The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Maria Teresa Petrucci - One of the best experts on this subject based on the ideXlab platform.
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autologous transplantation and maintenance therapy in multiple myeloma
The New England Journal of Medicine, 2014Co-Authors: Antonio Palumbo, Maria Teresa Petrucci, Francesco Di Raimondo, Federica Cavallo, Dina Ben Yehuda, Sara Pezzatti, Tommaso Caravita, Chiara Cerrato, Elena Ribakovsky, Mariella GenuardiAbstract:Background This open-label, randomized, phase 3 study compared Melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with Melphalan–prednisone–lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. Methods We randomly assigned 273 patients 65 years of age or younger to high-dose Melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. Results The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose Melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall su...
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lenalidomide Melphalan and prednisone followed by lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Jay Mei, Antonio PalumboAbstract:The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, Melphalan, and prednisone, or Melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P<0.05), Physical Functioning (P<0.01), and Side Effects of Treatment (P<0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences (P<0.05 for Physical Functioning). Therefore, lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. (Clinicaltrials.gov identifier NCT00405756).
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lenalidomide Melphalan and prednisone followed by lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Antonio PalumboAbstract:The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, Melphalan, and prednisone, or Melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life ( P <0.05), Physical Functioning ( P <0.01), and Side Effects of Treatment ( P <0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences ( P <0.05 for Physical Functioning). Therefore, lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. ( [Clinicaltrials.gov][1] identifier [NCT00405756][2]). [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00405756&atom=%2Fhaematol%2F98%2F5%2F784.atom
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persistent overall survival benefit and no increased risk of second malignancies with bortezomib Melphalan prednisone versus Melphalan prednisone in patients with previously untreated multiple myeloma
Journal of Clinical Oncology, 2013Co-Authors: Jesus San F Miguel, Meletios A. Dimopoulos, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria Teresa Petrucci, Antonio Palumbo, Olga SamoilovaAbstract:Purpose This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-Melphalan-prednisone (VMP) versus Melphalanprednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies.
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complete response correlates with long term progression free and overall survival in elderly myeloma treated with novel agents analysis of 1175 patients
Blood, 2011Co-Authors: Alessandra Larocca, Federica Cavallo, Mariella Genuardi, Pierre W Wijermans, Davide Rossi, R Schaafsma, Alessandra Romano, Anna Marina Liberati, Agostina Siniscalchi, Maria Teresa PetrucciAbstract:Complete response (CR) was an uncommon event in elderly myeloma patients until novel agents were combined with standard oral Melphalan-prednisone. This analysis assesses the impact of treatment response on progression-free survival (PFS) and overall survival (OS). We retrospectively analyzed 1175 newly diagnosed myeloma patients, enrolled in 3 multicenter trials, treated with Melphalan-prednisone alone (n = 332), Melphalan-prednisone-thalidomide (n = 332), Melphalan-prednisone-bortezomib (n = 257), or Melphalan-prednisone-bortezomib-thalidomide (n = 254). After a median follow-up of 29 months, the 3-year PFS and OS were 67% and 27% (hazard ratio = 0.16; P < .001), and 91% and 70% (hazard ratio = 0.15; P < .001) in patients who obtained CR and in those who achieved very good partial response, respectively. Similar results were observed in patients older than 75 years. Multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment. These findings highlight a significant association between the achievement of CR and long-term outcome, and support the use of novel agents to achieve maximal response in elderly patients, including those more than 75 years. This trial was registered at www.clinicaltrials.gov as #NCT00232934, #ISRCTN 90692740, and #NCT01063179.
Paul G Richardson - One of the best experts on this subject based on the ideXlab platform.
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melflufen a peptidase potentiated alkylating agent in clinical trials
Oncotarget, 2017Co-Authors: Malin Wickstrom, Peter Nygren, Rolf Larsson, Johan Harmenberg, Jakob Lindberg, Per Sjoberg, Markus Jerling, Fredrik Lehmann, Paul G RichardsonAbstract:Aminopeptidases like aminopeptidase N (APN, also known as CD13) play an important role not only in normal cellular functioning but also in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. An increased expression of APN has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes, suggesting APN as a potential therapeutic target. Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated alkylating agent. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. This targeting effect results in very high intracellular concentrations of its metabolite Melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs Melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome Melphalan-resistance in multiple myeloma cells. Furthermore, anti-angiogenic properties of melflufen have been described. Consequently, it is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with Melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma. This review summarizes the current preclinical and clinical knowledge of melflufen.
