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 ZweegmanHenk M. Lokhorst, Anjan Thakurta, Xiaozhong Qian, Tuna Mutis, Niels W.C.J. Van De Donk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)34009-34021
Number of pages13
JournalOncotarget
Volume9
Issue number74
Publication statusPublished - 1 Sep 2018

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