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1.
Expert Rev Hematol ; : 1-12, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32162982

RESUMO

Introduction: Multiple Myeloma (MM) is a very heterogeneous clonal plasma cell hematological malignancy for which new therapies and transplantation effectively improve Progression-free survival (PFS) and overall survival (OS). Maintenance seems to have made a significant contribution in achieving these advances, whereas the real role of consolidation is still controversial. Despite lenalidomide having been approved as maintenance therapy after autologous stem cell transplantation (ASCT), the optimal maintenance agent, drug combinations, schedules, and duration are still under investigation.Areas covered: This review summarizes data regarding maintenance and consolidation therapies for transplant-eligible patients, updating on the ongoing developments in this area. Papers published on PubMed and abstracts presented at the ASCO, ASH, and EHA meetings up to December 2019 were used.Expert opinion: The available studies demonstrate that maintenance therapy is very effective although results from ongoing clinical trials suggest that disease features and minimal residual disease (MRD) status may optimize the selection of agents, schedule, and duration of maintenance therapy. Consolidation with last-generation drugs seems to be more effective and it could replace transplantation in some subgroups of patients.

2.
Haematologica ; 105(1): 193-200, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31221778

RESUMO

Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15, P=0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months (P=0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41, P<0.001), in line with other prognostic factors. With the limits of the use of low sensitivity imaging techniques, that lead to an underestimation of extramedullary disease, we conclude that in patients treated with new drugs the detrimental effect of extramedullary disease at diagnosis is limited, that lenalidomide is effective as are proteasome inhibitors, and that these patients tend to acquire a more aggressive disease in later stages. (EUDRACT2005-004714-32, NCT01063179 NCT00551928, NCT01091831, NCT01093196, NCT01190787, NCT01346787, NCT01857115).

3.
Haematologica ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248973

RESUMO

Bortezomib-melphalan-prednisone and continuous lenalidomide-dexamethasone represent the standard treatment of transplant-ineligible, newly diagnosed, multiple myeloma patients. To date, no randomized trial has compared bortezomib-melphalan-prednisone to lenalidomide-dexamethasone, and there is no evidence of the optimal treatment for newly diagnosed multiple myeloma, particularly in high-risk cytogenetic patients (del(17p), t(4;14) or t(14;16)). We pooled together data from newly diagnosed myeloma patients treated with bortezomib-melphalan-prednisone or lenalidomide-dexamethasone induction followed by lenalidomide maintenance 10 mg enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate their efficacy in different patient subgroups, focusing on standard and high-risk cytogenetics. Overall, 474 patients were analyzed (bortezomib-melphalan-prednisone: 257 patients; lenalidomide-dexamethasone followed by lenalidomide maintenance: 217 patients). No difference in progression-free survival (Hazard Ratio: 0.96) and overall survival (Hazard Ratio: 1.08) was observed between bortezomib-melphalan-prednisone and lenalidomide-dexamethasone followed by lenalidomide in standard-risk, while a reduction in the risk of progression (Hazard Ratio: 0.54) and death (Hazard Ratio: 0.73) was seen in high-risk patients treated with bortezomib-melphalan-prednisone vs. lenalidomide-dexamethasone followed by lenalidomide. In particular, standard risk patients >75years benefited less from bortezomib-melphalan-prednisone than lenalidomide-dexamethasone followed by lenalidomide (Hazard Ratio for progression-free survival: 0.96; Hazard Ratio for overall survival: 1.81). In this non-randomized analysis, bortezomib-melphalan-prednisone and lenalidomide-dexamethasone followed by lenalidomide were equally effective in younger (≤75years), standard-risk patients, while older ones (>75years) benefited more from lenalidomide-dexamethasone followed by lenalidomide. In high-risk patients, bortezomib-melphalan-prednisone improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).

