RESUMO
Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin protein. MM is the second most common haematological malignancy, with an increasing global incidence. It remains incurable because most patients relapse or become refractory to treatments. MM is a genetically complex disease with high heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumour cells and changes in the bone marrow microenvironment. Symptomatic MM is diagnosed using the International Myeloma Working Group criteria as a bone marrow infiltration of ≥10% clonal plasma cells, and the presence of at least one myeloma-defining event, either standard CRAB features (hypercalcaemia, renal failure, anaemia and/or lytic bone lesions) or biomarkers of imminent organ damage. Younger and fit patients are considered eligible for transplant. They receive an induction, followed by consolidation with high-dose melphalan and autologous haematopoietic cell transplantation, and maintenance therapy. In older adults (ineligible for transplant), the combination of daratumumab, lenalidomide and dexamethasone is the preferred option. If relapse occurs and requires further therapy, the choice of therapy will be based on previous treatment and response and now includes immunotherapies, such as bi-specific monoclonal antibodies and chimeric antigen receptor T cell therapy.
Assuntos
Mieloma Múltiplo , Mieloma Múltiplo/terapia , Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Humanos , Dexametasona/uso terapêutico , Lenalidomida/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/uso terapêutico , Talidomida/uso terapêutico , Talidomida/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Multiple myeloma (MM) patients complain of pain and stiffness limiting motility. To determine if patients can benefit from vertebroplasty, we assessed muscle activation and co-activation before and after surgery. Five patients with MM and five healthy controls performed sitting-to-standing and lifting tasks. Patients performed the task before and one month after surgery. Surface electromyography (sEMG) was recorded bilaterally over the erector spinae longissimus and rectus abdominis superior muscles to evaluate the trunk muscle activation and co-activation and their mean, maximum, and full width at half maximum were evaluated. Statistical analyses were performed to compare MM patients before and after the surgery, MM and healthy controls and to investigate any correlations between the muscle's parameters and the severity of pain in patients. The results reveal increased activations and co-activations after vertebroplasty as well as in comparison with healthy controls suggesting how MM patients try to control the trunk before and after vertebroplasty surgery. The findings confirm the beneficial effects of vertebral consolidation on the pain experienced by the patient, despite an overall increase in trunk muscle activation and co-activation. Therefore, it is important to provide patients with rehabilitation treatment early after surgery to facilitate the CNS to correctly stabilize the spine without overloading it with excessive co-activations.
Assuntos
Eletromiografia , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/cirurgia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Vertebroplastia/métodos , Músculo Esquelético/fisiopatologia , Músculo Esquelético/cirurgia , Coluna Vertebral/cirurgia , Coluna Vertebral/fisiopatologia , Tronco/fisiopatologia , Tronco/cirurgia , Tronco/fisiologiaRESUMO
Objective Follicular helper T cells (Tfh) drive proliferation and differentiation of B cells into plasma cells, leading to antibody production; however, their role in multiple myeloma (MM) is unknown. We aimed to determine the alteration of Tfh subsets and their clinical significance in patients with MM.Method Forty-nine patients with MM were recruited in this study, including 12 newly diagnosed patients, 10 relapsed patients, and 8 patients who received autologous hematopoietic stem cell transplantation (ASCT) from Zhejiang Provincial People's Hospital. Total CD4 + CXCR5 + CD25lowCD127intermediate-high Tfh cells, CXCR3 + CCR6-Tfh1 cells, CXCR3-CCR6-Tfh2 cells, and CXCR3-CCR6 + Tfh17 cells from the peripheral blood of these patients were analyzed by flow cytometry.Result Although total Tfh cells were not significantly changed in patients with MM compared to that in healthy controls (HCs), the Tfh17/Tfh ratio was significantly elevated in patients with MM compared to that in HCs (P = 0.0001). Importantly, relapsed patients had higher Tfh17/Tfh ratio than the newly diagnosed patients (P = 0.0077). Moreover, the Tfh17/Tfh ratio was significantly decreased in patients with MM who received ASCT (post-ASCT) when compared to that in HCs and non-ASCT patients (P < 0.0001), but no change was observed between post-ASCT patients and HCs (P = 0.7498).Conclusion The Tfh17/Tfh ratio was significantly elevated in patients with MM, especially in relapsed patients, indicating that Tfh17 cells may play a critical role in the clinical progression of MM.
