SAN DIEGO, CA—Final results of the international, multicenter, Phase 3 VISTA trial confirmed that after 5 years of follow-up, bortezomib-melphalan-prednisone (VMP) demonstrated a persistent, significant overall survival (OS) benefit versus melphalan-prednisone (MP)—a 13.3 median month increase—in patients with previously untreated multiple myeloma (MM) ineligible for high-dose therapy investigators reported at the 53rd American Society of Hematology Annual Meeting and Exposition. Additionally, in data presented for the first time, an exploratory analysis showed no increased risk of second primary malignancies (SPMs).
Median OS for patients with MM has improved over the past two decades, associated with use of autologous stem cell transplantation for younger patients and novel agents such as bortezomib, thalidomide, and lenalidomide. Due to availability of multiple highly active treatment options for subsequent therapy upon relapse/progression, it is challenging to demonstrate improved OS with novel first-line therapy. One of the frequent criticism of studies that show positive results with experimental treatments are that data are preliminary, notably for OS; therefore, confirmation of benefit after long-term follow-up is essential.
The initial report of the VISTA trial demonstrated that VMP was superior to MP across all efficacy endpoints, including response rates, time to progression, and OS. Subsequently, centralized M-protein assessment for response/progression was stopped due to a highly significant initial benefit observed for TTP, the primary endpoint, which precluded subsequent updates of response rate and TTP. Per protocol, however, patients were to be followed for up to 4.5 years following the last-patient-in date for OS and use of subsequent anti-MM therapy.
After 36.7 months, a significant OS benefit was shown with VMP vs MP. Jesús F. San Miguel, MD, PhD, of Hospital Clinico Universitario, Salamanca, Spain, and colleagues then performed a final updated OS analysis of VISTA.
In the initial study, patients were randomized (1:1) to nine 6-week cycles of VMP (344 patients; bortezomib 1.3mg/m2 Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycles 1–4 and Days 1, 8, 22, and 29 of Cycles 5–9; melphalan 9mg/m2 Days 1–4, prednisone 60mg/m2 Days 1–4, all cycles) or MP alone (338 patients). Patients were followed at least every 12 weeks for survival and successive treatments. SPM information was collected for 655 (96%) of patients. As of the data cut-off point of March 24, 2011, only 16 patients (5%) in each arm had been lost to follow-up.
After a median follow up of 60.1 months, with 95% of patients available for follow-up, median OS was 56.4 months for patients who received VMP versus 43.1 months for patients who received MP (HR 0.695, P=0.0004). There was a 31% reduced risk of death with the VMP regimen. (See Figure). Five-year OS rates were 46.0% for VMP and 34.4% for MP. The OS benefit seen with VMP was seen across patient subgroups, including individuals aged ≥75 years (median 50.7 vs 32.9 months, HR 0.71), patients with International Staging System stage III MM (median 42.1 versus 30.5 months, HR 0.67), and those with CrCl <60mL/min (median 56.8 vs 36.7 months, HR 0.70). However, no significant difference was seen in patients with documented high-risk cytogenetics (46 patients).
Sixty-three percent of VMP and 73% of MP patients received subsequent MM treatments, which included thalidomide, lenalidomide, bortezomib, cyclophosphamide, melphalan, and dexamethasone. Use of rescue therapies were generally similar between arms, except for a lower proportion of VMP vs MP patients receiving subsequent bortezomib. Among patients who received subsequent therapies, investigator-assessed response rates to subsequent bortezomib were 50% vs 58% following VMP (ie, bortezomib retreatment vs following MP) and, to subsequent thalidomide, 46% and 55%, respectively.
In analyzing OS based on subsequent therapies, questions the investigators asked included, does VMP induce more resistant relapses? Is there also an OS benefit in favor of VMP in relapsing patients? And, what about using MP upfront and reserving bortezomib for time of relapse? Survival from start of subsequent therapy was found to be similar following VMP and MP, with VMP not inducing more resistant relapses. OS was prolonged with VMP as opposed to MP (median 55.7 months vs 46.4 months; HR 0.745, P=0.0162); OS was also prolonged with VMP vs using MP first-line followed by salvage bortezomib (HR 0.714; P<0.0029).
Another important issue in MM is risk of developing SPMs, Dr. San Miguel said. This is due to patients living longer from diagnosis. Population studies have shown that patients with MM are at increased risk of specific SPMs, notably acute myeloid leukemia. In particular, melphalan is associated with increased risk of secondary acute leukemia, and lenalidomide maintenance post-transplant and melphalan-lenalidomide have shown an imbalance in incidence of SPM, including myeloid and lymphoid leukemias.
An exploratory analysis for SPM risk with long-term bortezomib use in this study showed no difference in incidence proportions or exposure-adjusted incidence rates between arms. (See Table). The exposure period was found to be asymmetrical in that more patients remained alive longer in the VMP vs the MP arm. Rates on both arms were consistent with incidence rate in the general population aged 65–74 years (VMP 0.0166 per patient-year, MP 0.013 per patient-year) (0.019, from the Surveillance Epidemiology and End Results database).
The study investigators concluded the substantial long-term benefit conferred with VMP was demonstrated across patient subgroups and was maintained after 5 years of follow-up, despite substantial use of novel-agent-based salvage therapies, which continues to confirm the benefit of the experimental arm.