4.
Haematologica ; 104(8): 1640-1647, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30733270

RESUMO

Twice-weekly carfilzomib is approved at 27 and 56 mg/m2 to treat relapsed multiple myeloma patients. In the phase III study ARROW, once-weekly 70 mg/m 2 carfilzomib prolonged the median progression-free survival of relapsed multiple myeloma patients in comparison with twice-weekly 27 mg/m2 carfilzomib, without adding significant toxicity. Data were pooled from two phase I/II studies of newly diagnosed multiple myeloma patients who received nine induction cycles of carfilzomib (either 70 mg/m2 once-weekly or 36 mg/m2 twice-weekly), cyclophosphamide and dexamethasone, followed by carfilzomib maintenance. Overall, 121 transplant-ineligible patients with newly diagnosed multiple myeloma were analyzed (once-weekly, n=63; twice-weekly, n=58). We found no significant difference in median progression-free survival [35.7 months (95%CI: 23.7-not reached, NR) vs 35.5 months (95%CI: 24.3-NR); HR: 1.39; P=0.26] and 3-year overall survival [70% [95%CI: 59%-84%) vs 72% (95%CI: 60%-85%); HR: 1.27; P=0.5] between once-weekly and twice-weekly carfilzomib. From the start of maintenance, 3-year progression-free survival [47% (95%CI: 33%-68%) vs 51% (95%CI: 38%-70%); HR: 1.04; P=0.92] and overall survival [72% (95%CI: 58%-89%) vs 73% (95%CI: 59%-90%); HR: 0.82; P=0.71] were similar in the once- versus twice-weekly carfilzomib. The rate of grade 3-5 hematologic (24% vs 30%; P=0.82) and non-hematologic (38% vs 41%; P=0.83) adverse events was similar in the two groups. Once-weekly 70 mg/m2 carfilzomib as induction and maintenance therapy for newly diagnosed multiple myeloma patients was as safe and effective as twice-weekly 36 mg/m2 carfilzomib and provided a more convenient schedule. The trials are registered at clinicaltrials.gov identifiers: 01857115 (IST-CAR-561) and 01346787 (IST-CAR-506).

5.
J Hematol Oncol ; 12(1): 4, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626425

RESUMO

BACKGROUND: Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis. METHODS: Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-ß, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients' characteristics and with a group of non-MM patients as controls. RESULTS: No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response. CONCLUSION: FGF-2, HGF, VEGF, and PDGF-ß plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy. TRIAL REGISTRATION: Clinical trial information can be found at the following link: NCT01063179.

6.
J Antimicrob Chemother ; 74(4): 1062-1068, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649413

RESUMO

BACKGROUND: We evaluated the incidence of proven/probable invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP) in a 'real-life' setting of patients with AML receiving intensive consolidation therapy. METHODS: Cases of IA, observed during consolidation in adult/paediatric patients with AML between 2011 and 2015, were retrospectively collected in a multicentre Italian study. RESULTS: Of 2588 patients, 56 (2.2%) developed IA [43 probable (1.7%) and 13 proven (0.5%)]. IA was diagnosed in 34 of 1137 (2.9%) patients receiving no AP and in 22 of 1451 (1.5%) who were given AP (P = 0.01). Number-needed-to-treat calculation indicates that, on average, 71 patients should have received AP (instead of no AP) for one additional patient to not have IA. Initial antifungal therapy was 'pre-emptive' in 36 (64%) patients and 'targeted' in 20 (36%) patients. A good response to first-line therapy was observed in 26 (46%) patients, mainly those who received AP [16 of 22 (73%) versus 10 of 34 (29%); P = 0.001]. The overall mortality rate and the mortality rate attributable to IA by day 120 were 16% and 9%, respectively. In multivariate analysis, age ≥60 years (OR = 12.46, 95% CI = 1.13-136.73; P = 0.03) and high-dose cytarabine treatment (OR = 10.56, 95% CI = 1.95-116.74; P = 0.04) independently affected outcome. CONCLUSIONS: In our experience, AP appears to prevent IA from occurring during consolidation. However, although the incidence of IA was low, mortality was not negligible among older patients. Further prospective studies should be carried out particularly in elderly patients treated with high-dose cytarabine to confirm our data and to identify subsets of individuals who may require AP.

