María-Victoria Mateos, MD
A higher cumulative dose of the proteasome inhibitor bortezomib, 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. Abstract 1968
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% in 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 <.0001).
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 = .04).
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 two 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.
For older patients with multiple myeloma who are not candidates for stem cell transplantation, melphalan has a proven efficacy and has played a critical role in standard therapeutic regimens. The use of novel agents such as proteasome inhibitors and immunomodulatory agents has showed improved outcomes (SEER data 2003-2009); therefore, adding a novel agent to melphalan-containing regimens has become an effective strategy. At the 2013 annual meeting of the American Society of Hematology, two oral abstracts pertaining to the use of melphalan were presented that could lead to a change in the standard of care for this patient population.
of care for this patient population. The phase III VISTA trial had previously demonstrated improvement in overall survival (OS) in transplant-ineligible patients who were treated with a combination of bortezomib, melphalan, and prednisone versus melphalan and prednisone alone.1 During an oral abstract presentation, Maria-Victoria Mateos, MD, reported a retrospective analysis of the data from the VISTA trial showing a survival benefit in patients who received a higher cumulative dose of bortezomib. Patients who received the lower overall dose were slightly older and discontinued therapy more frequently for adverse effects, choice, disease progression, and mortality; those who received the higher cumulative doses—indicating longer duration of therapy—had improved OS. A strategy to achieve longer duration of therapy could be to modify doses or schedules and to manage toxicities, especially for older patients, thus maximizing cumulative doses of bortezomib.
While adding novel agents to melphalan-containing regimens can be efficacious and improve survival, the toxicities of melphalan cannot be ignored. Melphalan can cause significant cytopenias and is associated with a risk of secondary malignancies such as myelodysplasia or leukemia,2 an issue for patients who are surviving longer due to improved therapies.
During the plenary session, Thierry Facon, MD, presented the results of the FIRST trial, reporting the combination of continuous lenalidomide and low-dose dexamethasone (continuous Rd) versus melphalan, prednisone, and thalidomide improved progressionfree survival and may improve OS for older, transplant-ineligible patients. Patients who received continuous Rd were more likely to continue therapy, had a decreased incidence of secondary hematologic malignancies, and experienced less cytopenia.
This new data could ultimately lead to a shift in the standard of care away from melphalan and the associated toxicities. Unanswered questions remain as to the definitive impact on OS, although the trend is favorable. Clearly, for now, the use of continuous Rd can be an effective, safe, and tolerable regimen for older patients with myeloma.