Identification And Validation Of Imid-14 Model Predictive Of Imid Resistance In Multiple Myeloma

BACKGROUND : Immunomodulatory derivatives (IMiDs) have become an integral part of multiple myeloma (MM) treatment, both in newly diagnosed and relapsed refractory patients. Long-term treatment with IMiDs is inevitably associated with relapse and emerging resistance. The precise mechanisms of IMiDs resistance are not entirely clear. Gene-expression profiling (GEP) can be used to elucidate resistance/response signature associated with IMiDs. PATIENTS AND METHODS : GEP of paired samples of CD138-purified plasma cells, obtained from patients prior to and 48 hours after single-agent therapy with thalidomide (42 newly diagnosed MM), lenalidomide (18 relapsed/refractory MM), or pomalidomide (18 relapsed/refractory MM) were compared. Samples were hybridized to Affymetrix expression arrays. Affymetrix U133Plus2.0 arrays were used in the pomalidomide study and Affymetrix U95Av2 arrays were used for thalidomide and lenalidomide pharmacogenomics studies. Among 176 genes that significantly changed pre- and post IMiD treatment (P P values 2 -scale expression of the 4 prognosis-unfavorable (hazard ratio [HR] u003e 1) and the 10 prognosis-favorable (HR RESULTS : The IMiDs resistant group in TT2 (Thalidomide arm) training set exhibited significantly poor PFS ( P P st year followed by TD for 2 years), there were significant differences in outcome between patients whom IMiD14 model predicted to have IMiDs resistance versus others, 3-year PFS and OS rates for the predicted IMiDs resistant patients were 63% and 71%, whereas for the rest of patients the corresponding rates were 87% and 90% (PFS P = 0.01, OS P P = 0.002, OS P = 0.003). The discriminatory power of IMiD14 was also independently confirmed in the validation cohort HOVON65/GMMG-HD4 VAD arm (induction with vincristine, doxorubicin, and dexamethasone, and maintenance with thalidomide for 2 years); 3-year PFS and OS rates for the predicted IMiDs resistant patients were 16% and 38%, versus 54% and 82%, respectively for the rest of the patients (PFS P P CONCLUSION : We have identified IMiD14 gene expression signature that accurately predicts resistance to IMiD treatment and outcome in multiple myeloma patients. These predictive genes could provide novel targets for therapeutic intervention and are being evaluated in prospective datasets. Disclosures Barlogie: Celgene: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Novartis: Consultancy. Sonneveld: Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Usmani: Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Janssen Oncology: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array BioPharma: Honoraria, Research Funding.