RESUMO
OBJECTIVE: To describe determinants of persisting humoral and cellular immune response to the second COVID-19 vaccination among patients with myeloma. METHODS: This is a prospective, observational study utilising the RUDYstudy.org platform. Participants reported their second and third COVID-19 vaccination dates. Myeloma patients had an Anti-S antibody level sample taken at least 21 days after their second vaccination and a repeat sample before their third vaccination. RESULTS: 60 patients provided samples at least 3 weeks (median 57.5 days) after their second vaccination and before their third vaccination (median 176.0 days after second vaccine dose). Low Anti-S antibody levels (<50 IU/mL) doubled during this interval (p = .023) and, in the 47 participants with T-spot data, there was a 25% increase negative T-spot tests (p = .008). Low anti-S antibody levels prior to the third vaccination were predicted by lower Anti-S antibody level and negative T-spot status after the second vaccine. Independent determinants of a negative T-spot included increasing age, previous COVID infection, high CD4 count and lower percentage change in Anti-S antibody levels. CONCLUSIONS: Negative T-spot results predict low Anti-S antibody levels (<50 IU/mL) following a second COVID-19 vaccination and a number of biomarkers predict T cell responses in myeloma patients.
Assuntos
COVID-19 , Mieloma Múltiplo , Humanos , Linfócitos T , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Mieloma Múltiplo/terapia , Anticorpos , Vacinação , Anticorpos Antivirais , Imunidade CelularRESUMO
Daratumumab, bortezomib and dexamethasone (DVd) is approved for patients with relapsed multiple myeloma following the CASTOR phase 3 clinical trial. This retrospective multicentre analysis assesses the overall response rate (ORR) and progression-free survival (PFS) in routine clinical practice for patients at first relapse treated with DVd incorporating weekly bortezomib. Data were collected from 296 sequential patients treated across 15 UK centres. After a median follow-up of 21 months, the ORR was 82% (26% partial response, 56% very good partial response or better) and the median PFS was 16 months [95% confidence interval (CI) 12-20 months]. Results were similar regardless of prior lenalidomide exposure. The median time to next treatment was 20 months (95% CI 15-25 months) and the estimated overall survival at two years was 74%. Patients with high-risk features (by cytogenetics, International Staging System or extramedullary disease) and those treated within 18 months of initiation of progression-free treatment, or within 12 months of autologous stem cell transplant, had significantly inferior outcomes. The grade 2 and 3 peripheral neuropathy rate was 7%. DVd with weekly bortezomib was effective in a heterogenous real-world population at first relapse with a low rate of peripheral neuropathy. However, high-risk patients had inferior outcomes and should be considered for alternative treatments.
Assuntos
Mieloma Múltiplo , Humanos , Bortezomib/uso terapêutico , Estudos Retrospectivos , Dexametasona/efeitos adversos , Doença Crônica , Recidiva , Reino Unido/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
WHAT IS THIS SUMMARY ABOUT?: This is a summary of a clinical trial called MAIA. The trial tested 2 combinations of cancer drugs (daratumumab plus lenalidomide and dexamethasone compared with lenalidomide and dexamethasone) in people with newly diagnosed multiple myeloma. None of the participants who took part in the study had been treated before or were eligible to receive stem-cell transplants. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED?: A total of 737 participants took part. Half of the participants took daratumumab plus lenalidomide and dexamethasone, while the other half of the participants took only lenalidomide and dexamethasone. Once participants started taking the drugs, the cancer was monitored for improvement (response to treatment), worsening (disease progression), or no change. Participants' blood and urine were tested for myeloma protein to measure response to the treatment. Participants were also monitored for side effects. WHAT WERE THE RESULTS OF THE STUDY?: After approximately 56 months of follow-up, more participants who took daratumumab plus lenalidomide and dexamethasone were alive and had decreased myeloma protein levels (indicating improvement of cancer) than participants who took only lenalidomide and dexamethasone. The most common side effects were abnormally low white and red blood cell counts and increased lung infections. WHAT DO THE RESULTS OF THE STUDY MEAN?: In the MAIA study, participants with multiple myeloma who took daratumumab plus lenalidomide and dexamethasone lived longer and had decreased myeloma protein levels than participants who took only lenalidomide and dexamethasone, indicating survival could be more likely with daratumumab added. Clinical Trial Registration: NCT02252172 (Phase 3 MAIA study).
