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1.
Clin Cancer Res ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34992070

RESUMO

PURPOSE: In this study, the addition of ixazomib to lenalidomide maintenance post- autologous stem cell transplant (ASCT) in 64 newly diagnosed multiple myeloma (NDMM) patients was evaluated based on the observed benefit of lenalidomide-only maintenance in prior studies. METHODS: Patients were started on maintenance therapy with lenalidomide and ixazomib within 60-180 days of stem cell infusion. RESULTS: Response rates deepened over time from baseline post-ASCT for 39 patients. The complete response (CR)/stringent CR rate was 43% and median overall survival was not reached with a median follow-up of 62 months (range 25-82 months). Median PFS (mPFS) for all patients was 73 months and has not been reached for those with ISS stage 1 disease. mPFS in 9 patients who had ISS stage 3 disease and 14 patients who had high-risk cytogenetics was 34 and 25 months, respectively. Twenty-two patients had progressive disease, while 19 patients continue to receive dual maintenance. The most common grade 3/4 adverse events included neutropenia, leukopenia, thrombocytopenia, lung infections, diarrhea, and maculopapular rash. Second primary malignancies occurred in 9 patients. Toxicity led to dose reductions in ixazomib and lenalidomide in 20 and 31 patients, respectively. Discontinuation of ixazomib due to toxicity occurred in 4 patients. Grade 1/2 neuropathy occurred in 22 patients and led to reduction or discontinuation of ixazomib in 2 patients. CONCLUSIONS: The addition of ixazomib to lenalidomide maintenance demonstrated a better than expected PFS compared with historical data using lenalidomide alone and was safe and tolerable.

2.
Leuk Lymphoma ; : 1-12, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686083

RESUMO

Standard-of-care for newly-diagnosed, autologous hematopoietic stem cell transplantation (auto-HCT)-eligible, multiple myeloma (MM) patients includes bortezomib, lenalidomide, and dexamethasone (VRD) induction followed by melphalan 200 mg/m2 (Mel200)-conditioned auto-HCT and lenalidomide maintenance. We completed a retrospective case series assessing outcomes of 187 MM patients who received this regimen at our institution. The 100-day non-relapse mortality incidence was zero. Before auto-HCT, 9.6 and 52.9% of patients achieved a complete response (CR) or ≥ very good partial response (VGPR), respectively. At day-100 post-transplant, 29.4 and 74.9% had achieved a CR/stringent-CR (sCR) or ≥ VGPR, respectively. At the last evaluation, 57.2% of patients had CR/sCR and 87.1% had ≥ VGPR. Median follow-up, progression-free survival (PFS), and overall survival (OS) were 63.2, 50, and 101.7 months, respectively. The 5-year PFS and OS were 43.1 and 79%. High-risk cytogenetics was associated with worse outcomes. This study illustrates that VRD induction, Mel200-conditioned auto-HCT, and lenalidomide maintenance are associated with good outcomes in MM.

5.
JBMR Plus ; 5(8): e10518, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34368608

RESUMO

Bone disease is common in patients with multiple myeloma (MM), which manifests as bone pain and skeletal-related events (SREs) such as pathological fractures and spinal cord compression. Myeloma bone disease (MBD) can adversely affect the quality of life of patients and have negative effects on morbidity and mortality. The pathogenesis of MBD is complex, and several factors are involved in the dysregulation of bone metabolism and uncoupling of bone remodeling, which result in net bone loss and devastating SREs. Broadly speaking, elevated osteoclast activity, suppressed osteoblast activity, and an aberrant marrow microenvironment play a role in MBD. Interaction of MM cells with the main bone cell osteocytes also promote further bone destruction. This review focuses on the role of bone-modifying agents in the prevention and treatment of MBD. The mainstay of MBD prevention are antiresorptive agents, bisphosphonates and denosumab. However, these agents do not play a direct role in bone formation and repair of existing MBD. Newer agents with anabolic effects such as anti-sclerostin antibodies, parathyroid hormone, anti-Dickkopf-1 antibodies, and others have shown potential in repair of MBD lesions. With the development of several new agents, the treatment landscape of MBD is likely to evolve in the coming years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

