Asunto(s)

Enfermedad de Erdheim-Chester , Mieloma Múltiple , Humanos , Enfermedad de Erdheim-Chester/complicaciones , Enfermedad de Erdheim-Chester/patología , Enfermedad de Erdheim-Chester/diagnóstico , Mieloma Múltiple/complicaciones , Mieloma Múltiple/patología , Mieloma Múltiple/diagnóstico , Masculino , Persona de Mediana Edad , Femenino , Anciano

RESUMEN

INTRODUCTION: Patients with multiple myeloma (MM) face heightened infection susceptibility, particularly severe risks from COVID-19. This study, the first systematic review in its domain, seeks to assess the impacts of COVID-19 on MM patients. METHOD: Adhering to PRISMA guidelines and PROSPERO registration (ID: CRD42023407784), this study conducted an exhaustive literature search from January 1, 2020, to April 12, 2024, using specified search terms in major databases (PubMed, EMBASE, and Web of Science). Quality assessment utilized the JBI Critical checklist, while publication bias was assessed using Egger's test and funnel plot. The leave-one-out sensitivity analyses were performed to assess the robustness of the results by excluding one study at a time to identify studies with a high risk of bias or those that significantly influenced the overall effect size. Data synthesis involved fitting a random-effects model and estimating meta-regression coefficients. RESULTS: A total of 14 studies, encompassing a sample size of 3214 yielded pooled estimates indicating a hospitalization rate of 53% (95% CI: 40.81, 65.93) with considerable heterogeneity across studies (I2 = 99%). The ICU admission rate was 17% (95% CI: 11.74, 21.37), also with significant heterogeneity (I2 = 94%). The pooled mortality rate was 22% (95% CI: 15.33, 28.93), showing high heterogeneity (I2 = 97%). The pooled survival rate stood at 78% (95% CI: 71.07, 84.67), again exhibiting substantial heterogeneity (I2 = 97%). Subgroup analysis and meta-regression highlighted that study types, demographic factors, and patient comorbidities significantly contributed to the observed outcome heterogeneity, revealing distinct patterns. Mortality rates increased by 15% for participants with a median age above 67 years. ICU admission rates were positively correlated with obesity, with a 20% increase for groups with at least 19% obesity. Mortality rates rose by 33% for the group of patients with at least 19% obesity, while survival rates decreased by 33% in the same group. CONCLUSION: Our meta-analysis sheds light on diverse COVID-19 outcomes in multiple myeloma. Heterogeneity underscores complexities, and study types, demographics, and co-morbidities significantly influence results, emphasizing the nuanced interplay of factors.

Asunto(s)

COVID-19 , Mieloma Múltiple , Mieloma Múltiple/mortalidad , Mieloma Múltiple/epidemiología , Humanos , COVID-19/epidemiología , COVID-19/mortalidad , Medición de Riesgo/métodos , SARS-CoV-2/aislamiento & purificación , Hospitalización , Unidades de Cuidados Intensivos

Asunto(s)

Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Mieloma Múltiple , Talidomida , Humanos , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Talidomida/análogos & derivados , Talidomida/administración & dosificación , Talidomida/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos

RESUMEN

BACKGROUND: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. METHODS: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. RESULTS: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. CONCLUSIONS: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Asunto(s)

Neoplasias Hematológicas , Humanos , Animales , Línea Celular Tumoral , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/metabolismo , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteolisis/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Factor de Transcripción Ikaros/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales

RESUMEN

We present an unusual etiology of primary renal allograft dysfunction attributed to myeloma cast nephropathy in a patient with no history of multiple myeloma before kidney transplant. The patient, a 54-year-old woman, had been on hemodialysis for 6 months before transplant for presumed diabetic nephropathy; she developed graft dysfunction immediately after transplant. Graft biopsy specimens were consistent with myeloma cast nephropathy, and she was treated with bortezomib, cyclophosphamide, and dexamethasone. She achieved a complete hematological response and regained excellent graft function 3 months after transplant. The patient then received autologous stem cell transplant 8 months after kidney transplant. To our knowledge, this is the second report of a successful graft outcome after chemotherapy and the first report treated with autologous stem cell transplantation after remission of monoclonal disease.

