Multiparameter Flow Cytometry Remission Is the Most Relevant Prognostic Factor for Multiple Myeloma Patients Who Undergo Autologous Stem Cell Transplantation
Authors: Paiva Bruno , Vidriales Maria-Belén , Cerveró Jorge , Mateo Gema , Pérez Jose J. , Montalbán Maria Angeles , Sureda Anna , Montejano Laura , Gutiérrez Norma C. , de Coca Alfonso García , de las Heras Natalia , Mateos Maria Victoria , López-Berges Maria-Consuelo , García-Boyero Raimundo , Galende Josefina , Hernández José , Palomera Luis , Carrera Dolores , Martínez Rafael , de la Rubia Javier , Martín Alejandro , Blade Joan , Lahuerta Juan José , Orfao Alberto , San Miguel J. F. 
Published: October 2019

Abstract
Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol (VBMCP/VBAD induction plus autologous stem cell transplant [ASCT]). MRD status by MFC was determined at day 100 post-ASCT. Persistent myelomatous plasma cells (MM-PCs) were detected by MFC in 170 patients (58%), who were considered MRD-positive. Progression-free survival (PFS; median 71 vs 37 months, P < .0001) and overall survival (OS; median not reached vs 89 months, P = .002) were longer in patients who were MRD-negative versus MRD-positive at day 100 post-ASCT, with a 5-year PFS rate of 60% and 22% (P < .0001), respectively. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation (IFx) negative complete response post-ASCT. The 5-year PFS rate was 62% in MRD-negative patients (n=94) versus 30% in MRD-positive patients (n=53; P < .0001), and the respective 5-year OS rates were 87% versus 59% (P = .009). Moreover, MRD− IFx− and MRD− IFx+ patients had significantly longer PFS than MRD+ IFx− patients (median 71, 65, and 37 months, respectively, P = .0002). By multivariate analysis, only MRD status by MFC at day 100 post-ASCT and FISH cytogenetics were identified as independent prognostic factors for PFS, and only MRD status by MFC and age were identified for OS. The relative risks of progression and death among MRD-positive versus MRD-negative patients were 3.64 (P = .002) and 2.02 (P = .02), respectively. Finally, a subgroup of 157 patients in which MRD information was available both pre- and post-ASCT were analyzed. Patients who were MRD-positive both pre- and post-transplant (n=93) had the worst prognosis; patients who were MRD-positive pre-ASCT but improved to MRD-negative post-ASCT (n=48) had an intermediate prognosis, and patients who were MRD-negative both pre- and post-transplant (n=16) had the best prognosis. The 5-year PFS and OS rates in these three prognostic subgroups were 25%, 57%, and 80%, respectively (P = .0001), and 59%, 78%, and 100%, respectively (P = .06). In summary, our results show that MRD evaluation by MFC is a very useful technique to identify patients at different risk of progression. This type of analysis, particularly when performed post-ASCT, may contribute to the design of patient-specific maintenance treatment approaches, as well as the evaluation of the potential benefits of consolidation therapies.