Vorinostat Combined with Bortezomib In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Update on the Vantage Study Program
Authors: Siegel David S , Jagannath Sundar , Hajek Roman , Dimopoulos Meletios A. , Yoon Sung-Soo , Lonial Sagar , Laubach Jacob P. , Graef Thorsten , Pietrangelo Dina , Lupinacci Lisa , Reiser David , Anderson Kenneth C. 
Published: October 2019

Abstract
Abstract 1952

Background:
Initial clinical response rates have improved significantly with current treatments for multiple myeloma (MM). However, most patients eventually relapse or become refractory to approved agents, prompting the development of additional targeted agents and combination regimens. Vorinostat is a first-in-class oral histone deacetylase inhibitor that regulates the expression of genes and proteins involved in tumor growth and survival, and is approved in the United States for the treatment of patients with advanced cutaneous T-cell lymphoma in whom prior therapies have failed. Bortezomib, a reversible proteasome inhibitor, is approved for the treatment of patients with MM who have received at least 1 prior therapy. The synergistic effects of vorinostat and bortezomib have been shown in preclinical studies and confirmed in Phase I trials in patients with relapsed/refractory (RR) MM, producing objective response rates (ORRs; partial response or better) of up to 42% in all patients (including those with bortezomib-refractory disease) and overall clinical benefit of up to 90%.

Methods:
Vantage 088 is a global, Phase III, randomized, double-blind study to investigate the safety and efficacy of vorinostat vs placebo in combination with bortezomib in patients with relapsed MM and progressive disease after 1–3 prior antimyeloma regimens. The primary objective is to determine the duration of progression-free survival, with a planned enrollment of 742 patients. Overall survival, time to progression, ORR, tolerability, and patient-reported outcomes (PROs) will be included as secondary and exploratory outcomes. A distinctive aspect of this study design involves the evaluation of PROs using validated instruments, including quality-of-life (QoL) questionnaires for cancer patients (EORTC QLQ-C30) and myeloma patients (EORTC QLQ-MY20) and the EuroQoL-5D, presenting an opportunity to correlate PROs with efficacy and safety data. Interim analysis will take place when at least 126 events have occurred. Vantage 095 is a Phase IIB open-label study to investigate the efficacy and tolerability of vorinostat combined with bortezomib in patients with RR MM who had received ≥2 prior antimyeloma regimens; were refractory to bortezomib; and were relapsed, refractory to, intolerant of, or ineligible for other MM therapies, including immunomodulatory drugs (IMiDs). The primary objective is to determine the ORR, with a planned enrollment of 142 patients.
In both studies, patients receive 21-day cycles of intravenous bortezomib (1.3 mg/m2; days 1, 4, 8, and 11) combined with oral vorinostat 400 mg (or matching placebo in Vantage 088) once daily on days 1–14. Efficacy is assessed using European Bone and Marrow Transplantation Group criteria. Adverse events (AEs; including clinical and laboratory events) are assessed and recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

Results:
Vantage 088: As of June 11, 2010, 349 patients (range, 1–17 cycles) were randomized. Patients received a median of 2 prior regimens (range, 1–3 regimens; 25% prior bortezomib, 48% prior thalidomide, and 12% prior lenalidomide).
Vantage 095: As of June 11, 2010, 108 patients were enrolled. Patients (median age, 62 y; 57% men; 67% with Eastern Cooperative Oncology Group performance status 1) were heavily pretreated (median prior regimens, 5 [range, 2–17]). Interim efficacy data were reviewed in January 2010 by an independent data monitoring committee (DMC) for the first 43 patients enrolled; the futility threshold was passed, and final results are expected to be available 2Q2011.

Conclusion:
2 ongoing global, multicenter, investigational trials are evaluating the efficacy and safety of combined vorinostat and bortezomib in patients with RR MM and are rapidly accruing patients. The Vantage 088 trial has passed the initial safety evaluations by the DMC, while interim results from Vantage 095 suggest that combined vorinostat and bortezomib may have clinical activity in patients with RR MM who are refractory to bortezomib and IMiDs and ineligible for other regimens.

Disclosures:
Siegel: Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board, Consultancy. Off Label Use: Vorinostat Combined with Bortezomib for treatment in Multiple Myeloma. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Ortho Biotech: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Hajek:Janssen-Cilag: Honoraria; Celgene: Honoraria; Merck, Sharp, and Dohme: Honoraria. Dimopoulos:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Graef:Merck Research Laboratories: Employment. Pietrangelo:Merck Research Laboratories: Employment. Lupinacci:Merck Research Laboratories: Employment. Reiser:Merck Research Laboratories: Employment. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.