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

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.

We would like to acknowledge Arturo Touchard for outstanding data management and all the investigators of GEM/PETHEMA. This study was supported by the Centro de Investigación Biomédica en

Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369; CB16/12/00400; CB16/12/00233; CB16/12/00284), formerly named as Cooperative Research Thematic Network

(Grants No. RD12/0036/0058, RD12/0036/0048, RD12/0036/0046 and RD12/0036/0061) of the Red de Cancer (Cancer Network of Excellence); Instituto de Salud Carlos III/Subdirección General de

Investigación Sanitaria; funded in part by the European Regional Development Fund (FIS No. 98/1239, 00/10160, 01/0089, 02/0089, 02/0905, G03/136, PI051284, PI06033906/1354, PS09/01897/01370,

PI12/01761, PI12/ 02311, PI13/01469, PI14/01867, G03/136); Sara Borrell (No. CD13/00340); Asociación Española Contra el Cáncer (GCB120981SAN) and the Becas Leonardo a Investigadores y

Creadores Culturales 2017, Fundación BBVA. This study was also supported internationally by the Black Swan Research Initiative of the International Myeloma Foundation, the Qatar National

Research Fund (QNRF) Award No. 7-916-3-237, the AACR-Millennium Fellowship in Multiple Myeloma Research (15-40-38-PAIV), the Leukemia Research Foundation, and the European Research Council

(ERC) 2015 Starting Grant (MYELOMANEXT).

P Arana and B Paiva: These authors contributed equally to this work.

Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicadas (CIMA),

Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, 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

Institut Català d’Oncologia i Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona, Spain

IBSAL and Department of Medicine, Servicio General de Citometría-NUCLEOS, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Universidad de Salamanca, Salamanca, Spain

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