RESUMEN
In a short time, single-cell platforms have become the norm in many fields of research, including multiple myeloma (MM). In fact, the large amount of cellular heterogeneity in MM makes single-cell platforms particularly attractive because bulk assessments can miss valuable information about cellular subpopulations and cell-to-cell interactions. The decreasing cost and increasing accessibility of single-cell platform, combined with breakthroughs in obtaining multiomics data for the same cell and innovative computational programs for analyzing data, have allowed single-cell studies to make important insights into MM pathogenesis; yet, there is still much to be done. In this review, we will first focus on the types of single-cell profiling and the considerations for designing a single-cell profiling experiment. Then, we will discuss what have learned from single-cell profiling about myeloma clonal evolution, transcriptional reprogramming, and drug resistance, and about the MM microenvironment during precursor and advanced disease.
Asunto(s)
Mieloma Múltiple , Humanos , Mieloma Múltiple/metabolismo , Comunicación Celular , Evolución Clonal , Análisis de la Célula Individual , Microambiente TumoralRESUMEN
High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.
Asunto(s)
Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/diagnóstico , Melfalán/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Bortezomib/uso terapéutico , Lenalidomida/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad Crónica , Trasplante Autólogo , Dexametasona/uso terapéuticoRESUMEN
BACKGROUND: Obesity is an established risk factor for multiple myeloma (MM). Relatively few prior studies, however, have evaluated associations in Black populations. METHODS: Among 55,276 participants in the Black Women's Health Study, a prospective U.S. cohort established in 1995, we confirmed 292 incident diagnoses of MM over 26 years of follow-up. Multivariable Cox proportional hazard models, adjusted for age and putative MM risk factors, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of usual body mass index (BMI), BMI at age 18, height, and waist-to-hip ratio with MM. RESULTS: Compared to women with a usual adult BMI < 25 kg/m2, the HR associated with a usual adult BMI ≥ 35 kg/m2 was 1.38 (95% CI: 0.96, 1.98). For early adult BMI, the HR comparing women with BMI ≥ 25 vs. <25 kg/m2 was 1.57 (95% CI: 1.08, 2.28). Women who were heavy in both early and later life had the highest risk compared to those who were lean at both time points (HR: 1.60; 95% CI: 1.02, 2.52). Height was also associated with the risk of MM; the HR per 10 cm was 1.21 (95% CI: 1.02, 1.43). CONCLUSIONS: These results indicate that high early adult BMI is associated with a 57% increased risk of MM in Black women and potentially highlight the importance of weight control as a preventive measure.
Asunto(s)
Mieloma Múltiple , Adulto , Humanos , Femenino , Adolescente , Estudios Prospectivos , Mieloma Múltiple/epidemiología , Mieloma Múltiple/complicaciones , Obesidad/complicaciones , Obesidad/epidemiología , Tamaño Corporal , Factores de Riesgo , Salud de la Mujer , Índice de Masa Corporal , Modelos de Riesgos ProporcionalesRESUMEN
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. MM is a heterogeneous disease, featured by various molecular subtypes with different outcomes. With the advent of very efficient therapies including monoclonal antibodies, bispecific T-cell engagers and chimeric antigen receptor T cells (CAR T cells), most MM patients now have a prolonged survival. However, the disease remains incurable, and a subgroup of high-risk patients continue to have early relapse and short survival. Novel and highly sensitive methods have been developed allowing the detection of minimal residual disease (MRD) during or after treatment. Achievement of MRD negativity is a strong and independent prognostic factor in both prospective randomized clinical trials and in the real-world setting. While MRD assessment is now a validated endpoint in clinical trials, its incorporation in clinical practice is not yet established and its potential impact on guiding therapy remains under in-depth evaluation. Here we discuss the different methods available for MRD assessment and the role of MRD evaluation in MM management.
