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541 Definition and Clinical Significance of the MGUS-like Phenotype: A Study in 5,114 Patients (Pts) with Monoclonal Gammopathies

Program: Oral and Poster Abstracts
Type: Oral
Session: 652. Multiple Myeloma and Plasma cell Dyscrasias: Clinical and Epidemiological: Reoptimizing Standards and Redefining Approaches
Hematology Disease Topics & Pathways:
Adults, Health Outcomes Research, Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Sunday, December 12, 2021: 4:30 PM

Leire Burgos1*, Luis Esteban Tamariz-Amador, MD2*, Noemí Puig, MD, PhD3*, María Teresa Cedena, MD, PhD4*, Tomas Jelinek, MD, PhD5, Sarah K Johnson, PhD6, Paolo Milani, MD, PhD7, Lourdes Cordon8*, José J Pérez3*, Marta Lasa1*, Rosalinda Termini9*, Albert Oriol, MD10*, Miguel-Teodoro Hernández, MD, PhD11*, Luis Palomera, MD, PhD12*, Rafael Martinez Martinez13*, Javier de la Rubia, MD, PhD14*, Felipe De Arriba, PhD15*, Rafael Rios, MD, PhD16*, Maria Esther González17*, Mercedes Gironella, MD18*, Valentin Cabañas, MD19*, Maria Casanova, MD20*, Isabel Krsnik21*, Albert Pérez, MD22*, Veronica Gonzalez De La Calle, MD, PhD23*, Paula Rodríguez-Otero, MD, PhD24*, Vladimir Maisnar, MD25*, Roman Hajek, MD, PhD26, Frits van Rhee, MD PhD27, Victor H Jimenez-Zepeda, MD28, Giovanni Palladini29, Paolo Milani30*, Alberto Orfao, MD, PhD3, Laura Rosinol31*, Joan Bladé Creixenti32, Joaquín Martínez-López33*, Juan-José Lahuerta, MD, PhD34*, Maria-Victoria Mateos35, Jesús F. San-Miguel1 and Bruno Paiva, PhD1*

1Centro de Investigación Médica Aplicada, University of Navarra, IDISNA, CIBERONC, Clínica Universidad de Navarra, Pamplona, Spain
2Centro de Investigación Médica Aplicada, University of Navarra, IDISNA, CIBERONC, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
3Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
4Hematology Department, Hospital Universitario 12 de Octubre, CIBERONC, Instituto de Investigación IMAS12, Madrid, Spain
5Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
6Myeloma Center/Division of Hematology Oncology/Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR
7Amyloidosis Research and Treatment Center, Department of Molecular Medicine, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
8Hospital Universitario La Fe, Valencia, Spain
9Centro de Investigación Médica Aplicada, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain
10Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain
11Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
12Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
13Hospital Clínico San Carlos, Madrid, Spain
14Hematology Department, University Hospital La Fe, Valencia, Spain
15Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
16Hospital Universitario Virgen de las Nieves de Granada, Instituto de Investigación Biosanitaria IBS GRANADA, Granada, Spain
17Hospital de Cabueñes, Gijón, Spain
18Department of Hematology, University Hospital Vall d’Hebron, Barcelona, Spain
19Hospital Clínico Universitario Virgen de la Arrixaca. IMIB-Arrixaca. University of Murcia, Murcia, Spain
20Hematology Department, Hospital Costa del Sol Marbella, Marbella, Spain
21Hospital Universitario Puerta de Hierro, Hospital, Madrid, Spain
22Hospital Universitario Son Espases, Palma, Spain
23Departamento de Hematología, Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
24Clinica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Navarra, Spain
254th Department of Medicine - Haematology, Charles University Hospital, Hradec Králové, Czech Republic
26Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
27Myeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR
28Tom Baker Cancer Center, Department of Hematology, University of Calgary, Calgary, AB, Canada
29Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, PV, Italy
30Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matt, Pavia, ITA
31Amyloidosis and Myeloma Unit. Department of Hematology. Hospital Clínic de Barcelona. IDIBAPS., Barcelona, Spain
32Amyloidosis and Multiple Myeloma Unit, Department of Hematology, IDIBAPS, Hospital Clínic, Barcelona, Spain, Barcelona, Spain
33Haematological Malignancies Clinical Research Unit, Hospital 12 de Octubre Universidad Complutense, CNIO, CIBERONC, Madrid, Spain
34Hospital 12 de Octubre, CIBERONC, Madrid, Spain
35Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain

Background: Within the spectrum of monoclonal gammopathies, there are various subgroups with unique biological and clinical profiles. Namely, the presence of multiple myeloma (MM) and light-chain amyloidosis (AL) pts with MGUS-like phenotype has been hypothesized, but the criteria to identify this subgroup are poorly defined and lack clinical validation.

