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Definition and Clinical Significance of the Monoclonal Gammopathy of Undetermined Significance–Like Phenotype in Patients With Monoclonal Gammopathies

Authors: Leire Burgos, PhD, Luis-Esteban Tamariz-Amador, MD https://orcid.org/0000-0002-4088-0992, Noemi Puig, MD, PhD https://orcid.org/0000-0001-7535-3861, Maria-Teresa Cedena, MD https://orcid.org/0000-0001-5851-3720, Camila Guerrero, MSc https://orcid.org/0000-0003-1395-5140, Tomas Jelínek, MD, PhD https://orcid.org/0000-0002-5467-9253, Sarah Johnson, PhD, Paolo Milani, MD https://orcid.org/0000-0002-2268-9422, Lourdes Cordon, PhD https://orcid.org/0000-0002-8808-3423, Jose J. Perez, PhD, Marta Lasa, PhD https://orcid.org/0000-0002-2981-162X, Rosalinda Termini, MSc https://orcid.org/0000-0001-7263-8415, Albert Oriol, MD https://orcid.org/0000-0001-6804-2221, Miguel-Teodoro Hernandez, MD, PhD https://orcid.org/0000-0002-6576-7881, Luis Palomera, MD https://orcid.org/0000-0003-0359-7191, Rafael Martinez-Martinez, MD, Javier de la Rubia, MD https://orcid.org/0000-0002-8354-768X, Felipe de Arriba, MD, Rafael Rios, MD, PhD https://orcid.org/0000-0001-8193-1402, Maria-Esther Gonzalez, MD https://orcid.org/0000-0002-4238-0377, Mercedes Gironella, MD https://orcid.org/0000-0002-8106-8909, Valentin Cabañas, MD https://orcid.org/0000-0002-6248-2549, Maria Casanova, MD, Isabel Krsnik, MD https://orcid.org/0000-0002-2912-5072, Albert Perez-Montaña, MD, PhD https://orcid.org/0000-0003-2708-0090, Verónica González-Calle, MD, PhD https://orcid.org/0000-0002-5493-6707, Paula Rodriguez-Otero, MD, PhD https://orcid.org/0000-0001-5236-7785, Vladimir Maisnar, MD, Roman Hajek, MD, PhD https://orcid.org/0000-0001-6955-6267, Fritz Van Rhee, MD https://orcid.org/0000-0001-9959-1282, Victor Jimenez-Zepeda, MD, Giovanni Palladini, MD, PhD https://orcid.org/0000-0001-5994-5138, Giampaolo Merlini, MD, PhD https://orcid.org/0000-0001-7680-3254, Alberto Orfao, MD, PhD https://orcid.org/0000-0002-0007-7230, Javier de la Cruz, PhD, Joaquin Martinez-Lopez, MD, PhD https://orcid.org/0000-0001-7908-0063, Juan-Jose Lahuerta, MD, PhD https://orcid.org/0000-0002-3393-9570, Laura Rosiñol, MD, PhD https://orcid.org/0000-0002-2534-9239, Joan Blade, MD, PhD, Maria-Victoria Mateos, MD, PhD https://orcid.org/0000-0003-2390-1218, Jesus F. San-Miguel, MD, PhD https://orcid.org/0000-0002-9183-4857, and Bruno Paiva, PhD https://orcid.org/0000-0003-1977-3815 [email protected] on behalf of the PETHEMA/GEM Cooperative GroupAuthors Info & Affiliations
Publication: Journal of Clinical Oncology

Abstract

Purpose

The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)–like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated.

Patients and Methods

An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis.

Results

Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival.

Conclusion

We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.

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Data Supplement

Authors retain all rights in any data supplements associated with their articles

The ideas and opinions expressed in this Data Supplement do not necessarily reflect those of the American Society of Clinical Oncology (ASCO). The mention of any product, service, or therapy in this Data Supplement should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify approved uses, the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in this publication or to any errors or omissions. Readers should contact the corresponding author with any comments related to Data Supplement materials.

Prior Presentation

Presented as an oral abstract in the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, Atlanta, GA, December 11-14, 2021.

