PURPOSE: Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. METHODS: We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. RESULTS: Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. CONCLUSION: Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.

4th Department of Internal Medicine Hematology University Hospital Hradec Kralove Charles University Faculty of Medicine in Hradec Kralove Hradec Kralove Czech Republic

Babak Myeloma Group Department of Pathophysiology Faculty of Medicine Masaryk University Brno Czech Republic

Clinica Universidad de Navarra Centro de Investigacion Medica Aplicada CIBER ONC number CB16 12 00369 Pamplona Spain

Department of Biology and Ecology Faculty of Science University of Ostrava Ostrava Czech Republic

Department of Clinical Hematology University Hospital Brno Brno Czech Republic

Department of Hematooncology University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Czech Republic

Division of Hematologic Malignancies Dana Farber Cancer Institute Harvard Medical School Boston MA

Hospital 12 de Octubre CIBER ONC number CB16 12 00369 Madrid Spain

Hospital Universitario de Salamanca Instituto de Investigacion Biomedica de Salamanca CIBER ONC number CB16 12 00233 Salamanca Spain

Institute of Biostatistics and Analyses Ltd Brno Czech Republic

Plasma Cell Dyscrasia Center Department of Hematology Jagiellonian University Medical College Faculty of Medicine Cracow Poland

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$a More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma / $c T. Jelinek, R. Bezdekova, D. Zihala, T. Sevcikova, A. Anilkumar Sithara, L. Pospisilova, S. Sevcikova, P. Polackova, M. Stork, Z. Knechtova, O. Venglar, V. Kapustova, T. Popkova, L. Muronova, Z. Chyra, M. Hrdinka, M. Simicek, JJ. Garcés, N. Puig, MT. Cedena, A. Jurczyszyn, JJ. Castillo, M. Penka, J. Radocha, MV. Mateos, JF. San-Miguel, B. Paiva, L. Pour, L. Rihova, R. Hajek

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$a PURPOSE: Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. METHODS: We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. RESULTS: Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. CONCLUSION: Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.

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