Asunto(s)

Trasplante de Riñón , Mieloma Múltiple , Disfunción Primaria del Injerto , Humanos , Trasplante de Riñón/efectos adversos , Femenino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Resultado del Tratamiento , Biopsia , Disfunción Primaria del Injerto/etiología , Disfunción Primaria del Injerto/diagnóstico , Disfunción Primaria del Injerto/fisiopatología , Inmunosupresores/efectos adversos , Diagnóstico Erróneo , Aloinjertos , Trasplante Autólogo , Factores de Tiempo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos

RESUMEN

Given the early use of triplet and quadruplet regimens, most patients with multiple myeloma (MM) will be exposed and/or refractory to PIs, IMiDs, and anti-CD38 mAbs after first- or second-line treatment. Effective treatment for this group of triple class exposed/refractory (TCE/R) patients is crucial. Here we present a post-hoc subgroup analysis of TCE/R patients treated on the ALGONQUIN study of belantamab mafodotin plus pomalidomide-dexamethasone (belamaf-Pd) for relapsed MM. Of the 99 patients treated on the ALGONQUIN study, 69 were TCE and 56 were TCR and were included in this analysis. Patients had a median of three prior lines of therapy. The ORR was 86.4% in TCE patients and 84.9% in TCR patients, with ≥ very good partial response rates of 64% and 68% respectively. The median progression free survival was 18.3 months in TCE patients and 19.6 months in TCR patients, with overall survival not yet reached and 34.4 months, respectively for TCE and TCR patients. No new safety signals were identified. The most common Grade ≥ 3 AEs were keratopathy (48%), decreased visual acuity (42%), neutropenia (36%), thrombocytopenia (27%), and infection (25%). In this subgroup analysis of the ALGONQUIN study, patients with TCE/TCR disease treated with belamaf-Pd achieved high clinical response rates with durable remissions, comparable to other novel therapeutics in this space.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Mieloma Múltiple , Talidomida , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Talidomida/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Compuestos de Boro/uso terapéutico , Compuestos de Boro/administración & dosificación , Anciano de 80 o más Años , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resistencia a Antineoplásicos

RESUMEN

Multiple myeloma (MM) is a hematological malignancy whose curability is greatly challenged by recurrent patient relapses and therapy resistance. We have previously proposed the high expression of ADAM8, ADAM9 and ADAM15 (A Disintegrin And Metalloproteinase 8/9/15) as adverse prognostic markers in MM. This study focused on the so far scarcely researched role of ADAM8/9/15 in MM using two patient cohorts and seven human MM cell lines (HMCL). High ADAM8/9/15 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease. Furthermore, ADAM8/15 expression increased with MM progression and in relapsed/refractory MM compared to untreated patient samples. RNA sequencing and gene set enrichment analysis comparing ADAM8/9/15high/low patient samples revealed an upregulation of proliferation markers and proliferation-associated gene sets in ADAM8/9/15high patient samples. High ADAM8/9/15 expression correlated with high Ki67 and high ADAM8/15 expression with high MYC protein expression in immunohistochemical stainings of patient tissue. Conversely, siRNA-mediated knockdown of ADAM8/9/15 in HMCL downregulated proliferation-related gene sets. Western blotting revealed that ADAM8 knockdown regulated IGF1R/AKT signaling and ADAM9 knockdown decreased mTOR activation. Lastly, high ADAM8/9/15 expression levels were verified as prognostic markers independent of Ki67/MYC expression and/or high-risk abnormalities. Overall, these findings suggest that ADAM8/9/15 play a role in MM progression and proliferation signaling.

Asunto(s)

Proteínas ADAM , Proliferación Celular , Progresión de la Enfermedad , Proteínas de la Membrana , Mieloma Múltiple , Transducción de Señal , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Mieloma Múltiple/metabolismo , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Masculino , Femenino , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Biomarcadores de Tumor , Anciano

