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PURPOSE: TIGIT blockade in our ex vivo models of bone marrow (BM) reduced the number of malignant plasma cells (PCs) in only half of patients with multiple myeloma (MM). Here we wanted to investigate whether increased expression of TIGIT ligands may inhibit T cell immune response promoting resistance to TIGIT blockade. EXPERIMENTAL DESIGN: We first characterized the number and phenotype of BM macrophages in the different stages of disease by multi-parameter flow cytometry. We assessed the effect of TIGIT ligands on PC survival performing experiments with ex vivo BM model and analyzed changes in gene expression by using Nanostring technology and real-time PCR. RESULTS: Frequency of BM macrophages was significantly decreased in MM which was accompanied by changes in their immunophenotype. Moreover, we found a higher number of malignant PCs in ex vivo BM cells cultured onto PVR and nectin-2 compared to control, suggesting that both ligands may support PC survival. In addition, presence of PVR, but not nectin-2, overcame the therapeutic effect of TIGIT blockade or exogenous IL-2. Furthermore, presence of exogenous IL-2 increased TIGIT expression on both CD4+ and CD8+ T cells and, indirectly, PVR on BM macrophages. Consistently, PVR reduced the number of cytotoxic T cells and promoted a gene signature with reduced effector molecules. CONCLUSIONS: IL-2 induced TIGIT on T cells in the BM where increased PVR expression resulted in cytotoxic T cell inhibition promoting PC survival and resistance to TIGIT blockade.
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Chimeric antigen receptor (CAR) T-cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M-protein. Quantitative immunoprecipitation mass spectrometry (QIP-MS) can accurately measure serum M-protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP-MS in 33 patients treated with the academic BCMA-directed CAR T-cell ARI0002h (Cesnicabtagene Autoleucel). QIP-MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)-based next-generation flow cytometry (NGF). Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP-MS(+)/BM-based NGF(-) showed a non-significant shorter median progression free survival than those with QIP-MS(-)/BM-based NGF(-). In summary, we show the first experience to our knowledge demonstrating that QIP-MS could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in MM.
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The 2/20/20 International Myeloma Working Group (IMWG) score is the most employed risk score in clinical practice to evaluate the risk of progression from smoldering multiple myeloma (SMM) to symptomatic multiple myeloma. However, it faces a serious limitation: The risk score is applied at diagnosis and cannot be reapplied. Since a dynamic accurate patient risk assessment for progression is necessary, we aimed to investigate whether the detection of an evolving pattern in serum M-protein (SMP) improves the identification of high-risk patients. Eighty-three patients diagnosed with SMM between 2011 and 2020 were included. Patients were initially classified applying the 2/20/20 IMWG score at baseline and later reclassified depending on the presence of an SMP evolving pattern into six groups. We regrouped the patients into three final risk groups: low-risk, intermediate-risk, and high-risk. The risk of progression at two years for the high-risk group was 88% and all patients had progressed at 4 years. The performance measurements were superior for the new 2/20/20-Evolving score independently for the detection of high-risk patients. We show that the sequential measurement of the SMP is a noninvasive and widely available test that improves the 2/20/20 IMWG risk score.
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PURPOSE: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. PATIENTS AND METHODS: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. RESULTS: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. CONCLUSIONS: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.
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Antígeno de Maturação de Linfócitos B , Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B/imunologia , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Adulto , Biomarcadores Tumorais , Receptores de Antígenos Quiméricos/imunologia , Resultado do TratamentoRESUMO
PURPOSE: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.
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Antígeno de Maturação de Linfócitos B , Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/imunologia , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Feminino , Idoso , Imunoterapia Adotiva/métodos , Antígeno de Maturação de Linfócitos B/imunologia , Estados Unidos , Adulto , Receptores de Antígenos Quiméricos/imunologia , Europa (Continente) , Resultado do Tratamento , Recidiva Local de Neoplasia/terapiaRESUMO
The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination with hypomethylating agents (HMAs) in patients with HMA-naive revised International Prognostic System Score (IPSS-R) high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia.
