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2. Treatment Intensification With Autologous Stem Cell Transplantation and Lenalidomide Maintenance Improves Survival Outcomes of Patients With Newly Diagnosed Multiple Myeloma in Complete Response

Author

Mina, Roberto, Petrucci, Maria Teresa, Corradini, Paolo, Spada, Stefano, Patriarca, Francesca, Cerrato, Chiara, De Paoli, Lorenzo, Pescosta, Norbert, Ria, Roberto, Malfitano, Alessandra, Musto, Pellegrino, Baldini, Luca, Guglielmelli, Tommasina, Gamberi, Barbara, Mannina, Donato, Benevolo, Giulia, Zambello, Renato, Falcone, Antonietta Pia, Palumbo, Antonio, Nagler, Arnon, Calafiore, Valeria, Hájek, Roman, Spencer, Andrew, Boccadoro, Mario, and Bringhen, Sara

Published
2018
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3. Maintenance in myeloma patients achieving complete response after upfront therapy: a pooled analysis

Author

Cerrato, Chiara, Di Raimondo, Francesco, De Paoli, Lorenzo, Spada, Stefano, Patriarca, Francesca, Crippa, Claudia, Mina, Roberto, Guglielmelli, Tommasina, Ben-Yehuda, Dina, Oddolo, Daniela, Nozzoli, Chiara, Angelucci, Emanuele, Cascavilla, Nicola, Rizzi, Rita, Rocco, Stefano, Baldini, Luca, Ponticelli, Elena, Marcatti, Magda, Cangialosi, Clotilde, Caravita, Tommaso, Benevolo, Giulia, Ria, Roberto, Nagler, Arnon, Musto, Pellegrino, Tacchetti, Paola, Corradini, Paolo, Offidani, Massimo, Palumbo, Antonio, Petrucci, Maria Teresa, Boccadoro, Mario, and Gay, Francesca

Published
2018
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7. DREAM represses distinct targets by cooperating with different THAP domain proteins

Author

Gal, Csenge, Carelli, Francesco Nicola, Appert, Alex, Cerrato, Chiara, Huang, Ni, Dong, Yan, Murphy, Jane, Ahringer, Julie, Ahringer, Julie [0000-0002-7074-4051], and Apollo - University of Cambridge Repository

Subjects
FOS: Biological sciences, 1.1 Normal biological development and functioning, Genetics, 1 Underpinning research, Generic health relevance, 3101 Biochemistry and Cell Biology, humanities, psychological phenomena and processes, 31 Biological Sciences
Abstract

The DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell cycle and other genes, but its mechanism of action is unclear. Here we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z, and we find that DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses germline specific targets in the soma by facilitating H3K9me2 promoter marking. We further find that LIN-36 and LIN-15B differently regulate DREAM binding. In humans, THAP proteins have been implicated in cell cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function.

Published
2022
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8. Supplement to: Autologous Transplantation and Maintenance Therapy in Multiple Myeloma

Author

Palumbo, Antonio, Cavallo, Federica, Gay, Francesca, Di Raimondo, Francesco, Ben Yehuda, Dina, Petrucci, Maria Teresa, Pezzatti, Sara, Caravita, Tommaso, Cerrato, Chiara, Ribakovsky, Elena, Genuardi, Mariella, Cafro, Anna, Marcatti, Magda, Catalano, Lucio, Offidani, Massimo, Carella, Angelo Michele, Zamagni, Elena, Patriarca, Francesca, Musto, Pellegrino, Evangelista, Andrea, Ciccone, Giovannino, Omedé, Paola, Crippa, Claudia, Corradini, Paolo, Nagler, Arnon, Boccadoro, Mario, and Cavo, Michele

