26 results on '"Mario Boccadoro"'
Search Results
2. 2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: how to distinguish (and manage) Dr. Jekyll and Mr. Hyde
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Pellegrino Musto, Monika Engelhardt, Jo Caers, Niccolo’ Bolli, Martin Kaiser, Niels van de Donk, Evangelos Terpos, Annemiek Broijl, Carlos Fernández de Larrea, Francesca Gay, Hartmut Goldschmidt, Roman Hajek, Annette Juul Vangsted, Elena Zamagni, Sonja Zweegman, Michele Cavo, Meletios Dimopoulos, Hermann Einsele, Heinz Ludwig, Giovanni Barosi, Mario Boccadoro, Maria-Victoria Mateos, Pieter Sonneveld, and Jesus San Miguel
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and
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- 2021
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3. European Myeloma Network perspective on CAR T-Cell therapies for multiple myeloma
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Benedetto Bruno, Ralph Wäsch, Monika Engelhardt, Francesca Gay, Luisa Giaccone, Mattia D’Agostino, Luis-Gerardo Rodríguez-Lobato, Sophia Danhof, Nico Gagelmann, Nicolaus Kröger, Rakesh Popat, Niels W.C.J. van de Donk, Evangelos Terpos, Meletios A. Dimopoulos, Pieter Sonneveld, Hermann Einsele, and Mario Boccadoro
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.
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- 2021
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4. Standardization of flow cytometric minimal residual disease assessment in international clinical trials. A feasibility study from the European Myeloma Network
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Davine Hofste op Bruinink, Stefania Oliva, Lucie Rihova, Alexander Schmitz, Milena Gilestro, Jeroen te Marvelde, Romana Kralova, Helle Høholt, Annemiek Broijl, Hans Erik Johnsen, Roman Hajek, Mario Boccadoro, Pieter Sonneveld, Paola Omedè, and Vincent H.J. van der Velden
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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5. Lenalidomide-based induction and maintenance in elderly newly diagnosed multiple myeloma patients: updated results of the EMN01 randomized trial
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Sara Bringhen, Mattia D’Agostino, Laura Paris, Stelvio Ballanti, Norbert Pescosta, Stefano Spada, Sara Pezzatti, Mariella Grasso, Delia Rota-Scalabrini, Luca De Rosa, Vincenzo Pavone, Giulia Gazzera, Sara Aquino, Marco Poggiu, Armando Santoro, Massimo Gentile, Luca Baldini, Maria Teresa Petrucci, Patrizia Tosi, Roberto Marasca, Claudia Cellini, Antonio Palumbo, Patrizia Falco, Roman Hájek, Mario Boccadoro, and Alessandra Larocca
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone vs. 18.6 months with lenalidomide (hazard ratio 0.85, P=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; P=0.001). Grade ≥3 non-hematologic adverse events were rare (
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- 2020
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6. First-line therapy with either bortezomib-melphalan-prednisone or lenalidomide-dexamethasone followed by lenalidomide for transplant-ineligible multiple myeloma patients: a pooled analysis of two randomized trials
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Alessandra Larocca, Roberto Mina, Massimo Offidani, Anna Marina Liberati, Antonio Ledda, Francesca Patriarca, Andrea Evangelista, Stefano Spada, Giulia Benevolo, Daniela Oddolo, Vanessa Innao, Clotilde Cangiolosi, Annalisa Bernardini, Pellegrino Musto, Valeria Amico, Vincenzo Fraticelli, Laura Paris, Nicola Giuliani, Antonietta Pia Falcone, Renato Zambello, Lorenzo De Paoli, Alessandra Romano, Antonio Palumbo, Vittorio Montefusco, Roman Hájek, Mario Boccadoro, and Sara Bringhen
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).
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- 2020
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7. HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia
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Valentina Griggio, Candida Vitale, Maria Todaro, Chiara Riganti, Joanna Kopecka, Chiara Salvetti, Riccardo Bomben, Michele Dal Bo, Daniela Magliulo, Davide Rossi, Gabriele Pozzato, Lisa Bonello, Monia Marchetti, Paola Omedè, Ahad Ahmed Kodipad, Luca Laurenti, Giovanni Del Poeta, Francesca Romana Mauro, Rosa Bernardi, Thorsten Zenz, Valter Gattei, Gianluca Gaidano, Robin Foà, Massimo Massaia, Mario Boccadoro, and Marta Coscia
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study, we demonstrate that CLL cells from TP53-disrupted (TP53dis) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the TP53dis subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of HIF-1A mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53dis tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53dis leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL.
