Circulating tumor and immune cells for minimally invasive risk stratification of smoldering multiple myeloma
Rosalinda Termini 1 , David Zihala 2 , Evangelos Terpos 3 , Albert Pérez-Montaña 4 , Tomas Jelinek 5 , Marc Raab 6 , Niels Weinhold 7 , Elias K Mai 7 , Anna Luise Grab 7 , Jill Corre 8 , Francois Vergez 9 , Antonio Sacco 10 , Marco Chiarini 10 , Viviana Giustini 10 , Alessandra Tucci 11 , Sara Rodríguez 12 , Cristina Moreno 13 , Cristina Perez 14 , Catarina Maia 15 , Esperanza Martin-Sanchez 16 , Camila Guerrero 17 , Cirino Botta 18 , Juan-Jose Garcés 19 , Aitziber Lopez 14 , Luis-Esteban Tamariz-Amador 1 , Felipe Prósper 20 , Joan Bargay 21 , Maria-Elena Cabezudo 22 , Enrique M Ocio 23 , Roman Hájek 24 , Joaquin Martinez-Lopez 25 , Fernando Solano 26 , Rebeca Iglesias 27 , Artur Paiva 28 , Catarina Geraldes 29 , Helena Matos Silva 30 , Clara Gomez 31 , Felipe De Arriba 32 , Heinz Ludwig 33 , Antoni Garcia-Guiñon 34 , Maria Casanova 35 , Adrian Alegre 36 , Valentin Cabañas 37 , Maialen Sirvent 38 , Albert Oriol 39 , Javier De la Rubia 40 , José-Ángel Hernández-Rivas 41 , Luis Palomera 42 , Maria Sarasa 43 , Pablo Rios 44 , Noemi Puig 45 , Maria-Victoria Mateos 46 , Juan Flores-Montero 47 , Alberto Orfao 48 , Hartmut Goldschmidt 49 , Herve Avet-Loiseau 50 , Aldo M Roccaro 10 , Jesus F San-Miguel 51 , Bruno Paiva 52
Purpose: Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under and over-treatment. We hypothesized that replacing bone marrow (BM) plasma cells (PCs) for circulating tumor cells (CTCs), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model.
Experimental design: We report the outcomes of 150 SMM patients enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of three years since enrollment.
Results: Patients with >0.015% vs ≤0.015% CTCs at baseline had a median time-to-progression of 17 months vs not reached (hazard ratio: 4.9, P<.001). Presence of >20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio >20, >2g/dL M-protein, and >0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk-score based on the percentages of SLAN+ and SLAN- non-classical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient' stratification into low, intermediate-low, intermediate-high and high-risk disease with 0%, 20%, 39% and 73% rates of progression at two years.
Conclusions: This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.