Published
2014

10. Autologous Transplantation and Maintenance Therapy in Multiple Myeloma

Author

Palumbo, Antonio, Cavallo, Federica, Gay, Francesca, Di Raimondo, Francesco, Ben Yehuda, Dina, Petrucci, Maria Teresa, Pezzatti, Sara, Caravita, Tommaso, Cerrato, Chiara, Ribakovsky, Elena, Genuardi, Mariella, Cafro, Anna, Marcatti, Magda, Catalano, Lucio, Offidani, Massimo, Carella, Angelo Michele, Zamagni, Elena, Patriarca, Francesca, Musto, Pellegrino, Evangelista, Andrea, Ciccone, Giovannino, Omedé, Paola, Crippa, Claudia, Corradini, Paolo, Nagler, Arnon, Boccadoro, Mario, and Cavo, Michele

Published
2014
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11. Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients: A retrospective case-matched study

Author

Morabito, Fortunato, Bringhen, Sara, Larocca, Alessandra, Wijermans, Pierre, Victoria Mateos, Maria, Gimsing, Peter, Mazzone, Carla, Gottardi, Daniela, Omedè, Paola, Zweegman, Sonja, José Lahuerta, Juan, Zambello, Renato, Musto, Pellegrino, Magarotto, Valeria, Schaafsma, Martijn, Oriol, Albert, Juliusson, Gunnar, Cerrato, Chiara, Catalano, Lucio, Gentile, Massimo, Isabel Turel, Ana, Marina Liberati, Anna, Cavalli, Maide, Rossi, Davide, Passera, Roberto, Rosso, Stefano, Beksac, Meral, Cavo, Michele, Waage, Anders, San Miguel, Jesus, Boccadoro, Mario, Sonneveld, Pieter, Palumbo, Antonio, and Offidani, Massimo

Published
2014
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17. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial.

Author

Gay, Francesca, primary, Cerrato, Chiara, additional, Petrucci, Maria Teresa, additional, Zambello, Renato, additional, Gamberi, Barbara, additional, Ballanti, Stelvio, additional, Omedè, Paola, additional, Palmieri, Salvatore, additional, Troia, Rossella, additional, Spada, Stefano, additional, Gozzetti, Alessandro, additional, Caravita, Tommaso, additional, Spadano, Antonio, additional, Palumbo, Antonio, additional, Montefusco, Vittorio, additional, Musto, Pellegrino, additional, Cavo, Michele, additional, and Boccadoro, Mario, additional

Published
2019
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18. Carfilzomib-Lenalidomide-Dexamethasone (KRd) Induction-Autologous Transplant (ASCT)-Krd Consolidation Vs KRd 12 Cycles Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Induction-ASCT-KCd Consolidation: Analysis of the Randomized Forte Trial in Newly Diagnosed Multiple Myeloma (NDMM)

Author

Gay, Francesca, primary, Cerrato, Chiara, additional, Rota Scalabrini, Delia, additional, Galli, Monica, additional, Belotti, Angelo, additional, Zamagni, Elena, additional, Ledda, Antonio, additional, Grasso, Mariella, additional, Angelucci, Emanuele, additional, Liberati, Anna Marina, additional, Tosi, Patrizia, additional, Pisani, Francesco, additional, Spada, Stefano, additional, Annibali, Ombretta, additional, Baraldi, Anna, additional, Omedé, Paola, additional, Galieni, Piero, additional, Rizzi, Rita, additional, Pescosta, Norbert, additional, Ronconi, Sonia, additional, Vincelli, Donatella, additional, Cafro, Anna Maria, additional, Offidani, Massimo, additional, Palumbo, Antonio, additional, Musto, Pellegrino, additional, Cavo, Michele, additional, and Boccadoro, Mario, additional

Published
2018
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20. Chromatin accessibility dynamics across C. elegans development and ageing

Author

Jänes, Jürgen, primary, Dong, Yan, additional, Schoof, Michael, additional, Serizay, Jacques, additional, Appert, Alex, additional, Cerrato, Chiara, additional, Woodbury, Carson, additional, Chen, Ron, additional, Gemma, Carolina, additional, Huang, Ni, additional, Kissiov, Djem, additional, Stempor, Przemyslaw, additional, Steward, Annette, additional, Zeiser, Eva, additional, Sauer, Sascha, additional, and Ahringer, Julie, additional

