Lenalidomide combined with low-dose cyclophosphamide and prednisone modulates Ikaros and Aiolos in lymphocytes, resulting in immunostimulatory effects in lenalidomide-refractory multiple myeloma patients
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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
Niels W.C.J. van de Donk, email: firstname.lastname@example.org
Keywords: multiple myeloma; immunomodulation; lenalidomide; refractory; cyclophosphamide
Received: May 01, 2018 Accepted: September 10, 2018 Published: September 21, 2018
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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