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

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 naïve 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.