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Anticorpos Monoclonais , Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crônica , Síndromes Mielodisplásicas , Humanos , Azacitidina/uso terapêutico , Decitabina/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Receptor Celular 2 do Vírus da Hepatite A/uso terapêutico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Anticorpos/uso terapêutico , Resultado do TratamentoRESUMO
The proportion of non-transplant-eligible (NTE) newly diagnosed multiple myeloma (NDMM) patients excluded from clinical trials (CTs) and their prognosis is unknown. CT results may not be generalizable to real-world practice due to strict recruitment criteria. We analyzed causes of NTE-NDMM patient exclusion form CTs and their outcomes. A total of 211 NTE-NDMM patients were included. They were divided into three periods: 2003-2007, 2008-2012, and 2013-2017. Overall, 50% received non-trial treatment (NCT), while 50% participated in a CT (20% control group (CG) and 30% experimental group (EG)). Main causes for exclusion from CTs were comorbidities, ECOG > 2, and renal insufficiency. In the first two periods, the CR rate was similar regardless of treatment type, but in the last period, the EG group showed improved CR. Median PFS was similar in the first two periods, with a benefit seen only in the EG in the last period. The median OS was significantly longer in CT-included patients compared to NCT group in the last two periods. Conclusions: The presence of comorbidities and worsened ECOG were the main reasons for CT exclusion. Patients included in CTs had a longer OS than NCT. This OS benefit may be influenced by a selection bias, making it challenging to generalize CT results to real clinical practice.
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BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is a promising option for patients with heavily treated multiple myeloma. Point-of-care manufacturing can increase the availability of these treatments worldwide. We aimed to assess the safety and activity of ARI0002h, a BCMA-targeted CAR T-cell therapy developed by academia, in patients with relapsed or refractory multiple myeloma. METHODS: CARTBCMA-HCB-01 is a single-arm, multicentre study done in five academic centres in Spain. Eligible patients had relapsed or refractory multiple myeloma and were aged 18-75 years; with an Eastern Cooperative Oncology Group performance status of 0-2; two or more previous lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; refractoriness to the last line of therapy; and measurable disease according to the International Myeloma Working Group criteria. Patients received an initial fractionated infusion of 3 × 106 CAR T cells per kg bodyweight in three aliquots (0·3, 0·9, and 1·8 × 106 CAR-positive cells per kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 × 106 CAR T cells per kg bodyweight, at least 100 days after the first infusion. The primary endpoints were overall response rate 100 days after first infusion and the proportion of patients developing cytokine-release syndrome or neurotoxic events in the first 30 days after receiving treatment. Here, we present an interim analysis of the ongoing trial; enrolment has ended. This study is registered with ClinicalTrials.gov, NCT04309981, and EudraCT, 2019-001472-11. FINDINGS: Between June 2, 2020, and Feb 24, 2021, 44 patients were assessed for eligibility, of whom 35 (80%) were enrolled. 30 (86%) of 35 patients received ARI0002h (median age 61 years [IQR 53-65], 12 [40%] were female, and 18 [60%] were male). At the planned interim analysis (cutoff date Oct 20, 2021), with a median follow-up of 12·1 months (IQR 9·1-13·5), overall response during the first 100 days from infusion was 100%, including 24 (80%) of 30 patients with a very good partial response or better (15 [50%] with complete response, nine [30%] with very good partial response, and six [20%] with partial response). Cytokine-release syndrome was observed in 24 (80%) of 30 patients (all grade 1-2). No cases of neurotoxic events were observed. Persistent grade 3-4 cytopenias were observed in 20 (67%) patients. Infections were reported in 20 (67%) patients. Three patients died: one because of progression, one because of a head injury, and one due to COVID-19. INTERPRETATION: ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach. FUNDING: Instituto de Salud Carlos III (co-funded by the EU), Fundación La Caixa, and Fundació Bosch i Aymerich.
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COVID-19 , Mieloma Múltiplo , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Imunoterapia Adotiva/efeitos adversos , Antígeno de Maturação de Linfócitos B , Projetos Piloto , CitocinasRESUMO
Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell-free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele-specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r = 0.8; p < 0.001). CXCR4 C1013G was analysed in MYD88-mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r = 0.9; p < 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88-mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular-based risk classification.
