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1.
Ann Hematol ; 99(5): 1063-1072, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32248251

RESUMO

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6-36.7) and the median OS was 55.3 months (95% CI 51.6-NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Taxa de Sobrevida
2.
PLoS One ; 15(2): e0229469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084254

RESUMO

Treatment of transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM) requires a balance between disease control and maintaining quality of life (QoL). Patients value treatment-free remission periods in this incurable condition, as they are associated with better QoL. We set out to study clinical outcomes of consecutive TNE NDMM patients in routine care treated in Thames Valley Cancer Network between 2009 and 2017. The primary outcome was the evaluation of the treatment-free interval (TFI) after 1st and subsequent lines of therapy in the total cohort and in individual subgroups, according to age (≤75 vs. >75 years), and co-morbidities using Charlson Co-morbidity Index (CCI): mild: 0-2 vs. moderate: 3-4 vs. severe: ≥5). Secondary outcomes include response rates, overall survival (OS) and progression-free survival (PFS) between subgroups: according to age and according to co-morbidities. In a total cohort of 292 patients, median TFI (IQR) was longest after first-line therapy 6.9 months (1.4-16.9), reducing after second line therapy to 1.8 months (.7-6.9), and after third line therapy to 0.6 months (0.2-1.5). Median TFI followed the same trend across the different subgroups, by age (≤75, >75 years) and by CCI (0-2, 3-4, ≥5). Overall response rate (ORR) to first line therapy for total cohort was 67%, with responses categorised as complete response (CR): 21%, very good partial response: 16%, partial response: 30%, stable disease: 18%, and progressive disease: 8%. ORR in individual subgroups by age were (≤75: 70% vs. >75: 63%), and by CCI (0-2: 65% vs. 3-4: 71% vs. ≥5: 77%). Median OS and PFS for the total cohort were (30.2 months, 95% CI: 23.8-36.9), and (9 months, 95% CI: 7.9-9.8), respectively. Patients aged >75 years showed a significant reduction in OS and PFS compared to those ≤75 years of age: OS (49.0 vs. 22.4 months, p<0.0001, HR: 2.08, 95% CI: 1.5-2.8), PFS (9.7 vs. 8.0 months, p<0.01, HR: 1.47, 95% CI: 1.1-1.9). Median OS was significantly reduced with worsening co-morbidities: (CCI 0-2: 52.4 months vs. CCI 3-4: 33.0 months vs. CCI ≥5: 24.0 months, p = 0.01, HR: 1.43, 95% CI: 1.1-1.9). Median PFS was significantly reduced in the severely co-morbid subgroup (CCI 0-2: 9.4 months vs. CCI 3-4: 9.6 months vs. CCI ≥5: 7.1 months, p = 0.025, HR: 1.3, 95% CI: 1.0-1.6). This study demonstrated that first line therapy in the TNE NDMM setting resulted in the longest TFI which was modest at a median of 6.9 months, and decreased significantly following subsequent lines of therapy and across the different subgroups by age and by co-morbidities. Therapy objective should be to maximise the benefit of first line treatment. We envisage that the recent shift towards a continuous therapeutic approach will benefit TNE patients in view of improved survival data demonstrated by a number phase 3 trials. When continuous therapy is not appropriate due to patient choice or toxicities, an efficacious (not limited to thalidomide and bortezomib) but tolerable first line FDT strategy, which can maximise TFI and maintain a good QoL, remains a reasonable alternative approach.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Masculino , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/patologia , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Talidomida/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Reino Unido/epidemiologia
4.
Ann Hematol ; 99(3): 581-589, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31965271

