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1.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070363

RESUMO

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor-bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Mieloma Múltiplo , Neoplasias Experimentais , Animais , Bortezomib/farmacologia , Linhagem Celular Tumoral , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Radioisótopos/farmacologia , Rádio (Elemento)/farmacologia
2.
Lancet Oncol ; 22(6): 801-812, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34087126

RESUMO

BACKGROUND: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. METHODS: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0-2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1-21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. FINDINGS: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60-72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4-20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3-19·3] vs 6·9 months [5·5-9·3]; hazard ratio 0·63 [95% CI 0·47-0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. INTERPRETATION: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. FUNDING: European Myeloma Network and Janssen Research and Development.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neutropenia/induzido quimicamente , Neutropenia/patologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Talidomida/administração & dosagem , Talidomida/efeitos adversos
3.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071917

RESUMO

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones' hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton's Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones' interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/química , Tirosina Quinase da Agamaglobulinemia/metabolismo , Biomarcadores Tumorais , Medula Óssea/metabolismo , Medula Óssea/patologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade , Microambiente Tumoral/efeitos dos fármacos
4.
Medicine (Baltimore) ; 100(18): e25784, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950974

RESUMO

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) have been used in the treatment of relapsed and refractory multiple myeloma (RRMM). The response rate and the depth of responses induced by anti-BCMA CAR-T cells are impressive. However, despite this, remissions are not sustained, and the majority of patients eventually relapse. PATIENT CONCERNS: Two patients with multiple myeloma (MM) were selected to enroll in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113) because they did not have the good effect after traditional treatment. One is a 48-year-old male patient who received a diagnosis of IgG lambda MM in June 2015, he has received 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and obtained a complete response (CR). Approximately 11 months later, the disease progressed. Subsequent treatment included regimens incorporating liposomal doxorubicin, bortezomib, and dexamethasone (3 cycles); the response was poor, and the disease kept progressing. Another 65-year-old female patient received a diagnosis of IgG lambda MM in September 2016, she has received induction therapy with 1 cycle of bortezomib and dexamethasone (VD) and 4 cycles of lenalidomide and dexamethasone, the response was poor. DIAGNOSIS: Both patients were diagnosed with RRMM according to the International Myeloma Working Group criteria. INTERVENTIONS: Both patients received infusions of anti-BCMA CAR-T cells following an induction chemotherapy regimen of cyclophosphamide and fludarabine. OUTCOMES: Both of them achieved a stringent CR at the 30th day with minimal residual disease-negative bone marrow by flow cytometry and serum monoclonal protein was undetectable at 4 and 10 months after cell transfusion. The CR has persisted in the 2 patients for >36 months. CONCLUSIONS: Our findings demonstrate the anti-BCMA CAR-T cell treatment is a feasible therapeutic option for patients with RRMM. Fewer early lines of treatment may be beneficial to maintain the efficacy of CAR-T cells. TRIAL REGISTRATION: ChiCTR-OPC-16009113.


Assuntos
Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento
5.
Int J Hematol ; 114(1): 3-7, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33999338

RESUMO

Multiple myeloma (MM) is still extremely difficult to cure, and new therapeutic drugs are needed. We recently found that integrin ß7 is constitutively activated in MM cells, and chimeric antigen receptor (CAR) T cells targeting activated integrin ß7 have a significant anti-MM effect. In this study, we performed flow cytometry analysis of the expression of activated integrin ß7 in bone marrow cells from 137 symptomatic MM patients. In 60/137 (44%) MM patients, activated integrin ß7 was detected in most MM cells (> 80% of MM cells were in the positive gate). Activated integrin ß7 was highly expressed in MM cells even in heavily treated patients. It also showed high expression in many CD38lo/-CD138-CD19+B cells, which reportedly include clonotypic B cells, in the bone marrow of MM patients. Taken together, these results suggest that CAR T-cell therapy targeting activated integrin ß7 has the potential to benefit many patients with relapsed or refractory MM.


