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1.
Dev Cell ; 48(6): 793-810.e6, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30713076

RESUMO

Piwi-interacting RNAs (piRNAs) are important for genome regulation across metazoans, but their biogenesis evolves rapidly. In Caenorhabditis elegans, piRNA loci are clustered within two 3-Mb regions on chromosome IV. Each piRNA locus possesses an upstream motif that recruits RNA polymerase II to produce an ∼28 nt primary transcript. We used comparative epigenomics across nematodes to gain insight into the origin, evolution, and mechanism of nematode piRNA biogenesis. We show that the piRNA upstream motif is derived from core promoter elements controlling snRNA transcription. We describe two alternative modes of piRNA organization in nematodes: in C. elegans and closely related nematodes, piRNAs are clustered within repressive H3K27me3 chromatin, while in other species, typified by Pristionchus pacificus, piRNAs are found within introns of active genes. Additionally, we discover that piRNA production depends on sequence signals associated with RNA polymerase II pausing. We show that pausing signals synergize with chromatin to control piRNA transcription.


Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Cromatina/metabolismo , Epigenômica , RNA Polimerase II/metabolismo , RNA Interferente Pequeno/biossíntese , Animais , Sequência de Bases , Evolução Molecular , Loci Gênicos , Motivos de Nucleotídeos/genética , RNA Interferente Pequeno/genética , Transcrição Genética
2.
Expert Opin Biol Ther ; 18(12): 1209-1221, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30394809

RESUMO

INTRODUCTION: Multiple myeloma (MM) is a currently incurable hematologic tumor with heterogeneous clinical behavior and prognosis. During the last years, survival improved due to a better understanding of MM biology and the development of novel drugs, although it still remains unsatisfactory in many cases: new drugs and treatment strategies are needed. CD38 is uniformly expressed at high levels on MM cells and, to a lesser extent, on the surface of normal hematopoietic and non-hematopoietic cells, making this molecule an interesting target for immunotherapeutic approaches. AREAS COVERED: This review discusses the preclinical and clinical experience on different immunotherapeutic agents targeting CD38 in MM. EXPERT OPINION: Monoclonal antibodies (mAbs) targeting CD38 are currently changing the treatment scenario in MM, allowing physicians to reach unprecedented results, especially when anti-CD38 mAbs are used in combination with consolidated MM treatments. Other immunotherapies targeting CD38 - such as conjugated anti-CD38 mAbs, bispecific antibodies stimulating T cells to eliminate CD38+ MM cells, and CD38-specific chimeric antigen receptor T cells - are interesting strategies, currently at earlier developmental stages.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , ADP-Ribosil Ciclase 1/fisiologia , Imunoterapia/métodos , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/fisiologia , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/terapia , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Animais , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Glicoproteínas de Membrana/antagonistas & inibidores , Terapia de Alvo Molecular/tendências , Mieloma Múltiplo/imunologia , Linfócitos T/imunologia
3.
Elife ; 72018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30362940

RESUMO

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.


Assuntos
Envelhecimento/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Cromatina/metabolismo , Animais , Caenorhabditis elegans/genética , DNA/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Código das Histonas , Histonas/metabolismo , Anotação de Sequência Molecular , Regiões Promotoras Genéticas , Reprodutibilidade dos Testes , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição
4.
Clin Lymphoma Myeloma Leuk ; 18(8): 533-540, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29910180

