RESUMEN
ABSTRACT: Smoldering multiple myeloma (MM) is an asymptomatic clonal plasma cell condition considered as a premalignant entity that may evolve over time to symptomatic MM. Based on a "poorly defined" risk of progression, some well-intended investigators proposed prospective interventional trials for these individuals. We believe this may be a harmful intervention and favor a close "wait and watch" approach and rather enroll these patients in dedicated observational biological studies aiming to better identify patients who will evolve to MM, based on their plasma cells' biology, including genomics, epigenetics, and the immune microenvironment.
Asunto(s)
Mieloma Múltiple Quiescente , Humanos , Mieloma Múltiple Quiescente/diagnóstico , Mieloma Múltiple Quiescente/patología , Progresión de la Enfermedad , Microambiente Tumoral/inmunología , Células Plasmáticas/patología , Mieloma Múltiple/patología , Mieloma Múltiple/genética , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapiaRESUMEN
Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering myeloma and monoclonal gammopathy of uncertain significance and all are characterised by the presence of a monoclonal protein in the blood. Diagnosis and distinction between these conditions is based on blood tests, the bone marrow biopsy and cross sectional imaging. There are various risk stratification models that group patients with smouldering myeloma into risk groups based on risk of progression to symptomatic disease. Management is mainly observational for patients with smouldering myeloma although clinical trials for high-risk disease may be available. Restaging is required if evidence for progression.
Asunto(s)
Hematología , Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Mieloma Múltiple Quiescente , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Mieloma Múltiple/patología , Células Plasmáticas/patología , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Gammopatía Monoclonal de Relevancia Indeterminada/terapia , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mieloma Múltiple Quiescente/diagnóstico , Mieloma Múltiple Quiescente/terapia , Mieloma Múltiple Quiescente/patología , Progresión de la EnfermedadRESUMEN
All patients with a diagnosis of multiple myeloma (MM) have a preceding, asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM). While most patients with monoclonal gammopathy of undetermined significance have a very small rate of progression, SMM is a widely heterogeneous condition where a fraction of patients will progress to symptomatic MM rather quickly, while others will experience an indolent clinical course. The differentiation between progressive and stable precursor condition thus represents one of the most important unmet clinical needs in the MM community. The ability to identify patients at high-risk of progression before major clonal expansion and onset of end-organ damage would enable strategies for early prevention and perhaps more effective intervention. All proposed criteria to predict the progression of myeloma precursor conditions are built around indirect markers of disease burden and, therefore, are generally able to accurately identify only a small fraction of patients in whom progression to MM is already occurring. Leveraging whole genome and exome sequencing, it has been shown that patients with stable myeloma precursor conditions are characterized by either absence or lower prevalence of distinct genomic events that are detectable in progressive precursor condition years before the progression. In this review, we discuss evolving genomic concepts and tools; and their ability to differentiate myeloma precursor conditions into two distinct entities: one benign (monoclonal gammopathy of benign significance) and another malignant (asymptomatic multiple myeloma).
Asunto(s)
Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Mieloma Múltiple Quiescente , Progresión de la Enfermedad , Genómica , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mieloma Múltiple/patología , Mieloma Múltiple Quiescente/patologíaRESUMEN
Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Ciclo Celular , Evolución Molecular , Mieloma Múltiple/patología , Células Plasmáticas/patología , Complejo Represivo Polycomb 2/metabolismo , Mieloma Múltiple Quiescente/patología , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Células Plasmáticas/metabolismo , Complejo Represivo Polycomb 2/genética , Pronóstico , Transducción de Señal , Mieloma Múltiple Quiescente/genética , Mieloma Múltiple Quiescente/metabolismoRESUMEN
The adage for smoldering myeloma (SMM) has been to observe without treatment, until criteria for active multiple myeloma were satisfied. Definitions and risk stratification models have become more sophisticated, with prognostication tailored to include high-risk cytogenetics as per the most recent International Myeloma Working Group 2020 risk model. Moreover, progress in defining genomic evolution and changes in the bone marrow microenvironment through the monoclonal continuum have given insight into the complexities underlying the different patterns of progression observed in SMM. Given recent data showing improved progression-free survival with early intervention in high-risk SMM, the current dilemma is focused on how these patients should be treated. This case-based article maps the significant advancements made in the diagnosis and risk stratification of SMM. Data from landmark clinical trials will also be discussed, and ongoing trials are summarized. Ultimately, we outline our approach to SMM and hope to impart to the reader a sound concept of the current clinical management of SMM.