Published
2018
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21. Author response: Chromatin accessibility dynamics across C. elegans development and ageing

Author

Jänes, Jürgen, primary, Dong, Yan, additional, Schoof, Michael, additional, Serizay, Jacques, additional, Appert, Alex, additional, Cerrato, Chiara, additional, Woodbury, Carson, additional, Chen, Ron, additional, Gemma, Carolina, additional, Huang, Ni, additional, Kissiov, Djem, additional, Stempor, Przemyslaw, additional, Steward, Annette, additional, Zeiser, Eva, additional, Sauer, Sascha, additional, and Ahringer, Julie, additional

Published
2018
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22. Updated efficacy data and MRD analysis according to risk status in newly diagnosed myeloma patients treated with carfilzomib + lenalidomide or cyclophosphamide (FORTE trial).

Author

Gay, Francesca Maria, primary, Foà, Robin, additional, Musto, Pellegrino, additional, Cerrato, Chiara, additional, Gamberi, Barbara, additional, Zamagni, Elena, additional, Palmas, Angelo D., additional, Spadano, Antonio, additional, Omedè, Paola, additional, Caravita, Tommaso, additional, Giuliani, Nicola, additional, Ballanti, Stelvio, additional, Patriarca, Francesca, additional, Troia, Rossella, additional, Gentile, Massimo, additional, Desabbata, Giovanni, additional, Canepa, Letizia, additional, Palumbo, Antonio, additional, Cavo, Michele, additional, and Boccadoro, Mario, additional

Published
2018
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23. Chromatin accessibility is dynamically regulated across C. elegans development and ageing

Author

Jänes, Jürgen, primary, Dong, Yan, additional, Schoof, Michael, additional, Serizay, Jacques, additional, Appert, Alex, additional, Cerrato, Chiara, additional, Woodbury, Carson, additional, Chen, Ron, additional, Gemma, Carolina, additional, Huang, Ni, additional, Kissiov, Djem, additional, Stempor, Przemysław, additional, Steward, Annette, additional, Zeiser, Eva, additional, Sauer, Sasha, additional, and Ahringer, Julie, additional

Published
2018
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24. Prognostic Implication of Somatic Mutations by Next Generation Sequencing: an Analysis from the MMRF CoMMpass Study in Newly Diagnosed Multiple Myeloma Patients

Author

D'Agostino, Mattia, primary, Oliva, Stefania, additional, Spada, Stefano, additional, Gambella, Manuela, additional, DeRome, Mary, additional, Cavo, Michele, additional, Aglietta, Massimo, additional, Offidani, Massimo, additional, Yesil, Jennifer, additional, Oddolo, Daniela, additional, Cerrato, Chiara, additional, Rossi, Giuseppe, additional, Ledda, Antonio, additional, Canepa, Letizia, additional, Grasso, Mariella, additional, Roberto, Foà, additional, Auclair, Daniel, additional, Musto, Pellegrino, additional, Evangelista, Andrea, additional, Gay, Francesca, additional, Palumbo, Antonio, additional, Boccadoro, Mario, additional, and Larocca, Alessandra, additional

Published
2017
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25. Prognostic Implication of Somatic Mutations By Next Generation Sequencing: An Analysis from the Mmrf Commpass Study in Newly Diagnosed Multiple Myeloma Patients