Assuntos
Mieloma Múltiplo , Células Th17 , Humanos , Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/terapia , Células Th17/fisiologiaRESUMO
BACKGROUND: Multiple myeloma (MM) is a distinctive malignancy of plasma cell within the bone marrow (BM), of which alternative splicing factors play vital roles in the progression. Splicing factor arginine/serine-rich 8 (SFRS8) is the exclusive factor associated with MM prognosis, however its role in MM remains undefined. METHODS: The analyses of 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, immunohistochemistry, flow cytometry and xenograft model were performed to examine cell proliferation, cell cycle and apoptosis in SFRS8 overexpression or knockdown MM cells in vitro and in vivo. The SFRS8-regulated alternative splicing events were identified by RNA immunoprecipitation sequencing (RIP-seq) and validated by RIP-qPCR and Co-IP methods. Exosomes were extracted from the supernatant of myeloma cells by ultracentrifugation. Bone lesion was evaluated by TRAP staining in vitro and SCID/NOD-TIBIA mouse model. A neon electroporation system was utilised to deliver siRNA through exosomes. The effect of siRNA-loaded exosomes in vivo was evaluated by using a patient-derived tumor xenograft (PDX) model and SCID/NOD-TIBIA mouse model. RESULTS: SFRS8 was significantly upregulated in MM samples and positively associated with poor overall survival (OS) in MM patients. SFRS8 promoted MM cell proliferation in vitro and in vivo. Furthermore, calcyclin binding protein (CACYBP) was identified as the downstream target of SFRS8. Particularly, SFRS8 could reduce CACYBP isoform1 (NM_014412.3) and increase CACYBP isoform2 (NM_001007214.1) by mediating the alternative splicing of CACYBP, thereby altering the ubiquitination degradation of ß-catenin to promote MM progression. In addition, SFRS8 promoted osteoclast differentiation through exosomes in vitro and in vivo. More importantly, exosomal siRNA targeting CACYBP isoform2 inhibited tumour growth in PDX and SCID/NOD-TIBIA mouse models. CONCLUSION: Our findings demonstrate that targeting the SFRS8/CACYBP/ß-catenin axis may be a promising strategy for MM diagnosis and treatment.
Assuntos
Mieloma Múltiplo/genética , Neoplasias/etiologia , Fatores de Processamento de RNA/efeitos adversos , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/farmacologia , Linhagem Celular/efeitos dos fármacos , Humanos , Imunoquímica/métodos , Imunoquímica/estatística & dados numéricos , Estimativa de Kaplan-Meier , Mieloma Múltiplo/fisiopatologia , Neoplasias/genética , Neoplasias/fisiopatologia , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
INTRODUÇÃO: O mieloma múltiplo é uma neoplasia dos plasmócitos. Essas células neoplásicas proliferam na medula óssea impedindo o funcionamento das demais células hematológicas. As células neoplásicas produzem uma imunoglobulina monoclonal (proteína M) que é importante na fisiopatologia e no diagnóstico dessa doença. O mieloma múltiplo geralmente acomete adultos acima de 60 anos e estima-se que no Brasil a sua incidência anual esteja próximo à 1,2 indivíduos para cada 100.000 habitantes, com elevada letalidade. As manifestações clínicas mais comuns são dores ósseas, anemia e infecções recorrentes. As alterações mais comuns em exames de imagem e de laboratório incluem lesões líticas nos ossos, exames associados com insuficiência renal, hipercalcemia e anemia, além do achado da proteína M. Determinadas alterações citogenéticas estão associadas com o tratamento que deve ser instituído para o paciente e com o seu prognóstico. As alterações cromossômicas estudadas foram: t(4;14), del(17p13) e t(14;16). TECNOLOGIA: Citogenética por Hibridização in Situ por Fluorescência (FISH). PERGUNTA: Deve-se utilizar a citogenética por Hibridização In Situ por Fluorescência (FISH) versus citogenética convencional para detectar as alterações t(4:14), del(17p13) e t(14:16) em pacientes com mieloma múltiplo? EVIDÊNCIAS CLÍNICAS: Foi realizada busca de estudos que avaliassem a tecnologia nas bases de dados Embase, Medline (via Pubmed), Cochrane Library e LILACS. Após a triagem de 1346 relatos, 11 estudos observacionais foram selecionados. Nos domínios do QUADAS-2, a maioria dos estudos apresentou risco de viés incerto, exceto para o domínio