Assuntos
Cadeias beta de Integrinas/análise , Mieloma Múltiplo/patologia , Idoso , Células da Medula Óssea/patologia , Feminino , Citometria de Fluxo , Humanos , Imunoterapia Adotiva , Masculino , Mieloma Múltiplo/terapia , Plasmócitos/patologia
6.
Lancet Haematol ; 8(6): e422-e432, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34048681

RESUMO

Background Lenalidomide maintenance improves progression-free survival for patients with multiple myeloma, although its optimal duration is unknown. Clearance of minimal residual disease (MRD) in the bone marrow results in superior outcomes, although its attainment or sustainment does not alter clinical decision-making. Studies that have evaluated MRD serially are limited in length. We therefore aimed to evaluate longitudinal changes in MRD-status (dynamics) and their association with progression-free survival in patients with multiple myeloma. METHODS: In this single-centre, single-arm, phase 2 study, we enrolled patients aged 18 years and older from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) who had newly diagnosed multiple myeloma following unrestricted frontline therapy and an Eastern Cooperative Oncology Group Performance Status of 2 or lower, including patients who started maintenance before study enrolment. All participants received lenalidomide maintenance at 10 mg for 21 days of 28-day cycles until progression or unacceptable toxic effects for up to 5 years on protocol. The primary endpoint was progression-free survival at 60 months per protocol and key secondary endpoints were MRD rates after completion of the 12th, 24th, and 36th cycle of maintenance and the association between progression-free survival and annual measurement of MRD status. MRD was assessed from first-pull bone marrow aspirates at baseline and annually by flow cytometry per International Myeloma Working Group criteria, (limit of detection of at least 1 × 10-5) up to a maximum of 5 years. Patients who completed at least four cycles of treatment were included in the analysis of the primary endpoint, and patients who had completed at least one dose of treatment on protocol were assessable for secondary endpoints. The study was registered at ClinicalTrials.gov, NCT02538198, and is now closed to accrual. FINDINGS: Between Sept 8, 2015, and Jan 25, 2019, 108 patients (100 evaluable for the primary endpoint) were enrolled. Median follow-up was 40·7 months (95% CI 38·7-45·0). At 60 months, progression-free survival was 64% (95% CI 52-79). Median progression-free survival was unreached (95% CI unreached-unreached). MRD dynamics were assessed using 340 MRD assessments done over 5 years for 103 evaluable patients. Patients who sustained MRD negativity for 2 years (n=34) had no recorded disease progression at median 19·8 months (95% CI 15·8-22·3) past the 2-year maintenance landmark. By contrast, patients who lost their MRD-negative responses (n=10) were more likely to progress than those with sustained MRD negativity (HR infinite; p<0·0001) and those with persistent MRD positivity (HR 5·88, 95% CI 1·18-33·33; p=0·015) at the 2-year landmark. Haematological and non-haematological serious adverse events occurred in 19 patients (18%). The most common adverse events of grade 3 or worse were decreased lymphocyte count in 48 (44%) patients and decreased neutrophil count in 47 (44%) patients. One death occurred on study due to sepsis and heart failure and was considered unrelated to the study drug. INTERPRETATION: Serial measurements of MRD allow for dynamic assessment of risk for disease progression. Early intervention should be investigated for patients with loss of MRD negativity. Sustained MRD positivity is not categorically an unfavourable outcome and might portend prolonged stability of low-level disease. FUNDING: Memorial Sloan Kettering and Celgene.


Assuntos
Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Administração Oral , Idoso , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Gradação de Tumores , Neoplasia Residual , Intervalo Livre de Progressão
7.
Int J Nanomedicine ; 16: 3141-3160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33994784