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- 2020
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8. Elotuzumab, lenalidomide, and dexamethasone as salvage therapy for patients with multiple myeloma: Italian, multicenter, retrospective clinical experience with 300 cases outside of controlled clinical trials
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Massimo Gentile, Giorgina Specchia, Daniele Derudas, Monica Galli, Cirino Botta, Stefano Rocco, Concetta Conticello, Catello Califano, Nicola Giuliani, Silvia Mangiacavalli, Enrico Attingenti, Alessandra Lombardo, Marino Brunori, Elena Rossi, Elisabetta Antonioli, Roberto Ria, Renato Zambello, Nicola Di Renzo, Giuseppe Mele, Gianpaolo Marcacci, Pellegrino Musto, Silvana Capalbo, Nicola Cascavilla, Claudio Cerchione, Angelo Belotti, Clelia Criscuolo, Giuseppina Uccello, Paola Curci, Ernesto Vigna, Vincenzo Fraticelli, Donatella Vincelli, Angela Bonalumi, Agostina Siniscalchi, Raffaella Stocchi, Massimo Martino, Stelvio Ballanti, Dominella Gangemi, Alfredo Gagliardi, Barbara Gamberi, Alessandra Pompa, Anna Grazia Recchia, Giovanni Tripepi, Annalisa Pitino, Ferdinando Frigeri, Ugo Consoli, Sara Bringhen, Elena Zamagni, Francesca Patriarca, Valerio De Stefano, Francesco Di Raimondo, Salvatore Palmieri, Maria Teresa Petrucci, Massimo Offidani, Mario Boccadoro, Michele Cavo, and Fortunato Morabito
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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9. Carfilzomib, cyclophosphamide and dexamethasone for newly diagnosed, high-risk myeloma patients not eligible for transplant: a pooled analysis of two studies
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Roberto Mina, Francesca Bonello, Maria Teresa Petrucci, Anna Marina Liberati, Concetta Conticello, Stelvio Ballanti, Pellegrino Musto, Attilio Olivieri, Giulia Benevolo, Andrea Capra, Milena Gilestro, Piero Galieni, Michele Cavo, Agostina Siniscalchi, Antonio Palumbo, Vittorio Montefusco, Gianluca Gaidano, Paola Omedé, Mario Boccadoro, and Sara Bringhen
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Despite remarkable advances in the treatment of multiple myeloma in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with multiple myeloma receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard- versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard- vs. high-risk patients, we observed similar progression-free survival (3-year PFS: 52% vs. 43%, respectively; p=0.50), overall survival (3-year OS: 78% vs. 73%; p=0.38), and overall response rate (88% vs 95%; p=0.47), with no statistical differences between the two groups. No difference in terms of progression-free survival was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed multiple myeloma patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted into similar progression-free survival and overall survival, as compared to standard-risk patients. ClinicalTrials.gov IDs: NCT01857115 (IST-CAR-561) and NCT01346787 (IST-CAR-506).
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- 2020
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10. Outcome of paraosseous extra-medullary disease in newly diagnosed multiple myeloma patients treated with new drugs
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Vittorio Montefusco, Francesca Gay, Stefano Spada, Lorenzo De Paoli, Francesco Di Raimondo, Rossella Ribolla, Caterina Musolino, Francesca Patriarca, Pellegrino Musto, Piero Galieni, Stelvio Ballanti, Chiara Nozzoli, Nicola Cascavilla, Dina Ben-Yehuda, Arnon Nagler, Roman Hajek, Massimo Offidani, Anna Marina Liberati, Pieter Sonneveld, Michele Cavo, Paolo Corradini, and Mario Boccadoro
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15, P=0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months (P=0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41, P
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- 2020
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11. Chimeric antigen receptor T-cell therapy for multiple myeloma: a consensus statement from The European Myeloma Network
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Philippe Moreau, Pieter Sonneveld, Mario Boccadoro, Gordon Cook, Ma Victoria Mateos, Hareth Nahi, Hartmut Goldschmidt, Meletios A. Dimopoulos, Paulo Lucio, Joan Bladé, Michel Delforge, Roman Hajek, Heinz Ludwig, Thierry Facon, Jesus F. San Miguel, and Hermann Einsele
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Adoptive cellular therapy using chimeric antigen receptor T-cell (CART) therapy is currently being evaluated in patients with relapsed / refractory multiple myeloma (MM). The majority of CAR-T cell programs now being tested in clinical trials are targeting B-cell maturation antigen. Several recent phase I / II trials show promising preliminary results in patients with MM progressing on proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies targeting CD38. CAR-T cell therapy is a potentially life-threatening strategy that can only be administered in experienced centers. For the moment, CAR-T cell therapy for MM is still experimental, but once this strategy has been approved in relapsed/refractory MM, it will become one of the most important indications for this therapy in Europe and world-wide. This manuscript proposes practical considerations for the use of CAR-T cell therapy in MM, and discusses several important issues for its future development.
