RESUMO
n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (hazard ratio 0.85, P=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; P=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (hazard ratio 0.72, P=0.05) and lenalidomide-dexamethasone (hazard ratio 0.72, P=0.04). Likewise, a trend towards a better overall survival was noted for patients treated with melphalan-prednisone-lenalidomide or cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a full-dose triplet regimen, while intermediate-fit and frail patients benefit from gentler regimens. ClinicalTrials.gov registration number: NCT01093196.
Assuntos
Lenalidomida/uso terapêutico , Mieloma Múltiplo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Humanos , Quimioterapia de Manutenção , Melfalan/uso terapêutico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
OBJECTIVES: Morphology and cytogenetics are currently used to define prognosis in myelodysplastic syndromes (MDS). However, these parameters have some limits. Flow cytometry has been recently included in the diagnostic panel for MDS, and its prognostic significance is under evaluation. METHODS: Marrow aspirates from 424 MDS patients were analyzed by flow cytometry to evaluate the impact of bone marrow cell immunophenotype on overall survival (OS) and leukemia-free survival (LFS). The immature compartment of myeloblasts was analyzed by the quantitative expression of CD34 (<3% vs. ≥3%), CD117, and CD11b(-) /CD66b(-) (<5% vs. ≥5%); myeloid maturation was analyzed by the expression of CD11b(+) /CD66b(++) (<15% vs. ≥15%) and CD11b(+) /CD66b(+) (<25% vs. ≥25%). RESULTS: In univariate analysis, the expression of immaturity markers (CD34(+) , CD117(+) , and CD11b(-) /CD66b(-) ) was associated with shorter LFS and OS (P < 0.0001); higher expression of differentiation markers (CD11b(+) /CD66b(++) and CD11b(+) /CD66b(+) ) was associated with longer LFS (P < 0.0001 and P = 0.0002, respectively) and OS (P < 0.0001). In multivariate analysis, expression of CD34(+) (P = 0.007), CD117(+) (P = 0.013), and CD11b(+) /CD66b(++) (P = 0.023) retained independent prognostic value for OS, while only the expression of CD34(+) was a prognostic factor for LFS (P = 0.0003). Two different risk groups were defined according to the presence of 0-1 or ≥2 of these factors with significant different LFS and OS (P < 0.0001). This score showed prognostic value in predicting survival even in subanalysis according to IPSS and WHO subgroups. CONCLUSIONS: Flow cytometric analysis in MDS may provide meaningful prognostic information. Blast percentage expressed as CD117(+) or CD34(+) cells and the quantitative assessment of myeloid maturation showed prognostic value for survival.
Assuntos
Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Prognóstico , Análise de SobrevidaRESUMO
Tyrosine kinase inhibitors (TKIs) are the treatment of choice for BCR-ABL1-positive chronic myeloid leukemia (CML). Although TKIs have substantially improved prognosis of CML patients, their use is not free of adverse effects. Dasatinib is a second generation TKI frequently associated with pleural effusion in up to 33% of patients. This results in symptoms as dyspnea, cough and chest pain that may require therapy discontinuation. In the present report, we describe two exceptional cases of HHV8-negative large B-cell effusion-based lymphoma (EBL) confined to the pleura, incidentally, diagnosed in patients presenting with dasatinib-related pleural effusion. One patient (case 1) is alive and is in remission at 17 months from large B-cell EBL diagnosis while unfortunately the other patient (case 2) died of progressive disease and COVID-19 pneumonia 16 months from large B-cell EBL diagnosis. These cases raise concern about a possible association between large B-cell EBL and dasatinib, and the different clinical outcome of the two cases poses a challenge in treatment decision. For this reason, we strongly recommend cytological investigation in patients with persistent/relapsing pleural effusion under dasatinib, primarily to validate its possible association with lymphoma development and to improve the knowledge about this entity.