RESUMO

Introduction: Extracellular vesicles (EVs) are naturally secreted cellular lipid bilayer particles, which carry a selected molecular content. Owing to their systemic availability and their role in tumor pathogenesis, circulating EVs (cEVs) can be a valuable source of new biomarkers useful for tumor diagnosis, prognostication and monitoring. However, a precise approach for isolation and characterization of cEVs as tumor biomarkers, exportable in a clinical setting, has not been conclusively established. Methods: We developed a novel and laboratory-made procedure based on a bench centrifuge step which allows the isolation of serum cEVs suitable for subsequent characterization of their size, amount and phenotype by nanoparticle tracking analysis, microscopy and flow cytometry, and for nucleic acid assessment by digital PCR. Results: Applied to blood from healthy subjects (HSs) and tumor patients, our approach permitted from a small volume of serum (i) the isolation of a great amount of EVs enriched in small vesicles free from protein contaminants; (ii) a suitable and specific cell origin identification of EVs, and (iii) nucleic acid content assessment. In clonal plasma cell malignancy, like multiple myeloma (MM), our approach allowed us to identify specific MM EVs, and to characterize their size, concentration and microRNA content allowing significant discrimination between MM and HSs. Finally, EV associated biomarkers correlated with MM clinical parameters. Conclusion: Overall, our cEV based procedure can play an important role in malignancy biomarker discovery and then in real-time tumor monitoring using minimal invasive samples. From a practical point of view, it is smart (small sample volume), rapid (two hours), easy (no specific expertise required) and requirements are widely available in clinical laboratories.


Assuntos
Biomarcadores Tumorais/sangue , Vesículas Extracelulares/patologia , MicroRNAs/sangue , Mieloma Múltiplo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Vesículas Extracelulares/metabolismo , Feminino , Seguimentos , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/genética , Fenótipo , Prognóstico
8.
Nat Commun ; 12(1): 2559, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963182

RESUMO

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect "B cell-featured" plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.


Assuntos
Linfócitos B/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Recidiva Local de Neoplasia/genética , Microambiente Tumoral/imunologia , Idoso , Linfócitos B/citologia , Linfócitos B/imunologia , Linhagem da Célula , Evolução Clonal/genética , Estudos de Coortes , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Haplótipos , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Família Multigênica , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Mutação , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/imunologia , Proteínas Proto-Oncogênicas c-fos/sangue , Proteínas Proto-Oncogênicas c-jun/sangue , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Análise de Célula Única
9.
Acta Orthop Traumatol Turc ; 55(2): 159-165, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33847579

RESUMO

OBJECTIVE: This study aimed to assess the pain and functional status of patients who underwent various surgical interventions for the stabilization of selected multiple myeloma (MM) lesions in the extremities and pelvis and to investigate the rate of complications requiring reintervention. METHODS: Patients with MM who underwent various surgical interventions for the extremity or pelvic lesions were retrospectively reviewed. Change in the pain intensity was assessed using visual analogous scale (VAS) preoperatively, at the time of discharge, and at the final follow-up. Functional status was assessed using the musculoskeletal tumor society (MSTS) scoring system for both upper and lower extremities preoperatively and at the final follow-up. Postoperative complications requiring reintervention, including dislocation, loss of fixation/aseptic loosening of prosthesis, mechanical insufficiency, periprosthetic fracture, infection, or progression of the local disease, were recorded. RESULTS: A total of 49 (20 men and 29 women) previously (23) or newly (26) diagnosed patients with a mean age of 60.8±18.2 years were included in this study. Of these, 6 patients underwent multiple surgeries for different skeletal sites; in total, 57 procedures were performed. The mean follow-up was 47.7±21.63 months. The lesions were localized to the humerus (19), radius (1), pelvis (4), femur (30), and tibia (3). The surgical indications included therapy-refractory pain for 17 patients and pathological fractures due to progression of pre-existing lesions for 12 patients or newly diagnosed lesions with extensive bone destruction at initial presentation for 28 patients. Surgical procedures included prosthetic reconstruction in 32 patients, cement-augmented osteosynthesis in 9, and closed intramedullary nailing in 16. The mean VAS score decreased from 8.75±1.2 preoperatively to 3.21±1.56 at the time of discharge and 1.2±0.42 at the final follow-up. Although a significant decrease was detected between the preoperative and postoperative VAS scores at the time of discharge (p=0.0001), the decrease between the time of discharge and the final follow-up was statistically insignificant (p=0.086). The mean MSTS score significantly improved from 9.1%±6.4% (range: 0%-40%) preoperatively to 76%±14.9% (range: 40%-93.3%) at the final follow-up (p=0.0001). Significantly higher MSTS scores were obtained in the upper extremity than lower extremity/pelvis (p=0.04) and in isolated diaphyseal involvement than metaphyseal or articular involvement (p=0.032). A total of 11 complications requiring reintervention (19.2%) were observed, which included dislocation (3.5%), loss of fixation (5.2%), mechanical insufficiency (3.5%), infection (5.2%), and local tumor progression (1.7%). The rate of complications requiring reintervention was lower but statistically insignificant in the upper extremity (5%; 1/20) than lower extremity/pelvis (27%; 10/37) (p=0.076) and in isolated diaphyseal involvement (6.2%; 1/16) than metaphyseal or articular involvement (24.3%; 10/41) (p=0.079). CONCLUSION: Although different types of surgeries can achieve pain relief and good function in different anatomical localizations, better functional results with lower complication rates may be obtained following surgical management of MM lesions in the upper extremities and in diaphyseal localizations. LEVEL OF EVIDENCE: Level IV, Therapeutic Study.