7.
Cancer ; 127(22): 4198-4212, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34314018

RESUMO

BACKGROUND: On the basis of the DREAMM-2 study (ClinicalTrials.gov identifier NCT03525678), single-agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple myeloma (RRMM) who received ≥4 prior therapies, including anti-CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM-2 after 13 months of follow-up among patients who received belamaf 2.5 mg/kg. METHODS: DREAMM-2 is an ongoing, phase 2, open-label, 2-arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti-CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee. RESULTS: As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty-one of 97 patients (32%; 97.5% confidence interval [CI], 21.7%-43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression-free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6-3.6 months), respectively. Response and survival outcomes in patients who had high-risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow-up. CONCLUSIONS: Extended follow-up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.

8.
Front Cardiovasc Med ; 8: 626414, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34268341

RESUMO

Introduction: Patients with systemic AL amyloidosis (AL) should be evaluated for cardiac amyloidosis (CA), as prognosis is strongly related to cardiac involvement. We assessed the characteristics of patients referred to cardiac magnetic resonance (CMR) with suspected CA from a cancer center and determine predictors of mortality/heart failure hospitalizations (HFH). Methods: Forty-four consecutive patients referred for CMR with suspected CA were retrospectively included. Variables collected included cardiac biomarkers, in addition to echocardiographic and CMR variables. Survival analyses were performed to determine which variables were more predictive of mortality and HFH. Results: Of the 44 patients included, 55% were females. 73% of patients were diagnosed with CA by CMR; 56% of them had an established diagnosis of AL. Patients with CA by CMR had higher native T1, higher extracellular volume (ECV) fraction, higher T2, less negative GLS by Echo, and higher troponin I and B-type natriuretic peptide (BNP). Kaplan-Meier survival analysis revealed that the following were predictive of mortality: an ECV ≥ 0.50 (p = 0.0098), CMR LVEF < 50% (p = 0.0010), T2/ECV ≤ 100 (p = 0.0001), and troponin I > 0.03 (p = 0.0025). In a stepwise conditional Cox logistic regression model, the only variable predictive of a composite of mortality and HFH was ECV (HR: 1.17, 95% CI = 1.02-1.34 p = 0.030). Conclusion: ECV seems to be an important biomarker that could be a predictor of outcomes in cardiac AL amyloidosis. In combination, CMR and serum cardiac biomarkers might help to establish prognosis in patients with CA.

9.
N Engl J Med ; 385(1): 46-58, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192431

RESUMO

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
10.
Ann Hematol ; 100(9): 2325-2337, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33970288

RESUMO

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum's deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos de Boro/uso terapêutico , Bortezomib/uso terapêutico , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Idoso , Feminino , Glicina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento
12.
Transplant Cell Ther ; 27(3): 243.e1-243.e6, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781521

RESUMO

Numerous genetic abnormalities affect treatment outcomes in multiple myeloma. The role of coexistent trisomy or hyperdiploidy and high-risk cytogenetic abnormalities (CGAs) is not well defined. We assessed the influence of overlapping genetic abnormalities in patients who received frontline autologous stem cell transplantation. A total of 491 consecutive patients between January 2009 and January 2016 were identified. High-risk CGAs included del(17p), t(4;14), t(14;16), and gain 1q21 by fluorescence in situ hybridization and del(13) by conventional cytogenetics. Thirty-two percent had a trisomy, 27% had a high-risk CGA, and 11% had both. Among patients with any trisomy, 3-year progression-free survival (PFS) and overall survival (OS) were 60% and 90%, respectively, compared to 25% and 65%, respectively, for patients with any high-risk CGA. Patients with co-existent trisomy and high-risk CGAs had 3-year PFS and OS of 43% and 89%, respectively, whereas those with isolated high-risk CGAs without trisomy had 3-year PFS and OS of 13% and 49%, respectively. The PFS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.1 to 3.3; P = .02) and OS (HR, 4.5; 95% CI, 1.5 to 13; P = .006) were worse for high-risk CGAs without versus those with concurrent trisomies. Our findings suggest a protective impact of trisomies in patients with high-risk CGAs and a potential need for revised risk stratification assessments to account for overlapping genetic abnormalities.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Hibridização in Situ Fluorescente , Mieloma Múltiplo/genética , Transplante Autólogo , Resultado do Tratamento
13.
Future Oncol ; 17(19): 2499-2512, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33769076

RESUMO

Aim: To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed. Results: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events. Conclusion: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1. Clinical trial registration: NCT02761187 (ClinicalTrials.gov).

