Circulating tumor and immune cells for minimally invasive risk stratification of smoldering multiple myeloma
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Abstract
Purpose: Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), 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 patients with SMM 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 3 years since enrollment. Results: Patients with >0.015% versus ≤0.015% CTCs at baseline had a median time-to-progression of 17 months versus not reached (HR, 4.9; P < 0.001). Presence of >20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio >20, >2 g/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− nonclassical 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 2 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.
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In MGUS and SMM, MAFB translocations associate with high-risk genomic features but do not always predict progression.
“In the context of MGUS and SMM, these translocations still associate with high-risk genomic features,59,97,98 but strangely do not always predict progression as one might expect.9,90,99”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [90]
The Introduction and Discussion say that SMM risk categories do not perfectly predict progression, but they do not address whether MAFB translocations predict progression in MGUS or SMM. Searches for “MAFB” and “t(14;20) translocation” found no passage establishing that translocation-specific claim. (LLM, conf=0.75)
Experimental — accuracy not yet measuredMGUS/SMM may have distinct gene expression signatures capable of predicting progression to MM.
“From the transcriptomic point of view, it has been shown that MGUS/SMM may have distinct gene expression signatures capable of predicting progression to MM.89,90”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [90]
The Introduction says genomic abnormalities have prognostic value, and the Results describe immune-cell differences between stable and progressive SMM. Neither passage addresses transcriptomic gene-expression signatures in MGUS or SMM that predict progression to MM. Searches for gene-expression and transcriptomic signatures found no passage establishing that point in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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Zabaleta, A., Tamariz‐Amador, L., Kostopoulos, I. V., Sklavenitis‐Pistofidis, R., Smits, F., Rodríguez‐Otero, P., Roncal, C., Aranha, M. P., Žihala, D., Machu, M., et al. (2026) · Blood · doi:10.1182/blood.2025031744 · Cited by 4 · see citing works
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Self-citationHow to Identify and Manage High-Risk Smoldering Multiple Myeloma
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Early Detection of Precursor Diseases of Multiple Myeloma
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Self-citation
- Authors
- Termini, R., Žihala, D., Terpos, E., Perez-Montaña, A., Jelínek, T., Raab, M., Weinhold, N., Mai, E. K., Grab, A. L., Corre, J., Vergez, F., Sacco, A., Chiarini, M., Giustini, V., Tucci, A., Rodriguez, S., Moreno, C., Perez, C., Maia, C., Martín-Sánchez, E., Guerrero, C., Botta, C., Garces, J.-J., Lopez, A., Tamariz-Amador, L.-E., Prosper, F., Bargay, J., Cabezudo, M.-E., Ocio, E. M., Hájek, R., Martinez-Lopez, J., Solano, F., Iglesias, R., Paiva, A., Geraldes, C., Vitoria, H., Gomez, C., De Arriba, F., Ludwig, H., Garcia-Guiñon, A., Casanova, M., Alegre, A., Cabañas, V., Sirvent, M., Oriol, A., de la Rubia, J., Hernández-Rivas, J.-Á., Palomera, L., Sarasa, M., Rios, P., Puig, N., Mateos, M.-V., Flores-Montero, J., Orfao, A., Goldschmidt, H., Avet-Loiseau, H., Roccaro, A. M., San-Miguel, J. F., Paiva, B., & Groups, O. B. O. T. P. A. I. C.
- Affiliations
- Navarre Institute of Health Research (ES)
- University of Ostrava (CZ)
- National and Kapodistrian University of Athens (GR)
- 4Hospital Universitario Son Espases, Palma, Spain.
- 2Department of Hematooncology, University Hospital Ostrava and University of Ostrava, Ostrava, Czech Republic.
- Heidelberg University (DE)
- Inserm (FR)
- 6Centre de Recherche en Cancérologie de Toulouse, Unité 1037, INSERM, Toulouse, France.
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- 1Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CCUN, CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain.
- University of Palermo (IT)
- Hospital Son Llatzer (ES)
- Hospital de Sant Joan Despí Moisès Broggi (ES)
- Universidad de Cantabria (ES)
- 12Hospital Universitario 12 De Octubre, Universidad Complutense, CNIO Madrid, Spain.
- Hospital General Nuestra Señora del Prado (ES)
- MD Anderson Cancer Center Madrid (ES)
- Unidade Local de Saúde de Coimbra (PT)
- 16Centro Hospitalare Universitário de Coimbra (CHUC), Coimbra, Portugal.
- 17Hospital de Galdakao, Vizcaya, Spain.
