Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients.
The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first- to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10(-5); n = 54, 34%), MRD positive (between <10(-4) and ≥10(-5); n = 20, 12%), and MRD positive (≥10(-4); n = 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P = .007) and overall survival (OS) (HR, 3.1; P = .04), with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10(-4) and ≥10(-5) vs ≥10(-4) (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P = .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P = .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249.
Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
Bruno
B
Paiva
Hospital Universitario 12 de Octubre, Instituto de investigación 12 de Octubre, Madrid, Spain;
Maria-Teresa
MT
Cedena
Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
Noemi
N
Puig
Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
Paula
P
Arana
Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
Maria-Belen
MB
Vidriales
Hospital Universitario y Politécnico La Fe, Valencia, Spain;
Lourdes
L
Cordon
Servicio General de Citometría-NUCLEOS, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), IBSAL, and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
Juan
J
Flores-Montero
Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
Norma C
NC
Gutierrez
Hospital Universitario 12 de Octubre, Instituto de investigación 12 de Octubre, Madrid, Spain;
María-Luisa
ML
Martín-Ramos
Hospital Universitario 12 de Octubre, Instituto de investigación 12 de Octubre, Madrid, Spain;
Joaquin
J
Martinez-Lopez
Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
Enrique M
EM
Ocio
Hospital Universitario de Canarias, Tenerife, Spain;
Miguel T
MT
Hernandez
Hospital Clinico de Valencia, Valencia, Spain;
Ana-Isabel
AI
Teruel
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
Laura
L
Rosiñol
Hospital de Donostia, San Sebastian, Spain;
María-Asunción
MA
Echeveste
Hospital Clínico San Carlos, Madrid, Spain;
Rafael
R
Martinez
Hospital Vall d'Hebron, Barcelona, Spain;
Mercedes
M
Gironella
Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias I Pujol, Badalona, Spain;
Albert
A
Oriol
Hospital San Pedro de Alcántara, Cáceres, Spain;
Carmen
C
Cabrera
Hospital General Virgen del Rocío, Sevilla, Spain;
Jesus
J
Martin
Hospital Sont Llatzer, Palma de Mallorca, Spain;
Joan
J
Bargay
Hospital General Universitario Gregorio Marañón, Instituto de Investigacion Sanitaria Gregorio Marañón, Madrid, Spain;
Cristina
C
Encinas
Institut d'Oncologia Dr. Josep Trueta, Girona, Spain; and.
Yolanda
Y
Gonzalez
Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Jacques J M
JJ
Van Dongen
Servicio General de Citometría-NUCLEOS, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), IBSAL, and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
Alberto
A
Orfao
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
Joan
J
Bladé
Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
Maria-Victoria
MV
Mateos
Hospital Universitario 12 de Octubre, Instituto de investigación 12 de Octubre, Madrid, Spain;
Juan José
JJ
Lahuerta
Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
Jesús F
JF
San Miguel
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D003907:Dexamethasone / Q000008:administration & dosage; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007109:Immunity / Q000187:drug effects* / Q000502:physiology; D000077269:Lenalidomide; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D008991:Monitoring, Physiologic / Q000379:methods*; D009101:Multiple Myeloma / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D018365:Neoplasm, Residual; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D016019:Survival Analysis; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D014750:Vincristine / Q000627:therapeutic use
D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D013792:Thalidomide; D014750:Vincristine; D003907:Dexamethasone; D000077269:Lenalidomide; D008558:Melphalan; D011241:Prednisone