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Lenalidomide combined with low-dose cyclophosphamide and prednisone modulates Ikaros and Aiolos in lymphocytes, resulting in immunostimulatory effects in lenalidomide-refractory multiple myeloma patients

Laurens E. Franssen, Inger S. Nijhof, Chad C. Bjorklund, Hsiling Chiu, Ruud Doorn, Jeroen van Velzen, Maarten Emmelot, Berris van Kessel, Mark-David Levin, Gerard M.J. Bos, Annemiek Broijl, Saskia K. Klein, Harry R. Koene, Andries C. Bloem, Aart Beeker, Laura M. Faber, Ellen van der Spek, Reinier Raymakers, Pieter Sonneveld, Sonja Zweegman, Henk M. Lokhorst, Anjan Thakurta, Xiaozhong Qian, Tuna Mutis and Niels W.C.J. van de Donk _

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Oncotarget. 2018; 9:34009-34021. https://doi.org/10.18632/oncotarget.26131

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Abstract

Laurens E. Franssen1, Inger S. Nijhof1, Chad C. Bjorklund2, Hsiling Chiu2, Ruud Doorn3, Jeroen van Velzen3, Maarten Emmelot1, Berris van Kessel1, Mark-David Levin4, Gerard M.J. Bos5, Annemiek Broijl6, Saskia K. Klein7, Harry R. Koene8, Andries C. Bloem3, Aart Beeker9, Laura M. Faber10, Ellen van der Spek11, Reinier Raymakers12, Pieter Sonneveld6, Sonja Zweegman1, Henk M. Lokhorst1, Anjan Thakurta2, Xiaozhong Qian2, Tuna Mutis1 and Niels W.C.J. van de Donk1

1Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands

2Department of Translational Development, Celgene Corporation, Summit, NJ, USA

3Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

4Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands

5Department of Hematology, Maastricht University Medical Center, Maastricht, The Netherlands

6Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands

7Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands

8Department of Hematology, St. Antonius Hospital, Nieuwegein, The Netherlands

9Department of Internal Medicine, Spaarne Hospital, Hoofddorp, The Netherlands

10Department of Internal Medicine, Rode Kruis Hospital, Beverwijk, The Netherlands

11Department of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands

12Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands

Correspondence to:

Niels W.C.J. van de Donk, email: n.vandedonk@vumc.nl

Keywords: multiple myeloma; immunomodulation; lenalidomide; refractory; cyclophosphamide

Received: May 01, 2018     Accepted: September 10, 2018     Published: September 21, 2018

ABSTRACT

We recently showed that the outcome of multiple myeloma (MM) patients treated in the REPEAT study (evaluation of lenalidomide combined with low-dose cyclophosphamide and prednisone (REP) in lenalidomide-refractory MM) was markedly better than what has been described with cyclophosphamide-prednisone alone. The outcome with REP was not associated with plasma cell Cereblon expression levels, suggesting that the effect of REP treatment may involve mechanisms independent of plasma cell Cereblon-mediated direct anti-tumor activity. We therefore hypothesized that immunomodulatory effects contribute to the anti-MM activity of REP treatment, rather than plasma cell Cereblon-mediated effects. Consequently, we now characterized the effect of REP treatment on immune cell subsets in peripheral blood samples collected on day 1 and 14 of cycle 1, as well as on day 1 of cycle 2. We observed a significant mid-cycle decrease in the Cereblon substrate proteins Ikaros and Aiolos in diverse lymphocyte subsets, which was paralleled by an increase in T-cell activation. These effects were restored to baseline at day one of the second cycle, one week after lenalidomide interruption. In vitro, lenalidomide enhanced peripheral blood mononuclear cell-mediated killing of both lenalidomide-sensitive and lenalidomide-resistant MM cells in a co-culture system. These results indicate that the Cereblon-mediated immunomodulatory properties of lenalidomide are maintained in lenalidomide-refractory MM patients and may contribute to immune-mediated killing of MM cells. Therefore, combining lenalidomide with other drugs can have potent effects through immunomodulation, even in patients considered to be lenalidomide-refractory.


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