RESUMO

Patients always have different responses to the same treatment due to the heterogeneity of multiple myeloma (MM). However, the relationship between monoclonal protein (M-protein) reduction rates during treatment and survival prognosis in MM patients remains controversial. We retrospectively analyzed 198 newly diagnosed MM patients who received regular bortezomib-based chemotherapy for at least 2 cycles and subsequent autologous stem cell transplantation (ASCT) plus continuous maintenance. The relationship between the early M-protein reduction rates and survival prognosis was evaluated. This study is the first to divide patients into three patterns, namely, A, B, and C, according to the M-protein reduction rate during the first two therapy cycles. The results showed that pattern B patients with progressive reduction in M-protein had better progression-free survival (PFS) and overall survival (OS) than did pattern A or C patients with precipitating or slow M-protein reduction (75.33 ± 18.81 versus 41.23 ± 9.13 or 26.60 ± 6.67 months; P < 0.001; 117.33 ± 18.44 versus 71.00 ± 10.06 or 39.73 ± 24.10 months; P = 0.003, respectively). In addition, biological analysis showed that pattern A + C patients had higher international staging system (ISS) stage III proportions (P = 0.008) and lactate dehydrogenase (LDH) elevations (P = 0.044) than pattern B patients. Furthermore, pattern A + C was a significant independent adverse parameter for PFS and OS (HR = 2.62, P = 0.001; HR = 2.15, P = 0.022, respectively). Thus, our results demonstrate that pattern A + C indicates an inferior survival prognosis in MM.


Assuntos
Bortezomib/administração & dosagem , Imunoglobulinas/sangue , Mieloma Múltiplo , Proteínas do Mieloma/metabolismo , Transplante de Células-Tronco , Adulto , Idoso , Autoenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Taxa de Sobrevida
5.
Ann Hematol ; 99(1): 137-145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31768675

RESUMO

The combinations of melphalan, bortezomib, and prednisolone (VMP) and of lenalidomide and dexamethasone (Rd) are standard treatment strategies for transplant-ineligible newly diagnosed multiple myeloma (NDMM). To make the most of these two strategies, we investigated the efficacy and feasibility of first-line treatment with 4 cycles of VMP followed by continuous Rd therapy in a multi-institutional phase 2 study in Japanese patients with transplant-ineligible NDMM. Thirty-six patients of median age 74 years old with NDMM initially received 35-day cycles of VMP: oral melphalan (6 mg/m2) and prednisolone (60 mg/m2) on days 1 to 4 and bortezomib (1.3 mg/m2) on days 1, 8, 15, and 22. After 4 cycles of VMP, treatment was switched to 28-day cycles of Rd, which was continued until disease progression or emergence of an unacceptable adverse event (AE) in 33 patients, while one patient who achieved CR after VMP continued VMP at the physician's discretion. The overall response rates after VMP and after Rd were 66.7% and 86.1%, including CR rates of 5.6% and 36.1%, respectively. In a median follow-up period of 34.3 months, the progression-free survival and overall survival rates at 3 years were 43.2% and 81.3%, respectively. Grade 3-4 hematological AEs included neutropenia (39% with VMP and 24% with Rd) and thrombocytopenia (11% with VMP and 3% with Rd). There was no death due to an AE. In conclusion, sequential therapy with VMP followed by Rd is effective and mostly feasible for transplant-ineligible NDMM. The study is registered as UMIN000034815.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Mieloma Múltiplo/diagnóstico , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Taxa de Sobrevida
7.
Lancet ; 395(10218): 132-141, 2020 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-31836199

RESUMO

BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. METHODS: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). INTERPRETATION: D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. FUNDING: Janssen Research & Development.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Bortezomib/administração & dosagem , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Prednisona/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Ásia , Bortezomib/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Europa (Continente) , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , América do Norte , Prednisona/efeitos adversos , América do Sul , Análise de Sobrevida , Resultado do Tratamento
8.
Ann Hematol ; 98(12): 2781-2792, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673775

RESUMO

Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity. The primary endpoint was the proportion of flow-negative patients. Molecular response was assessed if patients were flow-negative or in stringent complete response (sCR). By intention to treat, the overall response rate was 89%. Neither median progression-free survival nor overall survival (OS) has been reached. The OS at 3 years was 83%. Flow-negativity was reached in 53% and PCR-negativity in 28% of the patients. With a median follow-up of 27 months, 29 (36%) patients are still on lenalidomide and 66% of them have sustained flow-negativity. Lenalidomide maintenance phase was reached in 8/16 high-risk patients but seven of them have progressed after a median of only 6 months. In low- or standard-risk patients, the outcome was promising, but high-risk patients need more effective treatment approach. Flow-negativity with the conventional flow was an independent predictor for longer PFS.