7.
Blood Rev ; 34: 84-94, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30683446

RESUMO

The introduction of new therapeutic agents in multiple myeloma (MM), including proteasome inhibitors, immunoregulatory drugs and monoclonal antibodies, has improved the outcomes of patients, but in parallel has changed the frequency and epidemiology of infections. Hence, the great strides in the indications and use of new active treatments for MM need parallel progresses on the best approach to prophylaxis and supportive therapy for infections. Moving from the recognition that the above issue represents an unmet clinical need in MM, an expert panel assessed the scientific literature and composed a framework of recommendations for optimal infection control in patients candidate to active treatment for MM. The present publication represents a consensus document from questionnaires and consensus meetings held during 2017. The issues tackled in the project dealt with: infectious risk assessment, risk management and prophylaxis, intravenous immunoglobulin replacement therapy, antiviral and antibacterial vaccination. Considering the lack of conclusive and/or enough large studies for certain topics several recommendations derived from the personal experience of the experts.


Assuntos
Controle de Infecções , /terapia , Mieloma Múltiplo/complicações , Anti-Infecciosos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Consenso , Gerenciamento Clínico , Prova Pericial , Humanos , Imunoglobulinas Intravenosas , Incidência , Controle de Infecções/métodos , /epidemiologia , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/terapia , Guias de Prática Clínica como Assunto , Pré-Medicação , Vacinas/uso terapêutico
8.
Cancer ; 125(5): 750-760, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561775

RESUMO

BACKGROUND: Minimal residual disease (MRD) is one of the most relevant prognostic factors in patients with multiple myeloma (MM); however, the impact of maintenance therapy on MRD levels remains unclear. Among patients with newly diagnosed MM (NDMM) who received lenalidomide maintenance until they developed disease progression, the role of MRD status as a predictor of progression-free survival (PFS) was evaluated by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) analysis. METHODS: Seventy-three patients with NDMM enrolled in the RV-MM-EMN-441 (clinical trials.gov identifier, NCT01091831) and RV-MM-COOP-0556 (clinicaltrials.gov identifier, NCT01208766; European Myeloma Network EMN02/HO95 MM Trial) phase 3 trials who achieved at least a very good partial response after intensification/consolidation were included. The median patient age was 57 years (interquartile range, 53-61 years), and all patients received lenalidomide maintenance until they developed progression. MRD was evaluated on bone marrow after intensification/consolidation, after 6 courses of maintenance, and every 6 months thereafter until clinical relapse using both ASO-RQ-PCR (sensitivity, 10-5 ) and MFC (sensitivity, from 10-4 to 10-5 ). RESULTS: After intensification/consolidation, 33 of 72 patients (46%) achieved a molecular complete response (m-CR), and 44 of 70 (63%) achieved a flow complete response (flow-CR). Almost 27% of patients who were MRD-positive after consolidation became MRD-negative during maintenance. After a median follow-up of 38 months, PFS was prolonged in patients who achieved negative MRD status during maintenance according to results from both ASO-RQ-PCR analysis (hazard ratio, 0.29; 95% confidence interval, 0.14-0.62; P = .0013) and MFC (hazard ratio, 0.19; 95% confidence interval, 0.09-0.41; P < .001). The impact of negative MRD status on PFS was similar in all subgroups (ASCT and no-ASCT; International Staging System stages I, II, and III; high-risk and standard-risk cytogenetics), and the two techniques were highly correlated. CONCLUSIONS: MRD status is a stronger predictor of PFS than standard risk factors, and lenalidomide maintenance further increases the rate of negative MRD results.


Assuntos
Fatores Imunológicos/administração & dosagem , Lenalidomida/administração & dosagem , Quimioterapia de Manutenção/métodos , Mieloma Múltiplo/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Humanos , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Resultado do Tratamento
9.
Crit Rev Oncol Hematol ; 132: 9-16, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30447931

