Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma

Author:

Paiva Bruno1,Puig Noemi2,Cedena Maria-Teresa3,Rosiñol Laura4,Cordón Lourdes5,Vidriales María-Belén2,Burgos Leire1,Flores-Montero Juan67,Sanoja-Flores Luzalba67,Lopez-Anglada Lucia3,Maldonado Roberto3,de la Cruz Javier3,Gutierrez Norma C.2,Calasanz Maria-Jose1,Martin-Ramos Maria-Luisa3,Garcia-Sanz Ramón2,Martinez-Lopez Joaquin3,Oriol Albert8,Blanchard María-Jesús9,Rios Rafael10,Martin Jesus11,Martinez-Martinez Rafael12,Sureda Anna13,Hernandez Miguel-Teodoro14,de la Rubia Javier515,Krsnik Isabel16,Moraleda Jose-Maria17,Palomera Luis18,Bargay Joan19,Van Dongen Jacques J.M.20,Orfao Alberto67,Mateos Maria-Victoria2,Blade Joan4,San-Miguel Jesús F.1,Lahuerta Juan-José3,

Affiliation:

1. Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada Instituto de Investigacion Sanitaria de Navarra, Pamplona, Spain

2. Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, Salamanca, Spain

3. Hospital 12 de Octubre, Madrid, Spain

4. Hospital Clínic Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

5. Hospital Universitario y Politécnico La Fe, Valencia, Spain

6. Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain

7. University of Salamanca, Salamanca, Spain

8. Institut Català d’Oncologia i Institut Josep Carreras, Badalona, Spain

9. Hospital Ramón y Cajal, Madrid, Spain

10. Hospital Virgen de las Nieves, Granada, Spain

11. Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Sevilla, Spain

12. Hospital Universitario San Carlos, Madrid, Spain

13. Institut Català d'Oncologia L’Hospitalet, Barcelona, Spain

14. Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain

15. Catholic University of Valencia, Valencia, Spain

16. Hospital Puerta de Hierro, Madrid, Spain

17. Hospital Virgen de la Arrixaca, Murcia, Spain

18. Hospital Clínico Lozano Blesa, Zaragoza, Spain

19. Hospital Son Llatzer, Palma de Mallorca, Spain

20. Leiden University Medical Center, Leiden, the Netherlands

Abstract

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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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