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Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma

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Abstract

Siltuximab, a chimeric monoclonal antibody with high affinity and specificity for interleukin-6, has been shown to enhance anti-multiple myeloma activity of bortezomib and corticosteroid in vitro. We evaluated the safety, pharmacokinetics, immunogenicity, and antitumor effect of siltuximab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma. This open-label, phase 1, dose-escalating study used two doses of siltuximab: 5.5 and 11.0 mg/kg (administered on day 1 of each 21-day cycle). In total, nine patients were treated. The most common grade 3/4 adverse events, lymphopenia (89 %) and thrombocytopenia (44 %), occurred in patients receiving both doses of siltuximab; however, no dose-limiting toxicities (DLTs) were observed. Following intravenous administration of siltuximab at 5.5 and 11.0 mg/kg, the maximum serum concentration and the area under the curve from 0 to 21 days and from 0 to infinity increased in an approximately dose-proportional manner. Mean half-life, total systemic clearance, and volume of distribution were similar at doses of 5.5 and 11.0 mg/kg. Across both doses, six of the nine patients had complete or partial response (22 and 44 %, respectively). In conclusion, as no DLT was observed, the recommended dose for this combination is 11.0 mg/kg once every 3 weeks. The study is registered at http://www.clinicaltrials.gov as NCT01309412.

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References

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860–73.

    Article  CAS  PubMed  Google Scholar 

  3. Palumbo A, Rajkumar SV. Treatment of newly diagnosed myeloma. Leukemia. 2009;23:449–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Voorhees PM, Manges RF, Sonneveld P, Jagannath S, Somlo G, Krishnan A, et al. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Br J Haematol. 2013;161:357–66.

    Article  CAS  PubMed  Google Scholar 

  5. Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, et al. SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J Biol Chem. 2000;275:27845–50.

    CAS  PubMed  Google Scholar 

  6. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988;332:83–5.

    Article  CAS  PubMed  Google Scholar 

  7. Klein B, Zhang XG, Lu ZY, Bataille R. Interleukin-6 in human multiple myeloma. Blood. 1995;85:863–72.

    CAS  PubMed  Google Scholar 

  8. van Rhee F, Fayad L, Voorhees P, Furman R, Lonial S, Borghaei H, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol. 2010;28:3701–8.

    Article  PubMed  Google Scholar 

  9. Wong RS, Casper C, Munshi N, et al. A multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with multicentric Castleman’s Disease. Blood. 2013;122: 505. https://ash.confex.com/ash/2013/webprogram/Paper58548.html.

  10. Kurzrock R, Voorhees PM, Casper C, Furman RR, Fayad L, Lonial S, et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 2013;19:3659–70.

    Article  CAS  PubMed  Google Scholar 

  11. Voorhees PM, Chen Q, Kuhn DJ, Small GW, Hunsucker SA, Strader JS, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res. 2007;13:6469–78.

    Article  CAS  PubMed  Google Scholar 

  12. Voorhees PM, Chen Q, Small GW, Kuhn DJ, Hunsucker SA, Nemeth JA, et al. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol. 2009;145:481–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Rowley M, Liu P, Van Ness B. Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. Blood. 2000;96:3175–80.

    CAS  PubMed  Google Scholar 

  14. Hardin J, MacLeod S, Grigorieva I, Chang R, Barlogie B, Xiao H, et al. Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood. 1994;84:3063–70.

    CAS  PubMed  Google Scholar 

  15. Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J. Interleukin-6 inhibits apoptosis of malignant plasma cells. Cell Immunol. 1995;162:248–55.

    Article  CAS  PubMed  Google Scholar 

  16. Balmanno K, Cook SJ. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 2009;16:368–77.

    Article  CAS  PubMed  Google Scholar 

  17. Angevin E, Tabernero J, Elez E, Cohen SJ, Bahleda R, van Laethem JL, et al. A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2014;20:2192–204.

    Article  CAS  PubMed  Google Scholar 

  18. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73.