Support

Supported by grants from the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00400 CB16/12/00233 and CB16/12/00284); Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI19/01451); the Cancer Research UK (C355/A26819), FCAECC and AIRC under the Accelerator Award Program (EDITOR); the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT/680200); the CRIS Cancer Foundation (PR_EX_2020-02), the Black Swan Research Initiative of the International Myeloma Foundation; and the Riney Family Multiple Myeloma Research Program Fund.

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 3019 - 3031
PubMed: 36930848

History

Published online: March 17, 2023
Published in print: June 01, 2023

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Data Sharing Statement

The data set will be made available to researchers who provide a methodologically sound proposal. The data will be provided after its deidentification in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.

Authors

Affiliations

Leire Burgos, PhD
Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
Luis-Esteban Tamariz-Amador, MD https://orcid.org/0000-0002-4088-0992
Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
Hematology Department, Hospital Universitario 12 de Octubre, CIBERONC, Instituto de Investigación IMAS12, Madrid, Spain
Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Sarah Johnson, PhD
Myeloma Center/Division of Hematology Oncology/Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR
Department of Molecular Medicine, University of Pavia and Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Hospital Universitario La Fe, Valencia, Spain
Jose J. Perez, PhD
Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain
Miguel-Teodoro Hernandez, MD, PhD https://orcid.org/0000-0002-6576-7881
Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
Rafael Martinez-Martinez, MD
Hospital Clínico San Carlos, Madrid, Spain
Hematology Department, University Hospital La Fe, Valencia, Spain
Felipe de Arriba, MD
Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
Hospital Universitario Puerta de Hierro, Hospital, Madrid, Spain
Maria-Esther Gonzalez, MD https://orcid.org/0000-0002-4238-0377
Hospital de Cabueñes, Gijón, Spain
Department of Hematology, University Hospital Vall d’Hebron, Barcelona, Spain
Hospital Clínico Universitario Virgen de la Arrixaca. IMIB-Arrixaca. University of Murcia, Murcia, Spain
Maria Casanova, MD
Hematology Department, Hospital Costa del Sol Marbella, Marbella, Spain
Hospital Universitario Puerta de Hierro, Hospital, Madrid, Spain
Albert Perez-Montaña, MD, PhD https://orcid.org/0000-0003-2708-0090
Hospital Universitario Son Espases, Palma, Spain
Verónica González-Calle, MD, PhD https://orcid.org/0000-0002-5493-6707
Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
Paula Rodriguez-Otero, MD, PhD https://orcid.org/0000-0001-5236-7785
Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
Vladimir Maisnar, MD
4th Department of Medicine—Haematology, Charles University Hospital, Hradec Králové, Czech Republic
Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Myeloma Center/Division of Hematology Oncology/Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR
Victor Jimenez-Zepeda, MD
Tom Baker Cancer Center, Department of Hematology, University of Calgary, Calgary, AB, Canada
Giovanni Palladini, MD, PhD https://orcid.org/0000-0001-5994-5138
Department of Molecular Medicine, University of Pavia and Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Giampaolo Merlini, MD, PhD https://orcid.org/0000-0001-7680-3254
Department of Molecular Medicine, University of Pavia and Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Hospital Universitario de Salamanca (HUSAL), IBSAL, Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service, University of Salamanca, CIBERONC, Salamanca, Spain
Javier de la Cruz, PhD
Hematology Department, Hospital Universitario 12 de Octubre, CIBERONC, Instituto de Investigación IMAS12, Madrid, Spain
Joaquin Martinez-Lopez, MD, PhD https://orcid.org/0000-0001-7908-0063
Hematology Department, Hospital Universitario 12 de Octubre, CIBERONC, Instituto de Investigación IMAS12, Madrid, Spain
Juan-Jose Lahuerta, MD, PhD https://orcid.org/0000-0002-3393-9570
Hematology Department, Hospital Universitario 12 de Octubre, CIBERONC, Instituto de Investigación IMAS12, Madrid, Spain
Amyloidosis and Myeloma Unit. Department of Hematology. Hospital Clínic de Barcelona. IDIBAPS., Barcelona, Spain
Joan Blade, MD, PhD
Amyloidosis and Myeloma Unit. Department of Hematology. Hospital Clínic de Barcelona. IDIBAPS., Barcelona, Spain
Maria-Victoria Mateos, MD, PhD https://orcid.org/0000-0003-2390-1218
Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
Jesus F. San-Miguel, MD, PhD https://orcid.org/0000-0002-9183-4857
Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
on behalf of the PETHEMA/GEM Cooperative Group