Author

D'Agostino, Mattia, primary, Oliva, Stefania, additional, Larocca, Alessandra, additional, Spada, Stefano, additional, Gambella, Manuela, additional, DeRome, Mary, additional, Cavo, Michele, additional, Aglietta, Massimo, additional, Offidani, Massimo, additional, Yesil, Jennifer, additional, Oddolo, Daniela, additional, Cerrato, Chiara, additional, Rossi, Giuseppe, additional, Ledda, Antonio, additional, Canepa, Letizia, additional, Grasso, Mariella, additional, Foa', Robert, additional, Auclair, Daniel, additional, Musto, Pellegrino, additional, Evangelista, Andrea, additional, Gay, Francesca, additional, Palumbo, Antonio, additional, and Boccadoro, Mario, additional

Published
2016
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28. Significant Survival Improvement with Maintenance in Patients Achieving a Complete Response: Pooled Analysis of 4 Italian Phase III Trials in Newly Diagnosed Multiple Myeloma Patients

Author

Cerrato, Chiara, primary, Gay, Francesca, additional, Petrucci, Maria Teresa, additional, Musto, Pellegrino, additional, Gaidano, Gianluca, additional, Offidani, Massimo, additional, Guglielmelli, Tommasina, additional, Salvini, Marco, additional, Patriarca, Francesca, additional, Ponticelli, Elena, additional, Semenzato, Gianpietro, additional, Di Raimondo, Francesco, additional, Mina, Roberto, additional, Cascavilla, Nicola, additional, Ben Yehuda, Dina, additional, Oddolo, Daniela, additional, Corradini, Paolo, additional, Catalano, Lucio, additional, Di Bartolomeo, Paolo, additional, Hájek, Roman, additional, Spencer, Andrew, additional, Boccadoro, Mario, additional, and Palumbo, Antonio, additional

Published
2015
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29. Impact of Complete Response on Survival with Either Autologous Stem Cell Transplantation or Conventional Chemotherapy: Results of a Pooled Analysis of 5 Phase III Trials in Newly Diagnosed Multiple Myeloma Patients

Author

Mina, Roberto, primary, Larocca, Alessandra, additional, Offidani, Massimo, additional, Bringhen, Sara, additional, Caravita, Tommaso, additional, Magarotto, Valeria, additional, Pantani, Lucia, additional, Di Raimondo, Francesco, additional, Bosi, Alberto, additional, Vincelli, Iolanda D., additional, Tacchetti, Paola, additional, Gaidano, Gianluca, additional, Grandi, Sonia, additional, Musolino, Caterina, additional, Cerrato, Chiara, additional, Pour, Ludek, additional, Astolfi, Monica, additional, Rossi, Giuseppe, additional, Rossini, Fausto, additional, Petrucci, Maria T., additional, Ria, Roberto, additional, Pezzi, Annalisa, additional, Hajek, Roman, additional, Cavo, Michele, additional, Spencer, Andrew, additional, Boccadoro, Mario, additional, and Palumbo, Antonio, additional

Published
2015
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30. Continuous Therapy Versus Fixed Duration of Therapy in Patients With Newly Diagnosed Multiple Myeloma

Author

Palumbo, Antonio, primary, Gay, Francesca, additional, Cavallo, Federica, additional, Di Raimondo, Francesco, additional, Larocca, Alessandra, additional, Hardan, Izhar, additional, Nagler, Arnon, additional, Petrucci, Maria T., additional, Hajek, Roman, additional, Pezzatti, Sara, additional, Delforge, Michel, additional, Patriarca, Francesca, additional, Donato, Francesca, additional, Cerrato, Chiara, additional, Nozzoli, Chiara, additional, Yu, Zhinuan, additional, Boccadifuoco, Luana, additional, Caravita, Tommaso, additional, Benevolo, Giulia, additional, Guglielmelli, Tommasina, additional, Vincelli, Donatella, additional, Jacques, Christian, additional, Dimopoulos, Meletios A., additional, Ciccone, Giovannino, additional, Musto, Pellegrino, additional, Corradini, Paolo, additional, Cavo, Michele, additional, and Boccadoro, Mario, additional

Published
2015
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31. Plasma cell leukemia: update on biology and therapy.

