ONX 0912 inhibits growth of xenografted human MM cells in mice. (A) MM.1S cells alone (3 × 107 cells/mouse) were implanted in the rear flank of female beige nude xid mice (5-7 weeks of age at the time of tumor challenge). On Day 30-33, mice were randomized to treatment groups and treated intravenously with carfilzomib (5 mg/kg) or orally with vehicle or ONX 0912 (30 mg/kg). Mice were treated for 2 consecutive days and the treatment repeated weekly for 7 weeks. Data are presented as mean tumor volume ± SEM (n = 9-10/group). One of the 2 representative experiments is shown. Bars indicate means ± SD. (B) Human fetal bone grafts (size range: 0.5-1.5 cm) were subcutaneously implanted into CB-17 SCID mice. Four weeks after bone implantation, INA-6 cells (2.5 × 106) were injected directly into the human fetal bone implant in SCID mice (5 mice each group), and mouse sera samples were serially analyzed for levels of secreted human soluble IL-6R (shIL-6R) by enzyme-linked immunosorbent assay as a measure of tumor burden. Upon detection of measurable shIL-6R in mice (3-4 wks after injection of cells), mice were treated with either vehicle alone or indicated doses of ONX 0912 (orally, 2 consecutive days every week for 4 weeks); mouse serum samples were subjected to analysis for shIL-6R (mean ± SD; P = .03 for both doses; n = 2). Bars indicate means ± SD (C) Kaplan-Meier survival plot shows a significant increase (P = .03) in survival of mice receiving ONX 0912 (30 or 50 mg/kg) compared with vehicle-treated control. The mean overall survival (OS) was 47.5 days (95% confidence interval; 40-55) in the untreated versus 70 days (95% confidence interval; 65-70) in ONX 0912–treated cohorts.