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a novel alkylating agent melflufen induces irreversible dna damage and cytotoxicity in multiple myeloma cells
British Journal of Haematology, 2016Co-Authors: Arghya Ray, Paul G Richardson, Dharminder Chauhan, Durgadevi Ravillah, Deepika Sharma Das, Yan Song, Eva Nordstrom, Joachim Gullbo, Kenneth C AndersonAbstract:Our prior study utilized both in vitro and in vivo multiple myeloma (MM) xenograft models to show that a novel alkylator Melphalan-flufenamide (Melflufen) is a more potent anti-MM agent than Melphalan and overcomes conventional drug resistance. Here we examined whether this potent anti-MM activity of melflufen versus Melphalan is due to their differential effect on DNA damage and repair signalling pathways via γ-H2AX/ATR/CHK1/Ku80. Melflufen-induced apoptosis was associated with dose- and time-dependent rapid phosphorylation of γ-H2AX. Melflufen induces γ-H2AX, ATR, and CHK1 as early as after 2 h exposure in both Melphalan-sensitive and -resistant cells. However, Melphalan induces γ-H2AX in Melphalan-sensitive cells at 6 h and 24 h; no γ-H2AX induction was observed in Melphalan-resistant cells even after 24 h exposure. Similar kinetics was observed for ATR and CHK1 in meflufen- versus Melphalan-treated cells. DNA repair is linked to Melphalan-resistance; and importantly, we found that Melphalan, but not melflufen, upregulates Ku80 that repairs DNA double-strand breaks. Washout experiments showed that a brief (2 h) exposure of MM cells to melflufen is sufficient to initiate an irreversible DNA damage and cytotoxicity. Our data therefore suggest that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome Melphalan-resistance in MM cells.
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a novel alkylating agent Melphalan flufenamide ethyl ester induces an irreversible dna damage in multiple myeloma cells
Blood, 2014Co-Authors: Arghya Ray, Paul G Richardson, Jakob Lindberg, Dharminder Chauhan, Durgadevi Ravillah, Deepika Sharma Das, Yan Song, Eva Nordstrom, Kenneth C AndersonAbstract:Background and Rationale The alkylating agent Melphalan is actively used in multiple myeloma therapy; however, dose-limiting toxicities and development of resistance limits its use. Melphalan flufenamide ethyl ester (melflufen) is an enzyme-activated analogue of Melphalan which allows for a more rapid and higher intracellular accumulation of Melphalan in tumor cells than is achievable by direct exposure to equimolar doses of Melphalan. Our earlier study showed that melflufen is a more potent anti-MM agent than Melphalan, that can overcome conventional drug resistance and induce synergistic anti-MM activity in combination with bortezomib, lenalidomide, or dexamethasone ( Chauhan et al, Clinical Cancer Res 2013, 19(11): 3019-3031 ). These preclinical studies provided the basis for an ongoing phase 1 clinical trial of melflufen in MM. Here we examined whether the potent anti-MM activity of melflufen versus Melphalan is due to their differential effect on DNA damage and repair signaling pathways. Material and Methods We utilized Melphalan-sensitive (MM.1S, RPMI-8226) and Melphalan-resistant (LR-5) human MM cell lines. Immunoblot analysis was performed using antibodies specific against γ-H2AX, ATR, CHK1, Ku80, or GAPDH. Cell viability, cell cycle analysis were performed using MTT and propidium iodide staining. Cell viability, cell cycle and immunoblot studies were performed using equimolar concentrations of melflufen to Melphalan, as in our prior study ( Chauhan et al, Clinical Cancer Res 2013, 19(11): 3019-3031 ). Statistical significance was determined from Student’s t test. Melflufen was obtained from Oncopeptides AB, and Melphalan was purchased from Sigma Chemical Company. Results Melflufen triggered cytotoxicity in MM cell lines including, Melphalan-resistant LR-5 cells. An early event in the response of mammalian cells to DNA double-strand breaks is the phosphorylation of histone H2AX (γ-H2AX) at the sites in proximity to DNA breaks. Melflufen-induced apoptosis was associated with dose- and time- dependent rapid phosphorylation of γ-H2AX. We next compared the kinetics of induction of γ-H2AX/ATR/CHK1/Ku80 in melflufen- versus Melphalan-treated MM cells. Cells were treated with equimolar concentrations of melflufen or Melphalan for 2h, 4h, 6h, and 24h; protein lysates were prepared and subjected to immunoblot analysis with antibodies specific against γ-H2AX, ATR, CHK1, Ku80, GAPDH. Melflufen, but not Melphalan, triggered induction of γ-H2AX, ATR, and CHK1 as early as after 2h exposure in both Melphalan-sensitive and –resistant cells. Melphalan triggered induction of γ-H2AX in MM.1S and RPMI-8826 cells at 6h and 24h, respectively; and as expected, no