Asunto(s)
Mieloma Múltiple Quiescente/diagnóstico , Mieloma Múltiple Quiescente/terapia , Manejo de la Enfermedad , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Mieloma Múltiple Quiescente/etiología , Mieloma Múltiple Quiescente/patologíaAsunto(s)
Neoplasias de Cabeza y Cuello , Histiocitosis , Neoplasias Cutáneas , Mieloma Múltiple Quiescente , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Histiocitosis/metabolismo , Histiocitosis/patología , Humanos , Persona de Mediana Edad , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Mieloma Múltiple Quiescente/metabolismo , Mieloma Múltiple Quiescente/patologíaRESUMEN
Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n = 15) are characterized by later initiation in the patient's life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.
Asunto(s)
Genoma Humano/genética , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Mieloma Múltiple/genética , Mieloma Múltiple Quiescente/genética , Variaciones en el Número de Copia de ADN/genética , Progresión de la Enfermedad , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mieloma Múltiple/patología , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Mieloma Múltiple Quiescente/patología , Secuenciación Completa del GenomaRESUMEN
Smoldering multiple myeloma is a heterogeneous asymptomatic precursor to multiple myeloma. Since its identification in 1980, risk stratification models have been developed using two main stratification methods: clinical measurement-based and genetics-based. Clinical measurement models can be subdivided in three types: baseline measurements (performed at diagnosis), evolving measurements (performed over time during follow-up appointments), and imaging (for example, magnetic resonance imaging). Genetic approaches include gene expression profiling, DNA/RNA sequencing, and cytogenetics. It is important to accurately distinguish patients with indolent disease from those with aggressive disease, as clinical trials have shown that patients designated as "high-risk of progression" have improved outcomes when treated early. The risk stratification models, and clinical trials are discussed in this review.
Asunto(s)
Medición de Riesgo , Mieloma Múltiple Quiescente/terapia , Ensayos Clínicos como Asunto , Citogenética , ADN/genética , Humanos , ARN/genética , Factores de Riesgo , Mieloma Múltiple Quiescente/genética , Mieloma Múltiple Quiescente/patologíaRESUMEN
Minimal residual disease (MRD) assessment is incorporated in an increasing number of multiple myeloma (MM) clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy. There is substantial heterogeneity across clinical trials in how MRD is assessed and reported, creating challenges for data interpretation and for the design of subsequent studies. We convened an international panel of MM investigators to harmonize how MRD should be assessed and reported in MM clinical trials. The panel provides consensus on which MM trials should include MRD, the recommended time points for MRD assessment, and expected analytical validation for MRD assays. We subsequently outlined parameters for reporting MRD results implementing the intention-to-treat principle. The panel provides guidance regarding the incorporation of newer peripheral blood-based and imaging-based approaches to detection of residual disease. Recommendations are summarized in 13 consensus statements that should be followed by sponsors, investigators, editors, and reviewers engaged in designing, performing, and interpreting MM trials.
Asunto(s)
Mieloma Múltiple/epidemiología , Mieloma Múltiple/patología , Neoplasia Residual/diagnóstico , Neoplasia Residual/epidemiología , Ensayos Clínicos como Asunto , Diagnóstico por Imagen , Manejo de la Enfermedad , Sensibilidad Colateral al uso de Fármacos , Salud Global , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Mieloma Múltiple/terapia , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Evaluación de Resultado en la Atención de Salud , Vigilancia de la Población , Reproducibilidad de los Resultados , Mieloma Múltiple Quiescente/epidemiología , Mieloma Múltiple Quiescente/patología , Factores de TiempoAsunto(s)
Mieloma Múltiple/epidemiología , Mieloma Múltiple Quiescente/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Biomarcadores de Tumor , Médula Ósea/patología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Cadenas kappa de Inmunoglobulina/sangre , Cadenas lambda de Inmunoglobulina/sangre , Masculino , Persona de Mediana Edad , Modelos Biológicos , Proteínas de Mieloma/análisis , Células Plasmáticas/patología , Modelos de Riesgos Proporcionales , Curva ROC , Riesgo , Medición de Riesgo , Índice de Severidad de la Enfermedad , Mieloma Múltiple Quiescente/sangreRESUMEN
Multiple myeloma (MM) is a highly heterogenous disease that exists along a continuous disease spectrum starting with premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) that inevitably precede MM. Over the past two decades, significant progress has been made in the genetic characterization and risk stratification of precursor plasma cell disorders. Indeed, the clinical introduction of highly effective and well-tolerated drugs begs the question: would earlier therapeutic intervention with novel therapies in MGUS and SMM patients alter natural history, providing a potential curative option? In this review, we discuss the epidemiology of MGUS and SMM and current models for risk stratification that predict MGUS and SMM progression to MM. We further discuss genetic heterogeneity and clonal evolution in MM and the interplay between tumor cells and the bone marrow (BM) microenvironment. Finally, we provide an overview of the current recommendations for the management of MGUS and SMM and discuss the open controversies in the field in light of promising results from early intervention clinical trials.