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- 2019
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12. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase I/II studies
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Sara Bringhen, Roberto Mina, Maria Teresa Petrucci, Gianluca Gaidano, Stelvio Ballanti, Pellegrino Musto, Massimo Offidani, Stefano Spada, Giulia Benevolo, Elena Ponticelli, Piero Galieni, Michele Cavo, Tommaso Caravita Di Toritto, Francesco Di Raimondo, Vittorio Montefusco, Antonio Palumbo, Mario Boccadoro, and Alessandra Larocca
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Twice-weekly carfilzomib is approved at 27 and 56 mg/m2 to treat relapsed multiple myeloma patients. In the phase III study ARROW, once-weekly 70 mg/m 2 carfilzomib prolonged the median progression-free survival of relapsed multiple myeloma patients in comparison with twice-weekly 27 mg/m2 carfilzomib, without adding significant toxicity. Data were pooled from two phase I/II studies of newly diagnosed multiple myeloma patients who received nine induction cycles of carfilzomib (either 70 mg/m2 once-weekly or 36 mg/m2 twice-weekly), cyclophosphamide and dexamethasone, followed by carfilzomib maintenance. Overall, 121 transplant-ineligible patients with newly diagnosed multiple myeloma were analyzed (once-weekly, n=63; twice-weekly, n=58). We found no significant difference in median progression-free survival [35.7 months (95%CI: 23.7-not reached, NR) vs. 35.5 months (95%CI: 24.3-NR); HR: 1.39; P=0.26] and 3-year overall survival [70% [95%CI: 59%-84%) vs. 72% (95%CI: 60%-85%); HR: 1.27; P=0.5] between once-weekly and twice-weekly carfilzomib. From the start of maintenance, 3-year progression-free survival [47% (95%CI: 33%-68%) vs. 51% (95%CI: 38%-70%); HR: 1.04; P=0.92] and overall survival [72% (95%CI: 58%-89%) vs. 73% (95%CI: 59%-90%); HR: 0.82; P=0.71] were similar in the once- versus twice-weekly carfilzomib. The rate of grade 3-5 hematologic (24% vs. 30%; P=0.82) and non-hematologic (38% vs. 41%; P=0.83) adverse events was similar in the two groups. Once-weekly 70 mg/m2 carfilzomib as induction and maintenance therapy for newly diagnosed multiple myeloma patients was as safe and effective as twice-weekly 36 mg/m2 carfilzomib and provided a more convenient schedule. The trials are registered at clinicaltrials.gov identifiers: 01857115 (IST-CAR-561) and 01346787 (IST-CAR-506).
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- 2019
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13. European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when
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Jo Caers, Laurent Garderet, K. Martin Kortüm, Michael E. O’Dwyer, Niels W.C.J. van de Donk, Mascha Binder, Sandra Maria Dold, Francesca Gay, Jill Corre, Yves Beguin, Heinz Ludwig, Alessandra Larocca, Christoph Driessen, Meletios A. Dimopoulos, Mario Boccadoro, Martin Gramatzki, Sonja Zweegman, Hermann Einsele, Michele Cavo, Hartmut Goldschmidt, Pieter Sonneveld, Michel Delforge, Holger W. Auner, Evangelos Terpos, and Monika Engelhardt
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The diagnosis of multiple myeloma can be challenging, even for experienced physicians, and requires close collaboration between numerous disciplines (orthopedics, radiology, nuclear medicine, radiation therapy, hematology and oncology) before the final diagnosis of myeloma is made. The definition of multiple myeloma is based on the presence of clinical, biochemical, histopathological, and radiological markers of disease. Specific tests are needed both at presentation and during follow-up in order to reach the correct diagnosis and characterize the disease precisely. These tests can also serve prognostic purposes and are useful for follow-up of myeloma patients. Molecular analyses remain pivotal for defining high-risk myeloma and are used in updated patient stratifications, while minimal residual disease assessment via flow cytometry, molecular techniques and radiological approaches provides additional prognostic information on patients’ long-term outcome. This pivotal information will guide our future treatment decisions in forthcoming clinical trials. The European Myeloma Network group updated their guidelines on different diagnostic recommendations, which should be of value to enable appropriate use of the recommendations both at diagnosis and during follow-up.
