Bortezomib Plus Melphalan–Prednisone Continues to Demonstrate a Survival Benefit Vs Melphalan–Prednisone in the Phase III VISTA Trial in Previously Untreated Multiple Myeloma After 3 Years' Follow-up and Extensive Subsequent Therapy Use.
Authors: Mateos Maria-Victoria , Richardson Paul G , Schlag Rudolf , Khuageva Nuriet K , Dimopoulos Meletios A. , Shpilberg Ofer , Kropff Martin , Spicka Ivan , Petrucci Maria Teresa , Palumbo Antonio , Samoilova Olga S , Dmoszynska Anna , Abdulkadyrov Kudrat M , Schots Rik , Jiang Bin , Esseltine Dixie-Lee , Liu Kevin , Cakana Andrew Z , van de Velde Helgi , Miguel Jesús F. San 
Published: October 2019

Abstract
Abstract 3859
Poster Board III-795
The initial results of the pivotal, international, phase III VISTA trial demonstrated the superiority of bortezomib (Velcade®) plus melphalan–prednisone (VMP) versus MP alone across all efficacy end points, including overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008). We conducted a planned updated survival analysis of VISTA after a median >3 years of follow-up and with the majority of patients having received subsequent therapy. We confirmed the previously demonstrated OS benefit of VMP versus MP, examined the use of subsequent therapy and its efficacy following VMP and MP, and evaluated the survival of patients who had received subsequent therapy. Patients were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, all cycles) or MP (N=338) alone. Response was assessed using EBMT criteria with central laboratory M-protein analysis. After disease progression, patients were followed for survival and subsequent therapy, including investigator-assessed best response to subsequent therapies. The median age of patients was 71 years, 30% were aged ≥75 years, 34% had ISS stage III MM, and 33% had β2-microglobulin >5.5 mg/L. After median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP vs MP (hazard ratio [HR] 0.653, p=0.0008); median OS was not estimable vs 43.1 months, and 3-year OS rates were 68.5% vs 54.0% with VMP vs MP, respectively. This OS benefit was seen consistently across patient subgroups predefined by baseline characteristics. Within the VMP arm, OS was longer among patients aged <75 vs ≥75 years (HR 1.664, p=0.011; 3-year OS: 74.1% vs 55.5%); by contrast, there were no significant differences, although there were trends to longer OS among patients with creatinine clearance ≥60 versus <60 mL/min (HR 1.291, p=0.238; 3-year OS: 74.5% vs 63.1%) and patients with standard- vs high-risk cytogenetics (HR 1.346, p=0.399; 3-year OS 71.6% vs 56.1%). At data cut-off (16 March 2009), 178 (52%) VMP and 233 (69%) MP patients had received subsequent therapy; median time to subsequent therapy (28.1 vs 19.2 months, HR 0.527, p<0.0001) and median treatment-free interval (17.6 vs 8.4 months, HR 0.543, p<0.0001) were superior with VMP vs MP. Receipt of and response to subsequent bortezomib-, thalidomide-, and lenalidomide-based therapy are summarized in the Table. Median survival from start of subsequent therapy following VMP and MP was 30.2 vs 21.9 months (HR 0.815, p=0.21) among all patients receiving subsequent therapy. This updated analysis of VISTA confirms that VMP results in significantly longer OS compared with MP, despite 50% of MP patients being rescued with bortezomib-based therapy in the relapsed setting. VMP treatment used upfront appears more beneficial than treating with conventional agents and saving bortezomib- and other novel-agent-based treatment until relapse. Subsequent therapies appeared similarly effective in the VMP and MP arms, with our analysis also demonstrating the benefit of retreatment with bortezomib-based therapies following VMP. In addition, post-relapse survival among all patients receiving subsequent therapy appeared longer following VMP, indicating that frontline bortezomib use does not induce more resistant relapses.
Table Response among patients who received subsequent therapy VMP (N=178) MP (N=233) Received subsequent therapy containing:*     Bortezomib, n (%) 43 (24) 116 (50)     Thalidomide, n (%) 81 (46) 110 (47)     Lenalidomide, n (%) 57 (32) 30 (13) Overall response rate (%) to subsequent therapy:     Bortezomib-based 47 59     Thalidomide-based 41 53     Lenalidomide-based 59 52 * Patients could have received >1 agent, either in combination or separately in different subsequent lines of therapy

Disclosures:
Mateos: Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho-Biotech: Consultancy, Honoraria. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Kropff:Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Janssen Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Millennium: Research Funding. Schots:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esseltine:Millennium: Employment, Equity Ownership. Liu:Johnson & Johnson: Employment, Equity Ownership. Cakana:Johnson & Johnson: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.