Lenalidomide Inhibits Multiple Myeloma Cell Proliferation in Vitro Via Its Effect On Expression of Oncogenes and Tumor Suppressor Genes.

Abstract 2855

Poster Board II-831

Lenalidomide is an oral anti-proliferative and immunomodulatory drug. In combination with dexamethasone, it is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. In this study we investigated direct antimyeloma effects of lenalidomide in vitro using a panel of human MM cell lines with various cytogenetic features and bone marrow cells from patients with active MM. We also assessed the effect of lenalidomide on expression of tumor suppressor and enhancer genes such as p21^cip1, SPARC, ING1/4, p57^kip2, p53, cyclin D1/2, IRF4/MUM1 and IRF8/ICSBP. At attainable plasma levels in treated patients, lenalidomide directly inhibited human MM cell proliferation. Lenalidomide strongly increased expression of tumor suppressor genes such as p21^waf1/cip1, SPARC, IRF8, ING4 and p57^kip2. In the MM cell lines tested, lenalidomide had partial but consistent inhibitory effects on expression of IRF4, an important MM survival factor. However, lenalidomide had no marked effect on expression of tumor enhancer genes such as VEGF, cyclin D1/2 and MAF or tumor suppressor genes such as ING1 and p53 in most lines of cells. This suggests that the antiproliferative effects of lenalidomide on MM cells may be related to the upregulation of some tumor suppressor gene expression. Statistical analyses show that the antiproliferative effect of lenalidomide is significantly correlated with the drug induced upregulation of SPARC and IRF8 expression (p=0.0016; p=0.012, respectively), but not with the drug induced changes of p21 (p> 0.05) and IRF4 expression (p> 0.05). Furthermore, the antiproliferative effect of lenalidomide was significantly correlated with the constitutive expression levels of cyclin D1 (p=0.021) and IRF4 (p=0.027), and inversely correlated with the constitutive level of cyclin D2 (p=0.041) in these MM cell lines. Using bone marrow myeloma cells from patients, we confirmed that the sensitivity of cells to lenalidomide was associated with SPARC and IRF8 upregulation and baseline levels of cyclin D1/2 and IRF4 expression. Using MM cell lines adapted to prolonged exposure (5 months) to lenalidomide, we found that cells became resistant to the drug in association with decreased baseline levels of cyclin D1 and IRF4. In conclusion, lenalidomide demonstrates direct inhibitory effects on proliferation various MM cells. These antimyeloma activities may help explain the clinical efficacy seen in patients treated with lenalidomide. Lenalidomide treatment of MM cells increased SPARC and IRF8 mRNA expression, whereas pre-treatment cyclin D1/2 and IRF4 mRNA levels were associated with increased sensitivity and may have prognostic potential for MM therapy with lenalidomide.