Assuntos
Neoplasias Ósseas , Extremidades , Mieloma Múltiplo , Procedimentos Ortopédicos , Pelve , Complicações Pós-Operatórias , Reoperação , Idoso , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Extremidades/patologia , Extremidades/cirurgia , Feminino , Fixação Intramedular de Fraturas/efeitos adversos , Fixação Intramedular de Fraturas/métodos , Fraturas Espontâneas/etiologia , Fraturas Espontâneas/cirurgia , Estado Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Mieloma Múltiplo/cirurgia , Procedimentos Ortopédicos/efeitos adversos , Procedimentos Ortopédicos/métodos , Procedimentos Ortopédicos/estatística & dados numéricos , Dor Pós-Operatória/cirurgia , Pelve/patologia , Pelve/cirurgia , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/cirurgia , Reoperação/métodos , Reoperação/estatística & dados numéricos , Estudos Retrospectivos
10.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923357

RESUMO

The development and effectiveness of novel therapies in multiple myeloma have been established in large clinical trials. However, multiple myeloma remains an incurable malignancy despite significant therapeutic advances. Accumulating data have elucidated our understanding of the genetic background of the malignant plasma cells along with the role of the bone marrow microenvironment. Currently, the interaction among myeloma cells and the components of the microenvironment are considered crucial in multiple myeloma pathogenesis. Adhesion molecules, cytokines and the extracellular matrix play a critical role in the interplay among genetically transformed clonal plasma cells and stromal cells, leading to the proliferation, progression and survival of myeloma cells. In this review, we provide an overview of the multifaceted role of the bone marrow microenvironment in the growth and development of malignant plasma cells in multiple myeloma.


Assuntos
Medula Óssea/patologia , Mieloma Múltiplo/patologia , Plasmócitos/patologia , Microambiente Tumoral/imunologia , Animais , Medula Óssea/imunologia , Humanos , Mieloma Múltiplo/imunologia , Plasmócitos/imunologia
11.
Front Immunol ; 12: 618610, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717112

