María-Victoria Mateos, MD
A higher cumulative dose of the proteasome inhibitor bortezomib (Velcade), including a longer duration of treatment and/or higher dose intensity, appears to improve overall survival (OS) in patients with previously untreated multiple myeloma (MM), according to a retrospective analysis of the phase III VISTA study.
Those patients in VISTA who received a cumulative bortezomib dose ≥39 mg/m2
had a median OS that was 20 months longer than those who received a cumulative dose <39 mg/m2
, said María-Victoria Mateos, MD, at the 55th Annual Meeting of the American Society of Hematology.
Continued bortezomib maintenance treatment to increase cumulative dose and drug exposure may, therefore, be important to improving OS in newly treated patients with MM, according to Mateos, from Hospital Universitario Salamanca, Spain.
“Continued bortezomib treatment following attainment of complete response may also be associated with improved OS,” she added.
In VISTA, 682 untreated, newly diagnosed patients with MM, who were not candidates for stem cell transplantation, were randomized to bortezomib in addition to melphalan and prednisone or melphalan plus prednisone alone. Patients randomized to bortezomib had a 35% reduction in risk of death at any time. Overall survival was 68.5% at 3 years, in the bortezomib group compared with 54% the melphalan and prednisone arm. At 5 years, the risk of mortality was reduced by
31% with the addition of bortezomib to the regimen, despite the significant use of subsequent therapy.
The current analysis examined the response in the 340 patients randomly assigned to bortezomib, half of whom received a cumulative dose <39 mg/m2
and half of whom received ≥39 mg/m2
. Median treatment durations were 2.5 months and 12.1 months, respectively. Patient characteristics were balanced between the two groups, except for age (mean age: 74 years vs 71 years, respectively; P
Median OS was 66.3 months in patients receiving ≥39 mg/m2
versus 46.2 months in those receiving <39 mg/m2
(hazard ratio [HR] = 0.53; P
<.0001). The HR for OS between the two groups when adjusted for age was .56 (P
= .0002) in favor of the higher cumulative dose group.
Among the patients who survived past the 180-day threshold, median OS was longer in the higher versus lower cumulative dose group (60.4 vs 50.3 months; HR = .709; P
An exploratory analysis assessed the impact of continuing treatment following attainment of a complete response (CR) on OS. Among the 102 patients in VISTA who achieved a CR, the median OS was 55.5 months for those who received 2 or fewer treatment cycles beyond CR compared with 64.6 months for those who received >2 treatment cycles beyond CR (HR = .71). The median duration of CR was 16.9 months and 20.3 months, respectively.
Eighty-six percent of patients in the higher cumulative dose group completed treatment, compared with 31% in the lower cumulative dose group. According to the authors, early discontinuation was primarily associated with toxicity and appeared more common in older patients. Reasons for discontinuation of therapy included adverse events (27% with <39 mg/m2
vs 4% with ≥39 mg/m2
), patient choice (17% vs 2%), disease progression (9% vs 5%), and mortality (8% vs 1%).
Maintenance bortezomib can be achieved through several approaches, the authors reported, including switching to the subcutaneous formulation, modifying the dose/schedule, and proactively managing adverse events.
Mateos M-V, Richardson PG, Shi H, et al. Higher cumulative bortezomib dose results in better overall survival (OS) in patients with previously untreated multiple myeloma (MM) receiving bortezomib-melphalan-prednisone (VMP) in the phase 3 VISTA study. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 1968.
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