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Leukemia. 2018 Apr;32(4):971-978. doi: 10.1038/leu.2017.320. Epub 2017 Nov 3.

Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1265 patients enrolled in four consecutive clinical trials.

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Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicadas (CIMA); Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, Spain.
Hospital 12 de Octubre, CIBERONC, Madrid, Spain.
Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), CIBERONC, Salamanca, Spain.
Hospital Universitario y Politécnico La Fe, CIBERONC, Valencia, Spain.
Hospital Universitario de Canarias, Tenerife, Spain.
Hospital Clínico de Valencia, Valencia, Spain.
Hospital Vall d'Hebron, Barcelona, Spain.
Hospital de Donostia, San Sebastian, Spain.
Hospital Clínic, IDIBAPS, Barcelona, Spain.
Hospital Clínico San Carlos, Madrid, Spain.
Institut Català d'Oncologia i Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona, Spain.
Servicio General de Citometría-NUCLEOS, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), IBSAL and Department of Medicine, Universidad de Salamanca, Salamanca, Spain.


Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19pos, CD27neg, CD38lo, CD45pos, CD81pos, CD117neg and CD138lo expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38lowCD81posCD117neg expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients.

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