RESUMO
The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of beta(2)-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Prednisona/administração & dosagem , Talidomida/administração & dosagem , Administração Oral , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Seguimentos , Humanos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: The goal of this retrospective study was to compare the efficacy and toxicity of lenalidomide-dexamethasone (len/dex) vs. melphalan-prednisone-lenalidomide (MPR) as upfront therapy for newly diagnosed elderly patients with myeloma. METHODS: Data from 51 patients enrolled in an Italian phase I/II trial and treated with MPR were analyzed and compared with data from 38 patients, seen at the Mayo Clinic, treated with len/dex and enrolled in phase II/III trials. RESULTS: On intention-to-treat analysis, time to progression (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.903), progression-free survival (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.926), and overall survival (2-yr overall survival: 86.2% in MPR vs. 89.1% in len/dex, P = 0.730) were not significantly different between the two groups. Results were confirmed when the analysis was restricted to MPR and len/dex matched pair mates. Hematologic grade 3-4 toxicities were more common with MPR (neutropenia: 66.7% vs. 21.1%, P < 0.001; thrombocytopenia: 31.4% vs. 2.6%, P < 0.001). Grade 3-4 gastrointestinal events (13.2% vs. 3.9%, P = 0.132), thrombotic events (13.2% vs. 5.9%, P = 0.279), and fatigue (10.5% vs. 3.9%, P = 0.395) were more common with len/dex. CONCLUSIONS: Results show that both MPR and len/dex are efficacious regimens for elderly patients with myeloma. Randomized trials are needed to confirm these results.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Melfalan/uso terapêutico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Prednisona/uso terapêutico , Talidomida/análogos & derivados , Idoso , Dexametasona/administração & dosagem , Feminino , Humanos , Lenalidomida , Masculino , Melfalan/administração & dosagem , Prednisona/administração & dosagem , Estudos Retrospectivos , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR. PATIENTS AND METHODS: A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21. RESULTS: Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 x 109/L, 1.43 x 109/L, and 2.11 x 109/L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 x 109/L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 x 109/L, 121 x 109/L, and 158 x 109/L, respectively. Median follow-up was 29.6 months, median progression-free survival was 28.5 months, and 2-year overall survival was 91%. CONCLUSION: MPR is a promising regimen with manageable hematologic toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Neutropenia/induzido quimicamente , Trombocitopenia/induzido quimicamente , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Lenalidomida , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/farmacocinética , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Neutropenia/sangue , Neutropenia/tratamento farmacológico , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/farmacocinética , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Talidomida/farmacocinética , Trombocitopenia/sangue , Trombocitopenia/tratamento farmacológicoRESUMO
BACKGROUND: Since 1960, oral melphalan and prednisone (MP) has been regarded as the standard of care in elderly multiple myeloma patients. This multicentre randomised trial compared oral MP plus thalidomide (MPT) with MP alone in patients aged 60-85 years. METHODS: Patients with newly diagnosed multiple myeloma were randomly assigned to receive oral MP for six 4-week cycles plus thalidomide (n=129; 100 mg per day continuously until any sign of relapse or progressive disease) or MP alone (n=126). Analysis was intention-to-treat. This study is registered at , number NCT00232934. RESULTS: Patients treated with thalidomide had higher response rates and longer event-free survival (primary endpoints) than patients who were not. Combined complete or partial response rates were 76.0% for MPT and 47.6% for MP alone (absolute difference 28.3%, 95% CI 16.5-39.1), and the near-complete or complete response rates were 27.9% and 7.2%, respectively. 2-year event-free survival rates were 54% for MPT and 27% for MP (hazard ratio [HR] for MPT 0.51, 95% CI 0.35-0.75, p=0.0006). 3-year survival rates were 80% for MPT and 64% for MP (HR for MPT 0.68, 95% CI 0.38-1.22, p=0.19). Rates of grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (p=0.0002). Introduction of enoxaparin prophylaxis reduced rate of thromboembolism from 20% to 3% (p=0.005). CONCLUSION: Oral MPT is an effective first-line treatment for elderly patients with multiple myeloma. Anticoagulant prophylaxis reduces frequency of thrombosis. Longer follow-up is needed to assess effect on overall survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Prednisona/administração & dosagem , Talidomida/administração & dosagemRESUMO