- 18Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain.
- 19Wilhelminen Cancer Research Institute, Clinic Ottakring, Vienna, Austria.
- 20Hospital Universitario Arnau de Vilanova, Lleida, Spain.
- 21Hospital Costa del Sol Marbella, Marbella, Spain.
- 22Hospital de la Princesa, Madrid, Spain.
- 23Hospital Virgen de la Arrixaca de Murcia, IMIB Arrixaca, Universidad de Murcia, Murcia, Spain.
- Donostiako Unibertsitate Ospitalea (ES)
- Institut Català d'Oncologia (ES)
- 26University Hospital de La Fe, School of Medicine and Dentistry, Catholic University of Valencia, CIBERONC CB16/12/00284, Valencia, Spain.
- 27Hospital Universitario Infanta Leonor, Departamento de Medicina, Universidad Complutense, Madrid, Spain.
- Hospital Clínico Universitario Lozano Blesa (ES)
- 29Hospital de Laredo, Laredo, Spain.
- Hospital Universitario Nuestra Señora de Candelaria (ES)
- 31Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
- Consejo Superior de Investigaciones Científicas (ES)
- 32Translational and Clinical Research Program, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Department of Medicine, Cytometry Service, Instituto de Investigación Biosanitaria de Salamanca (IBSAL) and CIBER-ONC (number CB16/12/00400), University of Salamanca, Salamanca, Spain.
- Corresponding author
- Paiva, Bruno
- ORCID
- Termini, Rosalinda
- Žihala, David
- Terpos, Evangelos
- Perez-Montaña, Albert
- Jelínek, Tomáš
- Raab, Marc
- Weinhold, Niels
- Mai, Elias K.
- Grab, Anna Luise
- Corre, Jill
- Vergez, Francois
- Sacco, Antonio
- Chiarini, Marco
- Giustini, Viviana
- Tucci, Alessandra
- Rodriguez, Sara
- Moreno, Cristina
- Perez, Cristina
- Maia, Catarina
- Martín-Sánchez, Esperanza
- Guerrero, Camilla
- Botta, Cirino
- Garces, Juan-Jose
- Lopez, Aitziber
- Tamariz-Amador, Luis-Esteban
- Prosper, Felipe
- Bargay, Joan
- Cabezudo, Maria-Elena
- Ocio, Enrique M.
- Hájek, Roman
- Martinez-Lopez, Joaquin
- Solano, Fernando
- Iglesias, Rebeca
- Paiva, Artur
- Geraldes, Catarina
- Vitoria, Helena
- Gomez, Clara
- De Arriba, Felipe
- Ludwig, Heinz
- Garcia-Guiñon, Antoni
- Casanova, Maria
- Alegre, Adrian
- Cabañas, Valentin
- Sirvent, Maialen
- Oriol, Albert
- de la Rubia, Javier
- Hernández-Rivas, José-Ángel
- Palomera, Luis
- Sarasa, Maria
- Rios, Pablo
- Puig, Noemi
- Mateos, Maria-Victoria
- Flores-Montero, Juan
- Orfao, Alberto
- Goldschmidt, Hartmut
- Avet-Loiseau, Hervé
- Roccaro, Aldo M.
- San-Miguel, Jesus F.
- Paiva, Bruno
- Venue
- Clinical Cancer Research
- Published
- 2022-09-08
- Volume
- 28
- Issue
- 21
- Pages
- 4771-4781
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W4294958648
- Cited by
- 54
- References
- 45
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 17 · 2023: 10
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Clinical Cancer Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- Funders
- Centro de Investigación Biomédica en Red de Cáncer (CB16/12/00369, PI20/00048)
- Cancer Research UK
- FCAECC (INVES211176MART)
- EDITOR
- Black Swan Research Initiative of the International Myeloma Foundation
- European Research Council (MYELOMANEXT grant 680200)
- CRIS Cancer Foundation (PR_EX_2020-02)
- Riney Family Multiple Myeloma Research Program Fund
- European Union (PFIS No. FI21/00293)
- European Hematology Association
- Multiple Myeloma Research Foundation
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- smoldering multiple myeloma, circulating tumor cells, bone marrow plasma cells, risk stratification, progression risk prediction, immunological markers, non-classical monocytes, cytotoxic NK cells, central memory T cells, minimally invasive monitoring
- MeSH terms
- Smoldering Multiple Myeloma, Humans, Immunoglobulin Light Chains, Multiple Myeloma, Prognosis, Disease Progression, Risk Assessment
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