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Ácidos Nucleicos Livres , Linfoma de Células B , Gamopatia Monoclonal de Significância Indeterminada , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Gamopatia Monoclonal de Significância Indeterminada/genética , Fator 88 de Diferenciação Mieloide/genética , Prognóstico , Mutação , Reação em Cadeia da Polimerase , Ácidos Nucleicos Livres/genética , Imunoglobulina M/genética , Receptores CXCR4/genéticaRESUMO
PURPOSE: Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). PATIENTS AND METHODS: Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non-Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). RESULTS: There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8-18.7], 25% (95% CI, 7.3-52.4), and 13% (95% CI, 6.9-20.6), respectively. CONCLUSIONS: While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Linfoma não Hodgkin , Trombocitopenia , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias Hematológicas/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
From January 1970 to December 2018, 1304 patients were diagnosed with multiple myeloma (MM) at our institution and 256 (19.6%) had plasmacytomas (Ps) (paraskeletal -PPs- 17.6%, extramedullary -EMPs-1.9%). Patients with Ps had lower serum M-protein and less advanced ISS stage than those without. At first relapse, 192 out of 967 patients (19.8%) developed Ps (PPs 14.6%, EMPs 5.1%). The only factor associated with Ps at relapse was the presence of Ps at diagnosis (46% vs 13%, p < 0.00001) with no impact with exposure to novel drugs or previous autologous stem-cell transplantation (ASCT). The median overall survival (OS) was 45, 44 and 20 months for patients without Ps, PPs and EMPs, respectively (p = 0.013). Patients with PPs who underwent ASCT had similar OS than those without Ps (98 vs. 113 months) and significantly longer than those with EMPs (98 vs 47 months, p = 0.006). In patients non-eligible for ASCT the presence of PPs or EMPs was associated with shorter OS compared with patients without Ps (32 vs. 24 vs. 6 months, p = 0.009). In the relapsed setting, a significant survival benefit was observed beyond the year 2000, but still with significant differences among patients without Ps, PPs and EMPs (37 vs 22 vs 16 months, p = 0.003). Importantly, rescue therapy with combinations of proteasome-inhibitors plus immunomodulatory drugs was associated with prolonged OS from first relapse (over 6 years), even in patients with EMPs.
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Mieloma Múltiplo , Plasmocitoma , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia , Plasmocitoma/diagnóstico , Plasmocitoma/terapia , Complexo de Endopeptidases do Proteassoma , Transplante AutólogoRESUMO
Introduction: Multiple myeloma (MM) is considered an incurable hematological neoplasm. For transplant-eligible patients, initial treatment includes an induction phase followed by an autologous stem cell transplantation (ASCT). Despite the introduction of several drugs in the past years, relapses still occur. Nevertheless, some patients achieve sustained responses after successful induction treatment and ASCT. Methods: We retrospectively evaluated all patients diagnosed with MM in our institution who underwent induction treatment and ASCT between 1990 and 2015. The subset of patients who achieved a sustained response (any degree) for 5 or more years after ASCT without further treatment or signs of progression were distinguished as "long-term responders" (LTRs). In the non-LTR group, a cohort referred to as "prolonged responders" (PLRs) showed sustained response of at least 5 years after ASCT but eventually relapsed. We collected and analyzed clinical and laboratory data. Results: Two hundred and fifty patients were diagnosed with MM and received induction treatment and ASCT at our institution in the study period. Among them, 54 (21.6%) patients met the criteria for LTR. Some diagnostic features such as a younger age, female gender, ECOG performance status of 0, lower International Staging System (ISS) stage, lower bone marrow plasma cell infiltration, and lower serum levels of calcium, C-reactive protein, and lactate dehydrogenase (LDH) were found to be more prevalent in LTR. Female gender, an ECOG performance status of 0, a localized Durie-Salmon stage, an ISS of I-II, the absence of bone disease, and an LDH within normal range were also predictive of longer progression-free survival (PFS) and overall survival (OS) in the whole cohort. The depth of the response achieved after induction and ASCT as well as the administration of an IMID-based maintenance regimen may play a role in the differences observed on PFS between cohorts. A detectable M-protein with a monoclonal gammopathy of undetermined significance (MGUS)-like behavior was detected in one-third of LTR after ASCT. Although relapses continue to occur in patients who achieve a 5-year treatment-free period after ASCT, a plateau is observed in the survival curves at approximately 21 years of follow-up.
