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The initial results of the VISTA study, evaluating efficacy and safety of bortezomib-melphalan-prednisone (VMP) compared to melphalan-prednisone (MP), demonstrated that whilst VMP provided a benefit over MP, the intensive dosing of bortezomib (1.3 mg/m2 twice weekly for four 6-week cycles followed by once weekly for five 6-week cycles) especially during the first four weeks was associated with increased risk of treatment-related toxicity.1
However, the received cumulative dose of bortezomib rather than the planned dose was shown to contribute to the optimal clinical outcome with VMP, with reduced toxicity but a similar level of efficacy seen in studies using a less intense, once-weekly dosing.2,3 Therefore, the recommended dosing schedule was modified and is currently nine 6-week cycles, once-weekly.4,5 The recent phase III ALCYONE trial, evaluating the combination of daratumumab, a CD38-targeting monoclonal antibody, with VMP vs VMP alone, used a different bortezomib dosing regimen (twice-weekly during Cycle 1 and once weekly during Cycles 2–9).6 Read about the updated results from the ALCYONE here.
In order to compare the efficacy of the original bortezomib dosing regimen with the less-frequent regimen over nine 6-week cycles, Dolly Parasrampuria and colleagues conducted a comparison of bortezomib exposure and outcomes using an exposure-response (E–R) analysis of VMP dosing schedule in VISTA and ALCYONE studies.7
The E–R analysis was performed on data from transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) enrolled in randomized, open-label, multicenter phase III studies VISTA (NCT00111319) and ALCYONE (NCT02195479). The dosing schedules were as follows:
For consistency in the comparisons to ALCYONE data, the primary endpoint of VISTA, which was time to disease progression, was re-analyzed based on the International Myeloma Working Group (IMWG) criteria. The authors assessed the potential association between cumulative bortezomib dose for VMP dosing schedules and response, including complete response (CR), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Table 1. Baseline disease and patient characteristics of patients receiving VMP
ISS, International Staging System; VMP, bortezomib-melphalan-prednisone *High cytogenetic risk was defined as the presence of t(4;14), t(14;16), or del17p abnormalities |
||
Characteristics |
VISTA (n = 344) |
ALCYONE (n = 356) |
---|---|---|
Age, years Median (range) ≥ 75, % |
71 (57–90) 31 |
71 (50–91) 30 |
ISS disease stage, % I II III |
19 47 35 |
19 45 36 |
Cytogenetic profile*, % Standard risk High risk |
85 15 |
85 15 |
Table 2. Cumulative bortezomib dose and duration of treatment for patients receiving VMP in VISTA and ALCYONE studies
IQR, interquartile range; SD, standard deviation; VMP, bortezomib-melphalan-prednisone |
||
Parameter |
VISTA (n = 340) |
ALCYONE (n = 354) |
---|---|---|
Cumulative bortezomib dose, mg/m2 Mean (SD) Median (IQR) |
36.6 (20) 38.5 (18.5–54.3) |
37.5 (15.2) 42.2 (27.2–50.6) |
Number of cycles Mean (SD) Median (IQR) |
5.8 (3.1) 6 (2–9) |
7.2 (2.8) 9 (5–9) |
Given as ≥ 39 mg/m2 vs < 39 mg/m2
The data from the E–R analysis of VMP dosing schedule in VISTA and ALCYONE trials suggests that a less frequent bortezomib dosing regimen offers equal benefits to patients as the intense dosing while improving tolerability and allowing longer treatment. However, the authors note that the intensive twice-weekly bortezomib dosing schedule is still the favored option for patients with renal impairment and extensive bone involvement.7,8
The VISTA trial was the phase III randomized trial published more than 10 years ago and demonstrated that bortezomib added to melphalan and prednisone in the non-transplant eligible population prolonged not only the PFS but the OS. Bortezomib was given twice a week during the first four cycles followed by weekly administration during the following five cycles and this resulted in a 13% and 14% of Grade 3–4 peripheral neuropathy and gastrointestinal toxicity, respectively. The Spanish Myeloma Group prompted a trial in 2005 to prove that twice a week bortezomib administration during the first cycle followed by weekly administration was equally effective and safer. The explanation was the bortezomib cumulative dose. The median was 39 mg/m2 in the VISTA, similar to that reported in the Spanish Myeloma Group and in the VISTA trial, patients receiving at least 39 mg/m2 as cumulative dose had a longer OS.
This was the rationale for using the same scheme in the ALCYONE trial based on bortezomib twice a week for the first cycle followed by weekly administration for the subsequent eight cycles and the median bortezomib cumulative dose was 42.2 mg/m2 indicating that the cumulative bortezomib dose is warranted.
In the ALCYONE study it was also demonstrated that the bortezomib cumulative dose higher than 39 mg/m2 was associated with longer OS
Conclusion
The bi-weekly administration of bortezomib during the first cycle of treatment followed by weekly administration in the non-transplant eligible population allow the patients to receive a less intensive scheme with better safety profile. This allows to maintain the scheme with lower rates of discontinuations and higher bortezomib cumulative doses with impact in the survival outcomes.
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