RESUMO

BACKGROUND: Risk-adapted therapy is a common strategy in curable hematologic malignancies: standard-risk patients receive less intensive treatment, whereas high-risk patients require a more intensive approach. This model cannot be applied in multiple myeloma (MM), which is still incurable. Continuous treatment (CT) is a key strategy for MM treatment, since it improves duration of remission. However, the role of CT according to standard- or high-risk baseline prognosis remains an open question. PATIENTS AND METHODS: We performed a pooled analysis of 2 phase III trials (GIMEMA-MM-03-05 and RV-MM-PI-209) that randomized patients to CT vs fixed-duration therapy (FDT). RESULTS: In the overall patient population (n = 550), CT improved progression-free survival1 (PFS1) (HR 0.54), PFS2 (HR 0.61) and overall survival (OS) (HR 0.71) vs FDT. CT improved PFS1 both in R-ISS I (HR 0.49) and R-ISS II/III patients (HR 0.55). Four-year PFS1 was 38% in R-ISS II/III patients receiving CT and 25% in R-ISS I patients receiving FDT, with similar trends for PFS2 and OS. High-risk patients benefited more from proteasome-inhibitor plus immunomodulatory-based CT than immunomodulatory alone. CONCLUSION: Good prognosis patients receiving FDT lose their prognostic advantage over high-risk patients receiving CT and high-risk patients may benefit from more intensive maintenance including proteasome inhibitors and immunomodulators.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Mieloma Múltiplo/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Esquema de Medicação , Humanos , Mieloma Múltiplo/diagnóstico , Prognóstico
10.
Crit Rev Oncol Hematol ; 130: 27-35, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30196909

RESUMO

INTRODUCTION: Early toxic death (≤60 days of diagnosis) in elderly multiple myeloma (MM) patients is attributable to active disease, age and co-morbidities. Rate of early toxic deaths is 10% with conventional chemotherapy mainly due to infection and renal failure. Novel agents have improved MM outcome at the expense of newer toxicity. METHODS: We analyzed 1146 individual patient data to assess toxic deaths during induction treatment with first-generation novel agents thalidomide, lenalidomide, bortezomib. RESULTS: During first-line therapy, 119/1146 patients (10%) died for any cause, and 47/1146 (4%) due to toxicity, including 12/1146 (1%) early deaths. The 24-month cumulative incidence was 4.1% without any difference between bortezomib (18/503 patients, 4%) and lenalidomide (29/643patients, 5%; p = 0.31). Toxic deaths occurred in 34/1039 (3%) patients <80 years and 13/107 (12%) patients ≥80 years. Causes were cardiac events (28%), infections (26%) and vascular complications (15%). In a multivariate analysis, older age and unfavorable ISS stage increased the risk of death. CONCLUSION: First-generation novel agents significantly reduced toxic deaths compared to conventional chemotherapy. One third of deaths during first-line therapy were due to cumulative drug-related toxicities, thus supportive approaches and prevention strategies should be optimized. The higher mortality rate for toxicity in octogenarians confirms the need for a careful frailty assessment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Bortezomib/administração & dosagem , Humanos , Lenalidomida , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Resultado do Tratamento
11.
JAMA Oncol ; 4(10): 1389-1397, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098165

RESUMO

Importance: Several trials demonstrated the impact of novel agent-based maintenance in newly diagnosed multiple myeloma (NDMM), but there is no current evidence demonstrating the superiority of one regimen over the other, owing to the lack of direct/indirect comparisons. Objective: To analyze and compare the effectiveness of different maintenance regimens in NDMM via a network meta-analysis. Data Sources: We performed 2 independent searches in PubMed and Cochrane databases, and then we identified all the records registered after 1999 and on or before November 20, 2017. Study Selection: By blinded review, we identified prospective phase 3 randomized trials evaluating novel agent-based maintenance in patients with NDMM; the included studies compared at least 2 maintenance approaches; comparators included placebo and no maintenance. From 364 screened records, 11 studies were included. Data Extraction and Synthesis: We followed (independent extraction) the guidelines provided by the PRISMA Report and the EQUATOR Network. The evidence was synthesized using a network meta-analysis (NMA). To allow comparison of all treatments, no maintenance was selected as common comparator and the effect of placebo was assumed to be the same as no treatment. The best option was identified by a Bayesian consistency model based on hazard ratio (HR), 95% credible interval (CrI), probability of being the best treatment (PbBT), and median ranking distribution (MedR). Main Outcomes and Measures: Outcomes of interest were progression-free survival (PFS) and overall survival (OS). Results: Eleven trials and 8 treatments including a total of 5073 participants were included. By PFS analysis, lenalidomide-based regimens (lenalidomide-prednisone, lenalidomide alone) were identified as the most effective options (HR, 0.39 [95% CrI, 0.28-0.53] and 0.47 [95% CrI, 0.39-0.55], respectively; MedR, 1 and 2; overall PbBT, 74%). Four treatments (thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, thalidomide alone) showed an HR in favor of maintenance. By OS analysis, lenalidomide alone was identified as the best option (HR, 0.76; 95% CrI, 0.51-1.16; MedR, 2; PbBT, 38%), followed by bortezomib-thalidomide and bortezomib-prednisone. Similar features were noticed in the restricted network including transplant trials, in the sensitivity analysis, and in most of the prognostic subgroups. Conclusions and Relevance: Based on PFS and OS results of this NMA, lenalidomide maintenance appears to be the best treatment option, by synthesizing the available evidence of novel agent-based maintenance in the past 20 years.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Lenalidomida/administração & dosagem , Quimioterapia de Manutenção/métodos , Mieloma Múltiplo/diagnóstico , Meta-Análise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Leukemia ; 32(8): 1697-1712, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29880892

