TY - JOUR
T1 - Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma
T2 - Impact of immune activation and cereblon targets
AU - Sehgal, Kartik
AU - Das, Rituparna
AU - Zhang, Lin
AU - Verma, Rakesh
AU - Deng, Yanhong
AU - Kocoglu, Mehmet
AU - Vasquez, Juan
AU - Koduru, Srinivas
AU - Ren, Yan
AU - Wang, Maria
AU - Couto, Suzana
AU - Breider, Mike
AU - Hansel, Donna
AU - Seropian, Stuart
AU - Cooper, Dennis
AU - Thakurta, Anjan
AU - Yao, Xiaopan
AU - Dhodapkar, Kavita M.
AU - Dhodapkar, Madhav V.
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015/6/25
Y1 - 2015/6/25
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84933567284&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-11-611426
DO - 10.1182/blood-2014-11-611426
M3 - Article
C2 - 25869284
AN - SCOPUS:84933567284
VL - 125
SP - 4042
EP - 4051
JO - Blood
JF - Blood
SN - 0006-4971
IS - 26
ER -