactions occurred in four (44%) patients and were Grade 1 or 2. Mean (SD) cumulative dose of daratumumab was 132.3 (108.5) mg/kg. Median duration of follow-up was 10.5 months (range 2.3, 16.4) for 8 mg/kg cohort and 9.9 months (range 1.7, 13.2) for 16 mg/kg cohort. The ORR (44%) comprised 1 and 3 partial responses in 8 and 16 mg/kg cohorts, respectively. The median PFS was 6 months for 8 mg/kg cohort, 9.5 months for 16 mg/kg cohort. Daratumumab serum exposure was increased with increasing dose. Antibodies against daratumumab were not observed. Daratumumab was safe and well-tolerated in Japanese patients with relapsed /refractory MM.


Daratumumab Efficacy Multiple myeloma Safety 


Compliance with ethical standards

Conflict of interest

M.A. and M.I. are employees of Janssen Pharmaceutical. K.S. received honoraria from Celgene and Janssen; S.I. from Celgene, Janssen, Ono Pharmaceutical, Takeda Pharmaceutical and Bristol-Myers; S.I., S.K., and M.R. received research funding from Ono Pharmaceutical, Lilly, Celgene, Janssen, Kyowa Hakko Kirin, Sanofi, Takeda Pharmaceutical, Novartis; S.I., S.K., and M.R. received subsidies or donations from Chugai Pharmaceutical, Kyowa Hakko Kirin, Teijin Pharma, Astellas, Toyama Chemical. The study was funded by Janssen Pharmaceutical. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors met the International Council of Medical Journal Editors’ criteria for authorship, and anyone who met those criteria is listed as an author. All authors have read and approved the final manuscript for submission.


  1. 1.
    Ozaki S, Handa H, Saitoh T, Murakami H, Itagaki M, Asaoku H, et al. Trends of survival in patients with multiple myeloma in Japan: a multicenter retrospective collaborative study of the Japanese Society of Myeloma. Blood Cancer J. 2015;5(9):e349.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906–17.CrossRefPubMedGoogle Scholar
  3. 3.
    Sonneveld P, Goldschmidt H, Rosiñol L, Bladé J, Lahuerta JJ, Cavo M, et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized controlled trials. J Clin Oncol. 2013;31(26):3279–87.CrossRefPubMedGoogle Scholar
  4. 4.
    Laubach JP, Voorhees PM, Hassoun H, Jakubowiak A, Lonial S, Richardson PG. Current strategies for treatment of relapsed/refractory multiple myeloma. Expert Rev Hematol. 2014;7(1):97–111.CrossRefPubMedGoogle Scholar
  5. 5.
    Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149–57.CrossRefPubMedGoogle Scholar
  6. 6.
    Iida S. Mechanisms of action and resistance for multiple myeloma novel drug treatments. Int J Hematol. 2016;104(3):271–2.CrossRefPubMedGoogle Scholar
  7. 7.
    de Weers M, Tai Y-T, van der Veer MS, Bakker JM, Vink T, Jacobs DCH, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol Baltim Md 1950. 2011;186(3):1840–8.Google Scholar
  8. 8.
    Nijhof IS, Groen RWJ, Lokhorst HM, van Kessel B, Bloem AC, van Velzen J, et al. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia. 2015;29(10):2039–49.CrossRefPubMedGoogle Scholar
  9. 9.
    Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384–94.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207–19.CrossRefPubMedGoogle Scholar
  11. 11.
    Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet Lond Engl. 2016;387(10027):1551–60.CrossRefGoogle Scholar
  12. 12.
    Research C for DE. Approved drugs—daratumumab injection [Internet]. Accessed 17 Jun 2016.
  13. 13.
    Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66.CrossRefPubMedGoogle Scholar
  14. 14.
    Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for mulitple myeloma. N Engl J Med. 2016;375:1319–31.CrossRefPubMedGoogle Scholar
  15. 15.
    Bladé J, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998;102(5):1115–23.CrossRefPubMedGoogle Scholar
  16. 16.
    Durie BGM, Harousseau J-L, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Rajkumar SV, Harousseau J-L, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008;27(13):2420–39.CrossRefPubMedGoogle Scholar
  19. 19.
    Plesner T, Arkenau HT, Gimsing P,  Krejcik J, Lemech C, Minnema MC, et al. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016;128:1821–28.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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(4):e306.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Shinsuke Iida
    • 1
  • Kenshi Suzuki
    • 2
  • Shigeru Kusumoto
    • 1
  • Masaki Ri
    • 1
  • Nobuhiro Tsukada
    • 2
  • Yu Abe
    • 2
  • Masayuki Aoki
    • 3
  • Mitsuo Inagaki
    • 3
  1. 1.Department of Hematology and OncologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
  2. 2.Department of HematologyJapanese Red Cross Medical CenterTokyoJapan
  3. 3.Janssen Pharmaceutical K.K.TokyoJapan

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