Author

Mina, Roberto, D'Agostino, Mattia, Cerrato, Chiara, Gay, Francesca, and Palumbo, Antonio

Subjects
PLASMA cell leukemia, STEM cell transplantation, PLASMA cell diseases, MULTIPLE myeloma, PLASMA cells
Abstract

Plasma cell leukemia (PCL) is a rare, but very aggressive, plasma cell dyscrasia, representing a distinct clinicopathological entity as compared to multiple myeloma (MM), with peculiar biological and clinical features. A hundred times rarer than MM, the disease course is characterized by short remissions and poor survival. PCL is defined by an increased percentage (>20%) and absolute number (>2 × 109/l) of plasma cells in the peripheral blood. PCL is defined as ‘primary’ when peripheral plasmacytosis is detected at diagnosis, ‘secondary’ when leukemization occurs in a patient with preexisting MM. Novel agents have revolutionized the outcomes of MM patients and have been introduced also for the treatment of PCL. Here, we provide an update on biology and treatment options for PCL. [ABSTRACT FROM PUBLISHER]

Published
2017
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32. Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients:A retrospective case-matched study

Author

Morabito, Fortunato, Bringhen, Sara, Larocca, Alessandra, Wijermans, Pierre, Victoria Mateos, Maria, Gimsing, Peter, Mazzone, Carla, Gottardi, Daniela, Omedè, Paola, Zweegman, Sonja, José Lahuerta, Juan, Zambello, Renato, Musto, Pellegrino, Magarotto, Valeria, Schaafsma, Martijn, Oriol, Albert, Juliusson, Gunnar, Cerrato, Chiara, Catalano, Lucio, Gentile, Massimo, Isabel Turel, Ana, Marina Liberati, Anna, Cavalli, Maide, Rossi, Davide, Passera, Roberto, Rosso, Stefano, Beksac, Meral, Cavo, Michele, Waage, Anders, San Miguel, Jesus, Boccadoro, Mario, Sonneveld, Pieter, Palumbo, Antonio, Offidani, Massimo, Morabito, Fortunato, Bringhen, Sara, Larocca, Alessandra, Wijermans, Pierre, Victoria Mateos, Maria, Gimsing, Peter, Mazzone, Carla, Gottardi, Daniela, Omedè, Paola, Zweegman, Sonja, José Lahuerta, Juan, Zambello, Renato, Musto, Pellegrino, Magarotto, Valeria, Schaafsma, Martijn, Oriol, Albert, Juliusson, Gunnar, Cerrato, Chiara, Catalano, Lucio, Gentile, Massimo, Isabel Turel, Ana, Marina Liberati, Anna, Cavalli, Maide, Rossi, Davide, Passera, Roberto, Rosso, Stefano, Beksac, Meral, Cavo, Michele, Waage, Anders, San Miguel, Jesus, Boccadoro, Mario, Sonneveld, Pieter, Palumbo, Antonio, and Offidani, Massimo

Abstract

Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52-0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32-0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ≥ 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.

Published
2014

33. Impact of Autologous Transplantation Vs. Chemotherapy Plus Lenalidomide in Newly Diagnosed Myeloma According to Patient Prognosis: Results of a Pooled Analysis of 2 Phase III Trials

Author

Gay, Francesca, primary, Cerrato, Chiara, additional, Hajek, Roman, additional, Di Raimondo, Francesco, additional, Caravita, Tommaso, additional, Falcone, Antonietta Pia, additional, Patriarca, Francesca, additional, Pulini, Stefano, additional, Finsinger, Paola, additional, Ciccone, Giovannino, additional, Corradini, Paolo, additional, Siniscalchi, Agostina, additional, Donato, Francesca, additional, Yehuda, Dina Ben, additional, Offidani, Massimo, additional, Minarik, Jiri, additional, Ria, Roberto, additional, Cavallo, Federica, additional, Catalano, Lucio, additional, Cavalli, Maide, additional, Pour, Ludek, additional, Petrucci, Maria Teresa, additional, Hardan, Izhar, additional, Boccadoro, Mario, additional, Spencer, Andrew, additional, and Palumbo, Antonio, additional