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- 2018
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14. Cardiovascular adverse events in modern myeloma therapy – Incidence and risks. A review from the European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA)
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Sara Bringhen, Alberto Milan, Claudio Ferri, Ralph Wäsch, Francesca Gay, Alessandra Larocca, Marco Salvini, Evangelos Terpos, Hartmut Goldschmidt, Michele Cavo, Maria Teresa Petrucci, Heinz Ludwig, Holger W. Auner, Jo Caers, Martin Gramatzki, Mario Boccadoro, Hermann Einsele, Pieter Sonneveld, and Monika Engelhardt
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Cardiovascular disease in patients with multiple myeloma may derive from factors unrelated to the disease (age, diabetes, dyslipidemia, obesity, prior cardiovascular diseases), related to the disease (cardiac AL-amyloidosis, hyperviscosity, high-output failure, arteriovenous shunting, anemia, renal dysfunction) and/or related to anti-myeloma treatment (anthracyclines, corticosteroids, alkylating agents, immunomodulatory drugs, proteasome inhibitors). Good knowledge of cardiovascular events, effective dose reductions, prevention and management of early and late cardiovascular side effects of chemotherapeutic agents are essential in current clinical practice. Myeloma experts are obliged to carefully balance the efficacy and toxicity of drugs for each individual patient. This review summarizes current data and novel insights into cardiovascular adverse events of today’s anti-myeloma treatment, focusing on carfilzomib, as a starting point for developing consensus recommendations on preventing and managing cardiovascular side effects in patients with multiple myeloma.
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- 2018
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15. Highly sensitive MYD88L265P mutation detection by droplet digital polymerase chain reaction in Waldenström macroglobulinemia
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Daniela Drandi, Elisa Genuardi, Irene Dogliotti, Martina Ferrante, Cristina Jiménez, Francesca Guerrini, Mariella Lo Schirico, Barbara Mantoan, Vittorio Muccio, Giuseppe Lia, Gian Maria Zaccaria, Paola Omedè, Roberto Passera, Lorella Orsucci, Giulia Benevolo, Federica Cavallo, Sara Galimberti, Ramón García Sanz, Mario Boccadoro, Marco Ladetto, and Simone Ferrero
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We here describe a novel method for MYD88L265P mutation detection and minimal residual disease monitoring in Waldenström macroglobulinemia, by droplet digital polymerase chain reaction, in bone marrow and peripheral blood cells, as well as in circulating cell-free DNA. Our method shows a sensitivity of 5.00×10−5, which is far superior to the widely used allele-specific polymerase chain reaction (1.00×10−3). Overall, 291 unsorted samples from 148 patients (133 with Waldenström macroglobulinemia, 11 with IgG lymphoplasmacytic lymphoma and 4 with IgM monoclonal gammopathy of undetermined significance) were analyzed: 194 were baseline samples and 97 were followup samples. One hundred and twenty-two of 128 (95.3%) bone marrow and 47/66 (71.2%) baseline peripheral blood samples scored positive for MYD88L265P. To investigate whether MYD88L265P detection by droplet digital polymerase chain reaction could be used for minimal residual disease monitoring, mutation levels were compared with IGH-based minimal residual disease analysis in 10 patients, and was found to be as informative as the classical, standardized, but not yet validated in Waldenström macroglobulinemia, IGH-based minimal residual disease assay (r2=0.64). Finally, MYD88L265P detection by droplet digital polymerase chain reaction on plasma circulating tumor DNA from 60 patients showed a good correlation with bone marrow findings (bone marrow median mutational value 1.92×10−2, plasma circulating tumor DNA value: 1.4×10−2, peripheral blood value: 1.03×10−3). This study indicates that droplet digital polymerase chain reaction assay of MYD88L265P is a feasible and sensitive tool for mutation screening and minimal residual disease monitoring in Waldenström macroglobulinemia. Both unsorted bone marrow and peripheral blood samples can be reliably tested, as can circulating tumor DNA, which represents an attractive, less invasive alternative to bone marrow for MYD88L265P detection.
