Impact of lenalidomide maintenance on the immune environment of multiple myeloma patients with low tumor burden after autologous stem cell transplantation

// Karel Fostier 1 , Jo Caers 2 , Nathalie Meuleman 3 , Katrijn Broos 4 , Jurgen Corthals 4 , Kris Thielemans 4 , Rik Schots 1 and Brenda De Keersmaecker 4 1 Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Hematology, Brussels, Belgium 2 Centre Hospitalier Universitaire (CHU) de Liege, Department of Hematology, Liege, Belgium 3 Institut Jules Bordet, Department of Hematology, Brussels, Belgium 4 Vrije Universiteit Brussel (VUB), Laboratory of Molecular and Cellular Therapy, Brussels, Belgium Correspondence to: Karel Fostier, email: Karel.Fostier@uzbrussel.be Keywords: lenalidomide; immunomodulation Received: July 26, 2017      Accepted: February 27, 2018      Published: April 17, 2018 ABSTRACT Lenalidomide is a potent anti-myeloma drug with immunomodulatory properties. It is increasingly used in a low-dose maintenance setting to prolong remission duration after standard treatment. Data on the in vivo effects of lenalidomide are scarce and sometimes different from the well-described in vitro effects. We therefore evaluated the numerical, phenotypical and functional impact of lenalidomide maintenance on several immune cell types in a cohort of seventeen homogeneously treated myeloma patients achieving a low residual myeloma burden after a bortezomib based-induction followed by autologous stem cell transplantation. Lenalidomide maintenance: 1) increased the fraction of naive CD8 + T cells and several memory T-cell subsets, 2) reduced the numbers of terminal effector CD8 + T cells, 3) resulted in a higher expression of co-stimulatory molecules on resting T cells and of the inhibitory checkpoint molecules LAG-3 on CD4 + T cells and TIM-3 on CD4 + and CD8 + T cells, 4) reduced the number of TIGIT + CD8 + T cells, 5) increased the number of regulatory T cells with a phenotype associated with strong suppressive capacity. Purified CD8 + T cells showed increased and more polyfunctional recall viral responses. However, PBMC responses were not enhanced during lenalidomide maintenance and CD4 + T-cell responses specific for the myeloma-associated antigen MAGE-C1 even tended to become lower. We conclude that lenalidomide maintenance after autologous stem cell transplantation has complex pleotropic effects on the immune environment. Immune interventions such as anti-myeloma vaccination should include measures to tackle an expanded inhibitory Treg compartment.