RESUMEN

OBJECTIVES: Circular RNA_0003489 (Circ_0003489) promotes multiple myeloma (MM) progression and bortezomib resistance in MM cells, while its potential as a biomarker in newly diagnosed MM (NDMM) patients is unclear. Thus, this study aimed to investigate the association of circ_0003489 expression with treatment response and survival in NDMM patients who received bortezomib-based induction therapy. METHODS: Bone marrow (BM) specimens from 85 NDMM patients at diagnosis or before treatment and from 15 donor controls during BM examination were retrieved in this retrospective study. Circ_0003489 derived from BM plasma cells was detected by reverse transcription-quantitative polymerase chain reaction and cut by quartile and median for further analysis. RESULTS: Circ_0003489 expression was increased in NDMM patients versus donor controls (P < 0.001). Circ_0003489 quartile was positively correlated with BM plasma cells (P = 0.040), international staging system (ISS) stage (P = 0.007), the revision of ISS stage (P = 0.003), beta-2-microglobulin (P = 0.011), and lactate dehydrogenase (P = 0.042) in NDMM patients. Increased circ_0003489 quartile was linked with a lower possibility of achieving complete response (P = 0.020) and partial response or better (P = 0.041) in NDMM patients. Elevated circ_0003489 expression cut by quartile (P = 0.020) and cut by median (P = 0.006) were linked with decreased progression-free survival (PFS) in NDMM patients. Increased circ_0003489 expression cut by median was associated with shortened overall survival (OS) in NDMM patients (P = 0.038). Meanwhile, higher circ_0003489 quartile independently forecasted poorer PFS (hazard ratio = 1.342, P = 0.045), but not OS in NDMM patients. CONCLUSION: Circ_0003489 expression is increased and reflects unfavorable treatment response and survival in NDMM patients who receive bortezomib-based induction therapy.

Asunto(s)

Bortezomib , Mieloma Múltiple , ARN Circular , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Bortezomib/uso terapéutico , ARN Circular/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Estudios Retrospectivos , Resultado del Tratamiento , Anciano de 80 o más Años , Pronóstico

RESUMEN

OBJECTIVE: The drug resistance of multiple myeloma (MM) cells is one of the main causes of relapse, refractory and progression of MM. METHODS: First, Western blot analysis was used to detect the expression levels of NLRP3, ASC, pro-IL-1ß and cleaved IL-1ß, and RT-qPCR was used to detect the mRNA expression levels of them. The expression levels of IL-1ß and IL-18 in the supernatant were detected by ELISA, and the expression levels of these factors in the activated group and the control group were compared to verify the activation of BMMCs and KM3. RESULT: 1. The protein expression of NLRP3 and cleavd-IL-1ß in the BMMCs cells was significantly higher than that of the control group (P < 0.05). The mRNA expression levels of caspase-1 and IL-1ß were higher than those of the control group (P = 0.03, P = 0.02). 2. The protein expression levels of NLRP3 and cleaved-IL-1ß in the KM3 cells were significantly higher than those of the control group (P < 0.05). The expressions of caspase-1 mRNA(P = 0.016) and IL-1ß mRNA(P = 0.037) were significantly increased compared with the control group. 3. The early apoptosis results of BMMCs showed that the apoptosis rate of the LPS+ATP+Dex group was lower than that of the Dex group (P = 0.017). The early apoptosis rate of the LPS+ATP+Dex+Vel group was decreased compared with the Dex+Vel group (P = 0.045). 4. The early apoptosis rate of KM3 in the LPS+ATP+Dex group was lower than that in the Dex group (P = 0.03). CONCLUSION: 1. LPS+ATP can activate NLRP3 inflammasome in multiple myeloma cells. 2. Activation of NLRP3 inflammasome inhibits the early apoptosis of myeloma cells induced by dexamethasone and bortezomib.

Asunto(s)

Inflamasomas , Mieloma Múltiple , Proteína con Dominio Pirina 3 de la Familia NLR , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Humanos , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Línea Celular Tumoral , Masculino , Femenino , Persona de Mediana Edad

RESUMEN

Objective: The aim of this research was to gain a thorough understanding of the processes involved in cell communication and discover potential indicators for treating multiple myeloma (MM) through the use of single-cell RNA sequencing (scRNA-seq). And explored the expression of multiple myeloma-related subgroups on metal ion-related pathways to explore the relationship between MM and metal ions. Methods: We performed a fair examination using single-cell RNA sequencing on 32 bone marrow specimens collected from 22 individuals at different points of MM advancement and 9 individuals without any health issues. To analyze the scRNA-seq data, we employed advanced computational algorithms, including Slingshot, Monocle2, and other methodologies. Specifically, Slingshot and Monocle2 enabled us to simulate the biological functionalities of different cell populations and map trajectories of cell developmental pathways. Additionally, we utilized the UMAP algorithm, a powerful dimension reduction technique, to cluster cells and identify genes that were differentially expressed across clusters. Results: Our study revealed distinct gene expression patterns and molecular pathways within each patient, which exhibited associations with disease progression. The analysis provided insights into the tumor microenvironment (TME), intra- and inter-patient heterogeneity, and cell-cell interactions mediated by ligand-receptor signaling. And found that multiple myeloma-related subgroups were expressed higher levels in MMP and TIMP pathways, there were some associations. Conclusion: Our study presents a fresh perspective for future research endeavors and clinical interventions in the field of MM. The identified gene expression patterns and molecular pathways hold immense potential as therapeutic targets for the treatment of multiple myeloma. The utilization of scRNA-seq technology has significantly contributed to a more precise understanding of the complex cellular processes and interactions within MM. Through these advancements, we are now better equipped to unravel the underlying mechanisms driving the development and progression of this complex disease.

