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• W2891486400 abstract "// Laurens E. Franssen 1 , Inger S. Nijhof 1 , Chad C. Bjorklund 2 , Hsiling Chiu 2 , Ruud Doorn 3 , Jeroen van Velzen 3 , Maarten Emmelot 1 , Berris van Kessel 1 , Mark-David Levin 4 , Gerard M.J. Bos 5 , Annemiek Broijl 6 , Saskia K. Klein 7 , Harry R. Koene 8 , Andries C. Bloem 3 , Aart Beeker 9 , Laura M. Faber 10 , Ellen van der Spek 11 , Reinier Raymakers 12 , Pieter Sonneveld 6 , Sonja Zweegman 1 , Henk M. Lokhorst 1 , Anjan Thakurta 2 , Xiaozhong Qian 2 , Tuna Mutis 1 and Niels W.C.J. van de Donk 1 1 Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Translational Development, Celgene Corporation, Summit, NJ, USA 3 Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands 5 Department of Hematology, Maastricht University Medical Center, Maastricht, The Netherlands 6 Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands 7 Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands 8 Department of Hematology, St. Antonius Hospital, Nieuwegein, The Netherlands 9 Department of Internal Medicine, Spaarne Hospital, Hoofddorp, The Netherlands 10 Department of Internal Medicine, Rode Kruis Hospital, Beverwijk, The Netherlands 11 Department of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands 12 Department 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." @default.
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• W2891486400 date "2018-09-21" @default.
• W2891486400 modified "2023-10-16" @default.
• W2891486400 title "Lenalidomide combined with low-dose cyclophosphamide and prednisone modulates Ikaros and Aiolos in lymphocytes, resulting in immunostimulatory effects in lenalidomide-refractory multiple myeloma patients" @default.
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• W2891486400 doi "https://doi.org/10.18632/oncotarget.26131" @default.
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