In a phase III study (VANTAGE 088 trial) reported in The Lancet Oncology, Meletios Dimopolous, MD, of the University of Athens, and colleagues assessed the addition of the oral HDAC inhibitor vorinostat (Zolinza) to bortezomib (Velcade) in patients with relapsed/refractory multiple myeloma. The study showed a small but significant progression-free survival advantage with vorinostat treatment, a difference that the investigators regarded as of unclear clinical relevance.
In this international double-blind trial, 637 adult patients with multiple myeloma that previously responded to treatment (1-3 regimens) but was currently progressing were randomly assigned to receive bortezomib (1.3 mg/m2 IV on days 1, 4, 8, and 11) plus either vorinostat 400 mg/day (n = 317) or placebo (n = 320) on days 1 to 14 of 21-day cycles. Patients had to have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, no continuing toxic effects from previous treatment, and disease not considered refractory to bortezomib. Progression-free survival was the primary endpoint.
The vorinostat and placebo groups were generally well balanced for baseline characteristics. Median ages were 61 and 63 years, 60% and 58% were male, 54% and 58% were white, and 38% and 37% were Asian. The three most common previous treatments were dexamethasone (85% and 83%), melphalan (63% and 69%), and thalidomide (Thalomid) (5% and 60%).
Median progression-free survival was 7.63 months in the vorinostat group and 6.83 months in the placebo group (hazard ratio [HR] = 0.77, P =.0100). Subgroup analysis showed significant differences in progression-free survival favoring vorinostat in patients without previous proteasome inhibitor treatment, those with previous immunomodulatory treatment, those with nonrefractory primary disease, those aged < 65 years, women, those with ISS score 1, and those with one previous treatment regimen. Median time to progression was 7.73 months vs 7.03 months (HR = 0.79, P = .0184).
Response Rate and Survival
Objective response was observed in 56% of vorinostat patients (complete response in 8%) vs 41% of placebo patients (complete response in 5%) (P < .001). After median follow-up of 14.2 months, there was no difference in overall survival between the vorinostat group (median not reached, 95% confidence interval [CI] = not estimable–not estimable) and the placebo group (median 28.07 months, 95% CI = 28.07–not estimable). At the time of analysis, death had occurred in 22% of vorinostat patients and 25% of placebo patients (HR = 0.858, P = .3496).
Grade 3 or 4 adverse events were more common in the vorinostat group, specifically blood and lymphatic system disorders, gastrointestinal disorders, and general or administration site disorders. The most common grade 3 or 4 adverse events were thrombocytopenia (45% and 24%), neutropenia (28% and 25%), and anemia (17% and 13%). Vorinostat patients also had a higher frequency of grade 3 or higher fatigue, nausea, vomiting, and diarrhea. Nine vorinostat patients had grade 3 upper respiratory tract infections compared with one placebo patient. Serious drug-related adverse events occurred in 19% vs 17% of patients and treatment was discontinued due to a drug-related adverse event in 18% vs 15%. Dose reduction of vorinostat or placebo occurred in 50% of vorinostat and 25% of placebo patients and dose reduction of bortezomib occurred in 63% and 49%.
The investigators concluded: “We showed that addition of vorinostat to bortezomib improves response rates, suggesting clinical synergism. Progression-free survival was not prolonged to a similar degree, possibly because of the toxicity of the combination, which required dose reductions or treatment interruption. Different treatment schedules of bortezomib with vorinostat might improve tolerability of the combination and thus enhance its activity.”
The study was funded by Merck.
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