Asunto(s)

Mieloma Múltiple , Análisis de la Célula Individual , Microambiente Tumoral , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Humanos , Análisis de la Célula Individual/métodos , Microambiente Tumoral/genética , Regulación Neoplásica de la Expresión Génica , Análisis de Secuencia de ARN , Perfilación de la Expresión Génica , Masculino , Femenino , Persona de Mediana Edad , Transcriptoma , Anciano , Biología Computacional/métodos , Algoritmos , Biomarcadores de Tumor/genética

RESUMEN

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.

Asunto(s)

Análisis Costo-Beneficio , Inmunoterapia Adoptiva , Lenalidomida , Mieloma Múltiple , Talidomida , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Mieloma Múltiple/tratamiento farmacológico , Lenalidomida/uso terapéutico , Lenalidomida/administración & dosificación , Inmunoterapia Adoptiva/economía , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Talidomida/economía , Talidomida/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Masculino , Femenino , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Persona de Mediana Edad , Supervivencia sin Progresión , Resultado del Tratamiento , Anciano , Resistencia a Antineoplásicos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/economía

RESUMEN

BACKGROUND: Chromosomal 1q gains and amplifications (+1q21) are frequently observed in patients with newly diagnosed multiple myeloma (NDMM). However, the interpretation of the high-risk (HR) prognostic implications stemming from 1q21 abnormalities remain challenging to implement effectively. METHODS: In a comprehensive analysis of 367 consecutive patients with symptomatic MM, we assessed the prognostic significance of +1q21 using FISH with a threshold of 7.4%. The patient cohort was randomly divided into a training set (66.5%, n = 244) and a validation set (33.5%, n = 133). A multivariate Cox regression analysis was conducted to identify significant prognostic factors associated with PFS. Weight scores were assigned to each risk factor based on the ß-value of the corresponding regression coefficient. A predictive risk-scoring model involving +1q21 was then developed, utilizing the total score derived from these weight scores. The model's discriminative ability was evaluated using the AUC in both the training and validation sets. Finally, we compared the performance of the +1q21-involved risk with the established R-ISS and R2-ISS models. RESULTS: Upon initial diagnosis, 159 patients (43.32%) exhibited +1q21, with 94 (59.11%) having three copies, referred to as Gain(1q21), and 65 (40.89%) possessing four or more copies, referred to as Amp (1q21). Both were significantly linked to a reduced PFS in myeloma (p < 0.05), which could be effectively mitigated by ASCT. The +1q21-involved risk model, with an AUC of 0.697 in the training set and 0.725 in the validation set, was constructed including Gain(1q21), Amp(1q21), no-ASCT, and TP53 deletion. This model, termed the ultra-high-risk (UHR) model, demonstrated superior performance in predicting shorter PFS compared to the R-ISS stage 3 and R2-ISS stage 4. CONCLUSION: The UHR model, which integrates the presence of +1q21 with no-ASCT and TP53 deletion, is designed to identify the early relapse subgroup among patients with +1q21 in NDMM.

Asunto(s)

Cromosomas Humanos Par 1 , Mieloma Múltiple , Centros de Atención Terciaria , Mieloma Múltiple/mortalidad , Mieloma Múltiple/genética , Mieloma Múltiple/diagnóstico , Humanos , Femenino , Masculino , Cromosomas Humanos Par 1/genética , Persona de Mediana Edad , China/epidemiología , Pronóstico , Anciano , Medición de Riesgo/métodos , Factores de Riesgo , Adulto , Anciano de 80 o más Años

RESUMEN

Lysosomes are crucial in the tumour immune microenvironment, which is essential for the survival and homeostasis in multiple myeloma (MM). Here, we aimed to identify lysosome-related genes for the prognosis of MM and predicted their regulatory mechanisms. Gene expression profiles of MM from the GSE2658 and GSE57317 datasets were analysed. Lysosome-related differentially expressed genes (DEGs) were identified and used for molecular subtyping of MM patients. A prognostic model was constructed using univariate Cox regression and LASSO regression analyses. The relationship between prognostic genes, immune cell types, and autophagy pathways was assessed through correlation analysis. RT-qPCR was performed to validate the expression of prognostic genes in MM cells. A total of 9,954 DEGs were identified between high and low immune score groups, with 213 intersecting with lysosomal genes. Molecular subtyping revealed two distinct MM subtypes with significant differences in immune cell types and autophagy pathway activities. Five lysosome-related DEGs (CORO1A, ELANE, PSAP, RNASE2, and SNAPIN) were identified as significant prognostic markers. The prognostic model showed moderate predictive accuracy with AUC values up to 0.723. Prognostic genes demonstrated significant correlations with various immune cell types and autophagy pathways. Additionally, CORO1A, PSAP and RNASE2 expression was up-regulated in MM cells, while ELANE and SNAPIN were down-regulated. Five lysosomal genes in MM were identified, and a new risk model for prognosis was developed using these genes. This research could lead to discovering important gene markers for the treatment and prognosis of MM.

Asunto(s)

Lisosomas , Mieloma Múltiple , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Humanos , Lisosomas/metabolismo , Lisosomas/genética , Pronóstico , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Autofagia/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/genética

RESUMEN

The influence of chimeric antigen receptor T (CAR-T) cell therapy on platelet function in relapsed/refractory (R/R) multiple myeloma (MM) has not been thoroughly investigated. Our cohort comprised fifty MM patients treated with CAR-T cells. The mean platelet closure time (PCT) induced by collagen/adenosine diphosphate (CADP) in peripheral blood was significantly prolonged before lymphodepletion (195.24 ± 11.740 s) and notably reduced post-CAR-T cell therapy (128.02 ± 5.60 s), with a statistically significant improvement (67.22, 95% CI 46.91-87.53, P < 0.001). This post-treatment PCT was not significantly different from that of healthy controls (10.64, 95% CI 1.11-22.40, P > 0.05). Furthermore, a pronounced enhancement in PCT was observed in patients with a response greater than partial remission (PR) following CAR-T cell infusion compared to pre-treatment values (P < 0.001). An extended PCT was also associated with a less favorable remission status. In patients with cytokine release syndrome (CRS) grades 0-2, those with a PCT over 240.5 s exhibited a shorter progression-free survival (PFS), with median PFS times of 10.2 months for the PCT > 240.5 s group versus 22.0 months for the PCT ≤ 240.5 s group. Multivariate analysis revealed that a PCT value exceeding 240.5 s is an independent prognostic factor for overall survival (OS) in R/R MM patients after CAR-T cell therapy. The study demonstrates that CAR-T cell therapy enhances platelet function in R/R MM patients, and PCT emerges as a potential prognostic biomarker for the efficacy of CAR-T cell therapy.

Asunto(s)

Plaquetas , Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Resultado del Tratamiento , Receptores Quiméricos de Antígenos , Síndrome de Liberación de Citoquinas/terapia , Pruebas de Función Plaquetaria

Asunto(s)

Alopecia , Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Mieloma Múltiple Quiescente , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/epidemiología , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Alopecia/epidemiología , Alopecia/diagnóstico , Mieloma Múltiple/epidemiología , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/complicaciones , Femenino , Masculino , Mieloma Múltiple Quiescente/diagnóstico , Mieloma Múltiple Quiescente/epidemiología , Persona de Mediana Edad , Anciano , Estudios de Cohortes , Adulto , Tamizaje Masivo/métodos

RESUMEN

The recently published DreaMM-7 and -8 trials1,2 demonstrate the benefit of triplet combination regimens including the anti-BCMA antibody drug conjugate belantamab mafodotin. Here, we describe the findings of these trials including efficacy and safety data and provide commentary on the implications for future use of belantamab in the relapsed myeloma space.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico

RESUMEN

Endothelial Activation and Stress Index (EASIX) has been proposed as a prognostic factor of adverse events or survival in hematological malignancies. Endothelial dysfunction has been associated with complications following stem cell transplantation and chimeric antigen receptor (CAR)-T therapy. This retrospective cohort study evaluated the utility of the EASIX score as a prognostic factor of cytokine release syndrome (CRS) in multiple myeloma/light-chain amyloidosis (MM/AL amyloidosis; N = 69) and large B-cell lymphoma (LBCL) cohorts (N = 65). Occurrence of CRS grade ≥3 was the primary endpoint. For both cohorts, the EASIX and simplified EASIX (s-EASIX) scores were calculated at four different time points before CAR-T infusion to assess its prognostic value. In the MM/AL amyloidosis cohort, neither EASIX nor s-EASIX scores calculated at any time point were associated with the occurrence of CRS grade ≥3. In the LBCL cohort, EASIX and s-EASIX scores measured before lymphodepletion (EASIX-pre and s-EASIX-pre) showed a significant relationship with CRS grade ≥3 (odds ratio [OR] = 1.06 and OR = 1.05, respectively). The cutoff value of 1.835 for EASIX-pre was associated with 4.59-fold increased OR of CRS grade ≥3 (95% confidence interval [CI]: 1.13-21.84), whereas s-EASIX-pre cutoff equaled 2.134 and was associated with 4.13-fold increased OR of CRS grade ≥3 (95% CI: 1.01-17.93). However, after internal validation with bootstrapping, the significance was lost both for the EASIX-pre and s-EASIX-pre cutoff. The presented findings indicate that the EASIX scores fail to predict CRS in MM/amyloidosis CAR-T patients, whereas they can be implemented as CRS grade ≥3 predictors in LBCL CAR-T patients.

Asunto(s)

Síndrome de Liberación de Citoquinas , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Femenino , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Pronóstico , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/diagnóstico , Anciano , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Receptores Quiméricos de Antígenos/inmunología , Adulto , Estudios de Cohortes

RESUMEN

Multiple myeloma (MM) is a heterogeneous and incurable tumor characterized by the malignant proliferation of plasma cells. It is necessary to clarify the heterogeneity of MM and identify new theranostic targets. We constructed a single-cell transcriptome profile of 48,293 bone marrow cells from MM patients and health donors (HDs) annotated with 7 continuous B lymphocyte lineages. Through CellChat, we discovered that the communication among B lymphocyte lineages between MM and HDs was disrupted, and unique signaling molecules were observed. Through pseudotime analysis, it was found that the differences between MM and HDs were mainly reflected in plasma cells. These differences are primarily related to various biological processes involving mitochondria. Then, we identified the key subpopulation associated with the malignant proliferation of plasma cells. This group of cells exhibited strong proliferation ability, high CNV scores, high expression of frequently mutated genes, and strong glucose metabolic activity. Furthermore, we demonstrated the therapeutic potential of WNK1 as a target. Our study provides new insights into the development of B cells and the heterogeneity of plasma cells in MM and suggests that WNK1 is a potential therapeutic target for MM.

Asunto(s)

Mieloma Múltiple , Análisis de la Célula Individual , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Humanos , Análisis de la Célula Individual/métodos , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Transcriptoma/genética , Linfocitos B/metabolismo , Heterogeneidad Genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica

RESUMEN

Lenalidomide, bortezomib, and dexamethasone (RVd) have previously been established as standard-of-care induction therapy for newly diagnosed multiple myeloma (NDMM). More recently, randomized phase 3 data have demonstrated the benefit of the addition of daratumumab (Dara-RVd) to the RVd backbone in terms of improved both depth of response and long-term survival benefit as measured by progression-free survival (PFS). Our group has previously published on a historical cohort of 1000 NDMM patients uniformly treated with RVd induction with impressive both PFS and overall survival. Here, we present a comparative analysis of our RVd cohort with a recent cohort of 326 patients induced with Dara-RVd at our institution with intent to transplant. This analysis demonstrates the utility of this regimen in real-world clinical practice and provides additional insights into D-RVd performance in patient subsets often underrepresented in clinical trials, as well as the impact of daratumumab in maintenance for NDMM patients.

Asunto(s)

Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Lenalidomida , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Lenalidomida/uso terapéutico , Lenalidomida/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Adulto , Anciano de 80 o más Años , Estudios de Cohortes

RESUMEN

TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) cytogenetic abnormalities. This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress. Collectively, our discoveries highlight TRIM44's significant role in MM progression and resistance to therapy, suggesting its potential value as a therapeutic target.

Asunto(s)

Mieloma Múltiple , Complejo de la Endopetidasa Proteasomal , Proteínas de Motivos Tripartitos , Mieloma Múltiple/patología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/genética , Humanos , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Pronóstico , Línea Celular Tumoral , Complejo de la Endopetidasa Proteasomal/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Autofagia/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Inhibidores de Proteasoma/farmacología , Resistencia a Antineoplásicos/genética , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Regulación Neoplásica de la Expresión Génica