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Mieloma Múltiplo , Humanos , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Lenalidomida/uso terapêutico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Ensaios Clínicos Fase III como AssuntoRESUMO
INTRODUCTION: Two phase 3 studies demonstrated superior efficacy of intravenous daratumumab (DARA IV) plus bortezomib/melphalan/prednisone (ALCYONE) or lenalidomide/dexamethasone (Rd; MAIA) versus standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma. In these studies, patients could switch from DARA IV to subcutaneous daratumumab (DARA SC) while receiving daratumumab monotherapy in ALCYONE (as of Cycle 11) or daratumumab plus Rd in MAIA. The phase 3 COLUMBA study demonstrated noninferiority of DARA SC to DARA IV. DARA SC reduced administration time, allowing patients to spend less time in healthcare settings, a relevant practical consideration for patient care in the COVID-19 pandemic/settings of limited healthcare resources. METHODS: DARA SC 1800â mg was administered every 4 weeks, per approved dosing schedules. We evaluated safety and patient-reported experience (ALCYONE only) among patients who switched from DARA IV to DARA SC. RESULTS: Fifty-seven patients in ALCYONE and 135 in MAIA switched to DARA SC. Three (2.2%; MAIA) patients reported injection-site reactions, all of which were mild. No infusion-related reactions occurred with DARA SC. In ALCYONE, >80% of patients preferred DARA SC over DARA IV. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 5.3% of patients in ALCYONE and 25.9% in MAIA; one (0.7%; MAIA) patient experienced a TEAE with an outcome of death. CONCLUSION: For transplant-ineligible newly diagnosed multiple myeloma, DARA SC (monotherapy/with Rd) was safe and preferred over DARA IV. ClinicalTrials.gov, NCT02195479/NCT02252172.
Assuntos
COVID-19 , Mieloma Múltiplo , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , PandemiasRESUMO
Myeloma patients frequently respond poorly to bacterial and viral vaccination. A few studies have reported poor humoral immune responses in myeloma patients to COVID-19 vaccination. Using a prospective study of myeloma patients in the UK Rudy study cohort, we assessed humoral and interferon gamma release assay (IGRA) cellular immune responses to COVID-19 vaccination post second COVID-19 vaccine administration. We report data from 214 adults with myeloma (n = 204) or smouldering myeloma (n = 10) who provided blood samples at least three weeks after second vaccine dose. Positive Anti-spike antibody levels (> 50 iu/ml) were detected in 189/203 (92.7%), positive IGRA responses were seen in 97/158 (61.4%) myeloma patients. Only 10/158 (6.3%) patients were identified to have both a negative IGRA and negative anti-spike protein antibody response. In all, 95/158 (60.1%) patients produced positive results for both anti-spike protein serology and IGRA. After adjusting for disease severity and myeloma therapy, poor humoral immune response was predicted by male gender. Predictors of poor IGRA included anti-CD38/anti-BCMA (B-cell maturation antigen) therapy and Pfizer-BioNTech vaccination. Further work is required to understand the clinical significance of divergent cellular response to vaccination.