15.
Blood Cancer J ; 11(2): 40, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602913

RESUMO

Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the 'efficacy' of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual's composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.


Assuntos
Mieloma Múltiplo/terapia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Gerenciamento Clínico , Humanos , Qualidade de Vida , Resultado do Tratamento
18.
Br J Haematol ; 193(1): 93-100, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33118614

RESUMO

Although new multiple myeloma (MM) therapies are effective in alleviating some disease-associated symptoms (e.g. bone pain, fatigue, functional decline), they can result in additional toxicities, further impacting health-related quality of life (HRQoL). Here, we compared HRQoL and safety of lenalidomide-bortezomib-dexamethasone [RVd (n = 445)], bortezomib-melphalan-prednisone [VMP (n = 77)] and Vd or VMP (n = 588) in patients with newly diagnosed MM (NDMM) from the Connect® MM Registry, a large, USA, multicentre, prospective observational cohort study. Functional Assessment of Cancer Therapy-Multiple Myeloma subscale, EuroQol-5D overall score and Bone Pain Inventory HRQoL scores were significantly improved with RVd versus Vd/VMP. Serious adverse event rates were similar in all groups. Treatment with RVd maintained HRQoL in this real-world, largely community-based population of patients with NDMM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/efeitos adversos , Bortezomib/uso terapêutico , Estudos de Casos e Controles , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Feminino , Humanos , Lenalidomida/efeitos adversos , Lenalidomida/uso terapêutico , Masculino , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Prospectivos , Qualidade de Vida/psicologia , Sistema de Registros , Segurança , Transplante de Células-Tronco/normas
19.
Mod Pathol ; 34(2): 327-335, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32908255

RESUMO

Gains or amplification (amp) of chromosome 1q21/CKS1B are reported to be a high-risk factor in myeloma. In this retrospective study, we analyzed the impact of CKS1B gain/amp on overall survival in the context of other genetic aberrations, such as TP53 deletion, FGFR3-IGH, IGH-MAF, MYEOV/CCND1-IGH, and RB1, as well as karyotype. The cohort included 132 myeloma patients with CKS1B gain/amp detected by fluorescence in-situ hybridization. There were 72 men and 60 women with a median age of 65 years (range 39-88 years). A normal, simple, or complex karyotype was observed in 39.5%, 5.4%, and 55% of patients, respectively. "Double hit," defined as CKS1B gain/amp coexisting with TP53 deletion, or "triple hit," defined as double hit plus t(4;14)FGFR3-IGH or t(14;16)IGH-MAF, were identified in 25 patients (18.9%) and five patients (3.8%), respectively. Double and triple hit were highly associated with a complex karyotype (p = 0.02). Ninety-nine patients (99/128, 77.3%) received stem cell transplantation. The median follow-up time was 48.2 months (range 2-104 months); 68 patients (51.5%) died, with a median overall survival of 58.8 months. Multivariate analysis (Cox model) showed that double hit with TP53 deletion (p = 0.0031), triple hit (p = 0.01), and complex karyotype (p = 0.0009) were each independently associated with poorer overall survival. Stem cell transplantation was associated with better overall survival, mainly in patients with a double or triple hit and complex karyotype (p = 0.003). These findings indicate that the inferior outcome of myeloma patients with CKS1B gain/amp is attributable to the high number of high-risk patients in this group. The prognostic impact of CKS1B gain/amp depends on the background karyotype and TP53 status.


Assuntos
Quinases relacionadas a CDC2 e CDC28/genética , Mieloma Múltiplo/genética , Proteína Supressora de Tumor p53/genética , Cariótipo Anormal , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Feminino , Amplificação de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estudos Retrospectivos
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