induction of γ-H2AX was observed in LR-5 Melphalan-resistant cells even after 24h treatment. Similar kinetics were observed for ATR and CHK1. We next examined the induction of DNA repair pathway in response to melflufen and Melphalan using Ku80 as a marker protein. Melphalan, but not melflufen, triggered induction of Ku80. These data suggest that 1) melflufen triggers an early, and rapid DNA damage versus Melphalan; 2) while Melphalan induces DNA repair, no mechanism of DNA repair process is activated in response to melflufen treatment. Reports that the mechanisms for Melphalan-resistance includes activation of DNA repair pathways, coupled with our findings showing lack of DNA repair pathway in melflufen-treated cells, suggest that melflufen overcomes Melphalan-resistance, at least in part, by triggering an irreversible DNA damage. To further validate these data, we performed drug washout experiments and analysis of cell viability. Cells were treated with equimolar doses of melflufen or Melphalan for 1h; cells were then washed with plain medium to remove drugs, cultured in fresh medium for additional 48h, and then analyzed for viability. One hour treatment of cells with melflufen, but not Melphalan, triggers cytotoxicity in MM cells. Similar findings were observed using cell cycle analysis: % Sub G0/G1 after melflufen treatment was 81.1% in MM.1S; 80% in RPMI-8226; and 77% in LR-5 cells. Of note, Melphalan-treated cells triggered only minimal (10%) accumulation of cells in Sub-G0/G1 phase. Conclusion Our data therefore suggest that melflufen triggers a rapid, robust and an irreversible DNA damage, which may account for its ability to overcome Melphalan-resistance in MM cells. Disclosures Nordstrom: Oncopeptides AB: Employment. Lindberg: Oncopeptides AB: Employment. Chauhan: Oncopeptides AB: Consultancy. Anderson: Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Gilead: Consultancy; Sanofi Aventis: Consultancy; BMS: Consultancy; Oncopep/Acetylon: Equity Ownership.
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bortezomib cumulative dose efficacy and tolerability with three different bortezomib Melphalan prednisone regimens in previously untreated myeloma patients ineligible for high dose therapy
Haematologica, 2014Co-Authors: Mariavictoria Mateos, Paul G Richardson, Sara Bringhen, Juan Jose Lahuerta, Alessandra Larocca, Albert Oriol, Mario Boccadoro, Ramon Garciasanz, Francesco Di Raimondo, Dixielee EsseltineAbstract: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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in vitro and in vivo antitumor activity of a novel alkylating agent Melphalan flufenamide against multiple myeloma cells
Clinical Cancer Research, 2013Co-Authors: Dharminder Chauhan, Paul G Richardson, Arghya Ray, Kristina Viktorsson, Jack Spira, Claudia Pabaprada, Nikhil C Munshi, Rolf Lewensohn, Kenneth C AndersonAbstract:Purpose: The alkylating agent Melphalan prolongs survival in patients with multiple myeloma; however, it is associated with toxicities and development of drug-resistance. Here, we evaluated the efficacy of Melphalan-flufenamide (mel-flufen), a novel dipeptide prodrug of Melphalan in multiple myeloma. Experimental Design: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft animal model were used to study the antitumor activity of mel-flufen. Results: Low doses of mel-flufen trigger more rapid and higher intracellular concentrations of Melphalan in multiple myeloma cells than are achievable by free Melphalan. Cytotoxicity analysis showed significantly lower IC 50 of mel-flufen than Melphalan in multiple myeloma cells. Importantly, mel-flufen induces apoptosis even in Melphalan- and bortezomib-resistant multiple myeloma cells. Mechanistic studies show that siRNA knockdown of aminopeptidase N, a key enzyme mediating intracellular conversion of mel-flufen to Melphalan, attenuates anti–multiple myeloma activity of mel-flufen. Furthermore, mel-flufen–induced apoptosis was associated with: (i) activation of caspases and PARP cleavage; (ii) reactive oxygen species generation; (iii) mitochondrial dysfunction and release of cytochrome c; and (iv) induction of DNA damage. Moreover, mel-flufen inhibits multiple myeloma cell migration and tumor-associated angiogenesis. Human multiple myeloma xenograft studies showed a more potent inhibition of tumor growth in mice treated with mel-flufen than mice receiving equimolar doses of Melphalan. Finally, combining mel-flufen with lenalidomide, bortezomib, or dexamethasone triggers synergistic anti–multiple myeloma activity. Conclusion: Our preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of Melphalan, overcome drug-resistance, and improve multiple myeloma patient outcome. Clin Cancer Res; 19(11); 3019–31. ©2013 AACR .