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- 2018
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16. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives
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Francesca Gay, Monika Engelhardt, Evangelos Terpos, Ralph Wäsch, Luisa Giaccone, Holger W. Auner, Jo Caers, Martin Gramatzki, Niels van de Donk, Stefania Oliva, Elena Zamagni, Laurent Garderet, Christian Straka, Roman Hajek, Heinz Ludwig, Herman Einsele, Meletios Dimopoulos, Mario Boccadoro, Nicolaus Kröger, Michele Cavo, Hartmut Goldschmidt, Benedetto Bruno, and Pieter Sonneveld
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival, although an overall survival benefit was not observed in all trials. Moreover, follow up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens such as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant has not been extensively evaluated. In the case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that, in young and fit patients, may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets, and chimeric antigen receptor-T cells. Despite encouraging preliminary results, longer follow up and larger patient numbers are needed before the clinical use of these novel therapies can be widely recommended.
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- 2018
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17. Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies
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Simona Caltagirone, Marina Ruggeri, Simona Aschero, Milena Gilestro, Daniela Oddolo, Francesca Gay, Sara Bringhen, Caterina Musolino, Luca Baldini, Pellegrino Musto, Maria T. Petrucci, Gianluca Gaidano, Roberto Passera, Benedetto Bruno, Antonio Palumbo, Mario Boccadoro, and Paola Omedè
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Multiple myeloma is a plasma cell disorder characterized by malignant plasma cell infiltration in the bone marrow, serum and/or urine monoclonal protein and organ damage. The aim of this study was to investigate the impact of chromosome 1 abnormalities in a group of elderly patients (>65 years) with newly diagnosed multiple myeloma enrolled in the GIMEMA-MM-03-05 trial and treated with bortezomib, melphalan and prednisone or bortezomib, melphalan, prednisone and thalidomide followed by bortezomib and thalidomide maintenance. We also evaluated the link between chromosome 1 abnormalities and other clinical, genetic and immunophenotypic features by a multivariate logistic regression model. Interphase fluorescence in situ hybridization on immunomagnetically purified plasma cells and bone marrow multiparameter flow cytometry were employed. A multivariate Cox model showed that chromosome 1 abnormalities, age >75 years and a CD19+/CD117− immunophenotype of bone marrow plasma cells were independent risk factors for overall survival in elderly patients with newly diagnosed multiple myeloma. Moreover, a detrimental effect of thalidomide, even when administered in association with bortezomib, was observed in patients with abnormal chromosome 1 as well as in those with 17p deletion, while the benefit of adding thalidomide to the bortezomib-melphalan-prednisone regimen was noted in patients carrying an aggressive CD19+/CD117− bone marrow plasma cell immunophenotype. This trial was registered at www.clinicaltri-als.gov as #NCT01063179.
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- 2014
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18. The bone marrow of myeloma patients is steadily inhabited by a normal-sized pool of functional regulatory T cells irrespectiveof the disease status
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Myriam Foglietta, Barbara Castella, Sara Mariani, Marta Coscia, Laura Godio, Riccardo Ferracini, Marina Ruggeri, Vittorio Muccio, Paola Omedé, Antonio Palumbo, Mario Boccadoro, and Massimo Massaia
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Conflicting data have been reported about the frequency and function of regulatory T cells in multiple myeloma. Most studies have investigated peripheral blood rather than bone marrow Tregs and side-by-side comparisons with bone marrow from healthy donors have still not been made. In this study, we show that regulatory T-cells total count, subset distribution, and expression of chemokine receptors are similar in the bone marrow of myeloma patients and healthy donors. Regulatory T cells are not recruited by myeloma cells in the bone marrow and their counts are unaffected by the tumor burden and the disease status. The diversity of T-cell receptor repertoire is highly preserved ensuring broad reactivity and effective suppressor function. Our results indicate that regulatory T cells may not be the main players of immunological tolerance to myeloma cells under base-line conditions, but their fully preserved immune competence may promote their inadvertent activation and blunt T-cell driven anti-myeloma immune interventions even after myeloma cells have successfully been cleared by chemotherapy.
