Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma
Bruno Paiva, Noemi Puig, Maria-Teresa Cedena, Laura Rosiñol, Lourdes Cordón, María-Belén Vidriales, Leire Burgos, Juan Flores-Montero, Luzalba Sanoja-Flores, Lucia Lopez-Anglada, Roberto Maldonado, Javier de la Cruz, Norma C Gutierrez, Maria-Jose Calasanz, Maria-Luisa Martin-Ramos, Ramón Garcia-Sanz, Joaquin Martinez-Lopez, Albert Oriol, María-Jesús Blanchard, Rafael Rios, Jesus Martin, Rafael Martinez-Martinez, Anna Sureda, Miguel-Teodoro Hernandez, Javier de la Rubia, Isabel Krsnik, Jose-Maria Moraleda, Luis Palomera, Joan Bargay, Jacques J M Van Dongen, Alberto Orfao, Maria-Victoria Mateos, Joan Blade, Jesús F San-Miguel, Juan-José Lahuerta, GEM (Grupo Español de Mieloma)/PETHEMA (Programa Para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group
Purpose: Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG).
Patients and methods: In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10-6. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial.
Results: Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001).
Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%.
Conclusion: The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.