Assuntos
Lenalidomida/administração & dosagem , Quimioterapia de Manutenção , Mieloma Múltiplo , Transplante de Células-Tronco , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoenxertos , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Taxa de Sobrevida
10.
Pharm Res ; 36(12): 176, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31686241

RESUMO

PURPOSE: This study aimed to explore the potential of sialic acid - related selectin targeting strategy in the treatment of leukemia and some solid tumors. We expected it could "actively" bind tumor cells and kill them, reducing non-specific toxicity to normal cells. METHODS: BOR-SA prodrug was synthesized by reacting an ortho-dihydroxy group in SA with a boronic acid group in BOR. Two kinds of leukemia cells (RAW264.7 and HL60 cells), one solid sarcoma cell model (S180 cells) and their corresponding normal cells (monocytes (MO), neutrophil (NE) and fibroblast (L929)) were selected for the in vitro cell experiments (cytotoxicity, cellular uptake, cell cycle and apoptosis experiments). The S180 tumor-bearing Kunming mice model was established for anti-tumor pharmacodynamic experiments. RESULTS: In vitro cell assay results showed that uptake of BOR-SA by HL60 and S180 cells were increased compared with the control group. BOR-SA induced a lower IC50, higher ratio of apoptosis and cell cycle arrest of tumor cells. In vivo anti-S180 tumor pharmacodynamics experiments showed that mice in the BOR-SA group had higher tumor inhibition rate, higher body weight and lower immune organ toxicity compared with the control group. CONCLUSIONS: sialic acid-mediated selectin targeting strategy may have great potential in the treatment of related tumors.


Assuntos
Antineoplásicos/farmacocinética , Bortezomib/farmacocinética , Leucemia/tratamento farmacológico , Ácido N-Acetilneuramínico/química , Pró-Fármacos/farmacocinética , Selectinas/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Bortezomib/administração & dosagem , Bortezomib/síntese química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Manitol/química , Manitol/metabolismo , Camundongos , Terapia de Alvo Molecular/métodos , Ácido N-Acetilneuramínico/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Selectinas/genética
11.
Lancet Haematol ; 6(12): e616-e629, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31624047

RESUMO

BACKGROUND: Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. METHODS: The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m2 subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS: Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related. INTERPRETATION: Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. FUNDING: Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Idoso , Bortezomib/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Terapia Neoadjuvante , Análise de Sobrevida , Resultado do Tratamento , Reino Unido/epidemiologia
12.
Medicine (Baltimore) ; 98(39): e17147, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574817

RESUMO

The study aims to examine the treatment effect and adverse reactions of patients with newly diagnosed MM receiving different bortezomib-based regimens.This was a retrospective study of patients with newly diagnosed MM and who were treated with bortezomib-based combined chemotherapy at the Department of Hematology of the 2 affiliated hospitals of Wenzhou Medical University between July 2009 and May 2016. Cox proportion hazard multivariate analyses were carried out to assess the differences in treatment effect and adverse events between standard (1.3 mg/m on days 1, 4, 8, 11) and weekly (1.6 mg/m on days 1, 8, 15) cohorts, as well as the differences between intravenous injection and subcutaneous injection therapy. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method and the log-rank test.Among the 117 patients, 78 patients were treated with bortezomib standard therapy and 39 patients were treated with bortezomib weekly therapy (all with intravenous injection). In all patients, the treatment strategy was not independently associated with PFS or OS. The patients in the weekly therapy group had less thrombocytopenia events than those in the standard therapy group. The subcutaneous route had similar treatment effect as the intravenous route, but the incidence of peripheral neuropathy was lower.The once-weekly bortezomib regimen was similar in effectiveness to standard therapy in treating patients with newly diagnosed MM, but the incidence of thrombocytopenia was lower with the weekly regimen compared with the standard regimen.


Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Idoso , Antineoplásicos/efeitos adversos , Bortezomib/efeitos adversos , China , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
13.
Ann Hematol ; 98(12): 2805-2814, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31620815

RESUMO

In the ALCYONE trial, daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) reduced the risk of disease progression or death by 50% versus bortezomib, melphalan, and prednisone (VMP) in patients with transplant-ineligible newly diagnosed multiple myeloma. Here, we report a subanalysis of East Asian patients from ALCYONE. After a median follow-up of 17.1 and 15.9 months for Japanese (n = 50) and Korean (n = 41) patients, respectively, median progression-free survival for D-VMP versus VMP was not reached (NR) versus 20.7 months in Japanese patients and NR versus 14.0 months in Korean patients. The overall response rate for D-VMP versus VMP was 96% versus 92% in Japanese patients and 91% versus 61% in Korean patients. Using next-generation sequencing, minimal residual disease negativity at 10-5 sensitivity for D-VMP versus VMP was 33% versus 8% among Japanese patients and 17% versus 0% among Korean patients. Rates of any grade and grade 3/4 pneumonia were consistent with the rates observed for the global safety population. Similar efficacy and safety findings were observed in the combined Japanese and Korean subgroup and ≥ 75 years of age subgroup. In conclusion, D-VMP was safe and efficacious in East Asian patients, consistent with the global ALCYONE population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Intervalo Livre de Doença , Extremo Oriente/epidemiologia , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Taxa de Sobrevida
14.
Ann Hematol ; 98(12): 2793-2803, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31650289

RESUMO

Multiple myeloma (MM) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies. Despite bortezomib is a promising new generation of drugs for MM, its clinical use is limited by peripheral neurotoxicity in the vast majority of patients, which can be severe and require a reduction of dose or even treatment withdrawal. Tumor necrosis factor-α (TNF-α), as the most important inflammatory factor, could induce the inflammatory response and expression of heparanase (HPSE), which may play a crucial role in peripheral neuropathy after chemotherapy. However, the role of TNF-α in bortezomib-induced peripheral neuropathy (BIPN) has not been reported. In this study, treatment-emergent neuropathy was assessed by total neuropathy score and electrophysiological examination. The expression level of TNF-α and HPSE were evaluated by enzyme-linked immunosorbent assay. The effects of anti-TNF-α on the evolution of neuropathy were tested in rat models of neurotoxicity. The results indicated that with the augment of cumulative dose of bortezomib, the incidence of neuropathy was increased. Moreover, bortezomib administration induced the expression of TNF-α. With the increased expression of TNF-α, neuropathy was exacerbated. TNF-α-induced expression of HSPE was secondary to the development of neuropathy. Co-administration of anti-TNF-α in bortezomib therapy has a potential neuroprotective effect on BIPN in rats. TNF-α participates in the pathogenesis of BIPN, which represents an attractive target for future therapeutic intervention.


Assuntos
Bortezomib/administração & dosagem , Glucuronidase/sangue , Mieloma Múltiplo , Proteínas de Neoplasias/sangue , Doenças do Sistema Nervoso Periférico , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ratos , Ratos Wistar
15.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 615-618, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642245

RESUMO

OBJECTIVE: To evaluate the clinical effect of bortezomib with different dose-frequency in the treatment of multiple myeloma. METHODS: 86 patients with multiple myeloma in our hospital from February 2011 to February 2017 were included in the study. The patients were randomly divided into the experimental group (43 cases) and the control group (43 cases). The patients in the control group were treated with high dose bortezomib (1.6 mg/m2) on day 1, day 8, day 15 and day 22, with 35 d as a chemotherapy cycle. The patients in experimental group was treated with low dose bortezomib (1.0-1.3 mg/m2) on day 1, day 4, day 8 and day 11, with 21 d as a chemotherapy cycle. The patients in both groups were given dexamethasone(40 mg/d) and doxorubicin (10 mg/m2) from day 1 to day 4, and thalidomide was given orally at the intervals of 6 chemotherapy cycles. The clinical effect and the incidence of adverse drug reactions were compared between the two groups. RESULTS: The overall response rate (ORR) and disease control rate (DCR) were 88.37% and 95.35% respectively in the experimental group, while those of the control group were 81.40% and 90.70% respectively. There was no significant difference in ORR and DCR between the two groups. In the incidence of leukopenia, thrombocytopenia and neutropenia showed no significant difference between the two groups. The incidences of grade Ⅲ to grade Ⅳ peripheral neuropathy, herpes zoster, fatigue and abdominal distension in the experimental group were 2.33%, 4.65%, 13.95% and 2.33% respectively, while those of the control group were 16.28%, 27.91%, 34.88% and 18.60% respectively. The differences of the above incidences between the two groups were significant (P < 0.05). All the patients were followed up for 24 months. There was no significant difference in the overall survival (OS) rate, progression-free survival (PFS) rate and cumulative recurrence rate between the two groups. CONCLUSIONS: The effect of bortezomib in the treatment of multiple myeloma was similar at different dose-frequency group. The patients treated with low dose bortezomib (day 1, day 4, day 8 and day 11) had the better tolerance and lower incidences of adverse drug reactions.


