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1.
J Investig Med High Impact Case Rep ; 9: 23247096211058488, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34894809

RESUMO

Nodular localized cutaneous amyloidosis is a rare form of cutaneous amyloidosis and is characterized by an extracellular deposition of insoluble amyloid fibrils which are either primarily cutaneous or a manifestation of an underlying systemic amyloidosis. Biopsy of the lesion is mandatory for the diagnosis, and histopathology shows diffuse amyloid deposits with plasmacytic infiltration. Apple-green birefringence characteristic of amyloidosis is observed when stained with Congo red and viewed under polarized light. Amyloid subtyping is done with laser microdissection followed by mass spectrometry. Majority of these lesions do not require any treatment but surgical excision, shave excision, laser therapy, and radiotherapy can be considered for symptomatic nodular localized primary cutaneous amyloidosis (NLPCA). We present a case of recurrent NLPCA in a 64-year-old woman who was treated with bortezomib and dexamethasone after failing several local therapies with excellent response.


Assuntos
Amiloidose Familiar , Amiloidose , Amiloidose/tratamento farmacológico , Bortezomib/uso terapêutico , Dexametasona , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia
2.
J Pak Med Assoc ; 71(11): 2659-2661, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34783755

RESUMO

Multiple Myeloma is a clonal proliferation of plasma cells with bone marrow as the primary site of occurrence. Extramedullary multiple myeloma is uncommonly seen either at presentation or later during the course of the disease. Central nervous system involvement by multiple myeloma is an extremely rare entity with a dismal outcome. This case report focuses on a 45-year-old male who presented with bone aches. Investigation findings leading to the diagnosis included elevated calcium levels, lytic lesions on radiological examination and clonal plasma cells in bone marrow biopsy. During his treatment, the patient was given chemotherapy regimens containing Lenalidomide, Bortezomib, Cyclophosamide, and Prednisolone. Thereafter, he developed neurological complications (CNS myelomatosis), which resulted in his demise. The clinical presentation, diagnosis, treatment and outcome of this rare condition is detailed below.


Assuntos
Mieloma Múltiplo , Biópsia , Medula Óssea , Bortezomib/uso terapêutico , Sistema Nervoso Central , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico
3.
Zhonghua Zhong Liu Za Zhi ; 43(11): 1209-1214, 2021 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-34794226

RESUMO

Objective: To compare the clinical features, clinical efficacy, and prognosis of patients with double-hit and non-double-hit high-risk multiple myeloma (MM) and explored the clinical significance of high-risk cell karyotype in MM development. Methods: The clinical data of 73 high-risk MM patients admitted to the Department of Hematology of Fujian Provincial Hospital from January 2011 to February 2019 were retrospectively analyzed. Interphase fluorescence in situ hybridization was used to detect their karyotypes. Based on mSMART 3.0 risk stratification, we divided the patients into a double-hit group (28 cases) and a non-double-hit group (45 cases). Results: Fifteen patients in the double-hit group and 26 in the non-double-hit group received bortezomib-based chemotherapy. The median progression-free survival (PFS) in the double-hit and the non-double-hit groups was 8.0 months and 22.0 months, and the median overall survival (OS) was 10.0 months and not reached, respectively. Ten patients in the double-hit group and 12 in the non-double-hit group received bortezomib combined with lenalidomide (RVD) chemotherapy. The median PFS in the double-hit group and the non-double-hit group was 12.0 months and 24.0 months, and the median OS was 14.0 months and not reached, correspondingly. Both the PFS and OS of the double-hit group were significantly shorter than those of the non-double-hit group (P<0.05). Univariate analysis results indicated that cytogenetic abnormalities, revised-international staging system (R-ISS), ß2 microglobulin, and calcium had significant effects on PFS in high-risk MM patients (P<0.05). The cytogenetic abnormalities, R-ISS, and ß2 microglobulin were associated with OS in high-risk MM patients (P=0.001). Multivariate Cox regression analysis showed that the cytogenetic grouping was an independent prognostic factor for OS and PFS in high-risk MM patients. The risk of disease progression was 3.160 times (95% CI: 1.364-7.318) and the risk of death was 2.966 times higher (95%CI: 1.205-7.306) in the double-hit group than those in the non-double-hit group. Calcium was an independent risk factor for PFS in the high-risk MM patients. Notably, the risk of disease progression in patients with calcium levels≥ 2.75 mmol/L was 2.667 times higher than that in patients with calcium<2.75 mmol/L (95% CI: 1.209-5.883). Conclusions: Double-hit patients are a highly specific group with worse high-risk MM prognosis. In such patients, the relapse is more common, the disease progression is faster, and the survival time is shorter than those in the non-double-hit patients.