Asunto(s)
Mieloma Múltiple , Neoplasia Residual , Neoplasia Residual/diagnóstico , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Mieloma Múltiple/patología , Humanos , Pronóstico , Manejo de la Enfermedad , Biomarcadores de TumorRESUMEN
Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non-IgM-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by VHDHJH recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre-germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.
Asunto(s)
Inmunoglobulina M/genética , Mieloma Múltiple/genética , Transcriptoma , Macroglobulinemia de Waldenström/genética , Variaciones en el Número de Copia de ADN , Centro Germinal/metabolismo , Humanos , Mieloma Múltiple/diagnóstico , Mutación , Translocación Genética , Macroglobulinemia de Waldenström/diagnósticoRESUMEN
Daratumumab as a single agent (sDARA) or in combination with chemotherapies (cDARA) leads to impressive hematologic and organ responses in AL amyloidosis. However, predictive factors associated with outcomes, and optimal duration of therapy remain unclear. We analyzed 107 patients with AL amyloidosis treated with daratumumab between 2017 and 2020. The median overall survival (OS) was not reached while the median major organ deterioration progression free survival (MOD-PFS) was 36 months in the sDARA cohort and not reached in the cDARA cohort, respectively. Hematologic response > VGPR was achieved in 81% of patients receiving sDARA and 86% of patients treated with cDARA. Several predictive factors were identified on a univariate analysis, including NTproBNP >8500 pg/mL but only achievement of at least VGPR and presence of 1q21 gain were independently associated with MOD-PFS and OS on a multivariate analysis. Finally, patients receiving > 12 cycles had significantly longer MOD-PFS (30 vs.13 months; (p = .0018) and OS (NR vs. 15 months; p < .0001). NTproBNP > 8500 pg/mL, presence of 1q21 gain and shorter duration of therapy (≤ 12 cycles) are strong negative predictive factors for outcomes with daratumumab therapy in AL amyloidosis.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.
Asunto(s)
Amiloidosis , Trasplante de Células Madre Hematopoyéticas , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Amiloidosis/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Longitudinales , Melfalán/uso terapéutico , Trasplante de Células Madre , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1, IDH2, HUWE1, KLHL6, and PTPN11 Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3, DIS3, and PRKD2; t(11;14) with mutations in CCND1 and IRF4; t(14;16) with mutations in MAF, BRAF, DIS3, and ATM; and hyperdiploidy with gain 11q, mutations in FAM46C, and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/genética , Mutagénesis , Oncogenes , Células Clonales , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Conjuntos de Datos como Asunto , Dosificación de Gen , Estudio de Asociación del Genoma Completo , Inestabilidad Genómica , Genómica , Humanos , Pérdida de Heterocigocidad , Mieloma Múltiple/patología , Mutación , Pronóstico , Translocación Genética , Resultado del Tratamiento , Secuenciación del ExomaRESUMEN
Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4) and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-extracellular signal-regulated kinase pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. This set of data supports PAK4 as an oncogene in myeloma and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Inhibidores de Proteínas Quinasas/farmacología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Quinasas p21 Activadas/genética , Regulación Alostérica , Animales , Apoptosis/efectos de los fármacos , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/enzimología , Células de la Médula Ósea/patología , Caspasas/genética , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 4 , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/enzimología , Leucocitos Mononucleares/patología , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , Mieloma Múltiple/enzimología , Mieloma Múltiple/patología , Cultivo Primario de Células , Unión Proteica , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal , Translocación Genética , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas p21 Activadas/antagonistas & inhibidores , Quinasas p21 Activadas/metabolismoRESUMEN