RESUMO

BACKGROUND: High-dose therapy with autologous stem cell transplantation (HDT-ASCT) and maintenance treatment with novel agents are the best options for patients with newly diagnosed multiple myeloma, increasing the rate of complete response (CR) and prolonging progression-free survival (PFS) and overall survival (OS). Indeed, the achievement of a CR is a predictor of long-term survival among transplant-eligible patients. However, it is unclear whether patients reaching a CR after induction treatment could receive less intense consolidation or avoid maintenance therapy. PATIENTS AND METHODS: We analyzed CR patients treated in 2 phase III trials, GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441, to compare HDT-ASCT with an R-Alk (lenalidomide, alkylator) regimen as consolidation, and lenalidomide (R) maintenance with no maintenance. The primary endpoints were PFS, second PFS (PFS2), and OS from consolidation and maintenance (_m). RESULTS: Overall, the data from 166 patients in CR were analyzed, 95 in the HDT-ASCT group and 71 in the R-Alk group. The CR patients who received HDT-ASCT had a better PFS (hazard ratio [HR], 0.55; P = .01), PFS2 (HR, 0.46; P = .02), and OS (HR, 0.42; P = .03) compared with patients randomized to R-Alk. The survival benefit with HDT-ASCT was confirmed among all the subgroups, according to age, International Staging System (ISS stage, cytogenetic profile, and receipt of maintenance therapy. CR patients who received lenalidomide maintenance had a better PFS_m (4 years: 54% vs. 19%; HR, 0.43; P = .02) compared with those who received no maintenance. However, no difference was observed in terms of PFS2_m (4 years: 72% vs. 58%; HR, 0.83; P = .67) and OS_m (4 years: 79% vs. 72%; HR, 0.82; P = .73) with maintenance therapy. CONCLUSION: Even in CR patients, outcomes were improved by an intensified approach with HDT-ASCT consolidation and lenalidomide-based maintenance therapy.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Lenalidomida/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Quimioterapia de Consolidação , Feminino , Humanos , Lenalidomida/efeitos adversos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Neoplasia Residual , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/mortalidade , Fatores de Tempo , Transplante Autólogo
5.
J Cancer Res Clin Oncol ; 144(7): 1357-1366, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29675792

RESUMO

PURPOSE: Maintenance demonstrated to improve survival in newly diagnosed multiple myeloma (NDMM) patients and the achievement of complete response (CR) is a strong predictor of survival. Nevertheless, the role of maintenance according to response after induction/consolidation has not been investigated so far. To evaluate the impact of maintenance according to response, we pooled together and retrospectively analyzed data from 955 NDMM patients enrolled in two trials (GIMEMA-MM-03-05 and RV-MM-PI-209). METHODS: Primary endpoints were progression-free survival (PFS)1, PFS2 and overall survival (OS) of CR patients randomized to maintenance and no maintenance. Secondary endpoints were PFS1, PFS2 and OS in very good partial response/partial response (VGPR/PR) patients. RESULTS: Overall, 213 patients obtained CR after induction/consolidation, 118 received maintenance and 95 no maintenance. In patients achieving CR, maintenance significantly improved PFS1 (HR 0.50, P < 0.001), PFS2 (HR 0.58, P 0.02) and OS (HR 0.51, P 0.02) compared with no maintenance; the advantage was maintained across all the analyzed subgroups according to age, International Staging System (ISS) stage, cytogenetic profile and treatment. Similar features were seen in VGPR/PR patients. CONCLUSION: Maintenance prolonged survival in CR and in VGPR/PR patients. The benefit in CR patients suggests the importance of continuing treatment in patients with chemo-sensitive disease. TRIAL REGISTRATION: The two source studies are registered at ClinicalTrials.gov: identification numbers NCT01063179 and NCT00551928.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Idoso , Intervalo Livre de Doença , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida
6.
Leuk Lymphoma ; 58(7): 1538-1547, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27819179

RESUMO

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.


Assuntos
Leucemia Plasmocitária/etiologia , Leucemia Plasmocitária/terapia , Animais , Biomarcadores , Terapia Combinada , Gerenciamento Clínico , Predisposição Genética para Doença , Genômica/métodos , Humanos , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/metabolismo , Fenótipo
7.
Expert Opin Pharmacother ; 17(2): 181-92, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26684262

RESUMO

INTRODUCTION: 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.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Transplante de Células-Tronco Hematopoéticas , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Inibidores de Proteassoma/uso terapêutico
8.
J Clin Oncol ; 33(30): 3459-66, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26282661

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Idoso , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Lenalidomida , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Talidomida/administração & dosagem , Talidomida/análogos & derivados
9.
N Engl J Med ; 371(10): 895-905, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-25184862

RESUMO

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 survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). CONCLUSIONS: Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco , Talidomida/análogos & derivados , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Quimioterapia de Consolidação , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Lenalidomida , Quimioterapia de Manutenção , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Neutropenia/induzido quimicamente , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Transplante de Células-Tronco/efeitos adversos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Transplante Autólogo
10.
Expert Rev Anticancer Ther ; 14(2): 217-28, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24308685

