A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma by Ajai Chari, Hearn J. Cho, Amishi Dhadwal, Gillian Morgan, Lisa.

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Presentation transcript:

A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma by Ajai Chari, Hearn J. Cho, Amishi Dhadwal, Gillian Morgan, Lisa La, Katarzyna Zarychta, Donna Catamero, Erika Florendo, Nadege Stevens, Daniel Verina, Elaine Chan, Violetta Leshchenko, Alessandro Laganà, Deepak Perumal, Anna Huo-Chang Mei, Kaity Tung, Jami Fukui, Sundar Jagannath, and Samir Parekh BloodAdv Volume 1(19):1575-1583 August 22, 2017 © 2017 by The American Society of Hematology

Ajai Chari et al. Blood Adv 2017;1:1575-1583 © 2017 by The American Society of Hematology

Progression-free survival for all patients. Progression-free survival for all patients. Kaplan-Meier PFS curve for all patients treated with FRD. Ajai Chari et al. Blood Adv 2017;1:1575-1583 © 2017 by The American Society of Hematology

Progression-free survival for lenalidomide-refractory patients. Progression-free survival for lenalidomide-refractory patients. Kaplan-Meier PFS curve for lenalidomide-refractory patients treated with FRD (n = 22). Ajai Chari et al. Blood Adv 2017;1:1575-1583 © 2017 by The American Society of Hematology

Overall survival. Overall survival. Kaplan-Meier overall survival curve for all patients treated with FRD (n = 27). Ajai Chari et al. Blood Adv 2017;1:1575-1583 © 2017 by The American Society of Hematology

Correlation of MAGE-A1 expression with PFS in patients treated with FRD and knockdown of MAGE-A in HMCLs. MAGE-A1 expression is correlated with resistance to FRD chemotherapy. Correlation of MAGE-A1 expression with PFS in patients treated with FRD and knockdown of MAGE-A in HMCLs. MAGE-A1 expression is correlated with resistance to FRD chemotherapy. (A) Analysis of gene expression profiling data by RNASeq from CD138+ myeloma cells obtained at screening based on PFS < 90 days (short PFS) vs PFS > 90 days (long PFS) enriched a set of 1898 differentially expressed genes (down- or upregulated relative to comparator). MAGEA1 was the most highly upregulated gene associated with short PFS (blue circle). (B) Quantitative analysis of MAGEA1 transcript abundance in short vs long PFS subjects demonstrated significantly higher expression associated with short PFS (P < .005). (C) Western blot for MAGE-A1 protein in lysates from screening specimens. OD, relative optical density = OD (MAGE-A1)/OD β-actin load control. (D) Quantitative analysis of MAGE-A1 relative OD in short vs long PFS subjects demonstrated significantly higher protein expression associated with short PFS (P < .05). (E-H) MM.1r (E,G) or H929 (F,H) HMCL were treated with MAGE-A shRNA lenti or controls for 24 hours (MM.1r) or 48 hours (H929) and then incubated with increasing concentrations of panobinostat (E-F) or lenalidomide (G-H). Cell viability was assessed 24 hours later by Cell TiterGlo assay (ProMega). Knockdown of MAGE-A was correlated with a significant increase in sensitivity to panobinostat-induced cell death. MM.1r (E), 50% inhibitory concentration (IC50) of shMA group = 3.8 nM vs IC50 of shNT group 5.6 nM, P < .005. H929 (F), IC50 (shMA) = 7.4 nM vs IC50 (shNT) = 9.2 nM, P < .01. Error bars indicate standard error of the mean; data pooled from 3 experiments. Con, control; mRNA, messenger RNA. Ajai Chari et al. Blood Adv 2017;1:1575-1583 © 2017 by The American Society of Hematology