Published
2014
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35. A Phase II Study With Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) For Newly Diagnosed Multiple Myeloma

Author

Bringhen, Sara, primary, Cerrato, Chiara, additional, Petrucci, Maria Teresa, additional, Genuardi, Mariella, additional, Gentilini, Fabiana, additional, Conticello, Concetta, additional, Oliva, Stefania, additional, Pantani, Lucia, additional, Offidani, Massimo, additional, Palladino, Carmela, additional, Benevolo, Giulia, additional, Montefusco, Vittorio, additional, Astolfi, Monica, additional, Villani, Oreste, additional, Siniscalchi, Agostina, additional, Rocci, Alberto, additional, De Paoli, Lorenzo, additional, Boccadoro, Mario, additional, Sonneveld, Pieter, additional, and Palumbo, Antonio, additional

Published
2013
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40. New pharmacotherapy options for multiple myeloma

Author

Mina, Roberto, Cerrato, Chiara, Bernardini, Annalisa, Aghemo, Elena, and Palumbo, Antonio

Abstract

ABSTRACTIntroduction: Novel agents and the availability of autologous stem-cell transplantation have revolutionized the treatment of patients with multiple myeloma. First-generation novel agents namely thalidomide, lenalidomide, and bortezomib have significantly improved response and survival of patients. Second-generation novel agents such as pomalidomide, carfilzomib, and monoclonal antibodies are being tested both in the newly diagnosed and relapse settings, and results are promising.Areas covered: In this review article, the main results derived from Phase III trials with thalidomide, lenalidomide, and bortezomib for the treatment of myeloma patients, both at diagnosis and at relapse, are summarized. Data about second-generation novel agents such as pomalidomide and carfilzomib are also reported. Newer effective drugs currently under investigation and the promising results with monoclonal antibodies are described.Expert opinion: The availability of new effective drugs has considerably increased the treatment options for myeloma patients. A sequential approach including induction, transplantation (when possible), consolidation, and maintenance is an optimal strategy to achieve disease control and prolong survival. Despite these improvements, the best combination, the optimal sequence, and the proper target of newer drugs need to be defined.

Published
2016
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41. The mechanism of action, pharmacokinetics, and clinical efficacy of carfilzomibfor the treatment of multiple myeloma

Author

Pautasso, Chiara, Bringhen, Sara, Cerrato, Chiara, Magarotto, Valeria, and Palumbo, Antonio

Abstract

Introduction:The development of novel agents, such as immunomodulatory drugs and proteasome inhibitors, has led to a considerable increment in the response rate (RR) and outcomes for multiple myeloma (MM) patients. Unfortunately, MM patients will inevitably relapse and become resistant to new drugs. This led to the continuous development of novel agents. Carfilzomibis a second-generation proteasome inhibitor, demonstrating promising results in relapsed/refractory (RR) and newly diagnosed (ND) MM patients.Areas covered:Herein, the authors review Phase I and II trials on carfilzomib for the treatment of MM. They also describe the profile of the drug during Phase I escalating doses and evaluate the efficacy of carfilzomib both alone and in combination. Finally, the authors also review and discuss the carfilzomib safety profile.Expert opinion:Clinical trials (Phases I and II) with carfilzomib, used both as single agent or in combination with other therapies, established the maximum tolerated dose and recommended schedule of administration. Preliminary data showed that it had a high efficacy and a good safety profile both in RRMM and NDMM patients. Carfilzomib seems to be effective in patients previously treated with bortezomib. Future Phase II and III studies will better define the role of carfilzomib in the treatment of MM as well as its optimum dose.