Assuntos
COVID-19 , Mieloma Múltiplo , Adulto , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Imunidade Humoral , Masculino , Mieloma Múltiplo/terapia , Estudos Prospectivos , SARS-CoV-2 , Linfócitos T , VacinaçãoRESUMO
BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%). CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Lenalidomida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Intervalo Livre de ProgressãoRESUMO
B-cell-depleting agents are among the most commonly used drugs to treat haemato-oncological and autoimmune diseases. They rapidly induce a state of peripheral B-cell aplasia with the potential to interfere with nascent vaccine responses, particularly to novel antigens. We have examined the relationship between B-cell reconstitution and SARS-CoV-2 vaccine responses in two cohorts of patients previously exposed to B-cell-depleting agents: a cohort of patients treated for haematological B-cell malignancy and another treated for rheumatological disease. B-cell depletion severely impairs vaccine responsiveness in the first 6 months after administration: SARS-CoV-2 antibody seroprevalence was 42.2% and 33.3% in the haemato-oncological patients and rheumatology patients, respectively and 22.7% in patients vaccinated while actively receiving anti-lymphoma chemotherapy. After the first 6 months, vaccine responsiveness significantly improved during early B-cell reconstitution; however, the kinetics of reconstitution was significantly faster in haemato-oncology patients. The AstraZeneca ChAdOx1 nCoV-19 vaccine and the Pfizer BioNTech 162b vaccine induced equivalent vaccine responses; however, shorter intervals between vaccine doses (<1 m) improved the magnitude of the antibody response in haeamto-oncology patients. In a subgroup of haemato-oncology patients, with historic exposure to B-cell-depleting agents (>36 m previously), vaccine non-responsiveness was independent of peripheral B-cell reconstitution. The findings have important implications for primary vaccination and booster vaccination strategies in individuals clinically vulnerable to SARS-CoV-2.
Assuntos
COVID-19 , Doenças Reumáticas , Vacinas contra COVID-19 , ChAdOx1 nCoV-19 , Humanos , Doenças Reumáticas/tratamento farmacológico , SARS-CoV-2 , Estudos SoroepidemiológicosRESUMO
BACKGROUND: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival. METHODS: MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0-2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1-2, once every 2 weeks in cycles 3-6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1-21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172. FINDINGS: Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7-59·9), median progression-free survival was not reached (95% CI 54·8-not reached) in the daratumumab group versus 34·4 months (29·6-39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43-0·66]; p<0·0001). Median overall survival was not reached in either group (daratumumab group, 95% CI not reached-not reached; control group, 95% CI 55·7-not reached; HR 0·68 [95% CI 0·53-0·86]; p=0·0013). The most common (>15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group. INTERPRETATION: Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation. FUNDING: Janssen Research & Development.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Intervalo Livre de Progressão , Taxa de SobrevidaRESUMO
BACKGROUND: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. METHODS: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. FINDINGS: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. INTERPRETATION: A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy. FUNDING: Karyopharm Therapeutics.
Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Hidrazinas/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Triazóis/administração & dosagem , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Hidrazinas/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Triazóis/efeitos adversosRESUMO
Emerging data from the management of patients with coronavirus disease 2019 (COVID-19) suggests multi-systemic involvement, including the hemopoietic system. The haematological manifestations of COVID-19 include blood count anomalies notably lymphopenia and neutrophilia which are of prognostic significance. Hyperferritinemia and elevated lactate dehydrogenase have also been associated with increased mortality. Furthermore, there is considerable evidence of a distinct coagulopathy associated with COVID-19 characterised by elevated D-dimers and an increased risk of thrombotic events. This comprehensive review summarises the latest evidence from published studies and discusses the implications of the various haematological manifestations of COVID-19 with a view to guiding clinical management and risk stratification in this rapidly evolving pandemic.
