Indatuximab ravtansine (BT062) combination treatment in multiple myeloma: pre-clinical studies
© The Author(s). 2017
Received: 26 November 2016
Accepted: 26 December 2016
Published: 11 January 2017
Indatuximab ravtansine is a monoclonal antibody-linked cytotoxic agent that specifically targets CD138-expressing cells. Monotherapy has been shown to significantly inhibit multiple myeloma tumour growth in vivo and improve host survival. Here, we show that in most cell lines tested, indatuximab ravtansine acts additively or even synergistically with clinically approved therapies for treatment of multiple myeloma. In addition, in vivo mouse xenograft models confirmed the activity of indatuximab ravtansine in combination with lenalidamide and lenalidomide/dexamethasone. Indatuximab ravtansine may therefore be a suitable combination partner for multiple myeloma, and a clinical study is ongoing.
KeywordsMultiple myeloma Pre-clinical Indatuximab ravtansine Drug combination Tumour regression
The anti-tumour activity of indatuximab ravtansine was also investigated in combination with both lenalidomide and dexamethasone in an aggressive xenograft model using the plasma cell myeloma cell line MMXF L363. In this xenograft model, indatuximab ravtansine treatment alone (2 and 4 mg/kg), as well as the combination of lenalidomide and dexamethasone resulted in tumour growth delay (Fig. 2b). When assessed alone, single-agent indatuximab ravtansine at a dose of 4 mg/kg achieved similar anti-tumour activity as the combination of lenalidomide and dexamethasone. Furthermore, a stronger effect on tumour growth was observed when indatuximab ravtansine 4 mg/kg was combined with lenalidomide and dexamethasone (Fig. 2b). Treatment with indatuximab ravtansine was well tolerated.
Single-agent indatuximab ravtansine has already been shown to have clinical activity in patients with relapsed/refractory multiple myeloma [7, 8]. These pre-clinical data provide a basis for the development of indatuximab ravtansine in combination with clinically approved anti-myeloma drugs such as lenalidomide and dexamethasone and in light of these results, a clinical phase I/IIa study has been initiated to evaluate the safety and efficacy of indatuximab ravtansine in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Promising initial results from this study have been reported , and the trial is currently ongoing.
We thank Ian Morgan, Sarah Diffen and Katrina Mullin from 4C Consultants International for editing and proofreading of the manuscript.
This study was funded by Biotest AG.
Availability of data and materials
The datasets supporting the conclusions of this article are included within this article and additional files.
All authors contributed to study design, acquisition of data, analysis and interpretation of data, manuscript drafting and approval.
During data collection, KS, CZ, TH, KB and CU were employees of Biotest AG. JP is an employee of ImmunoGen Inc.
Consent for publication
Ethics approval and consent to participate
MOLP-8 xenograft mouse experiments were performed at ImmunoGen Inc. (Waltham, USA). The study was conducted under Protocol PR-029.08 which was approved by ImmunoGen’s Institutional Animal Care and Use Committee. All procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals of the US National Institutes of Health. MMXF L363 xenograft experiments were carried out at Oncotest GmbH (Freiburg, Germany). The animal experiments were approved by the Committee on the Ethics of Animal Experiments of the regional council (permit number G-13/13) and conducted according to the guidelines of the German Animal Welfare Act (Tierschutzgesetz).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Bataille R, Jégo G, Robillard N, Barillé-Nion S, Harousseau JL, Moreau P, et al. The phenotype of normal, reactive and malignant plasma cells. Identification of “many and multiple myelomas” and of new targets for myeloma therapy. Haematologica. 2006;91(9):1234–40.PubMedGoogle Scholar
- Sanderson RD, Lalor P, Bernfield M. B lymphocytes express and lose syndecan at specific stages of differentiation. Cell Regul. 1989;1(1):27–35.PubMedPubMed CentralGoogle Scholar
- Ikeda H, Hideshima T, Fulciniti M, Lutz RJ, Yasui H, Okawa Y, et al. The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 2009;15(12):4028–37.View ArticlePubMedGoogle Scholar
- Ludwig H, Sonneveld P, Davies F, Bladé J, Boccadoro M, Cavo M, et al. European perspective on multiple myeloma treatment strategies in 2014. Oncologist. 2014;19(8):829–44.View ArticlePubMedPubMed CentralGoogle Scholar
- Orlowski RZ. Novel agents for multiple myeloma to overcome resistance in phase III clinical trials. Semin Oncol. 2013;40(5):634–51.View ArticlePubMedGoogle Scholar
- Ocio EM, Mitsiades CS, Orlowski RZ, Anderson KC. Future agents and treatment directions in multiple myeloma. Expert Rev Hematol. 2014;7(1):127–41.View ArticlePubMedGoogle Scholar
- Jagannath S, Chanan-Khan AA, Heffner LT, Avigan D, Zimmerman TM, Lonial S, et al. BT062, an antibody-drug conjugate directed against CD138, shows clinical activity in patients with relapsed or relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2011;118:305.Google Scholar
- Heffner LT, Jagannath S, Zimmerman TM, Lee KP, Rosenblatt J, Lonial S, et al. BT062, an antibody-drug conjugate directed against CD138, given weekly for 3 weeks in each 4 week cycle: safety and further evidence of clinical activity. Blood (ASH Annual Meeting Abstracts). 2012;120:4042.Google Scholar
- Kelly KR, Chanan-Khan A, Heffner LT, Somlo G, Siegel DS, Zimmerman TM, et al. Indatuximab ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in patients already exposed to lenalidomide and bortezomib. Blood (ASH Annual Meeting Abstracts). 2014;124:4736.Google Scholar