Fluxo e Temporalidade, em que 81,8% dos estudos apresentaram baixo risco de viés. Os estudos incluídos analisaram uma amostra de 781 pacientes com mieloma múltiplo. Destes, 653 foram avaliadas pelo FISH e 719 pela citogenética convencional. A t(4;14) foi detectada em 11,3% (58/518) das amostras por FISH e 0,17% (1/607) por citogenética convencional. Os resultados da meta-análise mostraram que o FISH aumentou em 12% a detecção da t(4;14) quando comparado a citogenética convencional (RD: 0,12 [IC 95%: 0,06-0,19]; p < 0,0001; I2 : 52%). Em relação à del(17p13), esta foi detectada em 12,2% (80/653) das amostras por FISH e 1,6% (10/607) por citogenética convencional. O FISH aumentou em 12% a detecção da del(17p13) em comparação à citogenética convencional (RD: 0,12 [IC 95%: 0,04-0,20]; p < 0,0001; I 2 : 77%). Por fim, a t(14;16) foi detectada em 0,42% (2/478) das amostras por FISH e 0,17% (1/607) por citogenética convencional. Não houve diferença entre o FISH e a citogenética convencional para detecção da t(14;16) (RD: 0,00 [IC 95%: -0,01-0,02]; p = 0,41; I2 : 0%). A qualidade da evidência, avaliada pelo GRADE, foi considerada muito baixa para todos os desfechos avaliados. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Foram elaborados dois cenários, proposto e alternativo, considerando as estratégias de estadiamento incluindo FISH e citogenética convencional, variando a porcentagem de pacientes submetidos ao teste citogenético por FISH. A incorporação do FISH para o estadiamento dos pacientes com mieloma múltiplo pode provocar um incremento orçamentário em R$239.206,38 para o primeiro ano (2022), atingindo R$1.246.915,77 no quinto ano (2026), quando inicialmente 5% dos pacientes são submetidos ao FISH e ocorre aumento progressivo de 5% ao ano. O impacto em cinco anos seria de R$ 3.691.966,50. Quando inicialmente 10% dos pacientes diagnosticados com mieloma múltiplo são estadiados por meio do FISH, com o aumento progressivo de 10% ao ano, mantendo-se porcentagem constante para a citogenética convencional, o impacto orçamentário incremental seria de R$478.412,76 para o primeiro ano (2022), atingindo R$2.493.831,54 no quinto ano de incorporação (2026), sendo o valor acumulado em cinco anos de R$ 7.383.933,00. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: As pesquisas nas bases de dados para monitoramento do horizonte tecnológico identificaram três modelos de sonda para o painel FISH em pacientes com mieloma múltiplo no FDA. No Clinical Trials nenhuma nova tecnologia para avaliação citogenética foi identificada. Em relação ao depósito de patentes, foi encontrado um depósito patentário chinês do ano de 2019. PERSPECTIVA DO PACIENTE: Foi abertaâ¯chamada pública conjunta para Perspectiva do Pacienteâ¯durante o período de 18/10/2021 a 24/10/2021,â¯queâ¯contou com quinze inscrições, sendo oâ¯representanteâ¯definidoâ¯por consenso do grupo.â¯No relato, o participante descreveu aspectos da suaâ¯vivência como paciente comâ¯mieloma múltiplo, destacando a rapidez na obtenção de diagnóstico, a realização do transplante de medula óssea e o uso de diferentes tecnologias durante o tratamento.â¯â¯Além disso, informou ter tidoâ¯boa resposta terapêutica à lenalidomida durante cinco anos, em virtude da progressão da doença depois desse intervalo temporal, passou a utilizar protocolo com daratumumabe, apresentando melhora geral do quadro clínico. CONSIDERAÇÕES FINAIS: O teste FISH já é realizado pelo Sistema Único de Saúde (SUS) no diagnóstico de outras doenças. Neste Relatório, foi analisado a ampliação de uso deste exame para o diagnóstico de mieloma múltiplo. Pelos achados desta revisão, o teste FISH foi superior à citogenética convencional no diagnóstico das alterações citogenéticas t(4;14) e del(17p13), que são alterações relativamente frequentes e relevantes para o tratamento e o prognóstico dos pacientes com esse tipo de câncer. A alteração t(14;16), por ter baixa prevalência nos pacientes com esse tipo de câncer, demanda que ela seja analisada em uma amostra maior de indivíduos para que seja evidenciada uma diferença significativa entre os dois métodos. No Brasil, os laboratórios de referência para doenças raras possuem a infraestrutura necessária para a realização dos exames e seria necessária a ampliação do uso por meio do SUS. Do ponto de vista da implementação, a capacitação de recursos humanos é um fator de extrema importância, uma vez que a maioria destes laboratórios, atualmente, não possui pessoal capacitado especificamente para analisar amostras de pacientes com mieloma múltiplo. As agências internacionais NICE e CADTH recomendam a realização do FISH como parte dos exames diagnósticos necessários para o estadiamento citogenético e a tomada de decisão quanto a estratégia terapêutica a ser empregada diante da classificação de risco dos pacientes com mieloma múltiplo. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 104ª Reunião da Conitec, no dia 08 de dezembro de 2021, deliberaram, por unanimidade, sem nenhum conflito de interesses, que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à ampliação de uso do teste citogenético por Hibridização in Situ por Fluorescência (FISH) na detecção de alterações citogenéticas de alto risco em pacientes com mieloma múltiplo. CONSULTA PÚBLICA: Por meio da Consulta Pública nº 116/2021, realizada entre os dias 27/12/2021 e 17/01/2022, foram recebidas 73 contribuições, todas favoráveis à ampliação do uso do FISH para detecção de alterações moleculares de alto risco em pacientes com mieloma múltiplo. As evidências científicas apresentadas reforçaram a importância do FISH enquanto método de identificação destas alterações moleculares, para as quais a citogenética convencional possui baixa sensibilidade. Na avaliação econômica e de impacto orçamentário, foram apontadas possibilidades de redução do custo do exame com a utilização de menor número de sondas de hibridização, dependendo do nível de treinamento dos profissionais. Pacientes e associações enfatizaram a necessidade de garantir o acesso ao exame pelo SUS e, como pontos negativos, o alto custo do exame na rede privada e a indisponibilidade atual do exame no sistema público de saúde. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário presentes na 105ª Reunião da Conitec, no dia 09/02/2022, deliberaram, por unanimidade, sem nenhuma declaração de conflito de interesses, recomendar a ampliação de uso do teste citogenético por Hibridização in Situ por Fluorescência (FISH) na detecção de alterações citogenéticas de alto risco em pacientes com mieloma múltiplo. Foi assinado o Registro de Deliberação nº 695/2022. DECISÃO: Ampliar o uso do teste citogenético por Hibridização in Situ por Fluorescência (FISH) na detecção de alterações citogenéticas de alto risco em pacientes com mieloma múltiplo, no âmbito do Sistema Único de Saúde SUS, conforme a Portaria nº 20, publicada no Diário Oficial da União nº 49, seção 1, página 95, em 14 de março de 2022.
Assuntos
Humanos , Hibridização in Situ Fluorescente/instrumentação , Transtornos Cromossômicos/diagnóstico , Análise Citogenética/métodos , Mieloma Múltiplo/fisiopatologia , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economiaRESUMO
Multiple myeloma (MM) is characterized by malignant plasma cell infiltration of the bone marrow. In extramedullary multiple myeloma (EMD), a subclone of these cells migrates out of the bone marrow. Out of 4 985 MM patients diagnosed between 2005 and 2017 in the Czech Republic, we analyzed 234 secondary EMD patients to clarify risk factors of secondary EMD development. We found younger age [<65 years; odds ratio (OR) 4·38, 95% confidence interval (CI): 2·46-7·80, P < 0·0001], high lactate dehydrogenase (LDH) levels (>5 µkat/l; OR 2·07, 95% CI: 1·51-2·84, P < 0·0001), extensive osteolytic activity (OR 2·21, 95% CI: 1·54-3·15, P < 0·001), and immunoglobulin A (IgA; OR 1·53, 95% CI: 1·11-2·11, P = 0·009) or the non-secretory type of MM (OR 2·83; 95% CI: 1·32-6·04, P = 0·007) at the time of MM diagnosis to be the main risk factors for secondary EMD development. Newly diagnosed MM (NDMM) patients with subsequent EMD had inferior median progression-free (PFS) and overall (OS) survival when compared to NDMM patients without future EMD [mPFS: 13·8 months (95% CI: 11·4-16·3) vs 18·8 months (95% CI: 17·7-19·9), P = 0·006; mOS: 26·7 months (95% CI: 18·1-35·4) vs 58·7 months (95% CI: 54·8-62·6), P < 0·001]. We found that NDMM patients with specific risk factors associated with secondary EMD development have a more aggressive disease course before secondary EMD develops.