Published
2013
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42. Evaluation of the pharmacokinetics, preclinical, and clinical efficacy of lenalidomidefor the treatment of multiple myeloma

Author

Bringhen, Sara, Gay, Francesca, Pautasso, Chiara, Cerrato, Chiara, Boccadoro, Mario, and Palumbo, Antonio

Abstract

Introduction:Lenalidomideis an oral immunomodulatory drug, which was recently introduced for the treatment of multiple myeloma (MM). It has been used for the treatment of newly diagnosed and relapsed MM patients, as both maintenance and preventive therapy. Available data show a progression-free survival and overall survival improvement associated with this drug.Areas covered:Efficacy results of lenalidomide in Phase I, II, and III trials in MM are reported herein. The recent use of lenalidomide as maintenance and preventive therapy is described. An overview of the most important adverse events is also presented, such as myelosuppression, thromboembolic events, fatigue, dermatologic toxicity, infections, teratogenic potential, and second primary malignancies. The literature reviewed consists of clinical trials published from 2001 to 2012.Expert opinion:Lenalidomide is one of the most important therapeutic agents for MM treatment. Various trials have confirmed its remarkable anticancer activity, alone or combined with high- or low-dose dexamethasone, or other drugs. Lenalidomide-related adverse events can be controlled with dose reductions, supportive therapy, and appropriate prophylaxis.

Published
2012
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43. Chromatin accessibility dynamics across C. elegans development and ageing

Author

Jänes, Jürgen, Dong, Yan, Schoof, Michael, Serizay, Jacques, Appert, Alex, Cerrato, Chiara, Woodbury, Carson, Chen, Ron, Gemma, Carolina, Huang, Ni, Kissiov, Djem, Stempor, Przemyslaw, Steward, Annette, Zeiser, Eva, Sauer, Sascha, and Ahringer, Julie

Subjects
chromosomes, promoter, chromatin accessibility, C. elegans, gene expression, genomics, genetics, ATAC-seq, enhancer, 3. Good health, regulatory element
Abstract

An essential step for understanding the transcriptional circuits that control development and physiology is the global identification and characterization of regulatory elements. Here, we present the first map of regulatory elements across the development and ageing of an animal, identifying 42,245 elements accessible in at least one Caenorhabditis elegans stage. Based on nuclear transcription profiles, we define 15,714 protein-coding promoters and 19,231 putative enhancers, and find that both types of element can drive orientation-independent transcription. Additionally, more than 1000 promoters produce transcripts antisense to protein coding genes, suggesting involvement in a widespread regulatory mechanism. We find that the accessibility of most elements changes during development and/or ageing and that patterns of accessibility change are linked to specific developmental or physiological processes. The map and characterization of regulatory elements across C. elegans life provides a platform for understanding how transcription controls development and ageing., The work was supported by Wellcome Trust Senior Research Fellowships to JA (054523 and 101863), a Wellcome Trust PhD fellowship to JJ (097679), a Sir Robert Edwards Scholarship from Churchill College, an English Speaking Union Graduate Scholarship, and funding from the Cambridge Trust to MS, a Medical Research Council DTP studentship to JS, and a Thouron award to CW. This study was also supported by the European Sequencing and Genotyping Infrastructure (funded by the EC, FP7/2007-2013) under Grant Agreement 26205 (ESGI) as part of the transnational access program. We thank Drs. Hans Lehrach and Marie-Laure Yaspo for generous support of the ESGI project, Dr. Marc Sultan for setting up sequencing technology platforms, and Mathias Linser and the rest of the sequencing team of the Department of Vertebrate Genomics at the Max Planck Institute for Molecular Genetics for technical assistance. We also acknowledge core support from the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492).

