High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma

• Published in: Journal of clinical oncology Vol. 40; no. 27; pp. 3120 - 3131
• Main Authors: Bertamini, Luca, Oliva, Stefania, Rota-Scalabrini, Delia, Paris, Laura, Morè, Sonia, Corradini, Paolo, Ledda, Antonio, Gentile, Massimo, De Sabbata, Giovanni, Pietrantuono, Giuseppe, Pascarella, Anna, Tosi, Patrizia, Curci, Paola, Gilestro, Milena, Capra, Andrea, Galieni, Piero, Pisani, Francesco, Annibali, Ombretta, Monaco, Federico, Liberati, Anna Marina, Palmieri, Salvatore, Luppi, Mario, Zambello, Renato, Fazio, Francesca, Belotti, Angelo, Tacchetti, Paola, Musto, Pellegrino, Boccadoro, Mario, Gay, Francesca
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health 20.09.2022
• Subjects: Humans; Multiple Myeloma - diagnosis; Neoplasm, Residual - diagnosis; Neoplastic Cells, Circulating; Plasma Cells - pathology; Prognosis; Treatment Outcome
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO.21.01393

PURPOSEHigh levels of circulating tumor plasma cells (CTC-high) in patients with multiple myeloma are a marker of aggressive disease. We aimed to confirm the prognostic impact and identify a possible cutoff value of CTC-high for the prediction of progression-free survival (PFS) and overall survival (OS), in the context of concomitant risk features and minimal residual disease (MRD) achievement.METHODSCTC were analyzed at diagnosis with two-tube single-platform flow cytometry (sensitivity 4 × 10-5) in patients enrolled in the multicenter randomized FORTE clinical trial (ClinicalTrials.gov identifier: NCT02203643). MRD was assessed by second-generation multiparameter flow cytometry (sensitivity 10-5). We tested different cutoff values in series of multivariate (MV) Cox proportional hazards regression analyses on PFS outcome and selected the value that maximized the Harrell's C-statistic. We analyzed the impact of CTC on PFS and OS in a MV analysis including baseline features and MRD negativity.RESULTSCTC analysis was performed in 401 patients; the median follow-up was 50 months (interquartile range, 45-54 months). There was a modest correlation between the percentage of CTC and bone marrow plasma cells (r = 0.38). We identified an optimal CTC cutoff of 0.07% (approximately 5 cells/µL, C-index 0.64). In MV analysis, CTC-high versus CTC-low patients had significantly shorter PFS (hazard ratio, 2.61; 95% CI, 1.49 to 2.97, P < .001; 4-year PFS 38% v 69%) and OS (hazard ratio, 2.61; 95% CI, 1.49 to 4.56; P < .001; 4-year OS 68% v 92%). The CTC levels, but not the bone marrow plasma cell levels, affected the outcome. The only factor that reduced the negative impact of CTC-high was the achievement of MRD negativity (interaction P = .039).CONCLUSIONIn multiple myeloma, increasing levels of CTC above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact. Circulating tumor plasma cells as a hallmark of high risk in patients with MM: results from FORTE trial.