RESUMO

The benefit of autologous stem cell transplantation (ASCT) in newly diagnosed myeloma patients, apart from supporting high dose chemotherapy, may include effects on T cell function in the bone marrow (BM). We report our exploratory findings on marrow infiltrating T cells early post-ASCT (day+100), examining phenotype and T cell receptor (TCR) repertoire, seeking correlations with timing of relapse. Compared to healthy donors (HD), we observed an increase in regulatory T cells (CD4+FoxP3+, Tregs) with reduction in CD4 T cells, leading to lower CD4:8 ratios. Compared to paired pre-treatment marrow, both CD4 and CD8 compartments showed a reduction in naïve, and increase in effector memory subsets, suggestive of a more differentiated phenotype. This was supported by increased levels of several immune-regulatory and activation proteins (ICOS, PD-1, LAG-3, CTLA-4 and GzmB) when compared with HD. Unsupervised analysis identified a patient subgroup with shorter PFS (p=0.031) whose BM contained increased Tregs, and higher immune-regulatory markers (ICOS, PD-1, LAG-3) on effector T cells. Using single feature analysis, higher frequencies of marrow PD-1+ on CD4+FoxP3- cells and Ki67+ on CD8 cells were independently associated with early relapse. Finally, studying paired pre-treatment and post-ASCT BM (n=5), we note reduced abundance of TCR sequences at day+100, with a greater proportion of expanded sequences indicating a more focused persistent TCR repertoire. Our findings indicate that, following induction chemotherapy and ASCT, marrow T cells demonstrate increased activation and differentiation, with TCR repertoire focusing. Pending confirmation in larger series, higher levels of immune-regulatory proteins on T cell effectors at day+100 may indicate early relapse.


Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/etiologia , Receptores Imunológicos/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Biomarcadores , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Reconstituição Imune , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Receptores Imunológicos/metabolismo , Subpopulações de Linfócitos T/patologia , Transplante Autólogo , Resultado do Tratamento
12.
Am J Hematol ; 96(7): 854-871, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33725367

RESUMO

The median overall survival in multiple myeloma is rapidly approaching 10 years; however, in nearly a fifth of patients the prognosis remains poor. Therefore, the modern-day management of myeloma patients should be individualized, with a more intense and continuous approach in these high-risk patients. This includes first-line treatment based on multi-drug combinations employing the most effective drug combinations, upfront autologous stem cell transplantation (in eligible patients with tandem transplantation being a consideration), and maintenance based on proteasome inhibitor-based combinations. This paper reviews the results of recent retrospective analyses and clinical trials, but also gives a glance into the future by presenting the ongoing trials.


Assuntos
Mieloma Múltiplo/terapia , Animais , Antineoplásicos/uso terapêutico , Quimioterapia de Consolidação , Gerenciamento Clínico , Humanos , Quimioterapia de Indução , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Transplante de Células-Tronco
13.
Nat Commun ; 12(1): 1861, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767199

RESUMO

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n = 15) are characterized by later initiation in the patient's life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.


Assuntos
Genoma Humano/genética , Gamopatia Monoclonal de Significância Indeterminada/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo Latente/genética , Variações do Número de Cópias de DNA/genética , Progressão da Doença , Humanos , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/patologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Mieloma Múltiplo Latente/patologia , Sequenciamento Completo do Genoma
14.
ACS Appl Mater Interfaces ; 13(13): 14920-14927, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33755428

RESUMO

Minimal residual disease (MRD) provides an independent prognostic factor for multiple myeloma (MM) patients. However, clinical MRD assays suffer from highly invasive sampling, insufficient detection sensitivity, and high cost. Herein, a stiMulus-Responsive ligand-Decorated microfluidic chip (MRD-Chip) was developed for efficient capture and controlled release of circulating myeloma cells (CMCs) in the peripheral blood for noninvasive myeloma evaluation. The CD138 antibody-decorated herringbone chip with a disulfide linker was designed to enhance the collision probability between blood cells and capture antibodies, leading to high capture efficiency of CMCs. More importantly, the captured CMCs can be nondestructively released via a thiol-exchange reaction, allowing them to be used for subsequent cellular and molecular analysis. By fluorescence in situ hybridization assay, we successfully identified the cytogenetic abnormalities (chromosome 1q21 amplification and p53 deletion) of CMCs in clinical samples. Overall, with the merits of noninvasive sampling, high capture efficiency (70.93%), high throughput (1.5 mL/h), and nondestructive release of target cells (over 90% viability) for downstream analysis, our strategy provides new opportunities for myeloma evaluation, such as prognosis assessment, efficacy monitoring, and mechanism research of disease relapse and drug resistance.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/instrumentação , Técnicas Analíticas Microfluídicas/instrumentação , Mieloma Múltiplo/genética , Células Neoplásicas Circulantes/metabolismo , Linhagem Celular Tumoral , Separação Celular/instrumentação , Desenho de Equipamento , Humanos , Mieloma Múltiplo/patologia , Células Neoplásicas Circulantes/patologia
15.
Front Immunol ; 12: 552429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717057