Assuntos
Mieloma Múltiplo , Bortezomib/uso terapêutico , Intervalo Livre de Doença , Humanos , Hibridização in Situ Fluorescente , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
4.
BMJ Case Rep ; 14(11)2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794974

RESUMO

Multiple myeloma (MM) patients live longer due to more effective treatment, and we now see previously uncommon manifestations of MM, like extramedullary disease. We present a case of a 74-year-old man known with MM that relapsed with extramedullary manifestations at different locations. One of them as a gastric plasmacytoma (GP). He was successfully treated with chemoradiotherapy (Daratumumab, Bortezomib and Dexamethasone), which resulted in clinical response for 8 months, confirmed by biopsy and histopathology. Perforation of the GP occurred, and he underwent partial gastrectomy (Billroth II gastrojejunostomy). The patient's disease progressed again 5 months after surgery, and he did not want any additional treatment. He accepted palliative care and died 10 months after the operation. A lack of knowledge about the characteristics and treatment of extramedullary MM exists, and prospective studies to investigate incidence, prognosis and treatment for extramedullary MM are needed for improving the poor prognosis of this manifestation.


Assuntos
Mieloma Múltiplo , Plasmocitoma , Idoso , Bortezomib/uso terapêutico , Humanos , Masculino , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia , Estudos Prospectivos
5.
Medicine (Baltimore) ; 100(41): e27521, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731142

RESUMO

ABSTRACT: To investigate the effect of a combined immune score including the lymphocyte-to-monocyte ratio (LMR) and uninvolved immunoglobulin (u-Ig) levels on the prognosis of newly diagnosed multiple myeloma (NDMM) patients treated with bortezomib.Clinical data of 201 NDMM patients were retrospectively analyzed. Patients with LMR ≥ 3.6 and LMR < 3.6 were scored 0 and 1, respectively. Patients with preserved u-Ig levels, suppression of 1 u-Ig, and suppression of at least 2 u-Igs were scored 0, 1, and 2, respectively. The immune score, established from these individual scores, was used to separate patients into good (0-1 points), intermediate (2 points), and poor (3 points) risk groups. The baseline data, objective remission rate (ORR), whether receive maintenance treatment regularly and overall survival of patients before treatment were analyzed.The ORR of the good-risk group was significantly higher than that of the intermediate-risk group (75.6% vs 57.7%, P = .044) and the poor-risk group (75.6% vs 48.2%, P = .007). The multivariate analysis results showed that age ≥ 65 years, International Staging System stage III, platelet count ≤ 100 × 109/L, lactate dehydrogenase (LDH) > 250 U/L, serum calcium > 2.75 mmol/L, no receipt of regular maintenance treatment, LMR < 3.6, suppressed u-Igs = 1, suppressed u-Igs ≥ 2, intermediate-risk group and poor-risk group were independent predictors of poor overall survival.In the bortezomib era, the LMR, u-Ig levels, and the immune score play an important role in the prognosis of NDMM patients. Among them, the immune score showed the strongest prognostic value, and it could be a beneficial supplement for the early identification of high-risk patients.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Fatores Etários , Idoso , Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Cálcio/sangue , Estudos de Casos e Controles , Feminino , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Imunoglobulinas/efeitos dos fármacos , Imunoglobulinas/imunologia , L-Lactato Desidrogenase/análise , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/imunologia , Estadiamento de Neoplasias/métodos , Contagem de Plaquetas/estatística & dados numéricos , Contagem de Plaquetas/tendências , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco
6.
Leuk Res ; 110: 106710, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34619433