Aim: Develop an algorithm based on a large flow cytometry dataset across the spectrum of monoclonal gammopathies, for automated identification of MM and AL pts with MGUS-like phenotype.

Methods: This study included 5,114 pts with monoclonal gammopathies and available flow cytometry data on the frequency of bone marrow (BM) plasma cells (PC) and the percentages of normal and clonal PC within the BM PC compartment, at diagnosis. An algorithm to classify pts with MGUS-like phenotype was developed based on these three parameters, obtained from 548 MGUS, 393 smoldering MM (SMM) and 2,011 MM pts. Newly diagnosed MM pts were homogeneously treated according to the GEM2000 (n = 486), GEM2005MENOS65 (n = 330), GEM2005MAS65 (n = 239), GEM2010MAS65 (n = 230), GEM2012MENOS65 (n = 450) and CLARIDEX (n = 276) protocols. The prognostic value of the MGUS-like phenotype was validated in 96 SMM pts studied in Arkansas and 1,859 MM pts treated outside clinical trials in Czech Republic. The clinical significance of the algorithm was investigated in two independent series of Spanish (n = 102) and Italian (n = 105) AL pts.

Results: The frequency of BM PC and of normal and clonal PC within the BM PC compartment were used to plot MGUS, SMM and MM pts in a principal component analysis (PCA). Lines defining 1.5 standard deviations of MGUS and MM pts were used as reference to classify each of the 5,114 cases. Once plotted against the dataset, individual pts were classified as MGUS-, intermediate- or MM-like, if their location in the PCA fell inside the MGUS, the overlapping or the MM reference lines, respectively.

In the training SMM series, patient classification into MGUS-, intermediate- and MM-like phenotype resulted in significantly different rates of disease progression (0%, 54% and 66% at 5y, respectively; P < .001). These results were validated in the Arkansas series (8%, 27% and 71% at 5y, respectively; P < .001). Only 5% of SMM pts with high-risk disease according to Mayo or PETHEMA criteria had an MGUS-like phenotype, and these had virtually no risk of progression at 5y.

In the training MM series, pts with MGUS-like phenotype showed significantly longer progression free (PFS) and overall survival (OS) vs the remaining pts. Median PFS was 10y vs 3y (hazard ratio [HR]: 0.46, P < .001) and median OS was not reached (NR) vs 6.5y (HR: 0.48, P < .001), respectively. These results were validated in the Czech Republic series with significant differences in PFS (HR: 0.45, P < .001) and OS (HR: 0.38, P < .001) between MGUS-like vs other MM pts.

MGUS-like classification in the training MM series retained independent prognostic value in multivariate analyses of PFS (HR: 0.48, P < .001) and OS (HR: 0.54, P = .033), together with ISS, LDH, cytogenetics, induction regimen, transplant-eligibility and complete remission (CR). MGUS-like pts showed similar PFS (P = .932) and OS (P = .285) regardless of having standard vs high risk cytogenetics. Notably, MGUS-like transplant-eligible MM pts treated with proteasome inhibitors, immunomodulatory drugs and corticoids during induction showed PFS and OS rates at 5y of 86% and 96%, respectively. Differences in PFS among MGUS-like MM pts achieving ≥CR vs <CR were not significant (median of 13y vs 9y, respectively; P = .122), which suggests that attaining CR is not mandatory to reach long-term survival in this subgroup of pts, treated with fixed-duration regimens.

Classification of AL pts into the MGUS-, intermediate- and MM-like phenotype resulted in significantly different PFS in the Spanish (median of 28, 20 and 1 months, respectively; P = .001) and Italian (median 32, 11 and 3 months, respectively; P < .001) cohorts.

Conclusions: We developed an algorithm that can be readily installed in clinical flow cytometry software, and requires three parameters that are routinely assessed at screening. Patient’ automated classification using the algorithm was validated in large series across the spectrum of monoclonal gammopathies. Because pts with MGUS-like phenotype have a distinct clinical behavior, their identification could become part of the diagnostic workup in SMM, MM and AL.

Disclosures: Cedena: Janssen, Celgene and Abbvie: Honoraria. Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Cordon: Cytognos SL: Research Funding. Oriol: Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy. de la Rubia: Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Celgene, Takeda, Janssen, Sanofi: Honoraria; Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy; Takeda: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Cabañas: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Honoraria. Gonzalez De La Calle: Celgene-BMS, Janssen, Amgen: Honoraria. Rodríguez-Otero: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and other expenses. Hajek: Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jimenez-Zepeda: BMS, Amgen, Takeda, Janssen: Honoraria. Palladini: Janssen Global Services: Honoraria, Other: advisory board fees; Pfizer: Honoraria; Siemens: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding.

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