Assuntos
Mieloma Múltiplo/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de SobrevidaRESUMO
OBJECTIVES: This study aimed to develop and assess the content validity of a patient-reported outcomes (PROs) instrument to measure symptoms and impacts experienced by patients with active multiple myeloma (MM). METHODS: The PRO instrument was developed using an iterative, mixed-methods approach. The list of concepts was generated based on a review of existing evidence (qualitative studies and literature) and post hoc psychometric evaluations of 2 PRO instruments in 3 clinical trials. A total of 30 adult patients with MM from the United States participated in hybrid concept elicitation/cognitive debriefing interviews to validate the content validity of the newly developed PRO instrument. Translatability assessment was completed in 8 languages. RESULTS: The item generation process resulted in 17 symptom and 9 impact concepts for evaluation. The concept elicitation interviews and analysis were based on the first 25 participants; evidence of saturation was observed. The cognitive debriefing interviews and analysis were based on the last 23 participants across 4 waves of interviews. On the basis patient feedback, 10 items were removed, and 1 item was added to the PRO instrument. The translatability assessment resulted in 1 minor revision. The multiple myeloma symptom and impact questionnaire (MySIm-Q) includes 11 symptom and 6 impact concepts, organized within 8 hypothesized subdomains, with each concept measured using a 5-point verbal rating scale and a 7-day recall period. CONCLUSIONS: The MySIm-Q instrument was developed using rigorous and mixed methodology and with direct input from patients who received a diagnosis of MM. The MySIm-Q has good content validity and is culturally relevant for use in global clinical trials.
Assuntos
Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/psicologia , Medidas de Resultados Relatados pelo Paciente , Inquéritos e Questionários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa QualitativaRESUMO
The clinical utility of histone/protein deacetylase (HDAC) inhibitors in combinatorial regimens with proteasome inhibitors for patients with relapsed and refractory multiple myeloma (MM) is often limited by excessive toxicity due to HDAC inhibitor promiscuity with multiple HDACs. Therefore, more selective inhibition minimizing off-target toxicity may increase the clinical effectiveness of HDAC inhibitors. We demonstrated that plasma cell development and survival are dependent upon HDAC11, suggesting this enzyme is a promising therapeutic target in MM. Mice lacking HDAC11 exhibited markedly decreased plasma cell numbers. Accordingly, in vitro plasma cell differentiation was arrested in B cells lacking functional HDAC11. Mechanistically, we showed that HDAC11 is involved in the deacetylation of IRF4 at lysine103. Further, targeting HDAC11 led to IRF4 hyperacetylation, resulting in impaired IRF4 nuclear localization and target promoter binding. Importantly, transient HDAC11 knockdown or treatment with elevenostat, an HDAC11-selective inhibitor, induced cell death in MM cell lines. Elevenostat produced similar anti-MM activity in vivo, improving survival among mice inoculated with 5TGM1 MM cells. Elevenostat demonstrated nanomolar ex vivo activity in 34 MM patient specimens and synergistic activity when combined with bortezomib. Collectively, our data indicated that HDAC11 regulates an essential pathway in plasma cell biology establishing its potential as an emerging theraputic vulnerability in MM.
Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Plasmócitos/metabolismo , Animais , Inibidores de Histona Desacetilases/farmacologia , Humanos , Camundongos , Mieloma Múltiplo/fisiopatologiaRESUMO
Despite significant advances in the treatment of multiple myeloma which had led to unprecedented rates of response and survival, patients still relapse, and cure remains elusive. We propose in this review a roadmap to achieve the dream of cure for multiple myeloma based on five complementary strategies. First, to increase knowledge about disease pathogenesis with a focus on the biology of circulating tumor cells, responsible for dissemination and extramedullary disease, and minimal residual disease clones who represent the reservoir of clonal evolution and disease recurrence. Second, to consider undetectable measurable residual disease (MRD), defined by high-sensitive techniques, as the new endpoint of therapy. Third, to treat disease causation instead of symptomatology through early detection and intervention. Thereby, by treating high-risk smoldering myeloma patients early, we may not only contribute to delay disease progression into active disease but also to increase the cure rates. Fourth, to use the most active scheme in standard-risk patients if the cure is in the horizon. Fifth, to investigate experimental therapies in newly diagnosed patients with high-risk MM, implementing early rescue intervention strategies with the goal of eradicating all tumor clones, and achieving minimal residual disease negativity.