RESUMO

In order to investigate the efficacy of lenalidomide, bortezomib and dexamethasone (VRD) induction chemotherapy regimen combined with tandem autologous stem cell transplantation (ASCT) in treating multi-hit multiple myeloma (MM), we analyzed 252 cases of newly diagnosed MM treated with the bortezomib-containing induction chemotherapy from June 2016 to June 2019. According to the fluorescence in situ hybridization (FISH) results on diagnosis, the patients were divided into multi-hit MM group (47 cases), single-hit MM group (81 cases), and standard-risk group (124 cases). Our analysis showed that R-ISS stageⅢ in transplantation group and R-ISS stageⅢ, multi-hit and VGPR or above was not achieved at the fourth cycle of chemotherapy in non-transplantation group were independent factors for poor prognosis by univariate and multivariate analyses. Moreover, the overall response rate (ORR) of VRD induction chemotherapy group was significantly higher than that of the non-VRD group in the single-hit and multi-hit groups (P = 0.021, P = 0.032); In terms of ASCT, tandem-ASCT can significantly improve the 2-year PFS (77.8 ± 3.9 %) and OS (83.3 ± 5.6 %) of multi-hit MM (P = 0.024, P = 0.037), while single-ASCT only has a limited effect on PFS (61.5 ± 3.0 %) and OS (71.9 ± 4.5 %) (P = 0.115, P = 0.155).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/mortalidade , Quimioterapia de Indução/mortalidade , Mieloma Múltiplo/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Terapia Combinada , Dexametasona/administração & dosagem , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo
7.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638592

RESUMO

The development of neuropathy and of mood alterations is frequent after chemotherapy. These complications, independent from the antitumoral mechanism, are interconnected due to an overlapping in their processing pathways and a common neuroinflammatory condition. This study aims to verify whether in mice the treatment with the proteasome inhibitor bortezomib (BTZ), at a protocol capable of inducing painful neuropathy, is associated with anxiety, depression and supraspinal neuroinflammation. We also verify if the therapeutic treatment with the antagonist of the prokineticin (PK) system PC1, which is known to contrast pain and neuroinflammation, can prevent mood alterations. Mice were treated with BTZ (0.4 mg/kg three times/week for 4 weeks); mechanical allodynia and locomotor activity were evaluated over time while anxiety (dark light and marble burying test), depression (sucrose preference and swimming test) and supraspinal neuroinflammation were checked at the end of the protocol. BTZ treated neuropathic mice develop anxiety and depression. The presence of mood alterations is related to the presence of neuroinflammation and PK system activation in prefrontal cortex, hippocampus and hypothalamus with high levels of PK2 and PKR2 receptor, IL-6 and TNF-α, TLR4 and an upregulation of glial markers. PC1 treatment, counteracting pain, prevented the development of supraspinal inflammation and depression-like behavior in BTZ mice.


Assuntos
Afeto/efeitos dos fármacos , Bortezomib/farmacologia , Inibidores de Proteassoma/farmacologia , Fator de Crescimento do Endotélio Vascular Derivado de Glândula Endócrina/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Biomarcadores/metabolismo , Citocinas/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/tratamento farmacológico , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
Prog Brain Res ; 266: 195-209, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34689859

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is a primary human brain tumor with the highest mortality rate. The prognosis for such patients is unfavorable, since the tumor is highly resistant to treatment, and the median survival of patients is 13 months. Chemotherapy might extend patients' life, but a tumor, that reappears after chemoradiotherapy, is resistant to temozolomide (TMZ). Using postgenome technologies in clinical practice might have a positive effect on the treatment of a recurrent GBM. METHODS: T98G cells of human GBM have been used. Radiation treatment was performed with Rokus-M gamma-therapeutic system, using 60Сo as a source of radionuclide emissions. High-performance liquid chromatography-mass spectrometry was used for proteome analysis. Mass spectrometry data were processed with MaxQuant (version 1.6.1.0) and Perseus (version 1.6.1) software, Max Planck Institute of Biochemistry (Germany). Biological processes, molecular functions, cells locations and protein pathways were annotated with a help of PubMed, PANTHER, Gene Ontology and KEGG and STRING v10 databases. Pharmaceutical testing was performed in vitro with a panel of traditional chemotherapeutic agents. RESULTS: GBM cells proliferation speed is inversely proportional to the irradiation dose and recedes when the dosage is increased, as expected. Synthesis of ERC1, NARG1L, PLCD3, ROCK2, SARNP, TMSB4X and YTHDF2 in GBM cells, treated with 60Gy of radiation, shows more than a fourfold increase, while the synthesis level of PSMA2, PSMA3, PSMA4, PSMB2, PSMB3, PSMB7, PSMC3, PSMD1, PSMD3 proteins increases significantly. Traditional chemotherapeutic agents are not very effective against cancer cells of the recurrent GBM. Combination of TMZ and CCNU with a proteasome inhibitor-bortezomib-significantly increases their ability to eradicate cells of a radioresistant GBM. CONCLUSIONS: Bortezomib and temozolomide effectively destroy cells of a radioresistant recurrent human glioblastoma; proteome mapping of the recurrent GBM cancer cells allows to identify new targets for therapy to improve the treatment results.