44. DREAM represses distinct targets by cooperating with different THAP domain proteins

Author

Gal, Csenge, Carelli, Francesco Nicola, Appert, Alex, Cerrato, Chiara, Huang, Ni, Dong, Yan, Murphy, Jane, Frapporti, Andrea, and Ahringer, Julie

Subjects
Cell Cycle Proteins, Retinoblastoma Protein, H3K9me2, retinoblastoma, Animals, Genetically Modified, Histones, THAP, transcriptional repression, Animals, quiescence, Protein Interaction Domains and Motifs, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Promoter Regions, Genetic, H2A.Z, DREAM, DNA Methylation, humanities, 3. Good health, E2F Transcription Factors, Gene Expression Regulation, lin-36, lin-15B, lin-35, psychological phenomena and processes, Protein Binding, Transcription Factors
Abstract

The DREAM (dimerization partner [DP], retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell-cycle and other genes, but its mechanism of action is unclear. Here, we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell-cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z, and we find that DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses germline-specific targets in the soma by facilitating H3K9me2 promoter marking. We further find that LIN-36 and LIN-15B differently regulate DREAM binding. In humans, THAP proteins have been implicated in cell-cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function.

45. Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma

Author

Tommasina Guglielmelli, Paolo Corradini, Luana Boccadifuoco, Michele Cavo, Maria Teresa Petrucci, Roman Hájek, Federica Cavallo, Francesca Patriarca, Izhar Hardan, Antonio Palumbo, Donatella Vincelli, Chiara Cerrato, Zhinuan Yu, Michel Delforge, Francesca De' Donato, Giovannino Ciccone, Tommaso Caravita, Giulia Benevolo, Christian Jacques, Alessandra Larocca, Sara Pezzatti, Francesco Di Raimondo, Meletios A. Dimopoulos, Arnon Nagler, Pellegrino Musto, Chiara Nozzoli, Mario Boccadoro, Palumbo, Antonio, Gay, Francesca, Cavallo, Federica, Di Raimondo, Francesco, Larocca, Alessandra, Hardan, Izhar, Nagler, Arnon, Petrucci, Maria T, Hajek, Roman, Pezzatti, Sara, Delforge, Michel, Patriarca, Francesca, Donato, Francesca, Cerrato, Chiara, Nozzoli, Chiara, Yu, Zhinuan, Boccadifuoco, Luana, Caravita, Tommaso, Benevolo, Giulia, Guglielmelli, Tommasina, Vincelli, Donatella, Jacques, Christian, Dimopoulos, Meletios A, Ciccone, Giovannino, Musto, Pellegrino, Corradini, Paolo, Cavo, Michele, and Boccadoro, Mario

Subjects
Oncology, Male, medicine.medical_specialty, Cancer Research, Population, multiple myeloma, PFS, Dexamethasone, Disease-Free Survival, Drug Administration Schedule, law.invention, Bortezomib, Aged, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Melphalan, Middle Aged, Multiple Myeloma, Prednisone, Thalidomide, Medicine (all), Randomized controlled trial, law, Internal medicine, medicine, education, Lenalidomide, Multiple myeloma, education.field_of_study, Random assignment, Proportional hazards model, business.industry, Hazard ratio, medicine.disease, Surgery, Clinical trial, business, medicine.drug
Abstract

Purpose Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent–based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma. Methods We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent–based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models. Results In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P < .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P < .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003). Conclusion In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials.

Published
2015

46. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials.

Author

Bringhen S, Mateos MV, Zweegman S, Larocca A, Falcone AP, Oriol A, Rossi D, Cavalli M, Wijermans P, Ria R, Offidani M, Lahuerta JJ, Liberati AM, Mina R, Callea V, Schaafsma M, Cerrato C, Marasca R, Franceschini L, Evangelista A, Teruel AI, van der Holt B, Montefusco V, Ciccone G, Boccadoro M, San Miguel J, Sonneveld P, and Palumbo A

Subjects
Age Factors, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cause of Death, Female, Humans, Male, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Neoplasm Staging, Prognosis, Proportional Hazards Models, Randomized Controlled Trials as Topic, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Multiple Myeloma mortality
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<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51-2.70; P<0.001), in those who experienced grade 3-4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75-3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12-2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.

Published
2013
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