Assuntos
Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Humanos , Recidiva Local de Neoplasia , Resultado do Tratamento
16.
Crit Rev Oncol Hematol ; 143: 102-116, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31563077

RESUMO

Choice of treatment for newly diagnosed transplant-ineligible multiple myeloma poses a difficult task due to an ever-increasing plethora of different regimens. Attempting to clarify this subject, we performed a systematic review and Bayesian network meta-analysis of 29 randomized clinical trials, enrolling 14,533 patients, and comparing 25 different treatment regimens regarding overall survival(OS), progression-free survival(PFS), complete response(CR), overall response rate(ORR) and toxicity. Head-to-head comparisons for all regimens and ranking of best treatments are reported. OS analysis showed superiority of lenalidomide(R) and bortezomib(V) containing regimens over thalidomide(T) protocols (e.g. Rd/CTD-HR:0.7;95%CrI:0.53-0.93, VMP/TD-HR:95%0.45;CrI:0.29-0.69). Concerning PFS, daratumumab(D) plus V (Dara-VMP) showed superior results over R (e.g. Dara-VMP/MPR-HR:0.52;95%CrI:0.34-0.77), V plus T (Dara-VMP/VTd-HR:0.56;95%CrI:0.37-0.65) and T (Dara-VMP/CTD-HR:0.34;95%CrI:0.23-0.49) containing regimens. Also, VRd and VMPT-VT performed well over other regimens. Dara-VMP showed superior response rates over R (ORR Dara-VMP/MPR-RR:6.27;95%CrI:2.18-18.95, CR Dara-VMP/MPR-RR:1.53;95%CrI:1.21-1.96) and T (ORR Dara-VMP/MPT-T-RR:4.05;95%CrI:1.19-13.26, CR Dara-VMP/MPT-T-RR:1.42;95%CrI:1.09-1.85; ORR Dara-VMP/CTD-RR:2.72;95%CrI:1.2-6.31, CR Dara-VMP/CTD-RR:1.2;95%CrI:1.05-1.36) including a higher rate of complete remission even when compared to VRd (RR:1.29;95%CrI:1.01-1.66). A higher rate of grade 3-4 adverse events was found for RD and CPR (thrombotic); VTd, VTP and VMPT-VT (neurological); RD and VAD (infectious); MPR-R and VAD (hematological); Vd and VTd (gastrointestinal); VAD, VMPCc and RD (cardiovascular). These results confirm obsolescence of classical regimens (such as VAD and MP) while pointing out benefits in efficacy resulting from incorporation of quadruplets and triplets combining new agents (Dara-VMP, VRd and VMPT-VT) and supports current rational of treatment until progression or prohibitive toxicity, especially when including lenalidomide. Based on this data, we would recommended incorporation of strategies combining novel agents (monoclonal antibodies, immunomodulatory imide drugs and proteasome inhibitors) in triplets or quadruplets and/or those comprising long term use of lenalidomide as standard frontline treatments. Moreover, this study settles daratumumab's place as an attractive alternative for upfront treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Teorema de Bayes , Bortezomib/administração & dosagem , Intervalo Livre de Doença , Humanos , Lenalidomida/administração & dosagem , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Talidomida/administração & dosagem , Resultado do Tratamento
17.
Blood ; 134(16): 1337-1345, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31484647

RESUMO

Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients aged ≤65 years with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with IV busulfan + melphalan vs melphalan and posttransplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the rates of a very good partial response or better were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 × 10-6 sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade ≥3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade ≥2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01916252 and EudraCT as #2012-005683-10.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Indução/métodos , Mieloma Múltiplo/tratamento farmacológico , Terapia Neoadjuvante/métodos , Adulto , Idoso , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Quimioterapia Adjuvante/métodos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Transplante Autólogo
18.
Pediatr Hematol Oncol ; 36(7): 438-444, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31524044