Assuntos
Glioblastoma , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Nucleares/farmacologia , Proteínas Nucleares/uso terapêutico , Complexo de Endopeptidases do Proteassoma/farmacologia , Complexo de Endopeptidases do Proteassoma/uso terapêutico , Temozolomida/farmacologia , Temozolomida/uso terapêutico
9.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502538

RESUMO

The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system.


Assuntos
Bortezomib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina/metabolismo , Ubiquitinação , Animais , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Inibidores de Proteassoma/uso terapêutico , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo
10.
Rinsho Ketsueki ; 62(8): 1149-1159, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497202

RESUMO

Multiple myeloma has been known as an incurable disease; however, since the approval of bortezomib in Japan in 2006 as the treatment for relapsed and refractory multiple myeloma, novel agents such as immunomodulatory drugs (IMIDs) and antibodies have been introduced one after another. Hence, progression-free survival and overall survival rates have markedly improved, regardless of the transplantation indication, and we have entered an era of a possible cure. Now that long-term survival can be expected, some clinical issues exist: 1) when to start treatment, 2) what regimen to choose for initial treatment, 3) how to continue treatment including maintenance therapy, 4) what to do for supportive care, and 5) what to choose for relapse treatment. The answers to these questions should be revised year-by-year according to the evidence from new clinical trials. This paper will discuss the current state of knowledge based on the latest evidence on treatment strategies for patients with myeloma who are ineligible for transplantation.


Assuntos
Mieloma Múltiplo , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Humanos , Japão , Mieloma Múltiplo/tratamento farmacológico
11.
Rinsho Ketsueki ; 62(8): 1160-1166, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497203

RESUMO

Systemic AL amyloidosis is a disease wherein amyloid proteins derived from monoclonal immunoglobulin light chains produced by abnormal plasma cells are deposited in the tissues through the whole body and cause organ failure. The treatment aims to minimize treatment-related toxicity and mortality to achieve a deeper and more persistent hematologic response as early as possible. Stem cell transplantation is preferred; however, only 20% of patients are eligible. Patients are selected as per strict transplant indication criteria. Transplant-ineligible patients receive chemotherapy with high efficacy, such as melphalan/dexamethasone, bortezomib/cyclophosphamide/dexamethasone, and daratumumab/bortezomib/cyclophosphamide/dexamethasone. The prognosis of advanced cardiac amyloidosis remains poor, and delays in diagnosis are fatal. Early diagnosis and early treatment are important to prevent and minimize organ damage.


Assuntos
Amiloidose , Amiloidose de Cadeia Leve de Imunoglobulina , Amiloidose/diagnóstico , Amiloidose/tratamento farmacológico , Bortezomib/uso terapêutico , Dexametasona , Humanos , Cadeias Leves de Imunoglobulina , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Melfalan
13.
Cells ; 10(9)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34571936

RESUMO

Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells. In the current study, both transcriptome and metabolome analysis were performed to comprehensively evaluate the underlying mechanism. It was demonstrated that pretreating MM cells with DHA/EPA before bortezomib potently decreased the cellular glutathione (GSH) level and altered the expression of the related metabolites and key enzymes in GSH metabolism, whereas simultaneous treatment only showed minor effects on these factors, thereby suggesting the critical role of GSH degradation in overcoming bortezomib resistance in MM cells. Moreover, RNA-seq results revealed that the nuclear factor erythroid 2-related factor 2 (NRF2)-activating transcription factor 3/4 (ATF3/4)-ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway may be implicated as the central player in the GSH degradation. Pathways of necroptosis, ferroptosis, p53, NRF2, ATF4, WNT, MAPK, NF-κB, EGFR, and ERK may be connected to the tumor suppressive effect caused by pretreatment of DHA/EPA prior to bortezomib. Collectively, this work implicates GSH degradation as a potential therapeutic target in MM and provides novel mechanistic insights into its significant role in combating bortezomib resistance.