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Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity. Literature regarding treatment and its outcomes in MGRS is sparse due to the rarity and misdiagnosis of MGRS. We retrospectively analyzed 280 adults with an MGRS diagnosis from 2003 to 2020 across 19 clinical centers from 12 countries. All cases required renal biopsy for the pathological diagnosis of MGRS. Amyloidosis-related to MGRS (MGRS-A) was present in 180 patients; nonamyloidosis MGRS (MGRS-NA), including a broad spectrum of renal pathologies, was diagnosed in 100 patients. The median overall survival in the studied cohort was 121.0 months (95% CI: 105.0-121.0). Patients with MGRS-A had a shorter overall survival than patients with MGRS-NA (HR = 0.41, 95%CI: 0.25-0.69; p = 0.0007). Both hematologic and renal responses were associated with longer survival. Achievement of ≥VGPR was generally predictive of a renal response (OR = 8.03 95%CI: 4.04-115.96; p < 0.0001), one-fourth of patients with ≥VGPR were renal nonresponders. In MGRS-A, factors associated with poor prognosis included elevated levels of creatinine, beta-2-microglobulin, and hemodialysis at diagnosis. In MGRS-NA, only age >65 years was associated with increased risk of death. Treatments provided similar hematologic response rates in both types of MGRS. Autologous stem cell transplantation led to better response than other treatments. This multicenter and international effort is currently the largest report on MGRS.
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Transplante de Células-Tronco Hematopoéticas , Nefropatias , Gamopatia Monoclonal de Significância Indeterminada , Paraproteinemias , Lesões Pré-Cancerosas , Adulto , Idoso , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Nefropatias/etiologia , Nefropatias/patologia , Nefropatias/terapia , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Gamopatia Monoclonal de Significância Indeterminada/terapia , Paraproteinemias/diagnóstico , Prognóstico , Estudos Retrospectivos , Transplante Autólogo/efeitos adversosRESUMO
The prognostic landscape of multiple myeloma (MM) has evolved significantly over the last few decades. There are, however, few data measuring such improvement in real-world patients. This study aimed to investigate trends in survival improvement over 45 years, and the associated clinical factors, in an unselected population of patients with MM. Between 1970 and 2015, 1 161 MM patients were included. Patients were classified into three calendar periods (1970-1984, 1985-1999, and 2000-2015), according to the treatment received; polychemotherapy, autologous stem cell transplantation, and novel drugs respectively. We analysed relative survival (RS) to accurately evaluate MM-related death rates after excluding the mortality expected in the general population. RS at five years increased from 27% in 1970-1984 to 38% and 56% in the next two calendar periods respectively. The improvement to survival was greater in the younger population, but it was also observed in elderly patients and those with poor performance status and more advanced disease. Although myeloma is still a non-curable disease, encouraging results have been observed in the last decades. Progress is expected to continue with the use of new generations of anti-myeloma drugs, and will, hopefully, be documented in real-world patients by the appropriate population-based studies.
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Mieloma Múltiplo/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Feminino , História do Século XX , História do Século XXI , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/história , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Gradação de Tumores , Estadiamento de NeoplasiasRESUMO
Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA)-CART which is currently being tested in a clinical trial for relapsed/refractory MM.We present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of an MM, successfully treated with CART therapy targeting BCMA. The patient received a fractioned dose of 3×106/kg BCMA-CARTs after lymphodepletion. At 3 months from infusion, the patient had already obtained a deep hematological response with negative measurable residual disease by flow cytometry in the bone marrow. After 12 months, the patient remains in hematological stringent complete remission and has achieved an organ renal response with a decrease of 70% of proteinuria.This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis.
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Resistencia a Medicamentos Antineoplásicos , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/terapia , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/imunologia , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/imunologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologiaRESUMO
Abstract Introduction: According to the World Health Organization (WHO) global estimates for 2017, 9.6% of children under 5 years old are stunted. Worldwide evidence shows that actions for preventing stunting and catching-up growth are relevant if addressed by all the sectors involved. Therefore, there is a need to identify 'intersectoral actions' to address the risk of stunting during pregnancy and the first 2 years of life. Objective: To identify and describe worldwide evidence for prevention, nutritional interventions, and 'intersectoral collaboration' efforts against stunting in infants. Materials and methods: We conducted a systematic review in 2019 (PROSPERO CRD42019134431). The search included PubMed, OVID, and Web of Science, as well as WHO and the Food and Agriculture Organization of the United Nations (FAO) official documents and expert recommendations. Results: We selected 231 studies: 86.1% described prevention-related factors, 30.7%, nutritional interventions, and 52.8% intersectoral collaboration efforts; 36.4% of the studies were conducted in multiple regions; 61% of the studies described the importance of interventions during pregnancy, 71.9% from birth up to 6 months old, and 84.8% from 6 months up to 2 years old. The most frequent variables described were antenatal care, nutritional counseling for the mother and the newborn, and counseling on micronutrient supplementation. Conclusions: Evidence-based understanding of actions geared towards monitoring the risk of stunting-associated factors from pregnancy up to 2 years old is critical.
