Author(s): S. Jagannath, D. S. Siegel, R. Hajek, M. A. Dimopoulos, S. Yoon, S. Lonial, T. Graef, L. Lupinacci, D. Reiser, K. C. Anderson
Background: Preclinical data show combined histone deacetylase (HDAC) and proteasome inhibition may have synergistic cytotoxicity in MM cells. In RR MM pts, V (oral HDAC inhibitor) plus B showed objective response rates (ORR; >PR) up to 42% in all pts, including B refractory in 2 Phase I trials. These preliminary data provided rationale for a large global program in RR MM (~900 pts) to assess the efficacy/safety of combined V and B for the treatment of RR MM (2 trials).
Methods: Vantage 088 (088) is a Phase III, randomized, double-blind study of V or placebo (P) plus B in MM pts with progressive disease after 1-3 prior anti-myeloma treatments. Primary endpoint (EP) is progression-free survival (PFS) with planned accrual of 742 pts. Vantage 095 (095) is a Phase IIb open-label study of V plus B in RR MM pts after >2 prior anti-myeloma therapies. All 095 pts are refractory to B and relapsed, refractory, intolerant, or ineligible for other MM therapies. Primary EP is ORR ( >PR) with planned accrual of 142 pts. In both, pts received iv B 1.3 mg/m2 on Days 1, 4, 8, and 11 and oral V 400 mg (or matching P in 088) qd on Days 1-14 of each 21-day cycle.
Results: As of Dec 2009, 140 and 65 pts, respectively, were enrolled in 088 and 095. In both, >40% have completed >3 cycles. Safety data from pts who received study drug (088, n=39; 095, n=30) were the earliest data evaluated by the independent data monitoring committee (DMC; cut-off Aug 2009). Grade >3 drug-related AEs seen in 9 pts in 088 (thrombocytopenia, 5 pts; nausea/vomiting, 2 pts) and 19 pts in 095 (most commonly thrombocytopenia, 8 pts; nausea, 5 pts); higher frequency of toxicities was expected in 095 due to population differences. DMC did not recommend study stop/change based on safety. Safety and efficacy data from interim analyses (IA) of the unblinded study will be reported; first formal IA (with futility/efficacy stopping rules) for 088 is planned when 25% (126 events) of PFS events seen, and IA from 095 was conducted after evaluation of >43 pts, where the defined futility threshold was surpassed.
Conclusions: Combined V and B is being investigated in 2 global, multicenter trials in RR MM pts to determine if the regimen is a viable option for RR MM pts.