Assuntos
Biomarcadores Tumorais/metabolismo , Bortezomib/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Humanos , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Transdução de Sinais , Células Tumorais Cultivadas
14.
Lancet Oncol ; 22(10): 1378-1390, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34529931

RESUMO

BACKGROUND: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only. METHODS: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants. FINDINGS: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment. INTERPRETATION: Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy. FUNDING: Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco , Talidomida/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Dexametasona/efeitos adversos , Esquema de Medicação , Europa (Continente) , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Intervalo Livre de Progressão , Transplante de Células-Tronco/efeitos adversos , Talidomida/efeitos adversos , Fatores de Tempo , Transplante Autólogo , Adulto Jovem
15.
BMC Cancer ; 21(1): 994, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488679

RESUMO

BACKGROUND: Many clinical trials have assessed the effect and safety of monoclonal antibodies (MAbs) in combination with proteasome inhibitors or immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma (MM). The treatment outcomes of comparing different MAbs in combination with the above-mentioned agents remained unclear. We performed the meta-analysis to indirectly compare the effect and safety of MAbs targeting CD38, SLAMF7, and PD-1/PD-L1 in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for patients with MM. METHODS: We searched thoroughly in the databases for randomised controlled trials (RCTs) in which at least one of the three MAbs were included. We included eleven eligible RCTs with 5367 patients in the meta-analysis. Statistical analysis was carried out using StataMP14 and Indirect Treatment Comparisons software. RESULTS: We calculated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and relative risk (RR) for overall response rate, complete response (CR) or better, very good partial response (VGPR) or better, VGPR, partial response, stable disease, and grade 3 or higher adverse events among the three groups. The HRs for PFS of the CD38 group vs SLAMF7 group, CD38 group vs PD-1/PD-L1 group, and SLAMF7 group vs PD-1/PD-L1 group were 0.662 (95%CI 0.543-0.806), 0.317 (95%CI 0.221-0.454), and 0.479 (95%CI 0.328-0.699), respectively. The HR for OS of the CD38 group vs SLAMF7 group was 0.812 (95%CI 0.584-1.127). The RR for CR or better in the CD38 group vs SLAMF7 group was 2.253 (95%CI 1.284-3.955). The RR for neutropenia of the CD38 group vs SLAMF7 group was 1.818 (95%CI 1.41-2.344). CONCLUSIONS: Treatment with the CD38 group had longer PFS and better treatment response than that with the SLAMF7 or PD-1/PD-L1 group. In addition, the SLAMF7 group prolonged PFS compared with the PD-1/PD-L1 group and was associated with a lower incidence of grade 3 or higher neutropenia than the CD38 and PD-1/PD-L1 group. In conclusion, MAbs targeting CD38 are the best, followed by those targeting SLAMF7; MAbs targeting PD-1/PD-L1 are the worst when in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for the treatment of MM.


Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Glicoproteínas de Membrana/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , ADP-Ribosil Ciclase 1/imunologia , Antígeno B7-H1/imunologia , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Humanos , Fatores Imunológicos/uso terapêutico , Glicoproteínas de Membrana/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Prednisona/administração & dosagem , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia
16.
Sci Rep ; 11(1): 17681, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480060

RESUMO

Although multiple myeloma (MM) is still considered as an incurable disease by current standards, the development of several combination therapies, and immunotherapy approaches has raised the hope towards transforming MM into an indolent, chronic disease, and possibly achieving a cure. We tried to shed light on the expression of PD1 and different Microparticles (MPs) in MM and their interplay as a mechanism of resistance to standardized treatments, in addition, find their associations with prognostic factors of symptomatic MM. Thirty patients with newly diagnosed and chemotherapy naïve active MM, along with 19 healthy participants of comparable age and sex were recruited, after diagnosis of MM; blood samples were collected from both patients and controls for flow cytometric detection of CD4+, CD8+, CD4+PD1+, and CD8+PD1+T cells, total MPs, CD138+ MPs, and platelet MPs. MM patients had statistically significant higher levels of TMPs, CD138+ MPs compared to their controls, while PMPs exhibited no significant difference between both groups. Statistically significant higher percentages of CD8+, PD1CD8+, PD1CD4+T cells were detected in patients compared to controls, while the latter group had a significantly higher percentage of CD4+T cells than MM patients, patients who did not achieve complete response, had significantly higher percentages of PMPs, CD138+MPs, PD1+CD8+, PD1+CD4+, and CD8+T cells (cutoff values = 61, 10.6, 13.5, 11.3 and 20.1 respectively), (p-values = 0.002, 0.003, 0.017, 0.001 and 0.008 respectively). Microparticles and PD1 expressions were associated with proliferative potential and resistance to Bortezomib-based treatments, our results suggested that they played a crucial role in myeloma progression.


