Continued Overall Survival Benefit After 5 Years' Follow-up with Bortezomib-Melphalan-Prednisone (VMP) Versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial
Authors: Miguel Jesús F San , Schlag Rudolf , Khuageva Nuriet K , Dimopoulos Meletios Athanasios , Shpilberg Ofer , Kropff Martin , Spicka Ivan , Petrucci Maria T , Palumbo Antonio , Samoilova Olga S , Dmoszynska Anna , Abdulkadyrov Kudrat M , Delforge Michel , Jiang Bin , Mateos María-Victoria , Anderson Kenneth C. , Esseltine Dixie-Lee , Liu Kevin , Deraedt William M , Cakana Andrew Z , van de Velde Helgi , Richardson Paul G. 
Published: October 2019

Abstract
Abstract 476FN2

Background:
Data from the initial report of the international, multicenter, phase 3 VISTA trial demonstrated that VMP was superior to MP across all efficacy endpoints, including response rates, time to progression, and overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy. Following this report, centralized assessment of response/progression was stopped and, per protocol, patients were followed for up to 4.5 years post-last patient in date for survival and the use of subsequent anti-MM therapy only. An updated analysis, conducted after a median follow-up of 36.7 months, demonstrated a continued significant OS benefit with VMP. Here we report the final updated OS analysis of VISTA after 5 years of follow-up, including an exploratory analysis of the risk of second primary malignancies (SPMs), an important issue for MM patients receiving long-term therapy.

Methods:
Patients were randomized (1:1) to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, days 1, 8, 22, and 29, cycles 5–9; melphalan 9 mg/m2 days 1–4, prednisone 60 mg/m2, days 1–4, all cycles) or MP (N=338) alone. Patients were followed at least every 12 weeks for survival and subsequent therapy use. Data on SPMs were collected during February 2011 by surveying all study sites to capture information for 655 (96%) patients.

Results:
After median follow-up of 60.1 months, with only 5% of patients lost to follow-up, median OS was 56.4 versus 43.1 months for patients randomized to VMP compared to MP (HR 0.695, p=0.0004), reflecting a 31% reduced risk of death with VMP (Figure); 5-year OS rates were 46.0% and 34.4%, respectively. This compares favorably with the 6.6-month increase in median OS in a meta-analysis of six phase 3 trials of MP-thalidomide vs MP (Fayers et al, Blood 2011). The OS benefit with VMP was seen across patient subgroups, including those aged ≥75 years (median 50.7 vs 32.9 months, HR 0.71), patients with ISS stage III MM (median 42.1 vs 30.5 months, HR 0.67), and those with creatinine clearance <60 mL/min (median 56.8 vs 36.7 months, HR 0.70), but no significant difference was observed in the small subgroup of patients with documented high-risk cytogenetics (n=46). At data cut-off (March 24, 2011), 63% of VMP and 73% of MP patients had received subsequent MM therapies; use of subsequent therapies was generally similar between arms, except for a higher proportion of MP patients receiving subsequent bortezomib (43% vs 22%). Time to next treatment (median 27.0 vs 19.2 months; HR 0.557, p<0.0001) and treatment-free interval (median 16.6 vs 8.3 months, HR 0.573, p<0.0001) were superior with VMP vs MP. Among all patients who had received subsequent therapies, OS was superior with VMP vs MP (median 55.7 vs 46.4 months; HR 0.745, p=0.0162). A 30-month landmark OS analysis demonstrated superior survival from landmark among all VMP patients (median not reached) and among VMP patients who had received any subsequent therapy (median 28.2 months) vs MP patients who had received subsequent bortezomib (median 23.0 months). Taking into account the longer observation period due to prolonged survival on the VMP arm, analyses of SPM risk (Table) showed no difference in incidence proportions or ‘exposure'-adjusted incidence rates between arms. Rates on both arms (VMP 0.0166, MP 0.013 per patient-year) were consistent with background incidence rate in the general population aged 65–74 years (0.019, SEER database).

Conclusions:
VMP resulted in a substantial long-term OS benefit vs MP (13.3-month increase in median), which was seen across patient subgroups and regardless of extensive subsequent therapy. There was no increased risk of SPMs identified with VMP vs expected background rates.

Disclosures:
San Miguel: Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho Biotech: Consultancy, Honoraria. Kropff:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Spicka:Janssen-Cilag: Honoraria; Celgene: Honoraria. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Janssen-Cilag: Research Funding. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Anderson:Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Liu:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Richardson:Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy.