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Circulating plasma cells (CPCs) are detected in most multiple myeloma (MM) patients, both at diagnosis and on relapse. A small subset, plasma cell leukemia (PCL), represents a different biology and has a poor prognosis. In this retrospective analysis, we evaluated patients with primary (pPCL, n = 35) or secondary (sPCL, n = 49), with ≥5% CPCs and a smaller subset with lower CPCs of 1-4% (n = 20). The median age was 61 years; 45% were men and 54% were Black. High-risk cytogenetics were found in 87% and extramedullary disease in 47%. For the entire cohort, 75% received a proteasome inhibitor, 70% chemotherapy, 54% an immunomodulatory drug, 24% a daratumumab-based regimen and 26% an autologous stem cell transplant (ASCT). The treatments marginally improved the overall survival (OS) for pPCL vs. sPCL (13 vs. 3.5 months p = 0.002). However, the 5-year survival for the whole cohort was dismal at 11%. High-risk cytogenetics, low platelets, extramedullary disease and high LDH were independently associated with poor outcomes. Further research is urgently needed to expand the treatment options and improve the outcomes in PCL.
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ABSTRACT: Idecabtagene vicleucel (ide-cel) was the first chimeric antigen receptor T-cell therapy to gain US Food and Drug Administration approval for patients with relapsed/refractory multiple myeloma (RRMM). The clinical outcomes of standard of care (SOC) ide-cel in racially and ethnically diverse populations have been understudied. This study pooled data from 207 patients with RRMM (28% patients of racial and ethnic minority groups) treated with SOC ide-cel across 11 institutions to examine racial and ethnic differences in the incidence of toxicities and adverse events, response to ide-cel, and survival. This study included 22 (11%) Hispanic, 36 (17%) non-Hispanic Black, and 149 (72%) non-Hispanic White patients with RRMM. Compared with Hispanic and non-Hispanic White patients, non-Hispanic Black patients had higher median levels of C-reactive protein (1.0, 0.8, and 3.5 mg/dL, respectively; P = .02) and baseline ferritin (362.0 vs 307.0 vs 680.5, respectively; P = .08) and were more likely to develop cytokine release syndrome (77%, 85%, and 97%, respectively; P = .04). Although best overall response rate was lower among Hispanic patients (59%) than among non-Hispanic Black (86%) and White patients (86%; P = .01), there were no racial and ethnic differences in progression-free or overall survival. We provide, to our knowledge, the first and largest investigation of clinical outcomes of SOC ide-cel by race and ethnicity. Despite differences in safety and response to ide-cel, our findings encourage the use of ide-cel in all patients with RRMM. These findings should be confirmed in larger samples of diverse patients with RRMM, with longer follow-up time.
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Mieloma Múltiplo , Neoplasias de Plasmócitos , Estados Unidos , Humanos , Mieloma Múltiplo/terapia , Imunoterapia Adotiva/efeitos adversos , Etnicidade , Grupos MinoritáriosRESUMO
There are significant disparities with regards to incidence, timely diagnosis, access to treatment, clinical trial participation and health care utilization that negatively impact outcomes for African American patients with multiple myeloma. Health care providers have a role in ameliorating these disparities with thoughtful consideration of historical, sociocultural, individual and disease characteristics that influence the care provided to African American patient population. This review by a group of experts committed to health disparity in multiple myeloma provides a snapshot of disparities at both biologic and non-biologic levels, barriers to clinical care, and best practices to ensure that African American patients receive the best care available.
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Negro ou Afro-Americano , Disparidades em Assistência à Saúde , Mieloma Múltiplo , Humanos , Atenção à Saúde , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/terapia , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
Here, the International Myeloma Working Group (IMWG) updates its clinical practice recommendations for the management of multiple myeloma-related renal impairment on the basis of data published until Dec 31, 2022. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and free light chains (FLCs) measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed. The IMWG criteria for the definition of renal response should be used. Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment. Mechanical approaches do not increase overall survival. Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment.
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Antineoplásicos , Mieloma Múltiplo , Insuficiência Renal , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Dexametasona , Antineoplásicos/efeitos adversos , Insuficiência Renal/etiologia , Insuficiência Renal/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/uso terapêuticoRESUMO
New therapies for multiple myeloma have improved outcomes, but are associated with therapy-related hematologic malignancies. We report eight patients with therapy-related B-lymphoblastic leukemias (t-B-ALL) in the setting of therapy for multiple myeloma, which included lenalidomide maintenance. A subset of patients had pancytopenia and low-level marrow involvement by acute leukemia, an unusual finding in de novo B-ALL. One patient died of chemotherapy complications; the other seven responded. No patient died of B-ALL (median follow up of 1.0 years). Our series suggests that t-B-ALL is clonally unrelated to myeloma, presents with diverse cytogenetic abnormalities, and responds well to B-ALL therapy.
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Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.
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Mieloma Múltiplo , Mieloma Múltiplo Latente , Humanos , Biomarcadores , Progressão da Doença , Fatores Imunológicos , Imunoterapia , Lenalidomida/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo Latente/terapia , Ensaios Clínicos Fase II como AssuntoRESUMO
BACKGROUND: Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma. METHODS: We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiple myeloma who had received at least two previous lines of therapy, including lenalidomide or pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalation cohort. Patients received escalating doses of oral iberdomide (0·3-1·6 mg on days 1-21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years] once per week). A dose-expansion cohort at the recommended phase 2 dose was planned for patients who had received at least three previous lines of therapy and had triple-class refractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort, phase 1) and overall response rate (defined as complete response or partial response; in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoing and is registered with ClinicalTrials.gov, NCT02773030. FINDINGS: Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone (90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort). In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male, 70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR 4-8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84 (79%) were White, and the median number of previous lines of therapy was 6 (IQR 5-8). At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0-13·7) in the dose-escalation cohort and 7·7 months (5·3-11·4) in the dose-expansion cohort. Two dose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed in the dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose. In the dose-escalation cohort, the overall response rate was 32% (95% CI 23-43; 29 of 90 patients) across all doses, and the maximum tolerated dose was not reached. In the dose-expansion cohort, the overall response rate was 26% (95% CI 18-36; 28 of 107 patients). The most common grade 3 or worse adverse events were neutropenia (48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia (23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%) treatment-related death (sepsis) and five (5%) patients discontinued iberdomide due to adverse events. INTERPRETATION: Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted. FUNDING: Bristol Myers Squibb.
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Mieloma Múltiplo , Humanos , Masculino , Feminino , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêuticoRESUMO
In current study, different feeding levels of Moringa oleifera formulated diet was compared to analyze the growth performance, feed conversion ratio, feed conversion efficiency and gut microbiology of Oreochromis niloticus. The study was comprised of four treatment groups including 4%, 8% and 12% Moringa oleifera and one control group which was devoid of Moringa leaves. The experimental trial was conducted at the Zoology laboratory of Pakistan Institute of Applied and Social Sciences, (PIASS) Kasur. The physicochemical parameters of water such as temperature, dissolve oxygen, pH, total dissolved solids and salinity in all aquaria were found non-significantly different from each other. In control condition T1, the average weight gain was 14.89±16.90a grams, while average length gain was 11.52±7.444a cm. However, the total viable count on Eosin methylene blue was 7.4×107, 5.8×107 on Tryptic soy agar and 5.8×107on Nutrient agar. In T2, the average weight gain was 16.22±16.09b grams and average length gain was 12.97±7.79b cm. The total viable count on Eosin methylene blue was 7×107, 5.5×107 on Tryptic soy agar and 5.8×107on Nutrient agar. In T3, the average weight gain was 37.88±27.43c grams, while the average length gain was recorded as 16.48±12.56c cm. However, the total viable count for treatment 3 was 6.4×10 on Eosin methylene blue, 4.8×107 on Tryptic soy agar and 5.2×107on Nutrient agar. In T4, the average weight gain was 44.22±31.67d grams, while the average length gain was 15.25±10.49d cm. The total viable count was 4.3×107on Eosin methylene blue, 3.1×107 on Tryptic soy agar and 3.8×107 on Nutrient agar. The effect of Moringa oleifera on the growth of Oreochromis niloticus was found to be significant and 12% Moringa extract showed maximum length and weight gain and minimum feed conversion ratio with the least microbial count in fish intestine.
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Dieta , Microbioma Gastrointestinal , Moringa oleifera , Tilápia , Ágar/análise , Animais , Dieta/veterinária , Amarelo de Eosina-(YS)/análise , Azul de Metileno/análise , Tilápia/crescimento & desenvolvimento , Tilápia/microbiologia , Aumento de PesoRESUMO
INTRODUCTION: Induction therapy for multiple myeloma is traditionally capped at 6 cycles of lenalidomide due to concerns that longer treatment compromises the ability to collect sufficient stem cells for autologous stem cell transplantation (ASCT). However, during the COVID-19 pandemic, many of our patients received prolonged lenalidomide induction due to concerns about proceeding to ASCT. We investigated whether prolonged induction with lenalidomide affects the efficacy of stem cell collection among patients mobilized with cyclophosphamide and/or plerixafor. PATIENTS AND METHODS: This single center, retrospective study included patients who were treated with lenalidomide induction regimens, received mobilization with cyclophosphamide or plerixafor, and underwent apheresis in preparation for ASCT. 94 patients were included, 40 of whom received prolonged induction with >6 cycles of lenalidomide containing regimen. RESULTS: Patients who received prolonged induction were more likely to require >1 day of apheresis (38% vs. 15%; OR 3.45; P = .0154), and there was a significant correlation between the duration of lenalidomide treatment and the apheresis time required to collect sufficient cells for transplant (R2 = 0.06423, P = .0148). However, there was no significant difference between patients who received prolonged induction and those who did not with respect to CD34+ stem cell yields at completion of apheresis (9.99 vs. 10.46 cells/Kg, P = .5513) or on the first day of collection (8.29 vs. 9.59 cells/Kg, P = .1788). CONCLUSION: Among patients treated with >6 cycles of lenalidomide, mobilization augmented with cyclophosphamide and/or plerixafor will likely facilitate sufficient stem cell harvest to permit ASCT.
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Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Lenalidomida , Mieloma Múltiplo , Benzilaminas/uso terapêutico , COVID-19 , Ciclamos/uso terapêutico , Ciclofosfamida/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Pandemias , Estudos Retrospectivos , Transplante AutólogoRESUMO
PURPOSE: Define incidence and risk factors of osteonecrosis of the jaw (ONJ) and explore oral microbial signatures and host immune response as reflected by cytokine changes in saliva and serum in multiple myeloma (MM) patients on bisphosphate (BP) therapy. PATIENTS AND METHODS: A single center observational prospective study of MM patients (n = 110) on >2 years of BP, none had ONJ at enrollment. Patients were followed every 3 months for 18 months with clinical/dental examination and serial measurements of inflammatory cytokines, bone turnover markers, and angiogenic growth factors. Oral microbiota was characterized by sequencing of 16S rRNA gene from saliva. RESULTS: Over the study period 14 patients (13%) developed BRONJ, at a median of 5.7 years (95% CI: 1.9-12.0) from MM diagnosis. Chronic periodontal disease was the main clinically observed risk factor. Oral microbial profiling revealed lower bacterial richness/diversity in BRONJ. Streptococcus intermedius, S. mutans, and S. perioris were abundant in controls; S. sonstellatus and S anginosus were prevalent in BRONJ. In the saliva, at baseline patients who developed BRONJ had higher levels of MIP-1ß; TNF-α and IL-6 compared to those without BRONJ, cytokine profile consistent with M-1 macrophage activation. In the serum, patients with BRONJ have significantly lower levels of TGF beta and VEGF over the study period. CONCLUSION: Periodontal disease associated with low microbial diversity and predominance of invasive species with a proinflammatory cytokine profile leading to tissue damage and alteration of immunity seems to be the main culprit in pathogenesis of BRONJ.
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Belantamab mafodotin (belamaf) demonstrated deep and durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM) in DREAMM-2 (NCT03525678). Corneal events, specifically keratopathy (including superficial punctate keratopathy and/or microcyst-like epithelial changes (MECs), eye examination findings with/without symptoms), were common, consistent with reports from other antibody-drug conjugates. Given the novel nature of corneal events in RRMM management, guidelines are required for their prompt identification and appropriate management. Eye examination findings from DREAMM-2 and insights from hematology/oncology investigators and ophthalmologists, including corneal specialists, were collated and used to develop corneal event management guidelines. The following recommendations were formulated: close collaboration among hematologist/oncologists and eye care professionals is needed, in part, to provide optimal care in relation to the belamaf benefit-risk profile. Patients receiving belamaf should undergo eye examinations before and during every treatment cycle and promptly upon worsening of symptoms. Severity of corneal events should be determined based on corneal examination findings and changes in best-corrected visual acuity. Treatment decisions, including dose modifications, should be based on the most severe finding present. These guidelines are recommended for the assessment and management of belamaf-associated ocular events to help mitigate ocular risk and enable patients to continue to experience a clinical benefit with belamaf.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Doenças da Córnea/induzido quimicamente , Doenças da Córnea/terapia , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Córnea/efeitos dos fármacos , Córnea/patologia , Doenças da Córnea/patologia , Gerenciamento Clínico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Equipe de Assistência ao PacienteRESUMO
Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562 .
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Hidrazinas/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Triazóis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bortezomib/farmacologia , Dexametasona/farmacologia , Feminino , Humanos , Hidrazinas/farmacologia , Masculino , Mieloma Múltiplo/patologia , Triazóis/farmacologiaRESUMO
OBJECTIVES: Operative vaginal birth (OVB) is an important skill for obstetricians. It is the most common emergency intervention in obstetrics and requires a high degree of skill. While there is a lot of data available on technical and non-technical factors affecting the outcome of OVBs little work has been done to investigate the factors that make obstetricians feel confident and competent when performing such a procedure. The objective of this study was therefore to identify the common factors that affect confidence and competence of obstetricians in operative vaginal births (OVB). Our hypothesis was that a qualitative research method would provide a rich approach where themes would be developed that the participants themselves identify as important. STUDY DESIGN: Qualitative research within two University Hospitals and one District Hospital in Ireland. Participants interviewed ranged from first year trainees to consultant obstetricians. Interviews using open ended questions. Interviews were recorded on audio and later transcribed. Thematic analysis was performed until saturation. RESULTS: 35 obstetricians were interviewed. The median number of years of experience was 5 years (range 3-20 years). The median number of OVB was 200 (range 20-1000+). Vacuum was the preferred choice amongst junior trainees. Preference shifted to forceps with increasing clinical experience. Seven clear themes emerged. Three themes were common to all participants: firstly, that all clinicians reported respect for the primiparous OVB in anticipation of possible complications, secondly the wish for senior midwifery support and finally the importance of clinical experience and exposure. Four themes were common to trainees only. Female clinicians in training reported significant self-doubt in their ability to perform an OVB and had concerns about causing harm. Clinicians in training wished to be trained by consultants during their first year on the labour ward. Experience was important. The final theme was a wish for more training in forceps OVB by clinicians in training. CONCLUSION: This qualitative study identified factors that can be used to design education and training in OVB in order to support trainees and ultimately improve care for the woman and baby.
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Obstetrícia , Médicos , Competência Clínica , Feminino , Humanos , Irlanda , Obstetrícia/educação , Parto , Gravidez , Pesquisa QualitativaRESUMO
BACKGROUND: CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL. METHODS: Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively. RESULTS: Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3-4) ICANS. Median time to development of ICANS was 5 days (range, 3-11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS. CONCLUSIONS: ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.
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Síndromes Neurotóxicas , Receptores de Antígenos Quiméricos , Biomarcadores , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia AdotivaRESUMO
Limited information has been offered regarding the association of mesothelin (MSLN) gene variants at the 3'-untranslated region with the risk of ovarian carcinoma. The primary objective of this work is to assess the impact of the MSLN (rs1057147 and rs57272256) variants on the progression of ovarian carcinoma among Egyptian women. The study was conceived based on 127 women diagnosed with ovarian carcinoma and 106 unrelated cancer-free controls. Genomic DNA of these MSLN variants was genotyped utilizing the PCR technique. The frequencies of the MSLN (rs1057147) variant revealed a significant association with increased risk of ovarian carcinoma under allelic and dominant models (P < .05). Nonetheless, ovarian cancer patients with the MSLN (rs57272256) variant did not attain considerable significance under all genetic models (P > .05). Together, our findings suggested that the MSLN (rs1057147) variant was associated with an increased risk of ovarian carcinoma, but not the MSLN (rs57272256) variant.
