Updated Follow-up and Results of Subsequent Therapy in the Phase III VISTA Trial: Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone in Newly Diagnosed Multiple Myeloma
Authors: Miguel Jesus F San , Schlag Rudolf , Khuageva Nuriet K , Dimopoulos Meletios A , Shpilberg Ofer , Kropff Martin H , Spicka Ivan , Petrucci Maria Teresa , Palumbo Antonio , Samoilova Olga S , Dmoszynska Anna , Abdulkadyrov Kudrat M , Schots Rik , Jiang Bin , Mateos Maria-Victoria , Anderson Kenneth C , Esseltine Dixie-Lee , Liu Kevin , Cakana Andrew , van de Velde Helgi , Richardson Paul 
Published: October 2019

Abstract
Based on the results of the large, international, phase III VISTA trial in previously untreated MM patients ineligible for high-dose therapy with stem cell transplantation (HDT-SCT), bortezomib (VELCADE®) was approved by the US FDA for the initial treatment of multiple myeloma (MM). Data from VISTA showed that bortezomib plus melphalan–prednisone (VMP) was superior to melphalan–prednisone (MP) across all efficacy end points, including response rates (overall and complete response [CR] rates), time to progression (TTP), time to subsequent therapy (TTNT), and overall survival (OS). Patients (N=682) from 151 centers in 22 countries in Europe, North and South America, and Asia were randomized (1:1) to 54 weeks treatment with VMP (N=344) or MP (N=338). Patients received nine 6-week cycles of bortezomib 1.3 mg/m2 (days 1, 4, 8, 11, 22, 25, 29, 32 in cycles 1–4 and days 1, 8, 22, 29 in cycles 5–9) with melphalan 9 mg/m2 and prednisone 60 mg/m2 (days 1–4 in cycles 1–9), or melphalan plus prednisone, per the dose and schedule described above. The primary end point was TTP, with progression determined using European Group for Blood and Marrow Transplantation (EBMT) criteria. Median age was 71 years; 30% of patients were aged ≥75 years. At baseline, 34% of patients had Karnofsky Performance Status (KPS) ≤70%, 33% had β2-microglobulin >5.5 mg/L, and 34% had International Staging System (ISS) Stage III disease. An Independent Data Monitoring Committee recommended the trial be stopped based on a protocol-specified interim analysis as the statistical boundary for the primary end point had been crossed. VMP was well tolerated, with patients remaining on VMP therapy for a median of 46 weeks (8 cycles) versus 39 weeks (7 cycles) with MP; median total dose of bortezomib received was 38.5 mg/m2. Collection of tumor assessment data was stopped after presentation of the positive interim analysis. Collection of survival data, subsequent therapy data and safety/recovery data continued. Updated follow-up through April 25, 2008 confirms a statistically significant survival benefit for VMP versus MP (HR=0.64, P=0.0032) after a median follow-up of 25.9 months. Three-year survival rates were 72% versus 59%, respectively. TTNT and treatment-free interval (TFI) were also significantly longer in the VMP arm (TTNT 28.1 vs 19.2 months, HR=0.53, P<0.000001; TFI 16.6 vs 8.4 months, HR=0.54, P<0.00001). Fewer patients in the VMP versus MP arm (38% vs 57%, respectively) required subsequent therapy. Of the patients receiving subsequent therapy in the VMP and MP arms, 16% and 43% received bortezomib, 49% and 44% received thalidomide, and 19% and 6% received lenalidomide, respectively. Re-treatment with bortezomib was effective in the VMP arm (6% CR) (Table); a 10% CR rate was reported in the MP arm after bortezomib-based therapy. Peripheral neuropathy (PN) in the VMP treatment arm improved or resolved in 79% of events (median 1.9 months), with 60% of PN events resolving completely (median 5.7 months). VMP is an active and well-tolerated treatment option for previously untreated MM patients and significantly prolongs survival and time to subsequent therapy. Patients can be successfully treated with subsequent immunomodulatory-based combination therapy and can also be retreated with bortezomib, achieving high response rates with manageable toxicity.
Table. Investigator-reported best responses with subsequent therapies per treatment arm
VMP arm (n=129)* MP arm (n=194) Subsequent therapy and number of patients who received therapy* Complete response (%) Partial response (%) Complete response (%) Partial response (%) * Other agents were used as subsequent therapy including dexamethasone; patients could receive multiple-agent regimens Bortezomib or bortezomib combination (n=105) 6 33 10 45 Thalidomide combination (n=149) 4 44 3 52 Lenalidomide Combination (n=37) 4 52 0 55