BACKGROUND: Bortezomib and thalidomide have shown synergy with melphalan and dexamethasone. We used this 4-drug combination as conditioning before autologous hematopoietic cell infusions. PATIENTS AND METHODS: Twenty-six patients with advanced-stage myeloma were treated with melphalan 50 mg/m(2) and bortezomib 1.3 mg/m(2) on days -6 and -3 in association with thalidomide 200 mg and dexamethasone 20 mg on days -6 through -3, followed by hematopoietic cell support on day 0. RESULTS: Nonhematologic toxicities included pneumonia, febrile neutropenia, and peripheral neuropathy. All patients had undergone autologous transplantation at diagnosis, and 13 patients (50%) underwent an additional transplantation at relapse. Responses occurred in 17 of 26 patients (65%), including 1 complete remission, 3 near complete remissions (12%), and 2 very good partial remissions (8%). Response rate was higher than that induced by the previous line of treatment in 12 patients (46%). CONCLUSION: Melphalan/bortezomib/thalidomide/dexamethasone showed encouraging antimyeloma activity in patients with advanced-stage myeloma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Ácidos Borônicos/administração & dosagem , Bortezomib , Terapia Combinada , Dexametasona/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Pirazinas/administração & dosagem , Recidiva , Terapia de Salvação , Análise de Sobrevida , Talidomida/administração & dosagemRESUMO
PURPOSE: To assess whether nonneoplastic Bcl-2/IgH rearrangements act as a confounding factor in the setting of minimal residual disease analysis by evaluating their incidence in a panel of lymphoma-free subjects, including cancer-free donors and chemotherapy-naive and chemotherapy-treated cancer patients. PATIENTS AND METHODS: A total of 501 nonlymphoma subjects have been assessed: 258 cancer-free patients and 243 patients with malignancies other than lymphoma, 112 of whom were chemotherapy-naive. Patients were primarily assessed by nested polymerase chain reaction (PCR), followed by real-time quantitative PCR if they scored positive. In addition, six initially PCR-positive cancer-free donors were prospectively reassessed by qualitative and quantitative PCR after 30 and 60 days. RESULTS: The overall incidence of Bcl-2/IgH positivity was 9.6%, with a median number of 11 rearrangements per 1,000,000 diploid genomes (range, 0 to 2,845 rearrangements), as assessed by real-time PCR. The incidence was similar in healthy subjects and cancer patients at diagnosis (12% and 12.5%; P = not significant). In contrast, the incidence of this translocation was only 2.3% in chemotherapy-treated patients (P <.001). In addition, three initially PCR-positive cancer-free donors showed persistence of their rearrangements when assessed after 30 and 60 days. CONCLUSION: The low incidence of nonneoplastic Bcl-2/IgH rearrangements following chemotherapy provides further evidence of the prognostic role of persistent PCR-positivity in the posttreatment molecular follow-up of follicular lymphoma patients.
Assuntos
Rearranjo Gênico , Cadeias Pesadas de Imunoglobulinas/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma Folicular/diagnóstico , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , Translocação GenéticaRESUMO
PURPOSE: The efficacy of low-dose thalidomide (THAL) plus dexamethasone (DEX) has been evaluated in myeloma. The clinical outcome of patients treated with THAL-DEX was compared with that of a control group treated with conventional chemotherapy (CC). EXPERIMENTAL DESIGN: A total of 120 relapsed/refractory patients to one (52%), or two or more(48%) lines of chemotherapy were treated with THAL 100mg/day (continuous) and DEX 40 mg (days 1-4 of each month). Their clinical outcome was compared to a control group of 120 patients frequency matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. Clinical characteristics were homogeneous in the two groups. RESULTS: In patients treated after one line of chemotherapy, THAL-DEX significantly improved outcome. Median progression-free survival (PFS) was superior in THAL-DEX group versus CC group (17 months versus 11 months, P = 0.0024). The median survival for THAL-DEX patients has not to been reached, but the probabilities of survival at 3 years were 60% after THAL-DEX and 26% after CC (P = 0.0016). The clinical outcome of patients receiving THAL-DEX or CC after two or more lines of chemotherapy, was similar. In the THAL-DEX group, the medianPFS was 11 months compared to 9 months in the CC group (P = NS). No differences in overall survival (OS) were observed (median OS 19 months for both THAL-DEX and CC). CONCLUSIONS: As first salvage regimen, THAL-DEX was superior to CC, as second or third salvage regimen, it was equivalent to CC. THAL-DEX is not myelotoxic. It postpones the delivery of effective salvage chemotherapy. This might explain the survival benefit.