Resumen Introducción. Según estimaciones mundiales de la Organización Mundial de la Salud (OMS) para el 2017, el 9,6 % de los niños menores de cinco años padecen retraso del crecimiento. La evidencia mundial ha demostrado que las acciones para prevenir el retardo del crecimiento o para tratarlo adquieren relevancia si las abordan todos los sectores involucrados. Por lo tanto, es necesario determinar las acciones intersectoriales para atender el riesgo de retraso del crecimiento durante el embarazo y los dos primeros años de vida. Objetivo. Rastrear y describir la evidencia mundial para la prevención, las intervenciones nutricionales y los esfuerzos de colaboración intersectorial contra el retraso del crecimiento en los lactantes. Materiales y métodos: Se hizo una revisión sistemática en el 2019 (PROSPERO CRD42019134431). La búsqueda incluyó PubMed, OVID y Web of Science, así como documentos oficiales de la OMS y la Organización para la Agricultura y la Alimentación de Naciones Unidas (FAO) y recomendaciones de expertos. Resultados. Se seleccionó un total de 231 estudios: 86,1 % describían factores relacionados con la prevención, 30,7 %, intervenciones nutricionales, y 52,8 %, esfuerzos de colaboración intersectorial; 36,4 % de ellos se llevaron a cabo en múltiples regiones. Del total, el 61 % de los estudios se enfocaba en la importancia de las intervenciones durante el embarazo, el 71,9 % desde el nacimiento hasta los seis meses y el 84,8 % desde los seis meses hasta los dos años. Las variables descritas con mayor frecuencia fueron la atención prenatal, el asesoramiento nutricional para la madre y el recién nacido, y el asesoramiento sobre la suplementación con micronutrientes. Conclusiones. La comprensión basada en la evidencia de las acciones orientadas a monitorear el riesgo de factores asociados al retraso del crecimiento desde el embarazo hasta los dos años, es fundamental.
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Desenvolvimento Infantil , Insuficiência de Crescimento , Prevenção Primária , Indicadores Básicos de Saúde , Colaboração Intersetorial , DesnutriçãoRESUMO
Abstract Ambitious state hygiene education projects designed during liberal governments in Colombia (1930-1946) faced not just the poverty of rural populations, but also the reluctance of local political forces. I analyze hygiene education programs during the first two liberal governments of the Liberal Republic. I argue that public health programs did not reach their audience due to local clientelism and political corruption. The sources of this article come mainly from Colombia's Ministry of Education reports and cultural magazines. The education sector also had health-related responsibilities and developed assessments of local needs, which contributed to public health programs. Latin America's public health historiography could be enriched by exploring failures in the implementation of projects in the history of social medicine.
Resumo Projetos governamentais de educação em saúde propostos por governos liberais da Colômbia (1930-1946) enfrentaram não apenas a pobreza das populações rurais, mas também a relutância de forças políticas. Analiso os programas de educação em saúde durante os dois primeiros governos da República Liberal. Argumento que os programas de saúde pública não alcançaram o público alvo por causa de clientelismo local e corrupção política. As fontes deste artigo foram, principalmente, relatórios do Ministério da Educação da Colômbia e revistas culturais. O setor da edução teve responsabilidades relacionadas à saúde e desenvolveu avaliações das necessidades locais, que contribuíram para programas de saúde pública. A historiografia da saúde pública na América Latina poderia se beneficiar se explorasse as falhas na implementação de projetos de medicina social.