RESUMO

Multiple myeloma is a disease typical of the elderly, and, because of the increase in life expectancy of the general population, its incidence is expected to grow in the future. Elderly patients represent a particular challenge due to their marked heterogeneity. Many new and highly effective drugs have been introduced in the last few years and results from clinical trials are promising. Besides the availability of novel agents, a careful evaluation of elderly patients showed to be a key factor for the success of therapy. A geriatric assessment is a valid strategy to better stratify patients. In particular, different scores are available today to appropriately assess elderly patients and define their fitness/frailty status. The choice of treatment-transplantation, triplets, doublets, or reduced-dose therapies including novel agents-should depend on the patient's fitness status (fit, intermediate-fit or frail). Second-generation novel agents have also been evaluated as salvage therapy in the elderly, and these new agents certainly represent a further step forward in the treatment armamentarium for elderly patients with multiple myeloma.


Assuntos
Avaliação Geriátrica/métodos , Mieloma Múltiplo/terapia , Assistência Centrada no Paciente/normas , Guias de Prática Clínica como Assunto/normas , Idoso , Europa (Continente) , Humanos , Mieloma Múltiplo/diagnóstico
13.
Health Qual Life Outcomes ; 16(1): 127, 2018 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-29914509

RESUMO

BACKGROUND: Treatment decision-making in patients with relapsed/refractory multiple myeloma (RRMM) is challenging for a number of reasons including, the heterogeneity of disease at relapse and the number of possible therapeutic approaches. This study broadly aims to generate new evidence-based data to facilitate clinical decision-making in RRMM patients. The primary objective is to investigate the prognostic value of patient self-reported fatigue severity for overall survival. METHODS: This multicenter prospective observational study will consecutively enroll 312 patients with multiple myeloma who have received at least 1 prior line of therapy and are considered as RRMM according to the International Myeloma Working Group (IMWG) criteria. Eligible RRMM participants will be adults (≥ 18 years old) patients and will be enrolled irrespective of comorbidities and performance status. At the time of study inclusion, data to calculate the frailty score are to be available. Patients will be followed up for 30 months and patient-reported outcome (PRO) assessment is planned at baseline and thereafter at 3, 6, 12, and 24 months. The following PRO validated questionnaires will be used: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the EORTC QLQ-MY20 and the EORTC QLQ-INFO25. Satisfaction with care and preference for involvement in treatment decisions will also be evaluated. Clinical, laboratory and treatment related information will be prospectively collected in conjunction with pre scheduled PRO assessments. Cox regression analyses will be used to assess the prognostic value of baseline fatigue severity (EORTC QLQ-C30) and other patient-reported health-related quality of life parameters. DISCUSSION: Clinical decision-making in RRMM is a challenge and outcome prediction is also an important aspect to enhance personalized treatment planning. Given the paucity of PRO data in this population, this prospective observational study aims to provide novel information that may facilitate patients' management in routine practice. TRIAL REGISTRATION: This trial is registered as identifier NCT03190525 .


