The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression
Open accessAbstract
Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.
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The primary reason for the controversy is the lack of highly accurate prediction models for defining high-risk SMM.
“The primary reason for this is the lack of highly accurate prediction models for defining high risk SMM.113”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [113]
The Introduction (page not available) says that several SMM risk-assessment models exist, but not all account for genomic architecture that could affect progression. This supports a limitation in the models, but the paper does not identify a lack of highly accurate models as the primary reason for a controversy. (LLM, conf=0.78)
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Research works printed but not linked: 1
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Evolution of Multiple Myeloma from a Genomic Perspective
Maura, F., Samur, M., & Munshi, N. (2026) · Blood · doi:10.1182/blood.2024026313 · Cited by 8 · see citing works
- Authors
- Medina-Herrera, A., Vazquez, I., Cuenca, I., Rosa-Rosa, J. M., Ariceta, B., Jimenez, C., Fernandez-Mercado, M., Larrayoz, M. J., Gutierrez, N. C., Fernandez-Guijarro, M., Gonzalez-Calle, V., Rodriguez-Otero, P., Oriol, A., Rosiñol, L., Alegre, A., Escalante, F., De La Rubia, J., Teruel, A. I., De Arriba, F., Hernandez, M. T., Lopez-Jimenez, J., Ocio, E. M., Puig, N., Paiva, B., Lahuerta, J. J., Bladé, J., San Miguel, J. F., Mateos, M. V., Martinez-Lopez, J., Calasanz, M. J., Garcia-Sanz, R., GEM/PETHEMA (Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group, Gonzalez-Calle, V., De La Rubia, J., De Arriba, F., Rios, R., Sureda, A., Blanchard, M. J., Martinez-Martinez, R., Moraleda, J. M., Bargay, J., Gironella, M., Palomera, L., Gonzalez-Montes, Y., Martí, J. M., Krsnik, I., Arguiñano, J. M., Gonzalez, M. E., Gonzalez, A. P., & Casado, L. F.
- Affiliations
- Universidad de Salamanca (ES)
- Universidad Complutense de Madrid (ES)
- Clinica Universidad de Navarra (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Hospital Clínic de Barcelona (ES)
- Hospital Universitario Quirónsalud Madrid (ES)
- Hospital Universitario de León (ES)
- Hospital Clínico Universitario de Valencia (ES)
- Universidad de La Laguna (ES)
- Universidad de Cantabria (ES)
- Hospital Universitario Virgen de las Nieves (ES)
- Institut Català d'Oncologia (ES)
- Hospital Universitario Ramón y Cajal (ES)
- Hospital Clínico San Carlos (ES)
- Hospital Universitario Virgen de la Arrixaca (ES)
- Hospital Son Llatzer (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Hospital Clínico Universitario Lozano Blesa (ES)
- Hospital Universitari de Girona Doctor Josep Trueta (ES)
- University Hospital Mútua de Terrassa (ES)
- Hospital Universitario Puerta de Hierro Majadahonda (ES)
- Complejo Hospitalario de Navarra (ES)
- Hospital Universitario De Cabueñes (ES)
- Hospital Universitario Central de Asturias (ES)
- Hospital Virgen de la Salud (ES)
- Corresponding author
- Jimenez, C.
- ORCID
- Medina-Herrera, A.
- Rosa-Rosa, J. M.
- Ariceta, B.
- Gutierrez, N. C.
- Rodriguez-Otero, P.
- Oriol, A.
- Rosiñol, L.
- Alegre, A.
- Escalante, F.
- Teruel, A. I.
- Hernandez, M. T.
- Lopez-Jimenez, J.
- Ocio, E. M.
- Paiva, B.
- Lahuerta, J. J.
- Bladé, J.
- San Miguel, J. F.
- Mateos, M. V.
- Martinez-Lopez, J.
- Calasanz, M. J.
- Garcia-Sanz, R.
- Moraleda, J. M.
- Gironella, M.
- Venue
- Blood Cancer Journal
- Published
- 2024-04-29
- Volume
- 14
- Issue
- 1
- Pages
- 74-74
- ISSN
- 2044-5385 (ISSN-L)
- PMC
- PMC11059156
- OpenAlex
- W4396220671
- Cited by
- 11
- References
- 36
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Blood Cancer Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
- Academica-e (Universidad Pública de Navarra) (submittedVersion, cc-by)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- Docusalut (Conselleria de Salut i Consum del Govern de les Illes Balears) (submittedVersion, cc-by)
- UCrea (University of Cantabria) (submittedVersion, cc-by)
- RIUCV (Universidad Católica de Valencia San Vicente Martír) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hispana (submittedVersion, cc-by)
- Funders
- Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (PMP21/00015)
- 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, high-risk smoldering myeloma, progression risk, treatment resistance, genomic profiling, FGFR3 mutation, 1q deletion, NRAS mutation, intensive treatment
- MeSH terms
- Smoldering Multiple Myeloma, Aged, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Male, Middle Aged, Mutation, Biomarkers, Tumor, Disease Progression, Drug Resistance, Neoplasm, High-Throughput Nucleotide Sequencing
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