Lenalidomide is one of the immunomodulatory drugs (IMiDs), which function efficiently as immune system modulator and interfere with tumor and its microenvironment via anti-angiogenic, anti-proliferative and anti-inflammatory effects, and also down regulate adhesion molecules in tumor cells. Lenalidomide has significantly improved survival outcome in multiple myeloma (MM) patients. Recently, we and others have shown that lenalidomide in combination with dexamethasone increased the immune suppressor cell numbers in MM patients (Muthu Raja et al, 2012; Minnema et al, 2009). Also, an in vivo study showed that anti-tumor properties of lenalidomide are not compromised by dexamethasone but lenalidomide induced immune modulatory effects are reduced. Here in this study, we aimed to compare the immune suppressor cells and other immune cells in multiple myeloma patients who are treated with lenalidomide plus prednisone (LP) and lenalidomide alone (L).
A total of 18 patients were included during maintenance therapy, these patients were randomized to receive LP or L until progression. Ten patients received LP and 8 patients received L. All patients were in the stage of ISS-1 (International Stage System) before the start of maintenance therapy. Using flow cytometric analysis, we quantified various immune cell subsets in these two cohorts including T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs), CD4, CD8 and total lymphocytes.
Tregs and MDSCs were phenotypically characterized as CD4+ CD25hi+FoxP3+ and CD33+CD11b+CD14-HLADR-, respectively. We analyzed these immune suppressor cells and other immune cells before and after each cycle of maintenance therapy, for a period of 4 cycles. In head to head analysis, no significant difference was observed between patients in LP arm and L arm for immune suppressors and immune cells before maintenance (Table 1). However, during maintenance, Treg and MDSC numbers were significantly increased in patients treated with LP compared to patients treated with L (P <0.05) (Table 1). When we compared CD4, CD8 and total lymphocyte numbers, no significant changes were seen between patients in LP arm and L arm (Table 1). Interestingly, L treated patients showed a trend of increase in CD4 and total lymphocyte counts compared to pre-L. On contrary, LP treated patients showed reduced or similar counts for CD4, CD8 and total lymphocytes while numbers of Tregs (P=0.033) and MDSCs were increased compared to pre-LP. Then, we compared immune cell subsets between before and after maintenance therapy with irrespective of the treatment arm. Comparative analysis showed that only Tregs were increased significantly after maintenance compared to pre-maintenance (median: 5.2 vs. 6.4; P=0.032) but not the other cells.
Our study clearly showed that immune suppressor cells including, Tregs and MDSCs were significantly increased in MM patients treated with lenalidomide plus prednisone compared to patients treated with lenalidomide alone. Increase in immune suppressor cells might be due to inclusion of prednisone with lenalidomide. This finding is also further supported by lenalidomide arm data, where no significant increase in immune suppressor cells was observed. Expanded immune suppressor cells in lenalidomide plus prednisone treated cohort might be more susceptible to infectious complications and progression risk.
Off Label Use: Lenalidomide and Prednisone.
This study was supported by grants MSM0021622434 and GACR P304/10/139.
Asterisk with author names denotes non-ASH members.