Assuntos
Mieloma Múltiplo/patologia , Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/terapia , HumanosRESUMO
BACKGROUND: Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention. RESULTS: Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment. CONCLUSIONS: Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/administração & dosagem , Metiltransferases/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Resistência a Medicamentos/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/farmacologia , Humanos , Metiltransferases/administração & dosagem , Mieloma Múltiplo/fisiopatologiaAssuntos
Amiloidose , Dexametasona/administração & dosagem , Cadeias Leves de Imunoglobulina/sangue , Lenalidomida/administração & dosagem , Mieloma Múltiplo , Ossos Pélvicos , Amiloidose/sangue , Amiloidose/diagnóstico , Amiloidose/fisiopatologia , Exame de Medula Óssea/métodos , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Humanos , Imunoensaio/métodos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/fisiopatologia , Nefelometria e Turbidimetria/métodos , Paraproteinemias/diagnóstico , Ossos Pélvicos/diagnóstico por imagem , Ossos Pélvicos/patologia , Multimerização Proteica , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Primary myeloma (PM) cells are short-lived in conventional culture, which limited their usefulness as a study model. Here, we evaluated if three-dimensional (3D) culture can significantly prolong the longevity of PM cells in-vitro. We employed a previously established 3D model for culture of bone marrow mononuclear cells isolated from 15 patients. We assessed the proportion of PM cells, viability and proliferation using CD38 staining, trypan blue exclusion assays and carboxy fluorescein succinimidyl ester (CFSE) staining, respectively. We observed significantly more CD38+ viable cells in 3D than in conventional culture (65% vs. 25%, p = 0.006) on day 3. CFSE staining showed no significant difference in cell proliferation between the two culture systems. Moreover, we found that PM cells in 3D culture are more STAT3 active by measure of pSTAT3 staining (66% vs. 10%, p = 0.008). Treatment of IL6, a STAT3 activator significantly increased CD38+ cell viability (41% to 68%, p = 0.021). In comparison, inhibition of STAT3 with Stattic significantly decreased PM cell viability in 3D culture (38% to 17% p = 0.010). Neither IL6 nor Stattic affected the PM cell viability in conventional culture. This study suggests that 3D culture can significantly improve the longevity of PM cells in-vitro, and STAT3 activation can further improve their viability.
Assuntos
Medula Óssea/patologia , Técnicas de Cultura de Células , Sobrevivência Celular , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/fisiopatologia , Fator de Transcrição STAT3/metabolismo , ADP-Ribosil Ciclase 1/biossíntese , Idoso , Proliferação de Células , Células Cultivadas , Óxidos S-Cíclicos/farmacologia , Feminino , Fluoresceínas/farmacologia , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/citologia , Masculino , Glicoproteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Succinimidas/farmacologiaRESUMO
OBJECTIVES: To investigate the effect of surgical stabilization for patients with metastatic spinal disease on objective mobility metrics. METHODS: A retrospective chart review identified patients who had mechanical back pain from metastatic spinal disease and underwent spinal stabilization during 2017. Mobility metrics, the Activity Measure for Post-Acute Care (AM-PAC) inpatient mobility short form (IMSF) and the Johns Hopkins Highest Level of Mobility (JH-HLM), were reviewed. RESULTS: A total of 26 patients were included in the analysis with median hospital stay of 8 days. Preoperative JH-HLM scores were available for 17 patients with a mean score of 5.4, increasing to mean score of 6.6 at last follow-up (P = 0.036). Preoperative AM-PAC IMSF scores were available for 14 patients with a mean score of 19.4, decreasing slightly to a mean score of 18.7 at last follow-up (P = 0.367). Last follow-up with mobility metrics occurred a median of 6.5 days postoperatively (range: 3-66 days). Multivariable analysis showed that American Spinal Injury Association and Karnofsky Performance Status scores were significantly associated with both JH-HLM and AM-PAC mobility scores at last follow-up. A higher JH-HLM or AM-PAC score was significantly associated with direct home discharge and a higher AM-PAC score was associated with shorter hospital stay. CONCLUSIONS: Surgical stabilization for patients with mechanical back pain secondary to metastatic spinal disease might lead to an objective improvement in JH-HLM score. JH-HLM and AM-PAC scores may be correlated with length of hospital stay and discharge disposition. Future studies are encouraged to further characterize the role of these mobility metrics in the management plan of these patients.