Assuntos
Antineoplásicos/uso terapêutico , Micropartículas Derivadas de Células/metabolismo , Mieloma Múltiplo/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Citometria de Fluxo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Resultado do Tratamento
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(8): 900-908, 2021 Aug 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34565737

RESUMO

Multiple myeloma (MM) is a highly heterogeneous malignant plasma cell disease. Proteasome inhibitors (PIs) are the first line of medicine for MM. Bortezomib, ixazomib, and carfilzomib are also widely used for MM. Marizomib, oprozomib, and KZR-616 are in clinical trials. However, the drug resistance of PIs in MM is still a problem. The mechanisms for PIs resistance to MM include ubiquitin-proteasome pathway, autophagy lysosome pathway, endoplasmic reticulum stress pathway, cell survival signal pathway, exosome-mediated resistance, and bone marrow microenvironment-mediated resistance.


Assuntos
Mieloma Múltiplo , Inibidores de Proteassoma , Autofagia , Medula Óssea , Bortezomib , Humanos , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Microambiente Tumoral
19.
Ann Hematol ; 100(11): 2745-2754, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34333665

RESUMO

The Vulnerable Elders Survey-13 (VES-13) is a well-studied simplified frailty screening tool for elderly patients in the oncology setting. We conducted a prospective clinical trial to evaluate the efficacy and safety of dose-adjusted treatment based on the VES-13 in transplant-ineligible patients with newly diagnosed multiple myeloma (MM). In the Fit group (VES-13 <3), patients were treated with 4 cycles of standard-dose VCD (bortezomib, cyclophosphamide, and dexamethasone) followed by 4 cycles of standard-dose VTD (bortezomib, thalidomide, and dexamethasone). In the Frail group (VES-13 ≥3), patients were treated with 4 cycles of reduced-dose VCD followed by 4 cycles of reduced-dose VTD. The median age was 75 years (66-86 years), and 34% of the cases were classified as PS 3. Among the Fit group (n=16), the overall response rate (ORR) was 87.5%. Among the Frail group (n=31), the ORR was 87.1%. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between the Fit and Frail groups (3-year PFS: 68.8% vs 53.3%, P = 0.658; 3-year OS: 70.0% vs 77.6%, P = 0.919). Personalized VCD-VTD sequential therapy based on the VES-13 was associated with high response rates and showed acceptable safety in elderly frail patients with MM. The study is registered as UMIN000011235.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso Fragilizado , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Hiponatremia/induzido quimicamente , Japão , Estimativa de Kaplan-Meier , Masculino , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Medicina de Precisão , Intervalo Livre de Progressão , Estudos Prospectivos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
20.
Cancer Invest ; 39(9): 777-782, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34344244

RESUMO

OBJECTIVE: Multiple myeloma is an incurable hematological malignancy. Currently, the use of proteasome inhibitors could be superior to chemotherapy-based regimen in the treatment of this disease. However, resistance to bortezomib combination therapy still occurs in some patients. So, this research work aims to assess CD69 and CD56 expression in these cases and their relation to the response to therapy. MATERIALS AND METHODS: Immunophenotyping by 4-color multi-parameter flow cytometry was carried out on 98 multiple myeloma cases. Clonal plasma cells were gated by co-expression of CD38 with CD138 with low SSC, negative or dim CD45. RESULTS: Double negative CD69 and CD56 (47.9%) multiple myeloma cases were associated with high serum ß2 microglobulin, creatinine, calcium and low serum albumin. There was also a significant correlation between the absence of these markers with osteolytic lesions and unfavorable cytogenetic t (4;14) (p < 0.001). Moreover, there was a highly significant correlation between CD69- and CD56- with non-response to bortezomib combination therapy in multiple myeloma patients (p < 0.0001). Regression analysis for the prediction of non- response to treatment in these cases using different prognostic indicators revealed that high serum ß2 microglobulin, unfavorable cytogenetic, advanced stage, and low expression of CD69 and CD56 were poor predictors of non-response. CONCLUSION: CD69 in association with CD56 could be an independent prognostic factor in multiple myeloma cases. It could be used in the routine laboratory assessment for refining stratification and timely therapeutic decision for highly cost therapy in developing countries.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antineoplásicos/uso terapêutico , Antígeno CD56/metabolismo , Lectinas Tipo C/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Idoso , Bortezomib/administração & dosagem , Feminino , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Prognóstico
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