Xavier Leleu, MD, PhD
Dr. Leleu indicated no relevant conflicts of interest.
San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31:448-455.
Enthusiasm for the use of new approaches to treatment can be influenced by clinical trial design. For example, a novel agent may be shown to be active as first-line therapy but may have a more important place in treatment of relapsed disease in patients who have failed standard therapy and are left with no effective second-line options. Another potential source of bias is length of follow-up when a survival benefit is demonstrated based on data analysis performed at an early time point calculated to yield a statistically significant benefit based on the number of patients enrolled in a particular study. Such relatively early analysis may also obscure adverse effects that become apparent only after a longer follow-up period. This latter issue is particularly important for patients with myeloma in whom the risk of developing a second primary malignancy may increase over time. Because of these concerns, physicians treating patients with multiple myeloma are certain to welcome the results of the rigorous studies of San Miguel and colleagues.
The combination of bortezomib (Velcade®), melphalan, and prednisone (VMP) became the standard of care for treatment of transplant-ineligible patients with multiple myeloma (MM), at least in Europe, following publication of the initial results of VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone), an international, phase III study that compared outcomes in patients randomized to receive VMP with those randomized to receive MP.1 That study served as the pivotal trial that led to approval in 2008 by both the U.S. FDA and the European Medicines Agency of bortezomib as initial therapy for myeloma in patients ineligible for transplant, including the elderly, and, consequently, VMP is one of the most frequently prescribed regimens worldwide. The data from the initial analysis, with its relatively short median follow-up of 16.3 months, showed that VMP was superior to MP across all efficacy endpoints, including response rates, time to progression, and overall survival (OS).
In the current study, the authors report the analysis of data from the VISTA trial after a median follow-up period of five years. This analysis was undertaken both to determine whether the significant OS benefit observed in the initial study was maintained after five years, taking into account the effects of salvage therapy, and to explore for the first time the incidence of second primary malignancies in the two treatment arms. OS benefit with VMP was confirmed across all prespecified patient subgroups that included patients 75 years and older, those with stage III disease, and those with renal insufficiency (creatinine clearance of < 60 ml/min). A 31 percent reduction in risk of death was observed for patients in the VMP arm, and the OS for the two groups was 56.4 months and 43.1 months for the VMP cohort and the MP cohort, respectively. Sixty-three percent of VMP patients and 73 percent of MP-treated patients received salvage therapy. Median time to next therapy was significantly longer for the VMP arm (30.7 months) compared with the MP arm (20.5 months), whereas survival from the start of subsequent therapy was similar for the two groups (28.1 months for the VMP group compared with 26.8 months for the MP group). Importantly, exposure-adjusted incidence rates for malignancies were similar for the two groups and consistent with background rates.
Demonstrating an OS benefit for VMP that included the longer follow-up period and that allowed for salvage therapy, including crossing over to bortezomib for the MP cohort, supports the conclusions drawn from the earlier analysis of the VISTA study that demonstrated superior efficacy for VMP. Notably, the OS for patients in the MP arm of VISTA was longer than the median OS observed for MP-treated patients reported in previous phase III trials and meta-analyses. Thus, the OS benefit observed in VISTA was not due to a substandard outcome for the MP-treated group. The current studies confirm the efficacy and safety of VMP, and based on the studies of San Miguel and colleagues, this regimen can be considered a standard of care for first-line treatment of transplant-ineligible patients with MM, and, consequently, for another regimen to become standard of care for this group of patients, superiority to VMP must be demonstrated.
1. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.
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