Assuntos
Dor nas Costas/cirurgia , Carcinoma/cirurgia , Laminectomia , Mieloma Múltiplo/cirurgia , Sarcoma/cirurgia , Fusão Vertebral , Neoplasias da Coluna Vertebral/cirurgia , Atividades Cotidianas , Idoso , Dor nas Costas/etiologia , Dor nas Costas/fisiopatologia , Neoplasias da Mama/patologia , Carcinoma/complicações , Carcinoma/fisiopatologia , Carcinoma/secundário , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/cirurgia , Estudos de Coortes , Descompressão Cirúrgica , Feminino , Humanos , Avaliação de Estado de Karnofsky , Neoplasias Renais/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/secundário , Procedimentos Neurocirúrgicos , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Sarcoma/complicações , Sarcoma/fisiopatologia , Sarcoma/secundário , Neoplasias da Coluna Vertebral/complicações , Neoplasias da Coluna Vertebral/fisiopatologia , Neoplasias da Coluna Vertebral/secundárioRESUMO
BACKGROUND: B-cell maturation antigen (BCMA) is expressed on malignant plasma cells from patients with multiple myeloma (MM). These patients have higher levels of serum (s)BCMA than healthy subjects, and levels correlate with disease status. The half-life of sBCMA is only 24-36 h, and levels are independent of renal function. OBJECTIVE: We determined whether baseline sBCMA values, a ≥ 25% increase, and a ≥ 50% decrease during treatment predicted progression-free survival (PFS) and overall survival (OS) among 81 patients with relapsed/refractory MM (RRMM) starting new treatments. METHODS: Serum was obtained on day 22 of each patient's 28-day cycle of new therapy. Kaplan-Meier survival analysis and log-rank comparison tests were used to determine the effect of baseline sBCMA. The effect of percentage change in sBCMA was investigated using time-dependent Cox proportional hazard models. RESULTS: Patients with baseline sBCMA levels above the median had a shorter PFS (p = 0.0077), and those in the highest quartile had a shorter PFS (p = 0.0012) and OS (p = 0.0022). A ≥ 25% increase at week 4, week 8, and anytime through week 12 predicted a shorter PFS (p = 0.0011, p = 0.0005, and p < 0.0001, respectively). A ≥ 50% decrease at week 4, week 8, and anytime through week 12 predicted a longer PFS (p = 0.0045, p = 0.029, p = 0.0055, respectively). A ≥ 25% increase in sBCMA occurred before progression according to International Myeloma Working Group criteria in 67.5% of patients. CONCLUSIONS: Our results indicate the potential for the use of sBCMA as a new biomarker for monitoring patients with RRMM.
Assuntos
Antígeno de Maturação de Linfócitos B/sangue , Mieloma Múltiplo/sangue , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/fisiopatologia , Análise de SobrevidaAssuntos
Antineoplásicos Imunológicos/efeitos adversos , Agentes de Imunomodulação/efeitos adversos , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/efeitos adversos , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Agentes de Imunomodulação/uso terapêutico , Rim/fisiopatologia , Nefropatias/fisiopatologia , Masculino , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/fisiopatologia , Inibidores de Proteassoma/uso terapêutico , Estados Unidos/epidemiologiaRESUMO
Hyperviscosity syndrome is a clinical condition characterized by the slowing of blood flow through the vessels and it may be associated with several diseases. The nosographic classification of primary hyperviscosity conditions (Wells classification 1970) divided the primary hyperviscosity syndromes in polycythaemic, sclerocytemic and sieric. Recent and personal laboratory observations have highlighted an unexpected behaviour of the erythrocyte deformability observed in some haematological disorders such as polycythemia vera, multiple myeloma and monoclonal gammopathy of undetermined significance. The interest of this observation depends on the fact that up to now, according to the Wells classification, the hemorheological alteration present in PV was related to the increase of RBC mass while that present in MM and MGUS was attributable to the abnormality of plasma or serum viscosity only. Through an extensive research among the literature, using MEDLINE/PubMed to identify all published reports on the hyperviscosity syndromes, issues that until now have been dealt with separately will therefore be analyzed in a unique paper, allowing a global view. The aim of this paper is to provide some suggestions for reflection and emphasizing the need of a nosographic framework of hyperviscosity that, probably, deserves to be reviewed.