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- 2014
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19. Bortezomib cumulative dose, efficacy, and tolerability with three different bortezomib-melphalan-prednisone regimens in previously untreated myeloma patients ineligible for high-dose therapy
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María-Victoria Mateos, Sara Bringhen, Paul G. Richardson, Juan Jose Lahuerta, Alessandra Larocca, Albert Oriol, Mario Boccadoro, Ramón García-Sanz, Francesco Di Raimondo, Dixie-Lee Esseltine, Helgi van de Velde, Avinash Desai, Anil Londhe, Jesús F. San Miguel, and Antonio Palumbo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Substantial efficacy has been demonstrated with bortezomib-melphalan-prednisone in phase III studies in transplant-ineligible myeloma patients using various twice-weekly and once-weekly bortezomib dosing schedules. In VISTA, the regimen comprised four 6-week twice-weekly cycles, plus five 6-week once-weekly cycles. In the GIMEMA MM-03-05 study, the bortezomib-melphalan-prednisone regimen was either per VISTA (‘GIMEMA twice-weekly’), or comprised nine 5-week once-weekly cycles (‘GIMEMA once-weekly’). In the GEM2005MAS65 study, the regimen comprised one 6-week twice-weekly cycle, plus five 5-week once-weekly cycles. We evaluated the cumulative bortezomib dose administered during bortezomib-melphalan-prednisone, as well as efficacy and tolerability, using patient-level study data. Over all bortezomib-melphalan-prednisone cycles (nine in VISTA/GIMEMA; six in GEM2005MAS65), the median cumulative bortezomib dose administered was 38.5, 42.1, 40.3, and 32.9 mg/m2 in VISTA, GIMEMA twice-weekly, GIMEMA once-weekly, and GEM2005MAS65, respectively, and the respective proportions of planned bortezomib dose actually delivered were 57.0%, 62.3%, 86.1%, and 90.4%. Response rates following bortezomib-melphalan-prednisone were 74–87% and appeared generally similar between studies. Three-year survival rates were 67.9–75.7% across studies. Grade 3/4 peripheral neuropathy rates were 13% in VISTA and 14% in GIMEMA twice-weekly, but were lower at 2% in GIMEMA once-weekly and 7% in GEM2005MAS65. Discontinuations and bortezomib dose reductions due to peripheral neuropathy were reduced in GIMEMA once-weekly versus VISTA and GIMEMA twice-weekly. Exclusive or predominant use of once-weekly bortezomib dosing in GIMEMA once-weekly and GEM2005MAS65 resulted in high efficacy, comparable with that demonstrated in VISTA, and similar cumulative bortezomib dose with reduced toxicity. Trials are registered with ClinicalTrials.gov: VISTA (Identifier:00111319), GIMEMA MM-03-05 (Identifier:01063179), and GEM2005MAS65 (Identifier:00443235).
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- 2014
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20. High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomib
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Manuela Gambella, Alberto Rocci, Roberto Passera, Francesca Gay, Paola Omedè, Claudia Crippa, Paolo Corradini, Alessandra Romano, Davide Rossi, Marco Ladetto, Mario Boccadoro, and Antonio Palumbo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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21. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma
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Monika Engelhardt, Evangelos Terpos, Martina Kleber, Francesca Gay, Ralph Wäsch, Gareth Morgan, Michele Cavo, Niels van de Donk, Andreas Beilhack, Benedetto Bruno, Hans Erik Johnsen, Roman Hajek, Christoph Driessen, Heinz Ludwig, Meral Beksac, Mario Boccadoro, Christian Straka, Sara Brighen, Martin Gramatzki, Alessandra Larocca, Henk Lokhorst, Valeria Magarotto, Fortunato Morabito, Meletios A. Dimopoulos, Hermann Einsele, Pieter Sonneveld, and Antonio Palumbo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).