BACKGROUND: Good syndrome (GS) is a rare condition in which thymoma is associated with hypogammaglobulinemia. It is characterized by increased susceptibility to bacterial, viral, and fungal infections, as well as autoimmunity. Most patients have no circulating B cells. METHODS: The French DEFicit Immunitaire de l'adulte cohort provides detailed clinical and immunological descriptions of 690 adults with primary hypogammaglobulinemia. Comparisons between patients with GS, those with common variable immunodeficiency (CVID), and those with B(-) CVID (circulating B cells <1%) were performed. RESULTS: Twenty-one patients had GS and 440 had CVID, including 39 B(-) CVID, with a median age at diagnosis of 60, 35, and 34 years, respectively. Invasive bacterial infections were observed in 90.5% of GS, 54% of CVID, and 72% of B(-) CVID patients. Eight patients with GS had opportunistic infections, despite normal peripheral CD4(+) T-cell numbers. Autoimmune complications were demonstrated in 76% of GS, 29% of CVID, and 26% of B(-) CVID patients. The spectrum of autoimmunity in GS was uncommon, consisting of oral lichen planus, graft-vs-host disease-like colitis, and pure red cell aplasia, different from the pattern observed in CVID patients. GS patients did not display lymphoid hyperplasia nor lymphoma, unlike those with CVID or B(-) CVID. CONCLUSIONS: GS differs notably from CVID and B(-) CVID: very late onset, no familial cases, and absence of lymphoid hyperplasia. The key observation is the very high frequency of invasive bacterial infections in GS, an issue that physicians should be aware of.
Asunto(s)
Autoinmunidad , Infecciones Bacterianas/etiología , Infecciones Bacterianas/inmunología , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/microbiología , Infecciones Oportunistas/etiología , Adulto , Agammaglobulinemia/complicaciones , Factores de Edad , Anciano , Linfocitos B/inmunología , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/microbiología , Colitis/diagnóstico , Colitis/etiología , Inmunodeficiencia Variable Común/complicaciones , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Humanos , Síndromes de Inmunodeficiencia/inmunología , Incidencia , Liquen Plano Oral/diagnóstico , Liquen Plano Oral/etiología , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/diagnóstico , Aplasia Pura de Células Rojas/diagnóstico , Aplasia Pura de Células Rojas/etiología , Linfocitos T/inmunología , Timoma/inmunologíaRESUMEN
Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m(2) and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Enfermedades Renales/fisiopatología , Mieloma Múltiple/tratamiento farmacológico , Macroglobulinemia de Waldenström/tratamiento farmacológico , Anciano , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Membrana Basal Glomerular/metabolismo , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Cadenas Pesadas de Inmunoglobulina/metabolismo , Cadenas Ligeras de Inmunoglobulina/metabolismo , Enfermedades Renales/inmunología , Enfermedades Renales/patología , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/complicaciones , Proteinuria/tratamiento farmacológico , Estudios Retrospectivos , Tasa de Supervivencia , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Macroglobulinemia de Waldenström/sangre , Macroglobulinemia de Waldenström/complicacionesRESUMEN