Asunto(s)
Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Gammopatía Monoclonal de Relevancia Indeterminada/tratamiento farmacológico , Mieloma Múltiple Quiescente/diagnóstico , Mieloma Múltiple Quiescente/tratamiento farmacológico , Progresión de la Enfermedad , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Factores de Riesgo , Mieloma Múltiple Quiescente/patologíaRESUMEN
We conducted a retrospective review of multiple myeloma (MM), smoldering multiple myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) patients seen at Mayo Clinic to determine whether a bone marrow biopsy (BM) is necessary in all patients diagnosed with a monoclonal protein. A total of 2254 MM, 397 SMM, and 5836 MGUS patients were included in the study. A total of 29 (1.3%) MM patients "without CRAB/FLC" were identified where BM or advanced imaging was critical for diagnosis, 8 (0.3% MM cohort) of whom were diagnosed with MM solely on BM findings (plasma cells > 60%). Without BM or advanced imaging none of these patients would be classified low-risk MGUS. A total of 314 (79%) MGUS-like SMM patients were identified where classification of SMM was based on BM findings. Without BM 97 would be classified as low/low-intermediate-risk MGUS and 151 intermediate or high-risk MGUS; 66 had missing information precluding classification. Only three (<1% SMM cohort) were low-risk MGUS without abnormalities in hemoglobin, calcium, and renal function. In patients presenting with low-risk MGUS and normal hemoglobin, calcium, and renal function, the risk of missing a diagnosis of SMM and MM by omitting BM is <1%. BM should be deferred in these patients in preference to clinical and laboratory monitoring.
Asunto(s)
Médula Ósea/patología , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mieloma Múltiple/patología , Células Plasmáticas/patología , Mieloma Múltiple Quiescente/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Mieloma Múltiple/diagnóstico , Estudios Retrospectivos , Mieloma Múltiple Quiescente/diagnóstico , Adulto JovenAsunto(s)
Infecciones por VIH/complicaciones , Hemangioma Capilar/complicaciones , Hemangioma Capilar/patología , Síndrome POEMS/complicaciones , Síndrome POEMS/patología , Mieloma Múltiple Quiescente/complicaciones , Mieloma Múltiple Quiescente/patología , Adulto , Femenino , Hemangioma Capilar/congénito , HumanosRESUMEN
Recent clinical trials have addressed the notion of early treatment of smoldering multiple myeloma (SMM). The results evidence improvement in progression-free survival and, in one study, overall survival. Although the treatment of SMM can be considered under specific circumstances, we propose here that careful interpretation of the clinical trials and the patient-specific data are needed before recommending therapy. In particular, many questions remain regarding the best regimen to be used as well as how to adapt based on the underlying disease biology. Hematologists should have a very thorough understanding of models designed to predict the progression from SMM to multiple myeloma, because their correct interpretation is paramount to establish proper care. Although there is no doubt that treatment should be started before overt end-organ damage, we do not believe that the current data support the widespread treatment of all SMM.
