Combination of Vorinostat Plus Bortezomib for the Treatment of Patients with Multiple Myeloma Who Have Previously Received Bortezomib

Abstract The proteasome inhibitor bortezomib represents an important advance for the treatment of both previously untreated and treated patients with multiple myeloma (MM). However, nearly all patients eventually relapse or become refractory to bortezomib therapy, so there is a continued need for new therapies. Vorinostat is a potent oral inhibitor of Class I and II histone deacetylases (HDACs) and has demonstrated antiproliferative and proapoptotic activity alone and in combination with bortezomib in preclinical models of MM. Preliminary results from an open-label, multicenter Phase I trial of oral vorinostat in combination with bortezomib have shown that the combination is generally well tolerated and effective in heavily pretreated patients with advanced MM (Weber et al. Haematologica2008;93(S1):0640). Patients (aged ≥18 years with an ECOG performance status 0–2) were sequentially enrolled on escalating doses of vorinostat combination therapy using a standard 3+3 design for ≤8 cycles. Cycles were repeated every 21 days and consisted of vorinostat 200 mg bid or 400 mg daily (Days 1–14) in combination with bortezomib 0.7 or 0.9 mg/m2 i.v. on Days 4, 8, 11, and 15 or escalated to 0.9, 1.1, or 1.3 mg/m2 i.v. on Days 1, 4, 8, and 11. The addition of oral dexamethasone 20 mg on Days 1–4 and 9–12 was allowed for disease progression. We now report the safety and efficacy results for a cohort of patients with relapsed/refactory MM who were previously treated with bortezomib but not within 3 months prior to study enrollment. To date, 13 patients who received prior bortezomib therapy have been enrolled in the trial. Drug-related adverse events (AEs) occurred in 11/13 patients; 90% of these AEs were mild to moderate in severity and 5 patients had serious AEs (7 events). One patient experienced Grade 4 thrombocytopenia, and 8 patients experienced Grade 3 drug-related AEs. The most common drug-related toxicities of any grade were fatigue, nausea and diarrhea. Eleven patients have now discontinued treatment: 6 due to progressive disease and 5 due to AEs. For the 13 patients previously treated with bortezomib, the best response was partial response in 5 patients (duration 99 to 203 days), minimal response in 1 patient (duration 122 days) and stable disease in 7 patients (duration 25 to 320 days). These preliminary data indicate that in this important subset of patients with MM who have relapsed while on, or were refractory to, previous bortezomib therapy, this combination of bortezomib and vorinostat (+/− dexamethasone) administered in a 21-day cycle shows activity, with acceptable tolerability. Further to these promising early findings, data will be presented according to whether patients had relapsed or refractory MM after prior bortezomib. The effect of adding dexamethasone to the combination of vorinostat and bortezomib will also be presented. Supplementary studies in patients clearly resistant to bortezomib are warranted to determine the additional effect of vorinostat in this combination.