Assuntos
Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Terapia de Salvação/métodos , Análise de Sobrevida , Talidomida/administração & dosagem , Fatores de TempoRESUMO
AIMS AND BACKGROUND: Multiple myeloma is the second most common hematological cancer. Although it accounts for only a relatively small percentage of all cancer types, the costs associated with managing multiple myeloma are considerable. Available studies are mainly focused on health care costs. The Costo del Mieloma Multiplo (Cost of MM, CoMiM) study investigated the cost of illness of multiple myeloma in Italy during one year of disease management. METHODS: CoMiM is a retrospective, prevalence-based, multi-center, cross-sectional study based on a stratified sample of patients seen during normal clinical practice (asymptomatic; symptomatic on drugs; symptomatic receiving autologous stem cell transplantation; plateau/remission). Demographics, clinical history, health care and non-health care resource consumption data were collected. Costs were evaluated from the societal viewpoint and expressed in Euro 2008. RESULTS: Data on 236 patients were analyzed (39 asymptomatic, 17%; 29 symptomatic receiving autologous stem-cell transplantation, 12%; 105 symptomatic receiving drugs, 44%; 63 plateau/remission, 27%). The total cost of illness reached 19,267.1 ± 25,078.6 (asymptomatic, 959.3 ± 1091.6; symptomatic receiving drugs, 21,707.8 ± 21,785.3; symptomatic receiving autologous stem-cell transplantation, 59,243.7 ± 24,214.0; plateau/remission, 8130.7 ± 15,092.5). The main cost drivers of total cost of illness were drugs and hospital admissions (46.1% and 29.4%, respectively). Antineoplastics and immunomodulators drove the cost of drugs (21.6% and 21.1% of the total cost of illness). Cost of antineoplastics was led by bortezomib (97.4%), whereas the cost driver for immunomodulators was lenalidomide (99.4%). Cost of hospitalization funded by the Italian National Health Service was strongly influenced by transplantation (94.6%), whereas chemotherapy and skeletal fractures did not exceed 1% and 2%, respectively. CONCLUSIONS: Despite some limitations, the CoMiM study provides Italian health care decision-makers with an insight into the stratified cost of illness of multiple myeloma patients.
Assuntos
Antineoplásicos/economia , Efeitos Psicossociais da Doença , Mieloma Múltiplo/economia , Mieloma Múltiplo/terapia , Transplante de Células-Tronco/economia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Estudos Transversais , Feminino , Custos de Cuidados de Saúde , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Estudos Retrospectivos , Transplante AutólogoRESUMO
PURPOSE To evaluate the effect of bortezomib as induction therapy before autologous transplantation, followed by lenalidomide as consolidation-maintenance in myeloma patients. PATIENTS AND METHODS Newly diagnosed patients age 65 to 75 years were eligible. Induction (bortezomib, doxorubicin, and dexamethasone [PAD]) included four 21-day cycles of bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11), pegylated liposomal doxorubicin (30 mg/m(2) on day 4), and dexamethasone (40 mg/d; cycle 1: days 1 to 4, 8 to 11, and 15 to 18; cycles 2 to 4: days 1 to 4). Autologous transplantation was tandem melphalan 100 mg/m(2) (MEL100) and stem-cell support. Consolidation included four 28-day cycles of lenalidomide (25 mg/d on days 1 to 21 every 28 days) plus prednisone (50 mg every other day), followed by maintenance with lenalidomide (LP-L; 10 mg/d on days 1 to 21) until relapse. Primary end points were safety (incidence of grade 3 to 4 adverse events [AEs]) and efficacy (response rate). Results A total of 102 patients were enrolled. In a per-protocol analysis, after PAD, 58% of patients had very good partial response (VGPR) or better, including 13% with complete response (CR); after MEL100, 82% of patients had at least VGPR and 38% had CR; and after LP-L, 86% of patients had at least VGPR and 66% had CR. After median follow-up time of 21 months, the 2-year progression-free survival rate was 69%, and the 2-year overall survival rate was 86%. During induction, treatment-related mortality was 3%; grade 3 to 4 AEs included thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%). During consolidation-maintenance, grade 3 to 4 AEs were neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). CONCLUSION Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance, is an effective regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Transplante de Células-Tronco , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Bortezomib , Quimioterapia Adjuvante , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Itália/epidemiologia , Estimativa de Kaplan-Meier , Lenalidomida , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Terapia Neoadjuvante , Polietilenoglicóis/administração & dosagem , Prednisona/administração & dosagem , Inibidores de Proteases/administração & dosagem , Pirazinas/administração & dosagem , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Fatores de Tempo , Transplante Autólogo , Resultado do TratamentoAssuntos
Antineoplásicos/uso terapêutico , Imunossupressores/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Talidomida/uso terapêutico , Terapia Combinada , Resistência a Medicamentos , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Transfusão de Plaquetas , Prednisona/uso terapêutico , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/terapia , RecidivaRESUMO
Treatment of multiple myeloma has changed in recent years. Advances in the understanding of the pathogenesis of the disease and the mechanism of drug resistance have led to the development of novel effective biological treatment agents such as thalidomide and bortezomib. Lenalidomide is an oral analogue of thalidomide that lacks the neurotoxic side effects associated with the parent drug, and has shown significant antimyeloma activity. Lenalidomide has now been approved by the US FDA and the European Medicines Agency for use in combination with dexamethasone in patients with at least one prior therapy. Several trials are testing lenalidomide-based regimens in both newly diagnosed and relapsed patients. This review summarizes the profile of lenalidomide and its current role in the treatment of multiple myeloma.
Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Dexametasona/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Humanos , Lenalidomida , Mieloma Múltiplo/fisiopatologia , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/uso terapêuticoRESUMO
BACKGROUND: The purpose was to evaluate the incidence and risk factors of thromboembolism associated with lenalidomide therapy in newly diagnosed myeloma. METHODS: A pooled analysis was performed of patients with previously untreated multiple myeloma enrolled in clinical trials of lenalidomide-based therapy at the Mayo Clinic, Rochester, Minnesota, and the Italian Myeloma Network, Italy. The incidence of thrombosis, the effect of risk factors such as steroid dose and erythropoietin supplementation, and the effect of prophylaxis were examined. RESULTS: In all, 125 patients enrolled in 3 clinical trials were identified. Patients were stratified based on the concomitant corticosteroid dose. Fifty-two patients were in the high-dose group (dexamethasone 40 mg, 12 days a month); 73 patients were in the low-dose group (prednisone at any dose; or dexamethasone 40 mg, 4 days a month). A total of 110 patients were initiated on thromboprophylaxis; of these, 104 patients (95%) received aspirin. Ten patients (8%) developed deep vein thrombosis, including 4 who were not receiving any thromboprophylaxis at the time of the event. The rate of thromboembolic events was not different between patients who received concomitant erythropoietin therapy and those who did not, 4.8% and 8.6%, respectively (P= .54). A higher number of venous thrombotic episodes occurred in the high-dose corticosteroid group compared with the low-dose corticosteroid therapy group (12% vs 6%), but the difference was not statistically significant (P= .3). CONCLUSIONS: The incidence of deep vein thrombosis is lower than previously reported in the literature. There was a trend to a higher incidence of thrombosis in patients receiving high-dose corticosteroid therapy.
Assuntos
Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Trombose Venosa/induzido quimicamente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/efeitos adversos , Dexametasona/uso terapêutico , Quimioterapia Combinada , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Incidência , Lenalidomida , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Agonistas Mieloablativos/uso terapêutico , Prednisona/uso terapêutico , Fatores de Risco , Taxa de Sobrevida , Talidomida/efeitos adversos , Trombose Venosa/prevenção & controleRESUMO
Recent studies have demonstrated that novel therapeutic combinations are challenging melphalan and prednisone (MP) as the standard of care in elderly patients with multiple myeloma. Combination regimens containing bortezomib or thalidomide can achieve response rates, especially complete response rates, which are superior to those seen with standard MP alone, and offer new possibilities for this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Bortezomib , Humanos , Melfalan/administração & dosagem , Prednisona/administração & dosagem , Pirazinas/administração & dosagem , Talidomida/administração & dosagem , Resultado do TratamentoRESUMO
Multiple myeloma (MM) is the second most common oncohematologic disease. Most patients are older than 65 years at diagnosis, and different therapeutic options are available depending on the age of the patient. For those younger than 65 years, autologous stem cell transplantation is the standard of care, whereas in older patients the better choice is conventional chemotherapy. The introduction of thalidomide, bortezomib, and lenalidomide, which target MM cells and the bone marrow microenvironment, has changed the therapeutic options in newly diagnosed patients with MM.