Assuntos
Humanos , População Rural , Medicina Social , Instituições Acadêmicas , Saúde Pública , ColômbiaRESUMO
Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous plasma cell disorder, with a highly variable clinical course. Immunoparesis, defined by total immunoglobulin measurements, has been shown to be an independent risk factor for progression to symptomatic disease. The heavy/light chain (HLC) assay allows precise measurement of the polyclonal immunoglobulin of the same isotype, enabling the evaluation of isotype-matched immunoparesis (IMI). In this study, we prospectively characterized immunoparesis, as determined by HLC measurements, in 53 SMM patients. Severe IMI was present in 51% of patients, while severe IP of uninvolved isotypes (HLC IP) was present in 39%. Most of the patients with severe HLC IP presented with severe IMI, but not the other way around. Isotype specificity of immune suppression was suggested by lower relative values of isotype-matched HLC pairs, both for IgG and IgA SMM. Severe IMI was associated with other risk factors for progression while patients with severe IMI and severe HLC IP showed an even higher risk profile. Both severe IMI and severe IgM HLC IP showed a significantly shorter time to progression. Finally, gene expression analysis demonstrated differences in the bone marrow microenvironment between patients with IMI and IMI plus HLC IP, with an increased expression of genes associated with cytolytic cells. In conclusion, our data supports isotype specificity of early immunoglobulin suppression mechanisms. While suppression of both involved and uninvolved isotypes is associated with risk of progression, the later appears to develop with more advanced disease and could be mediated by different mechanisms.
Assuntos
Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Leves de Imunoglobulina/sangue , Mieloma Múltiplo Latente/sangue , Idoso , Feminino , Seguimentos , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Monoclonal immunoglobulin deposition disease (MIDD) usually leads to kidney failure. Treatment of patients with a bortezomib-based regimen followed by autologous stem cell transplantation (SCT) has been increasingly used, with improvements in the response rates and allograft outcomes in kidney transplant recipients. The objective of this report was to analyze the outcomes of 6 patients who underwent kidney transplantation in our institution after treatment of MIDD between 2010 and 2019. Monoclonal immunoglobulin deposition disease was initially treated with bortezomib-based therapy followed by high-dose melphalan and autologous SCT with complete hematologic response, although all patients remained on dialysis. During a median follow-up of 20.5 months from kidney transplant (54 months from SCT), 1 patient experienced hematologic relapse and 2 had hematologic progression (one of them with MIDD relapse in the allograft) requiring treatment. The patient with organ relapse received daratumumab monotherapy, achieving complete hematologic response but with graft failure. The other 5 patients had functional grafts with median serum creatinine 1.68 mg/dL. These results support that, in patients with MIDD and sustained complete hematologic response, a kidney transplant can be considered. The optimal approach to treatment of hematologic relapse or recurrence of MIDD after kidney transplant remains to be determined.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transplante de Rim , Mieloma Múltiplo , Humanos , Recidiva Local de Neoplasia , Transplante Autólogo , Resultado do TratamentoRESUMO
We analyzed 171 patients with asymptomatic IgM monoclonal gammopathies (64 with IgM monoclonal gammopathy of undetermined significance-MGUS and 107 with smoldering Waldenström macroglobulinemia - SWM) who had a bone marrow (BM) evaluation performed at diagnosis. Abnormal free-light chain ratio (53% vs. 31%) and MYD88 mutation prevalence (66% vs. 30%) were higher in patients with SWM. No other differences were found among groups. With a median follow-up of 4.3 years, 14 patients progressed to Waldenström macroglobulinemia, 1 to amyloidosis, and 28 died without progression. The MYD88 mutation was found in 53% of patients (available in 160 patients). Multivariate analysis showed that immunoparesis (subhazard ratio-SHR 10.2, 95% confidence interval-CI: 4.2-24.8; p < 0.001) and BM lymphoplasmacytic infiltration ≥ 20% (SHR: 6, 95% CI: 1.6-22.1; p = 0.007) were associated with higher risk of progression. We developed a risk model based on these two risk factors. In the absence of both variables, an ultra-low risk group was identified (SHR 0.1, 95% CI 0.02-0.5; p = 0.004), with 3% and 6% of cumulative incidence of progression at 10 and 20 years, respectively. Bootstrap analysis confirmed the reproducibility of these results. This study finds immunoparesis and BM infiltration as biomarkers of progression as well as a low-risk group of progression in asymptomatic IgM monoclonal gammopathies.