Assuntos
Transtornos da Coagulação Sanguínea/etiologia , COVID-19/sangue , COVID-19/complicações , Linfopenia/etiologia , Anticoagulantes/uso terapêutico , Biomarcadores/sangue , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Mediadores da Inflamação/sangue , Transtornos Leucocíticos/sangue , Transtornos Leucocíticos/etiologia , Contagem de Linfócitos , Linfopenia/sangue , Neutrófilos , Pandemias , Fatores de Risco , SARS-CoV-2 , Trombose/sangue , Trombose/etiologia , Tratamento Farmacológico da COVID-19Assuntos
Vacinas contra COVID-19 , COVID-19 , Mieloma Múltiplo , SARS-CoV-2 , Vacinação , Humanos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , COVID-19/prevenção & controle , COVID-19/epidemiologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , SARS-CoV-2/imunologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos LongitudinaisAssuntos
Mieloma Múltiplo/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Estudos Multicêntricos como Assunto , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Prognóstico , Resultado do Tratamento , Reino UnidoAssuntos
Neoplasias da Medula Óssea/diagnóstico , Mieloma Múltiplo/diagnóstico , Idoso , Biomarcadores/metabolismo , Feminino , Humanos , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Cadeias Leves de Imunoglobulina/metabolismo , Imunoglobulina M/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Neoplasia Residual , Projetos Piloto , Plasmócitos , Estudos ProspectivosRESUMO
BACKGROUND: Elevated polyclonal serum free light chain (FLC) levels have been associated with increased mortality and disease activity in many conditions. Currently, polyclonal FLC quantification requires summation of individual FLCκ and FLCλ assays. Here we present a single assay for combined FLC (cFLC, Combylite) which reduces assay time and eliminates potential imprecision errors incurred by summating FLC assays (ΣFLC). METHODS: Sheep FLCκ- and FLCλ-specific antibodies were conjugated to latex microparticles to quantify FLCκ and FLCλ in a single assay. Combylite results were compared to ΣFLC (Freelite) in 132 healthy controls and 1127 patient samples. The utility of cFLC for predicting all-cause mortality in a haematological referral population was evaluated. RESULTS: cFLC and ΣFLC results were highly concordant (Passing-Bablok equation y=0.98x-1.59 mg/L, R²=0.96). Combylite assay imprecision was low at concentrations around the upper normal range [coefficient of variation (CV) 5.5%, 54 mg/L] and the upper limit of the measuring range (CV 5.5%, 170 mg/L). cFLC levels were significantly raised in disease states compared with healthy controls. Additionally, cFLC >65 mg/L was associated with shorter overall survival in a haematological referral population (hazard ratio=4.5, p<0.001). CONCLUSIONS: cFLC values obtained using Combylite were comparable to ΣFLC results over a wide concentration range, were elevated in diseases characterised by B cell activation and were associated with increased mortality in a haematological referral population. These observations indicate the Combylite assay has value for investigating the role of B cell activation in disparate disease groups and could be considered as a surrogate indication of B cell function.
Assuntos
Análise Química do Sangue/métodos , Imunoensaio , Cadeias Leves de Imunoglobulina/sangue , Nefelometria e Turbidimetria , Idoso , Animais , Anticorpos/química , Anticorpos/imunologia , Bilirrubina/química , Análise Química do Sangue/normas , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/patologia , Doenças Hematológicas/metabolismo , Doenças Hematológicas/mortalidade , Doenças Hematológicas/patologia , Hemoglobinas/química , Humanos , Imunoensaio/normas , Látex/química , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/mortalidade , Hepatopatias Alcoólicas/patologia , Microesferas , Pessoa de Meia-Idade , Nefelometria e Turbidimetria/normas , Valores de Referência , Ovinos , Taxa de SobrevidaRESUMO
T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples than in matched peripheral blood samples. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modeling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T-cell activity in MM. Finally, analysis of samples from cohorts of patients who had received treatment identified that CD8+ T-cell metabolic dysfunction resolves in patients with MM who are responsive to treatment but not in patients with relapsed MM, and is associated with substantial T-cell functional restoration.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Medula Óssea , Linfócitos T CD8-Positivos , Microambiente TumoralRESUMO