Assuntos
Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Idoso , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Bortezomib , Ensaios Clínicos como Assunto , Humanos , Lenalidomida , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/uso terapêutico , Transplante de Células-Tronco/métodos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Transplante Autólogo/métodosRESUMO
Melphalan is an alkylating agent approved for the treatment of multiple myeloma and ovarian cancer. The combination of oral melphalan and prednisone was first introduced in the 1960s and remains the standard therapy for elderly multiple myeloma patients. High-dose melphalan followed by autologous stem cell support became the standard treatment for younger patients since the 1990s. The occurrence of drug resistance is the major limiting factor for the long-term success of this therapy, and relapse always occurs. In recent years, advances in the understanding of the pathogenesis of myeloma and the mechanism of drug resistance have led to the development of novel targeted therapies that are able to overcome resistance and show additive or synergistic effects with melphalan. Thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous melphalan in younger patients, are changing the traditional treatment paradigm of multiple myeloma.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Melfalan/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , HumanosRESUMO
BACKGROUND: Baseline parameters that may be predictive of outcome after thalidomide treatment have been investigated to identify which myeloma patient subgroups will most benefit from this drug. METHODS: Thalidomide has been used as a salvage regimen at the study institution since 1999. A total of 102 myeloma patients who were diagnosed between January 1999 and February 2005 were evaluable for intention-to-treat analysis; 78 patients received thalidomide (at a dose of 100 mg/day continuously) and dexamethasone (at a dose of 40 mg/day on Days 1-4 each month) (TD) as salvage treatment whereas 24 patients died or were lost to follow-up before the initiation of TD. Several parameters such as serum beta2-microglobulin, serum C-reactive protein, immunoglobulin A isotype, hemoglobin, stage of disease, bone marrow plasmacytosis, age, serum creatinine, gender, stem cell transplantation at the time of diagnosis, and time to first disease progression were analyzed in association with overall survival (OS). RESULTS: The OS from the time of diagnosis was 43.8 months. Using univariate analysis, factors found to be associated with a shorter OS were a creatinine level > or =2 mg/dL (P = .05), stage III (P = .04), and time to first disease progression < or =12 months (P < .0001). The only factor that remained significantly associated with a shorter OS in multivariate models was time to first disease progression < or =12 months (P = .0006). Elevated serum beta2-microglobulin was not found to be predictive of poor OS. CONCLUSIONS: Time to first disease progression >12 months was found to be the best indicator of OS. Elevated serum beta2-microglobulin, generally considered to be a poor prognostic factor, was not found to be predictive of outcome.
Assuntos
Mieloma Múltiplo/tratamento farmacológico , Talidomida/uso terapêutico , Microglobulina beta-2/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína C-Reativa/análise , Creatinina/sangue , Dexametasona/administração & dosagem , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Terapia de Salvação , Análise de Sobrevida , Talidomida/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: Nearly all patients with multiple myeloma (MM) relapse or become refractory to front-line therapy. Several salvage therapies have been explored, but the optimal combination regimen has not been defined. We performed a case-matched study comparing patients with relapsed/refractory MM receiving thalidomide-dexamethasone alone or the combination thalidomide-dexamethasone-liposomal pegylated doxorubicin. METHODS: Forty-seven patients received thalidomide (100 mg/d), dexamethasone (40 mg p.o. on days 1-4 and 9-12), and pegylated liposomal doxorubicin (40 mg/m(2) on day 1 every 28 d) (ThaDD). Their clinical outcome was compared with that of 47 pair mates selected from patients treated at relapse with thalidomide (100 mg/d) and dexamethasone (40 mg p.o. on days 1-4) (Thal-Dex) and matched for age, beta2-microglobulin and previous therapy. RESULTS AND CONCLUSIONS: Overall response rate was significantly higher in ThaDD group (92% vs. 63.5%; P < 0.0001) as partial response rate (> or =PR) (75.5% vs. 59.5%; P = 0.077), very good partial response rate (> or =VGPR) (36% vs. 15%; P = 0.018) and near complete remission rate (> or =nCR) (30% vs. 10.5%; P = 0.002). Non-hematologic toxicity was similar in the two groups of patients whereas hematologic toxicity and infections were significantly higher in ThaDD patients. Median progression-free survival, event-free survival, and overall survival were significantly longer in patients receiving ThaDD than in those treated with Thal-Dex. ThaDD regimen significantly improved response rate and overall survival in comparison with Thal-Dex. Although the frequency of hematologic toxicity and infections resulted higher in ThaDD group compared with control group, they were not particularly frequent after adequate prophylaxis was added and were easily managed when occurred.