RESUMO

Isolated central nervous system involvement in multiple myeloma (CNS-MM) is rare and carries extremely poor prognosis. Chimeric antigen receptor T cell therapy (CART) targeting B-cell maturation antigen (BCMA) is demonstrated as a promising strategy in MM treatment, but the clinical safety and efficacy of BCMA-CART against isolated CNS-MM remain elusive. Here we report on a 56-year-old male with refractory isolated CNS-MM who received autologous BCMA-CART therapy and developed grade 4 neurological complications. Cerebrospinal fluid (CSF) analyses showed significant expansion of CART cells and a substantially elevated interleukin-6 (IL-6) level. Intravenous methylprednisolone was administered and the symptoms resolved gradually. Unexpectedly, the level of IL-6 in the CSF was maintained for another 3 days even after the relief of the neurological symptoms. A partial response was achieved and sustained for 5.5 months. This is the first report describing a patient with isolated CNS-MM treated using BCMA-CART therapy. The results demonstrated that BCMA-CART cells administered intravenously trafficked into the CSF, eradicated tumor cells, and induced severe but reversible neurological adverse events. This single-patient report suggests that BCMA-CART therapy can be considered as an alternative option for isolated CNS-MM. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03196414.


Assuntos
Neoplasias do Sistema Nervoso Central/secundário , Imunoterapia Adotiva/efeitos adversos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/terapia , Antígeno de Maturação de Linfócitos B/imunologia , Biomarcadores , Neoplasias do Sistema Nervoso Central/diagnóstico , Glucocorticoides/uso terapêutico , Humanos , Imunoterapia Adotiva/métodos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Síndromes Neurotóxicas/diagnóstico , Receptores de Antígenos Quiméricos/imunologia , Avaliação de Sintomas , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
16.
Ann Hematol ; 100(7): 1789-1801, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33715037

RESUMO

Pleural effusion (PE) is prevalent in unselected "real-life" populations of multiple myeloma (MM). However, its prognostic value on MM is currently elusive. This study aimed to explore the role of PE on MM prognosis and to develop a novel prognostic nomogram for a cohort of Chinese patients with MM. Patients diagnosed with MM form 2000 through 2017 were retrospectively enrolled. PE was evaluated by chest computed tomography (CT) scans. Independent predictors of overall survival (OS) were identified using a multivariable Cox regression model performed on variables selected by the least absolute shrinkage and selection operator (LASSO) algorithm. A nomogram was constructed based on these variables. The concordance index (C-index) and the calibration curve were used to evaluate the predictive performance of the nomogram. Among 861 patients analyzed, 368 patients developed PE. Multivariate cox regression and restricted mean survival time (RMST) analyses revealed that patients with PE experienced worse OS vs. patients without PE. A nomogram predictive of OS was constructed using PE, plasma cell proportion, international staging system (ISS) stage, Charlson comorbidity index (CCI), 1q21 gain, and autologous hematopoietic stem cell transplantation (HSCT). The nomogram showed satisfactory discrimination in the derivation cohort (C-index=0.729) and the validation cohort (C-index=0.684), outperforming the Durie-Salmon (DS) and ISS staging systems. Moreover, the nomogram accurately classified patients into two distinct high- and low-risk groups. PE is frequently encountered in the disease course for MM patients. We derivated and validated a novel nomogram for MM based on PE, outperforming the DS/ISS staging systems.


Assuntos
Mieloma Múltiplo/mortalidade , Nomogramas , Derrame Pleural/epidemiologia , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Comorbidade , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Estadiamento de Neoplasias , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/etiologia , Derrame Pleural Maligno/diagnóstico por imagem , Derrame Pleural Maligno/epidemiologia , Derrame Pleural Maligno/etiologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Tomografia Computadorizada por Raios X , Resultado do Tratamento
17.
Am J Hematol ; 96(6): 690-697, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33735453

RESUMO

Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event-defined endpoints in 91 studies (60.3%) and response-based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re-analysis.