    Article  CAS  PubMed  Google Scholar 

  19. Blade 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;102:1115–23.

    Article  CAS  PubMed  Google Scholar 

  20. Shah JJ, Orlowski RZ. Proteasome inhibitors in the treatment of multiple myeloma. Leukemia. 2009;23:1964–79.

    Article  CAS  PubMed  Google Scholar 

  21. Liu T, Fei Z, Gangavarapu KJ, Agbenowu S, Bhushan A, Lai JC, et al. Interleukin-6 and JAK2/STAT3 signaling mediate the reversion of dexamethasone resistance after dexamethasone withdrawal in 7TD1 multiple myeloma cells. Leuk Res. 2013;37:1322–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Fulciniti M, Hideshima T, Vermot-Desroches C, et al. A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res. 2009;15:7144–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Orlowski RZ, Gercheva L, Williams C, Sutherland HJ, Robak T, Masszi T, et al. Phase II, randomized, double blind, placebo-controlled study comparing siltuximab plus bortezomib versus bortezomib alone in pts with relapsed/refractory multiple myeloma. ASCO Meeting Abstracts. 2012;30: 8018. http://meetinglibrary.asco.org/content/96732-114.

  24. El-Osta HE, Kurzrock R. Castleman’s disease: from basic mechanisms to molecular therapeutics. Oncologist. 2011;16:497–511.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank all the patients who participated in this study and their families, the investigators, the nursing staff and study support staff from their sites, Niigata Cancer Center Hospital led by Dr. Takaaki Chou, and the employees of Janssen who contributed to the design and implementation of this study. They would also like to thank Dr. Kiyohiko Hatake of Cancer Institute Hospital for his contribution as an independent expert and Hisaya Otani of the clinical pharmacology department, Janssen Pharmaceutical K.K., who contributed to PK and immunogenicity analyses. Editorial support was sponsored by Janssen and provided by Veejaye Sinha, PharmD, of AlphaBioCom, King of Prussia, PA, USA, and Miyuki Ueda of Janssen Pharmaceutical K.K.

Conflict of interest

Janssen Pharmaceutical K.K. supported this study and supplied the investigational drugs. K. Suzuki, T. Suzuki, K. Anso, D. Maruyama, M. Kojima, M. Ogura, J. Kuroda, and Y. Abe have no conflicts of interest to disclose. M. Taniwaki has received grants from Janssen Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Celgene, and Kyowa Hakko Krin Co., Ltd. M. Achira and K. Iizuka are employees of Janssen Pharmaceutical K.K., Tokyo, Japan. H. Otani was an employee of Janssen Pharmaceutical K.K.M. Ogura was at Nagoya Daini Red Cross Hospital during the study conduct, and is now affiliated with Fujita Health University and Tohoku University as well as Nagoya Daini Red Cross Hospital. K. Iizuka was at Janssen Pharmaceutical K.K. during the study conduct, and is now affiliated with Janssen Diagnostics Inc., Raritan, NJ, USA.

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Authors and Affiliations

  1. Department of Hematology, Japanese Red Cross Medical Center, Hiroo 4-1-22 Shibuya-ku, Tokyo, 1508935, Japan

    Kenshi Suzuki & Yu Abe

  2. Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan

    Michinori Ogura & Tatsuya Suzuki

  3. Department of Hematology, National Cancer Center Hospital, Tokyo, Japan

    Kensei Tobinai & Dai Maruyama

  4. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan

    Kiyoshi Ando & Minoru Kojima

  5. Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Masafumi Taniwaki & Junya Kuroda

  6. Clinical Pharmacology Department, Quantitative Science Division, Research and Development, Janssen Pharmaceutical K.K., Tokyo, Japan

    Meguru Achira

  7. Oncology Department, Clinical Science Division, Research and Development, Janssen Pharmaceutical K.K., Tokyo, Japan

    Koho Iizuka

Authors
  1. Kenshi Suzuki
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  2. Michinori Ogura
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  3. Yu Abe
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  4. Tatsuya Suzuki
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  5. Kensei Tobinai
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  7. Masafumi Taniwaki
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  8. Dai Maruyama
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  9. Minoru Kojima
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  10. Junya Kuroda
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  11. Meguru Achira
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  12. Koho Iizuka
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Corresponding author

Correspondence to Kenshi Suzuki.

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Suzuki, K., Ogura, M., Abe, Y. et al. Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma. Int J Hematol 101, 286–294 (2015). https://doi.org/10.1007/s12185-015-1743-y

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  • DOI: https://doi.org/10.1007/s12185-015-1743-y

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