This retrospective analysis was conducted in 64 patients diagnosed with type I cryoglobulinaemia (CG) followed at two French centres. Median follow-up was 6·75 years. CG was IgG in 60% and IgM in 40% of all cases and was asymptomatic in 16 patients (25%). Cold-triggered ischaemic skin manifestations were observed in 33 patients (51%). Neurological manifestations were observed in 15 patients and renal manifestations in 13. Most of the patients with necrotic purpura (14/16, P = 0·009) and renal manifestations (11/13, P = 0·057) had IgG CG. IgG CG was associated with monoclonal gammopathy of undetermined significance (MGUS), myeloma, chronic lymphocytic leukaemia and lymphoplasmocytic lymphoma in 18, 13, 5 and 2 patients, respectively. IgM CG was associated with MGUS and Waldenström macroglobulinaemia in 8 and 18 cases, respectively. One third of patients did not receive any specific treatment. Various treatments, including rituximab, were administered to 25/31 patients with IgG CG and 6/25 patients with IgM CG due to CG-related symptoms. Rituximab was ineffective in all cases associated with a predominantly plasmacytic proliferation. To conclude, type I CG has specific clinico-biological characteristics compared to type II CG. Furthermore, there are differences in terms of related manifestations between type I IgG and type I IgM CG.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antineoplásicos/administración & dosificación , Crioglobulinemia , Inmunoglobulina G/sangre , Paraproteinemias , Macroglobulinemia de Waldenström , Anciano , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Antineoplásicos/efectos adversos , Crioglobulinemia/sangre , Crioglobulinemia/tratamiento farmacológico , Crioglobulinemia/patología , Femenino , Estudios de Seguimiento , Humanos , Isquemia/sangre , Isquemia/tratamiento farmacológico , Isquemia/patología , Riñón/patología , Enfermedades Renales/sangre , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Masculino , Paraproteinemias/sangre , Paraproteinemias/tratamiento farmacológico , Paraproteinemias/patología , Estudios Retrospectivos , Rituximab , Piel/irrigación sanguínea , Piel/patología , Enfermedades de la Piel/sangre , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/patología , Macroglobulinemia de Waldenström/sangre , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/patologíaRESUMEN
BACKGROUND: Neutrophilic dermatoses refer to a group of cutaneous inflammatory disorders characterized by neutrophilic infiltration of the skin. Neutrophilic dermatoses have been reported in association with various conditions including autoimmune diseases, inflammatory bowel diseases, and neoplasia. In the later condition, myeloproliferative disorders and monoclonal gammopathy (monoclonal immunoglobulin [MIg]) are the most frequent. Only few data are available in case of neutrophilic dermatoses associated with MIg regarding the pathophysiology and the clinical outcome. OBJECTIVE: We sought to gain further insight into clinical and biological aspects of neutrophilic dermatoses associated with MIg. METHODS: We report a retrospective series of 26 patients with neutrophilic dermatoses associated with MIg focusing on clinical and biological aspects, with a study of a large panel of cytokines, chemokines, and adhesion molecules. RESULTS: This study reveals an association between MIg IgA isotype and neutrophilic dermatoses, and a specific inflammatory pattern including elevated interleukin 6, vascular endothelial growth factor, monocyte chemotactic protein-1, epidermal growth factor, and intercellular adhesion molecule-1. LIMITATIONS: This is a retrospective study from a single institution with a limited number of participants. CONCLUSION: Our data highlight a strong association between IgA isotype and neutrophilic dermatoses, and the existence of a specific inflammatory profile involving several molecules.
Asunto(s)
Inmunoglobulina A/inmunología , Isotipos de Inmunoglobulinas/inmunología , Paraproteinemias/complicaciones , Paraproteinemias/inmunología , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Moléculas de Adhesión Celular/sangre , Quimiocinas/sangre , Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos , Paraproteinemias/diagnóstico , Estudios Retrospectivos , Enfermedades de la Piel/diagnósticoRESUMEN
The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.