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- 2014
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22. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials
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Sara Bringhen, Maria Victoria Mateos, Sonja Zweegman, Alessandra Larocca, Antonietta Pia Falcone, Albert Oriol, Davide Rossi, Maide Cavalli, Pierre Wijermans, Roberto Ria, Massimo Offidani, Juan Jose Lahuerta, Anna Marina Liberati, Roberto Mina, Vincenzo Callea, Martijn Schaafsma, Chiara Cerrato, Roberto Marasca, Luca Franceschini, Andrea Evangelista, Ana-Isabel Teruel, Bronno van der Holt, Vittorio Montefusco, Giovannino Ciccone, Mario Boccadoro, Jesus San Miguel, Pieter Sonneveld, and Antonio Palumbo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10–56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46–60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20–1.72; P
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- 2013
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23. Safety of thalidomide in newly diagnosed elderly myeloma patients: a meta-analysis of data from individual patients in six randomized trials
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Antonio Palumbo, Anders Waage, Cyrille Hulin, Meral Beksac, Sonja Zweegman, Francesca Gay, Peter Gimsing, Xavier Leleu, Pierre Wijermans, Gülsan Sucak, Sara Pezzatti, Gunnar Juliusson, Brigitte Pégourié, Martijn Schaafsma, Monica Galli, Ingemar Turesson, Brigitte Kolb, Bronno van der Holt, Ileana Baldi, Jürgen Rolke, Giovannino Ciccone, Marc Wetterwald, Henk Lokhorst, Mario Boccadoro, Philippe Rodon, and Pieter Sonneveld
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Treatment with melphalan-prednisone-thalidomide improves the outcome of patients with multiple myeloma and is now considered a standard of care for patients not eligible for transplantation. However, this treatment is a major source of morbidity. A meta-analysis of data from individual patients (n=1680) in six randomized trials was performed, comparing the effects of melphalan-prednisone-thalidomide versus melphalan-prednisone. The main objective was to estimate the risk of serious adverse events and their impact on outcome. The primary endpoints were the 2-year cumulative incidence of grade 3-4 hematologic and non-hematologic toxicities. At least 75% of the grade 3-4 toxicities occurred during the first 6 months of treatment in both treatment groups. The cumulative incidence of grade 3-4 hematologic toxicities was higher in the melphalan-prednisone-thalidomide group than in the melphalan-prednisone group (28% versus 22%; HR 1.32, 95% CI 1.05-1.66) as was the cumulative incidence of non-hematologic toxicities (39% versus 17%, HR 2.78, 95% CI 2.21-3.50). Grade 3-4 non-hematologic toxicities were significantly increased in patients with poor Performance Status. Occurrence of grade 3-4 non-hematologic toxicities had a negative impact on both progression-free survival (HR 1.24, 95% CI 1.07-1.45) and overall survival, (HR 1.23, 95% CI 1.03-1.47). Besides toxicities, progression-free and overall survival were also negatively affected by advanced International Staging System stage, high creatinine levels and poor Performance Status. Age had a negative impact on survival as well. Although melphalan-prednisone-thalidomide improved outcome, it increased toxicities, especially non-hematologic ones. Serious non-hematologic toxicities, older age, poor Performance Status, and high creatinine levels negatively affected survival.
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- 2013
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24. Multiple myeloma shows no intra-disease clustering of immunoglobulin heavy chain genes
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Simone Ferrero, Daniela Capello, Mirija Svaldi, Michela Boi, Daniela Gatti, Daniela Drandi, Davide Rossi, Sara Barbiero, Barbara Mantoan, Elisabetta Mantella, Manuela Zanni, Paola Ghione, Alessandra Larocca, Roberto Passera, Francesco Bertoni, Valter Gattei, Francesco Forconi, Luca Laurenti, Giovanni Del Poeta, Roberto Marasca, Sergio Cortelazzo, Gianluca Gaidano, Antonio Palumbo, Mario Boccadoro, and Marco Ladetto
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Characterization of the immunoglobulin gene repertoire has improved our understanding of the immunopathogenesis of lymphoid tumors. Early B-lymphocyte precursors of multiple myeloma are known to exist and might be susceptible to antigenic drive.Design and Methods To verify this hypothesis, we collected a database of 345 fully readable multiple myeloma immunoglobulin sequences. We characterized the immunoglobulin repertoire, analyzed the somatic hypermutation load, and investigated for stereotyped receptor clusters.Results Compared to the normal immunoglobulin repertoire, multiple myeloma displayed only modest differences involving only a few genes, showing that the myeloma immunoglobulin repertoire is the least skewed among mature B-cell tumors. Median somatic hypermutation load was 7.8%; median length of complementarity determining-region 3 was 15.5 amino acids. Clustering analysis showed the absence of myeloma specific clusters and no similarity with published chronic lymphocytic leukemia or lymphoma subsets.Conclusions Analysis of multiple myeloma immunoglobulin repertoire does not support a pathogenetic role for antigen selection in this tumor.
