title: Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets.
abstract: In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events. Both cohorts experienced similar event-free and overall survival. Both regimens led to a distinct pattern but similar degree of mid-cycle immune activation, manifested as increased expression of cytokines and lytic genes in T and natural killer (NK) cells. Pomalidomide induced poly-functional T-cell activation, with increased proportion of coinhibitory receptor BTLA(+) T cells and Tim-3(+) NK cells. Baseline levels of ikaros and aiolos protein in tumor cells did not correlate with response or survival. Pomalidomide led to rapid decline in Ikaros in T and NK cells in vivo, and therapy-induced activation of CD8(+) T cells correlated with clinical response. These data demonstrate that pomalidomide leads to strong and rapid immunomodulatory effects involving both innate and adaptive immunity, even in heavily pretreated multiple myeloma, which correlates with clinical antitumor effects. This trial was registered at www.clinicaltrials.gov as #NCT01319422.
authors: Department of Medicine.
authors: Kartik
authors: http://orcid.org/0000-0003-4391-6943
authors: K
authors: Sehgal
authors: Department of Medicine.
authors: Rituparna
authors: R
authors: Das
authors: Department of Medicine.
authors: Lin
authors: L
authors: Zhang
authors: Department of Medicine.
authors: Rakesh
authors: R
authors: Verma
authors: Yale Center for Analytic Sciences, and.
authors: Yanhong
authors: Y
authors: Deng
authors: Department of Medicine.
authors: Mehmet
authors: M
authors: Kocoglu
authors: Department of Pediatrics, Yale University, New Haven, CT;
authors: Juan
authors: J
authors: Vasquez
authors: Department of Medicine.
authors: Srinivas
authors: S
authors: Koduru
authors: Celgene Corporation, Summit, NJ;
authors: Yan
authors: Y
authors: Ren
authors: Celgene Corporation, Summit, NJ;
authors: Maria
authors: M
authors: Wang
authors: Celgene Corporation, Summit, NJ;
authors: Suzana
authors: S
authors: Couto
authors: Celgene Corporation, Summit, NJ;
authors: Mike
authors: M
authors: Breider
authors: Celgene Corporation, Summit, NJ;
authors: Donna
authors: D
authors: Hansel
authors: Department of Medicine, Yale Cancer Center, and.
authors: Stuart
authors: S
authors: Seropian
authors: Department of Medicine, Yale Cancer Center, and.
authors: Dennis
authors: D
authors: Cooper
authors: Celgene Corporation, Summit, NJ;
authors: Anjan
authors: A
authors: Thakurta
authors: Yale Center for Analytic Sciences, and Yale Cancer Center, and.
authors: Xiaopan
authors: X
authors: Yao
authors: Department of Pediatrics, Yale University, New Haven, CT; Yale Cancer Center, and.
authors: Kavita M
authors: KM
authors: Dhodapkar
authors: Department of Medicine, Yale Cancer Center, and Department of Immunobiology, Yale University, New Haven, CT.
authors: Madhav V
authors: MV
authors: Dhodapkar
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D013601:T-Lymphocytes / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D013792:Thalidomide; C467566:pomalidomide