Superior Outcomes Associated with Complete Response: Analysis of the Phase III VISTA Study of Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone
Authors: Harousseau Jean-Luc , Palumbo Antonio , Richardson Paul , Schlag Rudolf , Dimopoulos Meletios A , Shpilberg Ofer , Kropff Martin H , Delforge Michel , Schots Rik , Cavo Michele , Golenkov Anatoly , Komarnicki Mieczyslaw , Mateos Maria-Victoria , Cakana Andrew , Liu Kevin , Deraedt William , van de Velde Helgi , San Miguel Jesus F 
Published: April 2020

Abstract
Complete response (CR) has been shown to be prognostic for improved long-term outcomes, including progression-free survival and overall survival (OS), in previously untreated multiple myeloma (MM) patients receiving high-dose therapy and stem cell transplant (SCT; Harousseau et al, IMW 2007; van de Velde et al, Haematologica 2007). However, there is limited evidence of such a correlation in the non-transplant setting. In the large, international phase III VISTA study in previously untreated MM patients ineligible for SCT, bortezomib plus melphalan–prednisone (VMP) demonstrated superiority to MP across all efficacy end points, including response rates, time to progression (TTP), and OS. Here, we assess the differential prognostic impact of best response on time-to-event parameters in VISTA, and evaluate the impact of timing of CR on outcome in patients receiving VMP. A total of 682 patients (median age 71 years) were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, and days 1, 8, 22, 29, cycles 5–9, plus melphalan 9 mg/m2 and prednisone 60 mg/m2, days 1–4, cycles 1–9) or MP (N=338). The primary end point was TTP. Response and progression were determined using European Group for Blood and Marrow Transplantation (EBMT) criteria; in a post-hoc analysis, response was determined using International Myeloma Working Group (IMWG) uniform criteria. Associations between long-term outcomes and response were examined in the intent-to-treat population by multivariate Cox regression analysis with time-dependent covariates, adjusted for stratification factors (baseline β2-microglobulin and albumin; region), with age, sex, race, MM type, baseline Karnofsky Performance Status, and number of bone lesions as covariates. Among evaluable patients, response rates to VMP vs MP were 71% vs 35%, including 30% vs 4% CR, by EBMT criteria, and 74% vs 39%, including 33% vs 4% CR and 8% vs 4% VGPR, by IMWG criteria. Median TTP was 24.0 vs 16.6 months. CR by EBMT criteria was associated with significantly longer TTP (hazard ratio [HR] 0.45, p=0.004; Figure), time to next therapy (TNT; HR 0.44, p=0.014), and treatment-free interval (TFI; HR 0.37, p=0.004) vs PR, plus improved OS (medians not reached; clear separation between the curves; HR=0.59, p=0.265; statistical significance not seen likely due to a small number of deaths). Significant benefit was seen for CR and PR vs no response by EBMT criteria for all four parameters, including OS. Findings were similar for CR vs VGPR+PR vs no response by IMWG criteria. Importantly, CR was associated with significantly longer TTP (HR 0.45, p=0.019) and TFI (HR 0.39, p=0.026) vs VGPR, with a trend towards longer TNT (HR 0.54, p=0.126); no significant differences for these parameters were seen for VGPR vs PR. However, these findings should be interpreted with caution due to the small number of patients achieving VGPR. Among patients achieving CR (EBMT criteria) with VMP, there were no clear differences in clinical benefit associated with achieving CR early (cycles 1–4, within 24 weeks) vs later (cycle 5 onwards, after 24 weeks), although TTP and overall duration of response appeared slightly longer with later CRs, possibly due to the inherent slightly longer duration of therapy (mean 7.4 vs 8.5 cycles). In conclusion, this analysis demonstrates the prognostic significance of CR on long-term outcomes in the setting of non-intensive therapy. The data show that CR is associated with improved outcomes vs VGPR by IMWG criteria, and indicate that the clinical benefit of CR with VMP is similar regardless of time to achieve CR, supporting continuation of therapy to achieve maximal response.
Figure: TTP in patients achieving CR vs PR (EBMT criteria) with VMP Figure:. TTP in patients achieving CR vs PR (EBMT criteria) with VMP