Notes

Bruno Paiva, PhD, Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Av. Pío XII 55, 31008 Pamplona, Spain; Twitter: @BrunoPaiva_UNAV; e-mail: [email protected].
*
L.B., L.-E.T.-A., N.P., and M.-T.C. have all contributed equally to this study and should be considered as first authors.
*
J.F.S.-M. and B.P. have contributed equally to this study and should be considered as last authors.

Author Contributions

Conception and design: Jesus F. San-Miguel, Bruno Paiva
Administrative support: Juan-Jose Lahuerta
Provision of study materials or patients: Maria-Teresa Cedena, Paolo Milani, Lourdes Cordon, Rosalinda Termini, Miguel-Teodoro Hernandez, Javier de la Rubia, Felipe de Arriba, Rafael Rios, Valentin Cabañas, Maria Casanova, Isabel Krsnik, Verónica González-Calle, Paula Rodriguez-Otero, Fritz Van Rhee, Victor Jimenez-Zepeda, Giovanni Palladini, Joaquin Martinez-Lopez, Juan-Jose Lahuerta, Laura Rosiñol, Joan Blade, Maria-Victoria Mateos
Collection and assembly of data: Leire Burgos, Noemi Puig, Maria-Teresa Cedena, Tomas Jelínek, Sarah Johnson, Paolo Milani, Lourdes Cordon, Jose J. Perez, Marta Lasa, Rosalinda Termini, Albert Oriol, Miguel-Teodoro Hernandez, Rafael Martinez-Martinez, Javier de la Rubia, Felipe de Arriba, Rafael Rios, Valentin Cabañas, Maria Casanova, Isabel Krsnik, Albert Perez-Montaña, Verónica González-Calle, Paula Rodriguez-Otero, Vladimir Maisnar, Roman Hajek, Fritz Van Rhee, Victor Jimenez-Zepeda, Giovanni Palladini, Joaquin Martinez-Lopez, Juan-Jose Lahuerta, Laura Rosiñol, Joan Blade, Maria-Victoria Mateos, Bruno Paiva
Data analysis and interpretation: Leire Burgos, Luis-Esteban Tamariz-Amador, Noemi Puig, Maria-Teresa Cedena, Camila Guerrero, Paolo Milani, Jose J. Perez, Albert Oriol, Luis Palomera, Rafael Rios, Maria-Esther Gonzalez, Mercedes Gironella, Albert Perez-Montaña, Paula Rodriguez-Otero, Roman Hajek, Giovanni Palladini, Giampaolo Merlini, Alberto Orfao, Javier de la Cruz, Laura Rosiñol, Maria-Victoria Mateos, Jesus F. San-Miguel, Bruno Paiva
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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Leire Burgos, Luis-Esteban Tamariz-Amador, Noemi Puig, Maria-Teresa Cedena, Camila Guerrero, Tomas Jelínek, Sarah Johnson, Paolo Milani, Lourdes Cordon, Jose J. Perez, Marta Lasa, Rosalinda Termini, Albert Oriol, Miguel-Teodoro Hernandez, Luis Palomera, Rafael Martinez-Martinez, Javier de la Rubia, Felipe de Arriba, Rafael Rios, Maria-Esther Gonzalez, Mercedes Gironella, Valentin Cabañas, Maria Casanova, Isabel Krsnik, Albert Perez-Montaña, Verónica González-Calle, Paula Rodriguez-Otero, Vladimir Maisnar, Roman Hajek, Fritz Van Rhee, Victor Jimenez-Zepeda, Giovanni Palladini, Giampaolo Merlini, Alberto Orfao, Javier de la Cruz, Joaquin Martinez-Lopez, Juan-Jose Lahuerta, Laura Rosiñol, Joan Blade, Maria-Victoria Mateos, Jesus F. San-Miguel, Bruno Paiva, on behalf of the PETHEMA/GEM Cooperative Group
Journal of Clinical Oncology 2023 41:16, 3019-3031

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