Lenalidomide Is Highly Effective in Patients with Relapsed Multiple Myeloma Following Allogeneic Stem Cell Transplantation and Increases the Frequency of CD4+FOXP3+ T Cells.
Authors: Minnema Monique C. , van der Veer Michael , Aarts Tineke , Emmelot Maarten , Mutis Tuna , Lokhorst Henk M. 
Published: October 2019

Abstract
Lenalidomide has demonstrated significant clinical activity in patients with newly diagnosed and relapsed multiple myeloma (MM). Its actions are partly mediated by stimulation of cellular host anti–MM immunity. Given these potent immunomodulatory effects, we analysed whether lenalidomide could enhance graft versus tumour or graft versus Host (GvH) reactions and analysed the efficacy and toxicity of lenalidomide after allogeneic stem cell transplantation (allo-SCT). Lenalidomide 25 mg/day was given for 21 days followed by 1 week rest for a maximum of 6 cycles to 11 end-stage patients with relapsed MM following allo–SCT. Seven patients were refractory to their last treatment. From 5 patients peripheral blood was collected before, during and after lenalidomide treatment for analysis of CD4+, CD8+ T–cells, plasmacytoid and myeloid dendritic cells, regulatory T cells and NK cell populations by FACS. Also the percentage of CD4+FOXP3+ cells and IL–10 and IFN–γ producing CD4+ and CD8+ T cells were analysed by FACS. Dexamethasone 40 mg/day was added on day 1–4 and 15–18 at start of treatment in patients 2 and 5, or after 2 cycles in patients 3, 9 and 10. A high response rate was observed in these patients. Four patients developed complete (CR) or very good partial remissions (VGPR) after 1–5 treatment cycles. Three patients developed acute GvH disease (GvHD), grade 2–4. In 1 patient long lasting chronic GvHD was diminished, in another resolved. Other toxicities beyond CTC AE grade 1 were 1 patient with grade 3 diarrhoea, 1 with grade 3 muscular pain and 1 patient with grade 4 pulmonary embolism. There were 2 patients with leukocytopenia grade 3 and 4 and 2 patients with thrombocytopenia grade 2 and 3. Comprehensive immunomonitoring of 2 poor responders with stable disease (SD) or minimal response (MR) and 3 responders revealed generally no significant changes in dendritic cell populations, CD4+ and CD8+ T cells, CD56dim, CD56high and invariant NK cells. In 4/5 patients lenalidomide increased the frequency of IFN–γ producing CD4+ and CD8+ T cells. In 3/5 patients there was a decrease in the percentage of IL–10 producing CD8+ and CD4+ T cells. Remarkably, in 4/5 patients lenalidomide treatment induced a strong increase in the frequency of CD4+FOXP3+ T cells, which are considered to represent natural regulatory T cells (Tregs). In conclusion, our results reveal for the first time the potent effects with limited toxicity of lenalidomide in the allo–SCT setting with a response rate in 9 of 11 patients. In 4 of 5 patients tested we demonstrated an increase in Tregs and IFN–γ producing T cells, indicating that the action of lenalidomide is associated with immunomodulatory events involving both effector and Treg cell populations.
Nr Age/Sex Refractory to last treatment Max Response/nr cycli GvHD FOXP3♣ IFNγ♣ IL-10♣ 1 62/F yes PR/2 BOS↓ nd nd nd 2 67/F yes PR/2 no nd nd nd 3 44/M yes PR/2 no 2,5↑ 3↑ 2↓ 4 62/F yes CR/4 no 0,3↓ 0 0 5 49/M yes PR/1 BOS = nd nd nd 6 64/M no PR/2 no nd nd nd 7 64/M no CR/4 acute gr 2, chronic↓ nd nd nd 8 56/F* yes VGPR/1 acute gr 4 5↑ 5↑ 2↑ 9 43/M no SD/2 no 5↑ 2↑ 2↓ 10 66/M yes VGPR/5 no nd nd nd 11 63/M† yes MR/1 acute gr 3 6↑ 2↑ 3↓