Asunto(s)
Ensamble y Desensamble de Cromatina , Regulación Neoplásica de la Expresión Génica , Células Madre Mesenquimatosas , Mieloma Múltiple , Microambiente Tumoral , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Mieloma Múltiple/metabolismo , Humanos , Microambiente Tumoral/genética , Línea Celular Tumoral , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Transcripción Genética , Células de la Médula Ósea/metabolismo , Movimiento Celular/genética , Células del Estroma/metabolismo , Células del Estroma/patología , Femenino , MasculinoRESUMEN
Importance: Kidney light chain (AL) amyloidosis is associated with a risk of progression to kidney replacement therapy (KRT) and death. Several studies have shown that a greater reduction in proteinuria following successful anticlonal therapy is associated with improved outcomes. Objective: To validate graded kidney response criteria and their association with kidney and overall survival (OS). Design, Setting, and Participants: This retrospective, multicenter cohort was conducted at 10 referral centers for amyloidosis from 2010 to 2015 and included patients with kidney AL amyloidosis that was evaluable for kidney response and who achieved at least hematologic partial response within 12 months of diagnosis. The median follow-up was 69 (54-88) months. Data analysis was conducted in 2023. Exposure: Four kidney response categories based on the reduction in pretreatment 24-hour urine protein (24-hour UP) levels: complete response (kidCR, 24-hour UP ≤200 mg), very good partial response (kidVGPR, >60% reduction in 24-hour UP), partial response (kidPR, 31%-60% reduction), and no response (kidNR, ≤30% reduction). Kidney response was assessed at landmark points (6, 12, and 24 months) and best kidney response. Main Outcomes and Measures: Cumulative incidence of progression to KRT and OS. Results: Seven-hundred and thirty-two patients (335 women [45.8%]) were included, with a median (IQR) age of 63 (55-69) years. The median (IQR) baseline 24-hour proteinuria and estimated glomerular filtration rate was 5.3 (2.8-8.5) g per 24 hours and 72 (48-92) mL/min/1.73m2, respectively. In a competing-risk analysis, the 5-year cumulative incidence rates of progression to KRT decreased with deeper kidney responses as early as 6 months from therapy initiation (11%, 12%, 2.1%, and 0% for kidNR, kidPR, kidVGPR, and kidCR, respectively; P = .002) and were maintained at 12 months and 24 months and best kidney response. Patients able to achieve kidCR/kidVGPR by 24 months and at best response had significantly better OS compared with kidPR/kidNR. Kidney progression, defined as a 25% or greater decrease in estimated glomerular filtration rate, was associated with cumulative incidence of progression to KRT and OS. Conclusions and Relevance: The results of this cohort study suggest that graded kidney response criteria offers clinically and prognostically meaningful information for treating patients with kidney AL amyloidosis. The response criteria potentially inform kidney survival based on the depth of reduction in 24-hour proteinuria levels and demonstrate an OS advantage for those able to achieve kidCR/kidVGPR compared with kidPR/kidNR. Taken together, achievement of at least kidVGPR by 12 months is needed to ultimately improve kidney and patient survival.
RESUMEN
Xanthomas are a common manifestation of lipid metabolism disorders. They include hyperlipemic xanthoma, normolipemic xanthoma, and a related condition, necrobiotic xanthogranuloma (NXG). All 3 forms can be associated with monoclonal immunoglobulin (MIg). In an attempt to improve diagnosis, understanding, and treatment of this association, we retrospectively analyzed a personal series of 24 patients (2 hyperlipemic xanthoma, 11 normolipemic xanthoma, and 11 NXG) and 230 well-documented reports from the literature. With the exception of the nodules and plaques featured in NXG, the clinical presentation of xanthomatous lesions usually resembled that seen in common hyperlipidemic forms and could not be used to suspect MIg-associated xanthomas. Extracutaneous sites were not rare. The MIg was an IgG in 80% of cases. Myeloma was diagnosed in 35%. Hypocomplementemia with low C4 fraction was present in 80% of studied patients. Low C1 inhibitor serum levels were found in 53%. Cryoglobulinemia was detected in 27%. These abnormalities suggest immune complex formation because of interactions between the MIg and lipoproteins and argue in favor of a causal link between MIg and xanthomas. Monoclonal gammopathy therapy could thus be an option. Indeed, among the patients who received chemotherapy, hematologic remission was accompanied by improvement in xanthoma lesions in several cases.
Asunto(s)
Paraproteinemias/complicaciones , Paraproteinemias/terapia , Xantomatosis/complicaciones , Xantomatosis/terapia , Humanos , Paraproteinemias/diagnóstico , Paraproteinemias/patología , Estudios Retrospectivos , Piel/patología , Xantomatosis/diagnóstico , Xantomatosis/patologíaRESUMEN
PURPOSE: Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide. PATIENTS AND METHODS: This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival. RESULTS: 651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22% v 13.5% v 3.2%; P < .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively; P < .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation. CONCLUSION: Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.