Assuntos
Tomada de Decisão Clínica , Protocolos Clínicos , Mieloma Múltiplo/psicologia , Qualidade de Vida/psicologia , Feminino , Humanos , Masculino , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/psicologia , Medidas de Resultados Relatados pelo Paciente , Satisfação Pessoal , Prognóstico , Estudos Prospectivos
14.
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
15.
J Clin Oncol ; 36(20): 2035-2043, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29394124

RESUMO

Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to < 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate, < 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/fisiopatologia , Insuficiência Renal/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos de Coortes , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Estudos Prospectivos , Diálise Renal , Insuficiência Renal/etiologia , Insuficiência Renal/terapia , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Talidomida/farmacocinética
17.
Future Oncol ; 14(4): 319-329, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29091475

RESUMO

Monoclonal antibodies (mAb) represent a new frontier to treat newly diagnosed and relapsed-refractory multiple myeloma (MM). Elotuzumab, an mAb targeted SLAM7 in the plasma cells and natural killer cells surface, is the first mAb approved for the treatment of relapsed-refractory MM in combination with lenalidomide and dexamethasone. This approval was the final result of several preclinical and Phase I-II clinical studies leading to ELOQUENT-2 Phase III trial that demonstrated that elotuzumab adds a significant and durable value to standard therapy, paved the way of this new treatment strategy for MM. In this review we will describe elotuzumab mechanisms of action, clinical pharmacology and clinical studies that have led to these developments.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/efeitos adversos , Ensaios Clínicos como Assunto , Dexametasona/uso terapêutico , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Recidiva , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/genética
18.
Expert Opin Pharmacother ; 19(2): 137-149, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29265901

RESUMO

INTRODUCTION: Multiple Myeloma (MM) is a complex and heterogeneous plasma cell disorder. Sub-clones present before therapy and clonal evolution during therapy make this disease more resistant and finally refractory. These findings make us aware of the difficulty to target MM with few agents. Multi-drugs therapies allow us to target more pathways and more sub-clones both at diagnosis and in advanced disease. AREAS COVERED: In this review, the authors focus on the effectiveness and tolerability of three drug regimens (triplet) in comparison with two drug regimens (doublet) and discuss their implications in the present and future of MM therapy. EXPERT OPINION: It has been demonstrated that triplet regimens are better than doublet in terms of response rate and PFS in newly diagnosed, relapsed-refractory MM and in most patient subgroups. Whether this translates into OS improvement needs further demonstration. However, achievement of MRD negativity in most newly diagnosed and, firstly, in a consistent proportion of relapsed-refractory MM patients is very encouraging in this respect. However, not all patients are able to tolerate all triplet combinations; therefore, the choice should be based on patient characteristics, besides disease features. Finally, cost of triplets may be an important limitation in some countries.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Compostos de Boro/uso terapêutico , Glicina/análogos & derivados , Glicina/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Oligopeptídeos/uso terapêutico , Transplante de Células-Tronco , Talidomida/uso terapêutico
20.
Curr Cancer Drug Targets ; 17(9): 769-781, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27659429

RESUMO

High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains the standard of care for patients younger than 65 years of age with multiple myeloma (MM). However, this therapeutic approach has undergone substantial advances in this last decade, mainly due to the introduction of new drugs such as thalidomide, lenalidomide and bortezomib. These new drugs, in different combinations, have shown to significantly increase response rates after induction therapy and ASCT. Moreover, the positive results obtained with these agents in consolidation and maintenance strategies after ASCT strongly support the concept of continuous therapy, whose ultimate goal is the long-term control of the disease and the improvement of outcome. Preliminary data from studies investigating next generation proteasome inhibitors, such as carfilzomib and ixazomib, used upfront as well as at subsequent therapeutic lines, demonstrate the possibility of achieving molecular remission in most of the patients. The deeper responses obtained with new drugcombinations questioned the role of ASCT, and large, ongoing, phase 3 trials will shed light on the role and the timing of ASCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/terapia , Transplante de Células-Tronco/métodos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoenxertos , Bortezomib/uso terapêutico , Ensaios Clínicos como Assunto , Quimioterapia de Consolidação/métodos , Humanos , Lenalidomida , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Transplante Autólogo/métodos
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