Ramsower, Colleen A

AbstractIdentifying biomarkers associated with disease progression and drug resistance are important for personalized care. We investigated the expression of 121 curated genes, related to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) responsiveness. We analyzed 28 human multiple myeloma (MM) cell lines with known drug sensitivities and 130 primary MM patient samples collected at different disease stages, including newly diagnosed (ND), on therapy (OT), and relapsed and refractory (RR, collected within 12 months before the patients’ death) timepoints. Our findings led to the identification of a subset of genes linked to clinical drug resistance, poor survival, and disease progression following combination treatment containing IMIDs and/or PIs. Finally, we built a seven‐gene model (MM‐IMiD and PI sensitivity‐7 genes [IP‐7]) using digital gene expression profiling data that significantly separates ND patients from IMiD‐ and PI‐refractory RR patients. Using this model, we retrospectively analyzed RNA sequcencing (RNAseq) data from the Mulltiple Myeloma Research Foundation (MMRF) CoMMpass (n = 578) and Mayo Clinic MM patient registry (n = 487) to divide patients into probabilities of responder and nonresponder, which subsequently correlated with overall survival, disease stage, and number of prior treatments. Our findings suggest that this model may be useful in predicting acquired resistance to treatments containing IMiDs and/or PIs.

Abstract The objective of this study was to explore differences in outcomes between first-line rituximab plus bendamustine (R-B) and R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, dexamethasone, cytarabine, cisplatin) in transplant-eligible patients with mantle cell lymphoma (MCL). A population-based cohort of 97 patients aged 18 to 65 years with stage II-IV MCL, consecutively treated with R-B was retrospectively identified at BC Cancer. Baseline characteristics, response rates, and outcomes were compared with the cohort of 232 patients with MCL randomized to the R-CHOP/R-DHAP arm of the MCL Younger trial. The primary endpoint was the hazard ratio (HR) of the progression-free survival (PFS) comparison between both groups, adjusted for MCL International Prognostic Index (MIPI), Ki67 index, and blastoid/ pleomorphic morphology. Ann Arbor stage, lactate dehydrogenase, MIPI, blastoid morphology, and MCL35 assignments were similar between both groups. The overall response rate (ORR) to R-B was 90% (54% complete response [CR]); 77% of patients proceeded to autologous stem cell transplantation (ASCT) and 78% received maintenance rituximab (MR). The ORR to R-CHOP/R-DHAP was 94% (54% CR); 78% proceeded to ASCT and 2% received MR. There were no differences in PFS in unadjusted (HR, 0.87; 95% confidence interval [CI], 0.53-1.41; P = .56) or adjusted (HR, 0.79; 95% CI, 0.45-1.37; P = .40) comparisons. There were no clear differences in secondary endpoints in unadjusted or adjusted analyses. This retrospective adjusted comparison of 2 independent cohorts of younger patients with MCL suggests that R-B with ASCT and maintenance rituximab is a feasible and effective first-line treatment, with outcomes comparable to R-CHOP/R-DHAP with ASCT.