FOXM1 Is Associated with Development of Therapeutic Resistance in Multiple Myeloma

Despite advances in treatment resulting from development of novel therapies, multiple myeloma (MM) remains an incurable disease because of the emergence of therapeutic resistance. To explore mechanisms of acquired resistance to the IMiD^® immunomodulatory agent lenalidomide in patients with MM, we performed RNA-seq analysis on 12 paired newly diagnosed MM (NDMM) patient samples of sorted CD138⁺ cells obtained prior to lenalidomide treatment initiation and after development of resistance. Gene set enrichment analysis using gene ontology biological process categories indicated that a dominant process associated with proliferation was upregulated at relapse. Transcription factor target enrichment analysis revealed that among differentially expressed genes, targets of forkhead box protein M1 (FOXM1), a transcription factor that promotes cell proliferation, were significantly (≈ 50% of FOXM1 target genes, false discovery rate [FDR] < 0.01) upregulated at relapse. FOXM1 expression also was significantly (FDR < 0.01) upregulated by 2.8-fold at relapse. Subsequently, we explored the association of FOXM1 gene expression with response to the IMiD immunomodulatory drug pomalidomide in MM patients relapsed/refractory (RRMM) to prior lenalidomide and proteasome inhibitor-based therapy. This analysis showed that patients with high baseline FOXM1 expression levels had lower response rates and shorter progression-free (median 2.9 vs 7.0 months; nominal logrank P < 2.24×10^-6)and overall survival (median 10.4 vs 19.3 months; nominal logrank P < 8.43×10^-7) when compared with patients with low baseline FOXM1 expression. Additional in vitro experiments indicated that knockdown of FOXM1 gene expression by short hairpin RNA increased sensitivity of a cell line intrinsically resistant to lenalidomide and pomalidomide, demonstrating an association between lower FOXM1 expression and IMiD agent sensitivity. Although FOXM1 expression has been linked to poor prognosis in NDMM, this work suggests high FOXM1 expression could also be associated with development of resistance to lenalidomide and cross resistance to pomalidomide in RRMM.