Barlogie, B. (Bart)
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- Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance(American Society of Hematology, 2016) Gironella, M. (Mercedes); Bladé, J. (Joan); Barlogie, B. (Bart); García-Sanz, R. (Ramón); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Sanchez, M.L. (Maria Luz); Ocio, E.M. (Enrique M.); Gonzalez, Y. (Yolanda); Mateos, M.V. (María Victoria); Maiso, P. (Patricia); Arriba, F. (Felipe) de; Epstein, J. (Joshua); Rodriguez, I. (Idoia); Hernandez, M.T. (Miguel Teodoro); Puig, N. (Noemí); Burgos, L. (Leire); Alignani, D. (Diego); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Paiva, B. (Bruno); Oriol, A. (Albert); Corchete, L.A. (Luis A.); Barcena, P. (Paloma); San-Miguel, J.F. (Jesús F.); Johnson, S.K. (Sarah K.); Echeveste, M.A. (Maria Asuncion)Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered at www.clinicaltrials.gov as #NCT01237249.
- Differentiation stage of myeloma plasma cells: biological and clinical significance(Nature Publishing Group, 2017) Cedena, M.T. (María Teresa); Martínez-López, J. (Joaquín); Bladé, J. (Joan); Barlogie, B. (Bart); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Jong, B.G. (Britt G.) de; Gonzalez, Y. (Yolanda); Pascual, M. (Marien); Mateos, M.V. (María Victoria); Epstein, J. (Joshua); Hernandez, M.T. (Miguel Teodoro); Delgado, J.A. (Jose Antonio); Puig, N. (Noemí); Ruiz-Paz, Y; Morgan, G.J. (Gareth J.); Cordón, L. (Lourdes); Alignani, D. (Diego); Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Rapado, I. (Inmaculada); Dongen, J.J.M. (Jacques J. M.) van; Paiva, B. (Bruno); Oriol, A. (Albert); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); San-Miguel, J.F. (Jesús F.); Johnson, S.K. (Sarah K.); Echeveste, M.A. (Maria Asuncion); Martin-Subero, J.I. (Jose Ignacio); Van Zelm, M.C. (Menno C.)The notion that plasma cells (PCs) are terminally-differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly-diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully-differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+), and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR:1.7;P=.005) and overall survival (HR:2.1;P=.006). Longitudinal comparison of diagnostic vs. minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (e.g.:PAX5), and show distinct mutation profile vs. fully-differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harboring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
- Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project(Springer Nature, 2018) Durie, B. (B.); Attal, M. (Michele); Moreau, P. (Philippe); Lee, J.H. (Jae Hoon); Turesson, I. (Ingemar); Cavo, M. (Michele); Barlogie, B. (Bart); Usmani, S.Z. (Saad Z.); Hajek, R. (Roman); Kumar, S. (Shaji); Lenhof, S. (Stig); Morgan, G.J. (Gareth J.); Lahuerta, J.J. (Juan José); Goldschimdt, H. (Hartmut); Hoering, A. (Antje); Rajkumar, S.V. (S. Vincent); San-Miguel, J.F. (Jesús F.)Purpose: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. Patients & Methods: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan–Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. Results: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin ≥ 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels ≥ 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/μL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%. Conclusions: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival.