A subanalysis of the VISTA trial was presented at the ASH Congress in New Orleans, showing that a higher cumulative dose of bortezomib resulted in a better outcome in patients with previously untreated multiple myeloma. This would imply that a less intensive regimen is reasonable to ensure therapy in combination with melphalan and prednisone for a longer period of time and not to risk early discontinuations due to side effects.
(ag) Back in 2008, San Miguel and colleagues found in their VISTA (phase III) trial [1] that bortezomib-melphalan-prednisone (VMP) was significantly superior to melphalan and prednisone (MP) alone in terms of response rates (complete response at 30 vs. 4%), time to progression (24 vs. 16.6 months), and overall survival in patients with newly diagnosed multiple myeloma (MM) who were not eligible for high-dose therapy. In 2013, they were able to confirm the results and show that VMP, compared to MP, both maintained the benefit in overall survival during these five additional years of observation and did not increase the risk of secondary malignancies [2].
“The duration of VMP therapy dictated by the VISTA protocol was nine six-week cycles (54 weeks), which is the standard duration of MP therapy. However, there is no widely supported recommendation on the optimal duration of bortezomib treatment, and it is therefore unknown whether this period is necessary and reasonable for an optimal outcome with the particular bortezomib dose used. One may ask the question: Does a longer accumulation, that is, a longer accumulation of bortezomib doses, and therefore a higher total dose, lead to better survival data?” said Maria-Victoria Mateos, MD [3], Salamanca. “The goal of our analysis was to find out. Using data from the VMP arm of the VISTA trial, we wanted to check whether or not the increased cumulative dose of bortezomib causes a better long-term outcome and what the consequences may be for the patient.”
Administered at a median of 39 mg/m2
In the VISTA study regimen, bortezomib was administered at a dose of 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 in the induction phase (cycles 1-4) and on days 1, 8, 22, and 29 in the maintenance phase (cycles 5-9). Melphalan and prednisone doses were the same in both arms (VMP and MP). The planned maximum dose of bortezomib was 67.6 mg/m2, with a median total dose of 39 mg/m2. Using this limit, we now investigated the influence on overall survival.
Better overall survival with higher total dose
Among all 340 patients who received bortezomib at least once, the total dose given varied from 1.3 to 71.2 mg/m2 and the treatment duration from four to 424 days. Patients in the lower-dose group were older than those with higher total doses; otherwise, the characteristics within the two groups were well balanced.
Results: Indeed, overall survival was significantly longer in patients with a higher (≥39 mg/m2) cumulative dose than in those with a lower (<39 mg/m2), 66.3 vs. 46.2 months (p=0.0002). In addition, the reasons for treatment discontinuation differed greatly between the two groups: While there were early treatment discontinuations in the overall lower-dose group due to side effects, progressive disease, or death, this was less common in the higher-cumulation group.
After 180 days, an overall survival analysis was performed again to exclude some confounding factors from the initial phase of the study (early deaths due to toxicity, etc.) from the calculation. This study also confirmed the significantly better long-term survival in the cumulative higher-dose group (≥39 mg/m2), 60.4 versus 50.3 months in the lower-dose population (p=0.0356).
Less intensive regime for a longer time
“What do these results mean now? I think they clearly show that a higher cumulative dose of bortezomib leads to improved overall survival. This higher dose ultimately reflects a prolonged duration of therapy and/or a higher dose intensity. Accordingly, assuming that prolonged treatment yields better outcomes, it is advisable to maintain patients on bortezomib therapy by judiciously dividing doses and practicing good side effect management. This allows a higher total dose to be accumulated over a longer period of time,” Dr. Mateos concluded.
The reason for early discontinuation of therapy was mainly toxicity and apparently also older age. A less intensive VMP regimen could achieve a longer duration of therapy and thus a better outcome, which has also been shown in previous studies [4].
Source: 55th ASH Annual Meeting, December 7-10, 2013, New Orleans.
Literature:
- San Miguel JF, et al: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008 Aug 28; 359(9): 906-917. doi: 10.1056/NEJMoa0801479.
- San Miguel JF, 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 Feb 1; 31(4): 448-455. doi: 10.1200/JCO.2012.41.6180. epub 2012 Dec 10.
- Mateos MV, 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. ASH Abstract #1968.
- Mateos MV, et al: Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010 Oct; 11(10): 934-941. doi: 10.1016/S1470-2045(10)70187-X. Epub 2010 Aug 23.
InFo Oncology & Hematology 2014; 2(3): 27-28.