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Regiões 3' não Traduzidas , Proteínas Ligadas por GPI/genética , Neoplasias Ovarianas/genética , Polimorfismo Genético , Estudos de Casos e Controles , Egito , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Mesotelina , Pessoa de Meia-Idade , Análise Multivariada , Análise de Componente PrincipalRESUMO
OBJECTIVES: To describe progressive corneal microcyst-like epithelial changes (MECs) that developed in patients treated with the investigational drug belantamab mafodotin (belamaf) for refractory multiple myeloma (MM). METHODS: This is a single center case series of patients with MM receiving the investigational drug belamaf. RESULTS: All 12 patients included in this analysis who were treated with belamaf developed MECs that initially appeared in the peripheral cornea and progressed centrally with time. Cessation of therapy resulted in regression of the MECs first in the periphery then centrally. Microcyst-like epithelial changes recurred in all patients on retreatment. With prolonged therapy, eight patients developed corneal staining patterns suggestive of limbal stem cell dysfunction (LSCD). CONCLUSION: We describe MECs and LSCD associated with systemic administration of belamaf. Further study is needed to determine the etiology and composition of the MECs and the mechanism of limbal stem cell involvement.
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Doenças da Córnea , Epitélio Corneano , Limbo da Córnea , Mieloma Múltiplo , Anticorpos Monoclonais Humanizados , Córnea , Doenças da Córnea/induzido quimicamente , Humanos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de NeoplasiaRESUMO
The authors of the above mentioned article would like to highlight the following corrections, based upon recent changes to the FDA label and guidance on the use of belamaf.
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INTRODUCTION: Patients with relapsed or refractory multiple myeloma (RRMM) represent an unmet clinical need. Belantamab mafodotin (belamaf; GSK2857916) is a first-in-class antibody-drug conjugate (ADC; or immunoconjugate) that delivers a cytotoxic payload, monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study (NCT03525678), single-agent belamaf (2.5 mg/kg) demonstrated clinically meaningful anti-myeloma activity (overall response rate 32%) in patients with heavily pretreated disease. Microcyst-like epithelial changes (MECs) were common, consistent with reports from other MMAF-containing ADCs. METHODS: Corneal examination findings from patients in DREAMM-2 were reviewed, and the clinical descriptions and accompanying images (slit lamp microscopy and in vivo confocal microscopy [IVCM]) of representative events were selected. A literature review on corneal events reported with other ADCs was performed. RESULTS: In most patients receiving single-agent belamaf (72%; 68/95), MECs were observed by slit lamp microscopy early in treatment (69% had their first event by dose 4). However, IVCM revealed hyperreflective material. Blurred vision (25%) and dry eye (15%) were commonly reported symptoms. Management of MECs included dose delays (47%)/reductions (25%), with few patients discontinuing due to MECs (1%). The first event resolved in most patients (grade ≥2 MECs and visual acuity [each 77%], blurred vision [67%], and dry eye [86%]), with no reports of permanent vision loss to date. A literature review confirmed that similar MECs were reported with other ADCs; however, event management strategies varied. The pathophysiology of MECs is unclear, though the ADC cytotoxic payload may contribute to on- or off-target effects on corneal epithelial cells. CONCLUSION: Single-agent belamaf represents a new treatment option for patients with RRMM. As with other ADCs, MECs were observed and additional research is warranted to determine their pathophysiology. A multidisciplinary approach, involving close collaboration between eye care professionals and hematologist/oncologists, is needed to determine appropriate diagnosis and management of these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT03525678.
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INTRODUCTION: As we have just stepped into a new decade of hopes, the mountain of knowledge learned from multiple myeloma (MM) remains unmatched among cancers. In the last decade alone, this rapid-sequence learning curve has led to regulatory approvals of eight drugs with mechanisms of actions representing five different areas of cell biology some of which made to the frontline setting, sparking debates about how to best sequence them in the treatment continuum of induction, consolidation, and maintenance and gained momentum with the realization of the implications of an effective upfront therapeutic approach with potential impact on survival. AREAS COVERED: This review was written with an intent to introduce the reader to the current treatment approach of a newly diagnosed myeloma patient and acquaint with promising targets and mechanistic strategies. Medline and clinicaltrials.gov databases (2000-2020) and relevant meetings (ASH, ASCO, EHA, ESMO, IMW) reports were queried and guidelines (IMWG) were reviewed to distill to expert opinion in an inundating field. EXPERT OPINION: Future holds promise with new targets on the horizon. It is likely that the new age of myeloma will belong to quadruplets with the addition of acellular or cellular biologics to first-generation novel agents, leading to new paradigms.