Dexamethasone Synergizes with Lenalidomide to Inhibit Multiple Myeloma Tumor Growth, But Reduces Lenalidomide-Induced Immunomodulation of T and NK Cell Function

Abstract

To determine the effect of dexamethasone on the antimyeloma effects of lenalidomide, we tested in vitro proliferation, tumor suppressor gene expression, caspase activity, cell cycling, and apoptosis levels in a series of multiple myeloma (MM) and plasma cell leukemia cell lines treated with lenalidomide and dexamethasone, alone or in combination. The effect of dexamethasone on the immunomodulatory activities of lenalidomide such as T cell and natural killer (NK) cell activation was measured via interleukin [IL]-2 production, and interferon-gamma and granzyme B production respectively. Lenalidomide inhibited proliferation in most cell lines tested, and this effect was enhanced by dexamethasone. This effect was observed in MM cells containing the high-risk cytogenetic abnormalities t(4;14), t(14;16), del17p, del13, and hypodiploidy. Mechanistically, lenalidomide plus dexamethasone synergistically induced expression of the tumor suppressor genes Egr1, Egr2, Egr3, p15, p21, and p27 in MM cell lines and MM patient cells. The combination activated caspases 3, 8, and 9; and induced cell cycle arrest and apoptosis. Lenalidomide alone increased T cell production of IL-2, and NK cell production of interferon-gamma and granzyme B. Notably, dexamethasone antagonized these immunostimulatory effects of lenalidomide in a dose-dependent manner. These data further elucidate the mechanism of action of lenalidomide and dexamethasone in MM, and suggest that use of low-dose dexamethasone with lenalidomide may retain the antiproliferative effect of lenalidomide while permitting greater immunomodulatory effects of this combination regimen.

Lenalidomide alone or lenalidomide plus dexamethasone significantly inhibit IgG and IgM in vitro…A possible explanation for their mechanism of action in treating multiple myeloma

“…Len also promotes CD4-cell secretion of IL-2 [14]. In one study, in which T cells were stimulated with anti-CD3, 1 μM len promoted the maximum synthesis of IL-2, but when len/dex (10 nM) was used, IL-2 was suppressed [15]. Our findings are in partial agreement with this finding.…”

Activation of NK cells and disruption of PD-L1/PD-1 axis: two different ways for lenalidomide to block myeloma progression

“…Notably, Lenalidomide displays anti-tumor abilities on malignant plasma cells, affecting multiple mechanisms involved in tumor development and survival [97]. For example, Lenalidomide display anti-osteoclastogenic properties and induces cell cycle arrest and increases the expression of Cyclin-dependent kinase (CDK) inhibitors on MM cells, thus inhibiting their proliferation and promoting their apoptosis [97, 109–111] (Figure 2). Recent findings also show that Lenalidomide partially reversed the exhaustion of effector cells promoted by stromal microenvironment Myeloid-derived suppressor cells (MDSC) [112] and DC [35] (Figure 2).…”

Current Trends of Renal Impairment in Multiple Myeloma

“…Lenalidomide is a second-generation immunomodulatory agent which has direct tumoricidal activity in MM [92,93,94,95]. The kidney is the primary route of elimination, with 84% of the drug secreted in the urine in patients with normal renal function.…”