RESUMO

Despite a high cure rate in childhood BCP-ALL, 20% of children still presents with relapse, mostly due to a persistent leukemic clone during the first-line treatment. In this context, obtaining a molecular remission is crucial for reaching a successful allogeneic hematopoietic stem cell transplantation. Bortezomib was effectively administered to children with resistant/relapsed (r/r) BCP-ALL. Moreover, high risk ALL is characterized by the increasing expression of CD20. For the first time we reported two children with r/r BCP-ALL who received a treatment schema including Bortezomib and Rituximab, achieving morphological and molecular remission. Children with high risk features, such as persistent minimal residual disease during induction, will benefit from this combination. Is it time to move toward the first line?


Assuntos
Bortezomib/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Rituximab/administração & dosagem , Aloenxertos , Criança , Humanos , Masculino
19.
Pharm Res ; 36(11): 160, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520196

RESUMO

PURPOSE: Bortezomib (BTZ) is a proteasome inhibitor used for multiple myeloma and mantle cell lymphoma treatment. BTZ's aqueous in solubility is the main hindrance in its successful development as a commercial formulation. The main objective of the present study is to develop and characterize folic acid-glycine-poly-L-lactic acid (FA-Gly4-PLA) based nanoformulation (NPs) to improve solubility and efficacy of BTZ. METHODS: BTZ loaded FA-Gly4-PLA NPs were prepared and characterized for size, zeta potential, in vitro studies such as release, kinetics modeling, hemolytic toxicity, and cell line-based studies (Reactive Oxygen Species: ROS and cytotoxicity). RESULTS: BTZ loaded NPs (BTZ-loaded FA-Gly4-PLA) and blank NPs (FA-Gly4-PLA) size, zeta, and PDI were found to be 110 ± 8.1 nm, 13.7 ± 1.01 mV, 0.19 ± 0.03 and 198 ± 9.01 nm, 8.63 ± 0.21 mV, 0.21 ± 0.08 respectively. The percent encapsulation efficiency (% EE) and percent drug loading (% DL) of BTZ loaded FA-Gly4-PLA NPs was calculated to be 78.3 ± 4.1 and 12.38 ± 2.1. The Scanning Electron Microscopy (SEM) showed that NPs were slightly biconcave in shape. The in vitro release of BTZ from FA-Gly4-PLA NPs resulted in the sustained manner. The prepared NPs were less hemolytic than BTZ. CONCLUSIONS: BTZ loaded Gly4-PLA NPs apoptotic index was found to be much higher than BTZ but lesser than BTZ loaded FA-Gly4-PLA against breast cancer cell lines (MDA-MB-231). ROS intracellular assessment assay indicated that BTZ and BTZ loaded FA-Gly4-PLA NPs exhibited higher ROS production. Conclusively, the BTZ loaded FA-Gly4-PLA NPs were able to encapsulate more BTZ than BTZ loaded Gly4-PLA NPs and were found to be more effective as per as in vitro anti-cancer effect is concerned.


Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Glicina/química , Nanocápsulas/química , Poliésteres/química , Antineoplásicos/química , Bortezomib/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Composição de Medicamentos/métodos , Feminino , Humanos
20.
Anticancer Res ; 39(9): 5003-5007, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519607

RESUMO

Incorporating bortezomib and/or lenalidomide in the management of plasmablastic lymphoma is an attractive option due to the reported high response rates. However, concerns about overlapping toxicities can deter clinicians from incorporating these novel agents into chemotherapy. In this case report we describe a patient with plasmablastic lymphoma, who received both lenalidomide and bortezomib as part of upfront treatment for a high-risk plasmablastic lymphoma. After completing intensive chemotherapy, the patient was transitioned to a regimen of daily lenalidomide and biweekly bortezomib to decrease the chance of relapse. This maintenance phase was given for 6 months and was well tolerated. Despite having multiple adverse risk factors, the patient remains in remission, 18 months following diagnosis.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Linfoma Plasmablástico/tratamento farmacológico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Bortezomib/administração & dosagem , Gerenciamento Clínico , Feminino , Humanos , Quimioterapia de Indução , Imagem por Ressonância Magnética , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Linfoma Plasmablástico/diagnóstico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
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