Objectives: Daratumumab is the first anti-CD38 monoclonal antibody (Mab) used to treat myeloma in the newly diagnosed setting and in the relapsed setting. Isatuximab, another Mab targeting a specific epitope on the CD38 receptor, was recently approved in the UK in combination with pomalidomide and dexamethasone (IsaPomDex) to treat myeloma patients who received three prior lines of therapy. However, there is a lack of understanding of whether using a prior anti-CD38 Mab (e.g. daratumumab) can affect the efficacy of another Mab (e.g. isatuximab), when the latter is used to treat a subsequent relapse.Methods: We performed a UK-wide outcomes study of IsaPomDex in the real-world. In this case series, we report a detailed descriptive analysis of the characteristics and clinical outcomes of five IsaPomDex patients in UK routine practice (Patients I to V), with a prior exposure to daratumumab.Results: Age range was 51-77 years with two patients >70 and three patients <70 years. The cytogenetic risk was standard in two patients, high in two patients and not known in one patient. Prior daratumumab regimen were monotherapy (dara-mono) in one patient (II), and daratumumab with bortezomib and dexamethasone (DVd) in four patients. Responses to prior daratumumab were: very good partial response (VGPR) in two patients (I and III), minor response-stable disease (MR-SD) in one patient (II), and progressive disease (PD) in two patients (IV and V). Median (range) number of IsaPomDex cycles received was 2 (1-4). Outcomes of IsaPomDex were PD in three patients (II, IV and V) and a response in two patients. Response categories were: MR-SD in patient I and PR in patient III.Discussion: Despite the limitations of our case series, we described the first UK real-world report of IsaPomDex outcomes in myeloma patients with a prior exposure to daratumumab.Conclusion: Large prospective studies are required to further evaluate myeloma outcomes in this setting.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Talidomida/análogos & derivados , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Idoso , Anticorpos Monoclonais/uso terapêutico , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
Objectives: To determine the seroprevalence of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibody status amongst healthcare workers (HCWs) working through the first wave of the Coronavirus (COVID-19) pandemic in 2020. To examine the association of seroprevalence and self-reported COVID-19 symptoms with occupation, sex, and ethnicity; and how these factors were associated with physical and mental wellbeing. Design: Single-centre cohort study. Setting: Large public hospital in the United Kingdom. Intervention: All HCWs who had been tested for anti-SARS-CoV-2 immunoglobulin (Ig) G nucleocapsid antibody in summer 2020 were asked to complete an electronic survey focusing on their physical and mental health in Winter 2020-21. This survey was comprised of the Short Form 12v2, Physical Component Summary (PCS), Mental Component Summary (MCS), and Generalised Anxiety Disorder 7-item (GAD-7) questionnaires. Results: 7604/9781 (77.7%) HCWs were antibody tested, of which 1082 completed the full survey. Antibody testing was conducted between 17/06/20-30/07/20, during which time our seroprevalence rate was 28% (299/1082). Of those self-reporting COVID-19 symptoms, 51% (201/395) were antibody positive. Antibody-positive participants had lower PCS scores (p = 0.016), indicating poorer physical health. Lower PCS scores were also found in those deemed high risk for COVID-19 by their GP (p = 0.001), and those aged >44 years (p = 0.009). Antibody-negative participants had lower MCS scores (p = 0.044), indicating poorer mental health. Those who self-reported COVID-19 symptoms had lower PCS scores (p=<0.001) than those with no symptoms. Lower MCS scores were found in women (p = 0.001), Caucasians (p = 0.018), non-clinicians (p = 0.001), and those aged <44 years (p = 0.009). Significantly higher GAD-7 anxiety scores were evident in staff aged <44 years (p = 0.023), and those with self-reported COVID symptoms (p = 0.031). Doctors had lower GAD-7 anxiety scores (p = 0.009). Conclusion: Self-reported symptoms did not correlate with seroprevalence; data surrounding this can be useful for future workforce planning. Interventions are needed to reduce the mental and physical burden of the pandemic on HCWs. Further work is needed to identify which particular HCWs may require further support, to ensure well-being and effective patient care. Trial registration: Sponsor Protocol number - 2020COV112, Clinicaltrials.gov number -NCT04527432.