Reports

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MEDI-NEWS - Based on: Mateos et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: Updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol 2010;28(13):2259-66.

June 2010

New extended data from the multinational VISTA (Velcade as Initial Standard Therapy in multiple myelomA) study that established a combination of bortezomib/melphalan/prednisone (VMP) as the first-line standard for multiple myeloma in patients who are not candidates for high-dose chemotherapy has found that the overall survival (OS) advantage persisted through subsequent rescue therapies. In the phase III study, the numerous advantages of VMP over the previous standard of melphalan and prednisone (MP) included OS as well as progression-free survival (PFS) (San Miguel et al. N Engl J Med 2008;359:906-17). In the extended follow-up, the relative survival advantage persisted, eliminating any concern that upfront use of bortezomib adversely affects subsequent options for therapy.

In the initial VISTA report, there was a median follow-up of 16.3 months at which time 13% of the VMP patients vs. 22% of the MP patients had died, associating VMP with an overall 39% reduction in the risk of death (HR 0.61; P=0.008). The most recent study provides data on an extended median follow-up of 36.7 months, during which time most patients had received rescue therapies. After this extended follow-up, the overall reduction in the risk of dying was almost unchanged at 35% (HR 0.65; P<0.001) for those whose initial treatment was VMP rather than MP. The median time of OS in the MP group at the most recent follow-up was 43 months but median OS had not yet been reached in the VMP group. At three years, 68.5% of the VMP patients vs. 54% of the MP patients remained alive.

Consistent Results with Rescue Therapy

Consistent with these results, those who were initially randomized to VMP generally achieved a similar response to subsequent rescue therapies upon relapse, including regimens containing thalidomide, lenalidomide or bortezomib. This addressed concerns that early use of bortezomib might limit subsequent options. Survival rates with rescue therapies did not differ significantly when those who did or did not receive bortezomib upfront were compared. Instead, the data suggest that the initial advantage persists irrespective of subsequent therapies. This has been increasingly difficult to show due to the introduction of novel rescue therapies that dilute the importance of the first course of treatment.

According to authors, this confirmed survival advantage represents an important finding as an OS benefit has not been consistently reported in other studies of novel agent-based regimens vs. MP. They noted, in particular, that three phase III studies comparing a combination of melphalan/prednisone/thalidomide (MPT) to MP failed to show a survival advantage despite greater initial response rates. Although one hypothesis was that early use of aggressive therapy limited the efficacy of subsequent treatments, it is perhaps more likely that the advantage was diluted by the confounding impact of subsequent therapies containing novel agents. It is increasingly difficult to prove that one upfront oncologic regimen is better than another as measured by an independent, statistically significant improvement in OS. In VISTA, the OS benefit with VMP vs. MP was seen both overall and in an analysis restricted to patients who had received a subsequent therapy, despite 50% of patients treated with MP being rescued with bortezomib-based therapy in the relapse setting, as the authors reported. At the time that the most recent analysis was completed, 69% of those in the MP group (52% in the VMP group) had received subsequent therapy.

Safety

The extended data also reinforced the safety of first-line VMP. At the most recent follow-up, treatment-related deaths had been recorded in 2% of each of the VMP and MP study arms. Discontinuation rates for adverse events were 15% on VMP and 14% on MP. The types of grade 3 or 4 adverse events that occurred in 5% or more of patients were similar, including neutropenia, thrombocytopenia and anemia, with the exception of peripheral neuropathy, which occurred in 13% of the VMP group but in none of the MP group. However, the newest follow-up demonstrated that the difference in grade 3 and 4 adverse events was concentrated in the first four cycles, when the rates for grade 3 or 4 events was 80% for VMP vs. 66% for MP. In cycles five to nine, the rates were 62% and 63%, respectively. Rates of peripheral neuropathy, in particular, declined over greater exposure and did not appear to limit the ability of patients to take subsequent rescue therapies, including those containing bortezomib.

After prolonged follow-up, the rate of improvement or resolution of peripheral neuropathy events on the VMP arm was 79%, demonstrating that this toxicity is reversible in the majority of cases. Indeed, 60% of events had resolved completely to baseline by data cutoff (in this most recent analysis) within a median of 5.7 months, reported the authors. They noted that these findings are corroborated by other published studies showing reversible peripheral neuropathy with bortezomib.

OS Benefit Across Subgroups

The survival advantage of VMP relative to MP is attributed to the longer time to next treatment and longer treatment failure intervals. However, the OS benefit was observed both in the total study population and in those who received second- or third-line therapy. It was also observed specifically in those who received bortezomib as one of these second- or third-line therapies. The authors emphasized that this demonstrates that using bortezomib-based treatment in the first-line setting provides greater survival benefit to patients compared with the approach of administering first-line treatment with conventional agents and saving bortezomib and other novel-based treatment for salvage.

The data were evaluated across a variety of subgroups in an effort to detect anyone who might not have achieved a relative benefit with VMP over MP, but none was found. Although patients older than age 75 had a shorter OS than younger patients, the effect appeared to be age-related, not treatment-related. In those with impaired renal function (creatinine clearance <60 mL/min), survival after the start of second-line therapy was shorter than those without renal impairment if the subsequent regimen contained thalidomide or lenalidomide, but the difference was not significant for those who received second-line bortezomib. The authors cautioned that these are retrospective analyses without clear implications for clinical practice but they did indicate that the overall data support a consistent advantage of VMP over MP.

Summary

The extended follow-up of the VISTA trial, which was credited with changing the first-line standard treatment of multiple myeloma in individuals who are not candidates for high-dose chemotherapy, has confirmed an OS advantage extending through subsequent treatments, including second- or third-line therapies containing bortezomib. The ability to demonstrate a survival advantage across subsequent therapies has been increasingly difficult because of the availability of novel and effective rescue therapies, making the newly released results a particularly strong confirmation of the value of the VMP regimen over the previous standard.