Multiple myeloma is a growing health concern for the elderly. In Western Countries, age-adjusted annual incidence for multiple myeloma is 5.6 per 100,000. Median age of multiple myeloma patients at diagnosis is ≥70 years of age. Individuals less than 65 years old comprise 37% of newly diagnosed multiple myeloma patients; 26% of newly diagnosed patients are 65 to 74 years of age, and 37% are older than 75 years of age. Like disease prevalence, estimated five-year relative survival rates for multiple myeloma decrease with age. Survival rates have increased over the last two decades due to the availability of novel therapeutic agents for multiple myeloma. Overall, survival rates have increased by 29% to 35%.1
Multiple myeloma is an incurable, but treatable, disease. Oncologists who treat multiple myeloma patients have a large diversity of therapeutic agents at their disposable. The challenges of treatment-refractoriness and disease relapse have necessitated continuous development of novel therapeutic agents and repurposing of current standard therapies. A quick search of the clinicaltrials.gov database displays the large diversity of ongoing and completed clinical trials for emerging therapies in multiple myeloma, many of which were presented at the 53rd Annual Meeting of the American Society for Hematology (ASH) in December, 2011.
Vorinostat (Zolinza)
Vorinostat is being investigated in Phase 3 clinical trials for the treatment of multiple myeloma, the results of which were presented at ASH 2011. Vorinostat, an oral histone deacetylase (HDAC) inhibitor manufactured by Merck, that was previously approved by the Food and Drug Administration for the treatment of cutaneous T-cell lymphoma, has also shown promising activity in patients with relapsed and/or refractory multiple myeloma. Preclinically, vorinostat has been shown to inhibit the enzymatic activity of several HDAC molecules: HDAC-1, HDAC-2, HDAC-3, and HDAC-6, at low nanomolar concentrations (IC50 <86nM). The drug has been investigated in an international, Phase 3, multicenter, randomized, double-blind study that compared several outcome measures and the safety profile of vorinostat alone or in combination with bortezomib in 637 participants with progressive multiple myeloma. Merck presented these results as VANTAGE 088 (Vorinostat in Combination with Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma: A Global, Randomized Phase 3 Trial) at ASH 2011.2
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VANTAGE 088 met its primary end point: time to disease progression. Progression-free survival data were collected from 417 participants and analyzed. Statistical analysis revealed that vorinostat-bortezomib yielded a 23% reduction in risk of disease progression compared to bortezomib monotherapy (HR=0.774, P=0.01).3 Overall response rate (ORR) was also significantly increased with vorinostat-bortezomib combination therapy compared to bortezomib monotherapy (56% vs. 41%, respectively, P<0.0001). Overall survival was also increased in participants treated with vorinostat combination therapy, although no statistical significance was found. Participants treated with vorinostat experienced more adverse events than bortezomib monotherapy: diarrhea (62% vs. 43%), nausea (61% vs. 39%), thrombocytopenia (55% vs. 33%), vomiting (45% vs. 26%) and fatigue (40% vs. 31%); P<0.05 for all grades.3
At ASH 2011, Merck also presented the complete results from the VANTAGE 095 trial (Vorinostat in Combination with Bortezomib in Salvage Multiple Myeloma Patients: A Global Phase 2b Trial [Abstract# 480]).4 This open-label, single-arm study investigated the use of a vorinostat-bortezomib regimen in two patient populations: bortezomib-refractory patients and patients that were considered to be refractory, intolerant or ineligible for immunomodulator-based multiple myeloma regimens. This international, multicenter study enrolled 143 participants from 41 centers in 12 countries across Asia-Pacific, Europe, and North America. Other inclusion criteria included a history of treatment with at least two anti-myeloma regimens and/or a history of relapse or disease progression following systemic therapy.
