The VISTA clinical trial: bortezomib plus melphalan and prednisone for treatment of transplant ineligible patients

In a randomized, open-label, phase 3 study, the use of melphalan plus prednisone (MP) either with or without the addition of bortezomib, was compared in a cohort of previously untreated Multiple Myeloma (MM) patients who were ineligible for high-dose therapy. Patients (n=682) were recruited from December 2004 to September 2006 across 151 centers worldwide. The study, published in the New England Journal of Medicine in August 2008, was led by Jesús San Miguel and Paul G. Richardson, currently based at the Clinica Universidad de Navarra, Pamplona, Spain, and The Dana Faber Cancer Institute, Boston, USA, respectively. The primary end point was time to disease progression (TTP). Secondary end points included the rate of complete response (CRR), duration of response (DoR), time to subsequent myeloma therapy, and overall survival (OS).

Treatment:

• Pts were randomly assigned (1:1) to the control group (MP alone, n = 338) or the bortezomib group (MP+Bort, n = 344)
• Treatment was administered in 9x 6-week cycles of: melphalan (9 mg/m² of body-surface area) and prednisone (60 mg/m²) on days 1-4 either with/without bortezomib (1.3 mg/m²) on days 1, 4, 8, 11, 22, 25, 29, and 32, during cycles 1- 4 and on days 1, 8, 22, and 29 during cycles 5-9; treatment duration = 54 weeks
• Treatment was discontinued on withdrawal of the patient's consent, disease progression, or the occurrence of unacceptable toxic effects

Key Findings:

All data are given as bortezomib group vs control group:

• Pts still receiving treatment at data cut-off = 14% vs 10%
• Median TTP = 24.0 vs 16.6 months; HR (bortezomib group) = 0.48; (P<0.001)
• TTP benefit was independent of age, sex, race, clinical stage and biochemical markers
• Pts evaluated: bortezomib, n= 337; control, n = 331
• Rate of PR or better (according to EBMT criteria) = 71% vs 35% (P<0.001)
• CRR = 30% vs 4% (P<0.001) 
• Post hoc analysis of response (International Uniform Response Criteria) = 33% vs 4%
• Median DoR (EBMT criteria) = 19.9 vs 13.1 months
• Median DoR among patients with a CR = 24.0 vs 12.8 months
• Pts starting second-line treatment within 2 years: 35% vs 57%
• Deaths at median follow-up (16.3 months) = 13% vs 22%; HR (bortezomib group) = 0.61, P=0.008; median survival not reached in either group
• Sub-group analysis in pts with poor prognosis:
  • pts ≥75 years of age vs <75 years - Median TTP: identical for both age groups; CRR: 26% vs 32%, P=0.29; median OS: slightly shorter (P= 0.17)
  • pts with impaired renal function (n = 185) vs those with normal renal function - CRR: 28% vs 32%, TTP (P=0.09), and overall rate of survival (P=0.99)
  • pts with high-risk cytogenetic profile (n = 26) including t(4;14), t(14;16) translocation or a 17p deletion vs pts with standard risk profile - CRR = 28% for both, similar TTP (P=0.55) and OS (P=0.99); inclusion of 75 patients with a 13q deletion did not affect the data

Safety Analysis:

• Median no. of treatment cycles = 8 vs 7
• Death rates during treatment = 5% vs 4%
• Treatment-related death = 1% vs 2%
• No differences observed in hematologic toxic effects between the two groups
• Peripheral sensory neuropathy more frequent in bortezomib group: grade 1 = 14%, grade 2 = 17%, grade 3 = 13%, and grade 4 in 1 patient (<1%); 56% resolved, 18% decreased by at least one toxicity grade within a median of 2 months
• Grade 3 or 4 gastrointestinal symptoms = 19% vs 5%; any grade herpes zoster = 13% vs 4%
• Rate of serious AEs = 46% vs 36%
• Discontinuation due to AEs: 15% vs 14%; treatment-related events = 11% vs 10%
• Discontinuation of bortezomib alone = 19%

In conclusion, the addition of bortezomib to the standard MP regimen for transplant-ineligible patients gave a significant 7.4-month benefit in TTP, and was observed across all patient subgroups. In addition, bortezomib did not dramatically affect the safety profile, and therefore the addition of bortezomib to MP was recommended for routine care of this patient set, at this time, and signalled a move towards triplet drug regimens.