Antonio Palumbo - One of the best experts on this subject based on the ideXlab platform.
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autologous transplantation and maintenance therapy in multiple myeloma
The New England Journal of Medicine, 2014Co-Authors: Antonio Palumbo, Maria Teresa Petrucci, Francesco Di Raimondo, Federica Cavallo, Dina Ben Yehuda, Sara Pezzatti, Tommaso Caravita, Chiara Cerrato, Elena Ribakovsky, Mariella GenuardiAbstract:Background This open-label, randomized, phase 3 study compared Melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with Melphalan–prednisone–lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. Methods We randomly assigned 273 patients 65 years of age or younger to high-dose Melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. Results The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose Melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall su...
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lenalidomide Melphalan and prednisone followed by lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Jay Mei, Antonio PalumboAbstract:The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, Melphalan, and prednisone, or Melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P<0.05), Physical Functioning (P<0.01), and Side Effects of Treatment (P<0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences (P<0.05 for Physical Functioning). Therefore, lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. (Clinicaltrials.gov identifier NCT00405756).
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lenalidomide Melphalan and prednisone followed by lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Antonio PalumboAbstract:The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, Melphalan, and prednisone, or Melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life ( P <0.05), Physical Functioning ( P <0.01), and Side Effects of Treatment ( P <0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences ( P <0.05 for Physical Functioning). Therefore, lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. ( [Clinicaltrials.gov][1] identifier [NCT00405756][2]). [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00405756&atom=%2Fhaematol%2F98%2F5%2F784.atom
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persistent overall survival benefit and no increased risk of second malignancies with bortezomib Melphalan prednisone versus Melphalan prednisone in patients with previously untreated multiple myeloma
Journal of Clinical Oncology, 2013Co-Authors: Jesus San F Miguel, Meletios A. Dimopoulos, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria Teresa Petrucci, Antonio Palumbo, Olga SamoilovaAbstract:Purpose This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-Melphalan-prednisone (VMP) versus Melphalanprednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies.
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bortezomib plus Melphalan and prednisone for initial treatment of multiple myeloma
The New England Journal of Medicine, 2008Co-Authors: Jesus San F Miguel, Meletios A. Dimopoulos, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria Teresa Petrucci, Antonio Palumbo, Olga SamoilovaAbstract:The time to progression among patients receiving bortezomib plus Melphalan– prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving Melphalan–prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P = 0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and Melphalan–prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P = 0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). Conclusions Bortezomib plus Melphalan–prednisone was superior to Melphalan–prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)
Olga Samoilova - One of the best experts on this subject based on the ideXlab platform.
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persistent overall survival benefit and no increased risk of second malignancies with bortezomib Melphalan prednisone versus Melphalan prednisone in patients with previously untreated multiple myeloma
Journal of Clinical Oncology, 2013Co-Authors: Jesus San F Miguel, Meletios A. Dimopoulos, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria Teresa Petrucci, Antonio Palumbo, Olga SamoilovaAbstract:Purpose This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-Melphalan-prednisone (VMP) versus Melphalanprednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies.
