Opposing Effects of Dexamethasone on Lenalidomide Activity in Multiple Myeloma: Additive/Synergistic Effects on Anti-Proliferative Activity on Myeloma Cells and Antagonistic Effects on Immune Function

Abstract

Lenalidomide (Revlimid®) is approved for the treatment of previously treated multiple myeloma (MM) in combination with dexamethasone. Single agent lenalidomide has direct antiproliferative activity against MM cells and direct immunomodulatory activity via costimulation of T cell and natural killer (NK) cell responses. The ECOG Phase III trial in newly diagnosed MM (E4A03) reported that low dose (40 mg/d on days 1, 8, 15 & 22 of a 28-day cycle) dexamethasone in combination with lenalidomide showed an overall survival advantage when compared with the higher, standard-dose (40 mg/d on days 1-,4, 9–12 & 17–20 of a 28-day cycle) of dexamethasone that is used in combination with lenalidomide. We have examined the pharmacological activity of lenalidomide in combination with dexamethasone with respect to direct MM antiproliferative and T/NK cell stimulation in vitro. Antiproliferative activity against various MM cell lines was associated with increased expression of tumor suppressor genes, including Egr1, Egr3, p21, and p27. The specific tumor suppressor genes induced varied among the MM cell lines, even among those that were sensitive to lenalidomide. Lenalidomide and dexamethasone induced cell cycle arrest in G0/G1 phase, activation of caspases 3/7, and apoptosis in the sensitive cell lines. The combination of lenalidomide and dexamethasone was partially additive in most MM cell lines, while the most dramatic combination effect observed was induction of p21 gene expression and apoptosis in LP-1 MM cells. In contrast to its synergistic effect on MM cell proliferation, dexamethasone was strongly antagonistic to the T and NK cell costimulatory effects of lenalidomide. Specifically, in primary human T cells dexamethasone inhibited lenalidomide-enhanced IL-2 production. Furthermore, in primary human NK cells dexamethasone inhibited lenalidomide-enhanced IFN-γ production. These findings suggest that the lenalidomide plus low-dose dexamethasone regimen may be able to facilitate the MM cell killing via induction of tumor suppressor gene expression, cell cycle arrest, and apoptosis, while allowing lenalidomide to enhance T and NK cell function to a greater magnitude. The enhanced survival with the low-dose dexamethasone schedule in MM patients suggests exploring further dosing schedules of dexamethasone in combination with lenalidomide in this population, with measurement of biomarkers of T and NK cell function.

A steroid‐independent regimen of bortezomib, liposomal doxorubicin and thalidomide demonstrate high response rates in newly diagnosed multiple myeloma patients

“…Also, high‐dose steroid treatment can increase susceptibility to infectious complications due to their immunosuppressive effects. Recent translational studies have noted an inhibitory effect of steroids on lenalidomide‐mediated natural killer (NK) cell stimulation, suggesting that steroids may compromise the efficacy of immunomodulating agents in patients with MM (Schafer, 2008; Hsu et al , 2011). This hypothesis is substantiated by a recent large phase III study that demonstrated improved survival in newly diagnosed MM patients treated with the combination of lenalidomide and low dose dexamethasone as compared to lenalidomide and high dose dexamethasone (Rajkumar et al , 2010).…”

Past, Present, and a Glance into the Future of Multiple Myeloma Treatment

“…Interestingly, both CK1α and CK2 have been shown to sustain activation of important signaling pathways such as JAK/STAT, NF-κB, and PI3K/AKT [ 95 , 97 , 98 ]. IMiDs also inhibit the proliferation of PCs by inhibiting the cyclin-dependent kinase pathway through inducing P21 [ 99 ]. Moreover, IMiDs induce direct apoptosis in PCs by activation of Fas-mediated cell death [ 100 , 101 ].…”