RESUMO

Many advances have been made in the treatment of patients with multiple myeloma including elderly subjects. The introduction of novel agents, such as thalidomide, lenalidomide, bortezomib, have revolutionized the treatment paradigm of this neoplasm, and second-generation molecules are currently being tested to offer patients a wider variety of treatment options and to improve outcome. The efficacy of a regimen should be carefully balanced against its toxicity profile. Elderly patients are particularly susceptible to adverse events that may lead to early treatment discontinuation. Thus, a more accurate distinction within the elderly population and a more appropriate treatment allocation is necessary. Here we describe the major and more recent treatment options available today for elderly patients with multiple myeloma.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Fatores Etários , Idoso , Antineoplásicos/efeitos adversos , Desenho de Drogas , Humanos , Mieloma Múltiplo/patologia , Resultado do Tratamento
11.
Am J Hematol ; 89(4): 355-62, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24273190

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Estudos de Casos e Controles , Intervalo Livre de Doença , Avaliação de Medicamentos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Doenças do Sistema Nervoso/induzido quimicamente , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prognóstico , Modelos de Riscos Proporcionais , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
12.
Clin Lymphoma Myeloma Leuk ; 13 Suppl 2: S349-54, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24290220

RESUMO

Multiple myeloma is a highly treatable but still incurable malignancy. Many advances have been made in the treatment of this disease, particularly thanks to the introduction of the immunomodulatory drugs, thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib. Different trials have supported the inclusion of consolidation/maintenance therapy as part of a sequential approach after induction therapy and transplantation (for eligible patients). This therapeutic strategy aims to maintain or even improve response obtained after induction, and ultimately to prolong survival. The role of consolidation/maintenance therapy has been assessed in patients eligible and ineligible for transplantation, and proved to be a valuable option. The improved outcome reported with consolidation/maintenance therapy should, however, be balanced against the toxicity profile of such an approach. Prolonged exposure to a drug might in fact increase toxicity, and prompt management of adverse events is necessary.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Quimioterapia de Consolidação/métodos , Humanos , Lenalidomida , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados
13.
Semin Oncol ; 40(5): 577-84, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24135402

RESUMO

During the last two decades, many steps forward have been made in the treatment of multiple myeloma (MM) thanks to the introduction of the novel agents thalidomide, lenalidomide, and bortezomib. Despite this, MM remains an incurable disease. Elderly patients (≥65 years) represent the majority of subjects. Differently from younger (<65 years) and fit patients, elderly patients are usually not eligible for transplantation. Gentler approaches with novel agents plus conventional chemotherapy with melphalan-prednisone are commonly adopted in this setting. Data show that a sequential approach including induction followed by consolidation/maintenance therapy is an optimal strategy to improve patient outcome. In addition, second-generation novel agents are currently under investigation and may represent valuable alternative treatment options in the future.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Fatores Etários , Idoso , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Bortezomib , Ensaios Clínicos como Assunto , Humanos , Lenalidomida , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Prognóstico , Pirazinas/uso terapêutico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Resultado do Tratamento
14.
Expert Opin Drug Metab Toxicol ; 9(10): 1371-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23834482

RESUMO

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. Carfilzomib is 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.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/farmacocinética , Ácidos Borônicos , Bortezomib , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Oligopeptídeos/administração & dosagem , Inibidores de Proteassoma , Pirazinas
15.
Korean J Intern Med ; 28(3): 263-73, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23682217

RESUMO

Many advances in the treatment of multiple myeloma have been made due to the use of transplantation and the introduction of novel agents including thalidomide, lenalidomide, and bortezomib. The first step is recognizing the symptoms and starting prompt treatment. Different strategies should be selected for young and elderly subjects. Young patients are commonly eligible for transplantation, which is now considered the standard approach for this setting, and various inductions therapies containing novel agents are available before transplantation. Elderly patients are usually not eligible for transplantation, and gentler approaches with new drugs combinations are used for their treatment.


Assuntos
Mieloma Múltiplo/terapia , Fatores Etários , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Bortezomib , Humanos , Fatores Imunológicos/uso terapêutico , Lenalidomida , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Prognóstico , Pirazinas/uso terapêutico , Transplante de Células-Tronco , Talidomida/análogos & derivados , Talidomida/uso terapêutico
16.
Haematologica ; 98(6): 980-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23445873

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mieloma Múltiplo/mortalidade , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Causas de Morte , Feminino , Humanos , Masculino , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Expert Opin Drug Metab Toxicol ; 8(9): 1209-22, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22862790

RESUMO

INTRODUCTION: Lenalidomide is 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.


Assuntos
Fatores Imunológicos/farmacocinética , Fatores Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações de Medicamentos , Humanos , Lenalidomida , Talidomida/farmacocinética , Talidomida/uso terapêutico
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