Assuntos
Mieloma Múltiplo/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Biomarcadores , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Humanos , Estudos Multicêntricos como Assunto/métodos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Neoplasia Residual , Intervalo Livre de Progressão , Qualidade de Vida , Análise de Sobrevida , Fatores de Tempo
18.
Am J Hematol ; 96(6): E193-E196, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33661527
19.
Ann Hematol ; 100(5): 1241-1249, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33660034

RESUMO

The objective of this study is to evaluate the prognostic features of multiple myeloma (MM) using whole-body low-dose computed tomography (WBLDCT). One hundred three patients with biopsy-proven MM who underwent WBLDCT were retrospectively enrolled. The evolution of osteolytic lesions overtime was performed by measuring the maximum axial diameter at the baseline (T0) and the end of follow-up (Te), by using a cut-off value of 10 mm. The location and dimension of up to three lesions were registered. The time-to-fracture (TTF) was recorded. Sixty-three percent of patients presented a focal pattern, 22% a diffuse pattern, and 15% a combined one. Seventy-two percent of patients with lesions ≤ 10 mm presented stability, 27% a dimensional increase, and 1% a decrease. Patients with lesions >10 mm showed a statistically significant difference regarding the mean difference of axial diameter between T0 and Te (p = 0.015). Patients with lesions >10 mm showed an odds ratio (OR) of 29.8 (95%CIs 3.8-230.5) to develop at least one fracture. Mean TTF was significantly lower in patients with lesions >10 mm in comparison with lesions ≤ 10 mm (9 ± 3 vs 23 ± 7 months, respectively, p = 0.011). WBLDCT represents a reliable imaging-based tool for proper management of MM patients, showing that diffuse form or small lytic lesions may deserve a less frequent follow-up.


Assuntos
Mieloma Múltiplo/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias/métodos , Doses de Radiação , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Imagem Corporal Total/métodos
20.
Ann Hematol ; 100(5): 1251-1260, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33686491

RESUMO

The prognostic value of chromosomal 1q21 gain in newly diagnosed multiple myeloma (NDMM) remains controversial. Add-on Myc aberrations may further worsen the outcome. To investigate whether specific genes located at the 1q21 region, such as myeloid cell leukemia 1 (Mcl-1), are involved in NDMM progression, we examined bone marrow cytogenetic abnormalities in 153 patients with NDMM by fluorescence in situ hybridization. Their response to treatment and survival was also analyzed. C-Myc and Mcl-1 expressions in bone marrow samples were analyzed by RT-PCR. The expression of Mcl-1 was evaluated in bone marrow sections by immunohistochemistry. MM cell lines were transfected with Mcl-1 siRNA. 1q21 gain was present in 55/153 (35.9%) patients and strongly associated with Myc rearrangement (31/153, 20.3%, P = 0.004). A positive correlation was observed between Myc and Mcl-1 mRNA levels in bone marrow cells from 47 patients (r = 0.57, P < 0.001). The combination of 1q21 gain and Myc rearrangement was associated with poorer overall survival than Myc rearrangement alone (16.8 vs. 27.9 months, P = 0.077) or 1q21 gain alone (16.8 vs. 60.7 months, P < 0.01). High Mcl-1 protein expression in bone marrow plasma cells was associated with Myc rearrangement. Mcl-1 silencing by siRNA inhibited Myc protein expression in three myeloma cell lines. Treatment with the small-molecule Mcl-1 inhibitor, UMI-77, produced similar results. Overall, the combination of Myc rearrangement and 1q21 gain was associated with particularly poor prognosis in patients with MM. Furthermore, our data are consistent with Mcl-1-dependent Myc protein activation.


Assuntos
Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Aberrações Cromossômicas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Prognóstico , RNA Mensageiro/genética
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