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- 2012
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25. Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial
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Antonio Palumbo, Alessandra Larocca, Mariella Genuardi, Katarzyna Kotwica, Francesca Gay, Davide Rossi, Giulia Benevolo, Valeria Magarotto, Federica Cavallo, Sara Bringhen, Cecilia Rus, Luciano Masini, Massimo Iacobelli, Gianluca Gaidano, Constantine Mitsiades, Kenneth Anderson, Mario Boccadoro, and Paul Richardson
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen.Design and Methods This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1–4, prednisone at a dose of 1.5 mg/kg also on days 1–4 and thalidomide at a dose of 50–100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1–4 and 1.6, 3.2, or 4.8 g on days 5–35.Results Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3–4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient.Conclusions This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1–4 followed by 4.8 g p.o. on days 5–35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978).
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- 2010
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26. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase I/II studies
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Maria Teresa Petrucci, Mario Boccadoro, Roberto Mina, Massimo Offidani, Pellegrino Musto, Vittorio Montefusco, Stefano Spada, Elena Ponticelli, Giulia Benevolo, Piero Galieni, Antonio Palumbo, Gianluca Gaidano, Michele Cavo, Sara Bringhen, Tommaso Caravita di Toritto, Francesco Di Raimondo, Stelvio Ballanti, Alessandra Larocca, Bringhen, Sara, Mina, Roberto, Petrucci, Maria Teresa, Gaidano, Gianluca, Ballanti, Stelvio, Musto, Pellegrino, Offidani, Massimo, Spada, Stefano, Benevolo, Giulia, Ponticelli, Elena, Galieni, Piero, Cavo, Michele, Di Toritto, Tommaso Caravita, Di Raimondo, Francesco, Montefusco, Vittorio, Palumbo, Antonio, Boccadoro, Mario, and Larocca, Alessandra
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Male ,medicine.medical_specialty ,Cyclophosphamide ,Antineoplastic Agents ,carfilzomib,multiple myeloma ,Gastroenterology ,Article ,Plasma Cell Disorders ,Drug Administration Schedule ,Maintenance Chemotherapy ,chemistry.chemical_compound ,Maintenance therapy ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Adverse effect ,Survival analysis ,Multiple myeloma ,Dexamethasone ,Aged ,Aged, 80 and over ,business.industry ,Induction chemotherapy ,Hematology ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Prognosis ,Carfilzomib ,Survival Analysis ,Treatment Outcome ,chemistry ,Female ,business ,Multiple Myeloma ,Oligopeptides ,medicine.drug - Abstract
Twice-weekly carfilzomib is approved at 27 and 56 mg/m(2) to treat relapsed multiple myeloma patients. In the phase III study ARROW, once-weekly 70 mg/m 2 carfilzomib prolonged the median progression-free survival of relapsed multiple myeloma patients in comparison with twice-weekly 27 mg/m(2) carfilzomib, without adding significant toxicity. Data were pooled from two phase I/II studies of newly diagnosed multiple myeloma patients who received nine induction cycles of carfilzomib (either 70 mg/m(2) once-weekly or 36 mg/m(2) twice-weekly), cyclophosphamide and dexamethasone, followed by carfilzomib maintenance. Overall, 121 transplant-ineligible patients with newly diagnosed multiple myeloma were analyzed (once-weekly, n=63; twice-weekly, n=58). We found no significant difference in median progression-free survival [35.7 months (95%CI: 23.7-not reached, NR) vs 35.5 months (95%CI: 24.3-NR); HR: 1.39; P=0.26] and 3-year overall survival [70% [95%CI: 59%-84%) vs 72% (95%CI: 60%-85%); HR: 1.27; P=0.5] between once-weekly and twice-weekly carfilzomib. From the start of maintenance, 3-year progression-free survival [47% (95%CI: 33%-68%) vs 51% (95%CI: 38%-70%); HR: 1.04; P=0.92] and overall survival [72% (95%CI: 58%-89%) vs 73% (95%CI: 59%-90%); HR: 0.82; P=0.71] were similar in the once- versus twice-weekly carfilzomib. The rate of grade 3-5 hematologic (24% vs 30%; P=0.82) and non-hematologic (38% vs 41%; P=0.83) adverse events was similar in the two groups. Once-weekly 70 mg/m(2) carfilzomib as induction and maintenance therapy for newly diagnosed multiple myeloma patients was as safe and effective as twice-weekly 36 mg/m(2) carfilzomib and provided a more convenient schedule. The trials are registered at clinicaltrials.gov identifiers: 01857115 (IST-CAR-561) and 01346787 (IST-CAR-506).
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- 2019
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