Assuntos
Viscosidade Sanguínea , Deformação Eritrocítica , Gamopatia Monoclonal de Significância Indeterminada/fisiopatologia , Mieloma Múltiplo/fisiopatologia , Policitemia Vera/fisiopatologia , Animais , Humanos , Modelos Cardiovasculares , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Policitemia Vera/sangue , Policitemia Vera/diagnósticoRESUMO
Immunoglobulin A (IgA)-albumin complexes may be associated with pathophysiology of multiple myeloma, although the etiology is not clear. Detailed structural analyses of these protein-protein complexes may contribute to our understanding of the pathophysiology of this disease. We analyzed the structure of the IgA-albumin complex using various electrophoresis, mass spectrometry, and in silico techniques. The data based on the electrophoresis and mass spectrometry showed that IgA in the sera of patients was dimeric, linked via the J chain. Only dimeric IgA can bind to albumin molecules leading to IgA-albumin complexes, although both monomeric and dimeric forms of IgA were present in the sera. Molecular interaction analyses in silico implied that dimeric IgA and albumin interacted not only via disulfide bond formation, but also via noncovalent bonds. Disulfide bonds were predicted between Cys34 of albumin and Cys311 of IgA, resulting in an oxidized form of albumin. Furthermore, complex formation prolongs the half-life of IgA molecules in the IgA-albumin complex, leading to excessive glycation of IgA molecules and affects the accumulation of IgA in serum. These findings may demonstrate why complications such as hyperviscosity syndrome occur more often in patients with IgA dimer producing multiple myeloma.
Assuntos
Imunoglobulina A/metabolismo , Mieloma Múltiplo/metabolismo , Albumina Sérica Humana/metabolismo , Idoso , Idoso de 80 Anos ou mais , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/química , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Mieloma Múltiplo/sangue , Mieloma Múltiplo/fisiopatologia , Oxirredução , Ligação Proteica , Multimerização Proteica , Albumina Sérica Humana/químicaAssuntos
Hematopoiese Clonal , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/fisiopatologia , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Quimioterapia de Manutenção , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Condicionamento Pré-Transplante , Transplante Autólogo , Trombose Venosa/induzido quimicamente , Trombose Venosa/etiologiaRESUMO
INTRODUCTION: Multiple myeloma (MM) is an incurable malignancy, marked by end-organ damage that is frequently irreversible. Progressive disease (PD) can be defined as morbid PD, associated with new-onset hypercalcemia, renal insufficiency, anemia, or lytic bone lesions (CRAB symptoms), or as asymptomatic biochemical progression. The frequency of morbid versus asymptomatic PD and its effect on survival is unknown. Our aim was to determine the incidence of morbid PD, and to evaluate if this influences survival. PATIENTS AND METHODS: Data from 2 phase III trials of transplant-ineligible patients with newly diagnosed MM were included in a post hoc analysis. RESULTS: Of 2082 patients enrolled, 1243 (59.7%) experienced PD. At first progression, 543 (43.7%) patients had morbid PD; 12 (2.2%) had hypercalcemia, 271 (49.9%) had renal insufficiency, 370 (68.1%) developed anemia, and 79 (14.5%) developed new or enlarged bone lesions. A total of 700 (56.3%) patients had asymptomatic PD. Patients with morbid PD had worse second progression-free survival (PFS) versus patients with asymptomatic biochemical PD (median second PFS, 11.5 months vs. 20.0 months; hazard ratio, 1.63; 95% confidence interval, 1.43-1.85; P < .0001) and worse overall survival (OS) (median OS, 23.2 months vs 39.3 months; hazard ratio, 1.51; 95% confidence interval, 1.30, 1.74; P < .0001). CONCLUSIONS: Morbid PD occurs frequently and is associated with inferior second PFS and OS. As CRAB symptoms may not reverse with therapy, morbid PD is a meaningful event, and its association with a shortened PFS adds validity to PFS as a relevant endpoint in patients with MM.