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bortezomib plus Melphalan and prednisone for initial treatment of multiple myeloma
The New England Journal of Medicine, 2008Co-Authors: Jesus San F Miguel, Meletios A. Dimopoulos, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria Teresa Petrucci, Antonio Palumbo, Olga SamoilovaAbstract:The time to progression among patients receiving bortezomib plus Melphalan– prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving Melphalan–prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P = 0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and Melphalan–prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P = 0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). Conclusions Bortezomib plus Melphalan–prednisone was superior to Melphalan–prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)
Meletios A. Dimopoulos - One of the best experts on this subject based on the ideXlab platform.
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lenalidomide Melphalan and prednisone followed by lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Jay Mei, Antonio PalumboAbstract:The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, Melphalan, and prednisone, or Melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P<0.05), Physical Functioning (P<0.01), and Side Effects of Treatment (P<0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences (P<0.05 for Physical Functioning). Therefore, lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. (Clinicaltrials.gov identifier NCT00405756).
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lenalidomide Melphalan and prednisone followed by lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Antonio PalumboAbstract:The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, Melphalan, and prednisone, or Melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life ( P <0.05), Physical Functioning ( P <0.01), and Side Effects of Treatment ( P <0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences ( P <0.05 for Physical Functioning). Therefore, lenalidomide, Melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. ( [Clinicaltrials.gov][1] identifier [NCT00405756][2]). [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00405756&atom=%2Fhaematol%2F98%2F5%2F784.atom
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persistent overall survival benefit and no increased risk of second malignancies with bortezomib Melphalan prednisone versus Melphalan prednisone in patients with previously untreated multiple myeloma
Journal of Clinical Oncology, 2013Co-Authors: Jesus San F Miguel, Meletios A. Dimopoulos, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria Teresa Petrucci, Antonio Palumbo, Olga SamoilovaAbstract:Purpose This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-Melphalan-prednisone (VMP) versus Melphalanprednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies.
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bortezomib plus Melphalan and prednisone for initial treatment of multiple myeloma
The New England Journal of Medicine, 2008Co-Authors: Jesus San F Miguel, Meletios A. Dimopoulos, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria Teresa Petrucci, Antonio Palumbo, Olga SamoilovaAbstract:The time to progression among patients receiving bortezomib plus Melphalan– prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving Melphalan–prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P = 0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and Melphalan–prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P = 0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). Conclusions Bortezomib plus Melphalan–prednisone was superior to Melphalan–prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)
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gene specific formation and repair of dna monoadducts and interstrand cross links after therapeutic exposure to nitrogen mustards
Clinical Cancer Research, 2003Co-Authors: Vassilis L Souliotis, Meletios A. Dimopoulos, Petros P SfikakisAbstract:Purpose: To investigate the possibility of measuring the gene-specific DNA damage after therapeutic exposure to nitrogen mustards and to examine its relationship with the clinical response. Experimental Design: The kinetics of gene-specific monoadducts and interstrand cross-link formation/repair were measured in the p53 and N-ras genes. DNA extracted from human peripheral lymphocytes following in vitro exposure to Melphalan or therapeutic exposure to Melphalan or cyclophosphamide was used. Results: When lymphocytes were treated in vitro with biologically relevant doses of Melphalan, monoadducts accumulated rapidly in both p53 and N-ras genes, reaching maximal levels within 2 h, whereas the highest interstrand cross-link levels were found within 8 h. Thereafter, the adducts were repaired with half-lives of 14.5 ± 0.3 h (p53) or 18.8 ± 1.5 h (N-ras) for monoadducts and 12.4 ± 0.8 h (p53) or 14.1 ± 2.2 h (N-ras) for interstrand cross-links. Moreover, peak levels of monoadducts in both genes were observed 2 h after treatment in peripheral leukocytes from patients with multiple myeloma treated with high-dose i.v. Melphalan, supported by autologous stem cell transplantation, whereas interstrand cross-links were maximal within 8 h. Of seven patients examined, the three who showed the least levels of DNA damage did not respond to the high-dose Melphalan. Conclusions: This is the first report showing that it is feasible to measure gene-specific DNA damage in a readily accessible tissue of humans exposed to bifunctional alkylating drugs and to examine, at the level of the individual patient, the relationships between the induction/repair of cytotoxic DNA damage and clinical response or long-term complications.