Asunto(s)
Mieloma Múltiple Quiescente/terapia , Progresión de la Enfermedad , Humanos , Pronóstico , Mieloma Múltiple Quiescente/patologíaRESUMEN
Fluorine-18 (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET) allows evaluation of elevated glucose metabolism in malignancies. There has been increasing interest in FDG PET/CT for plasma cell disorders since the International Myeloma Working Group outlined multiple applications of this imaging modality, including distinguishing smoldering myeloma from active multiple myeloma, confirmation of solitary plasmacytoma, and multiple indications in patients with known multiple myeloma, including determining extent of initial disease, monitoring therapy response, and detection of residual disease following therapy. The field of molecular imaging is now shifting focus from evaluation of metabolism to targeted evaluation of specific tumor markers. Targeted PET imaging targeted of CXCR4 and CD38 has advanced into translational clinical trials, bringing us closer to powerful imaging options for myeloma. In this review we discuss the current applications of FDG PET/CT in plasma cell disorders, as well as advances in targeted PET imaging.
Asunto(s)
Fluorodesoxiglucosa F18/metabolismo , Proteínas de Neoplasias/genética , Plasmacitoma/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Mieloma Múltiple Quiescente/diagnóstico por imagen , ADP-Ribosil Ciclasa 1/genética , ADP-Ribosil Ciclasa 1/metabolismo , Antígeno de Maduración de Linfocitos B/genética , Antígeno de Maduración de Linfocitos B/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Médula Ósea/metabolismo , Médula Ósea/patología , Progresión de la Enfermedad , Expresión Génica , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasia Residual , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Plasmacitoma/genética , Plasmacitoma/metabolismo , Plasmacitoma/patología , Radiofármacos/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Mieloma Múltiple Quiescente/genética , Mieloma Múltiple Quiescente/metabolismo , Mieloma Múltiple Quiescente/patologíaRESUMEN
Multiple myeloma, a bone marrow cancer, is preceded by precursor stages called monoclonal gammopathy of unknown significance and smoldering multiple myeloma. Over the past few years, highly effective and safe therapies have been made available to treat multiple myeloma. This represents a major breakthrough and has major therapeutic implications. Treatment for multiple myeloma has evolved to include treatment of precursor stages (early treatment) as these therapies are shown to be safe and effective also in smoldering myeloma. Randomized studies have shown that early treatment can delay the onset of multiple myeloma and even improve overall survival compared to observation in smoldering myeloma. The best therapeutic course and selection of patients with smoldering myeloma to treat is still a matter of debate. In this manuscript, we review the definition, management, clinical implications of smoldering myeloma and early detection of myeloma in the current context and with up-to-date data.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Lenalidomida/uso terapéutico , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Mieloma Múltiple/diagnóstico , Oligopéptidos/uso terapéutico , Mieloma Múltiple Quiescente/diagnóstico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Médula Ósea/patología , Dexametasona/uso terapéutico , Progresión de la Enfermedad , Esquema de Medicación , Detección Precoz del Cáncer , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/tratamiento farmacológico , Gammopatía Monoclonal de Relevancia Indeterminada/mortalidad , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Neoplasia Residual , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Mieloma Múltiple Quiescente/tratamiento farmacológico , Mieloma Múltiple Quiescente/mortalidad , Mieloma Múltiple Quiescente/patología , Análisis de SupervivenciaRESUMEN
Smouldering multiple myeloma (SMM) presents without MM defining symptoms. We aimed to identify patients with SMM with an 80% risk of progression within 2 years using only serum parameters. In total, 527 patients with SMM were included and divided into a training group (287 patients from the Czech Myeloma Group [CMG]) and an independent validation group (240 patients from Heidelberg). The median follow-up was 2·4 and 2·5 years, respectively. Progression to MM occurred in 51·9% of the CMG and 38·8% of the Heidelberg patients, respectively. The median risk of progression was 11·0% (CMG) and 9·7% (Heidelberg) per year, during the 5 years after diagnosis. A serum involved/uninvolved free light-chain ratio of >30, immunoparesis, and serum monoclonal (M) protein of ≥2·3 g/dl emerged as powerful predictors of 2-year progression rate with a hazard ratio (HR) of 2·49 (95% confidence interval [CI] 1·49-4·17), HR of 2·01 (95% CI 1·36-2·96) and HR of 2·00 (95% CI 1·44-2·79) (P < 0·001) in univariate Cox regression analysis, respectively. Based on this, the CMG model identified patients with SMM with a 2-year risk of progression of 78·7% (95% CI 53·1-95·7; HR 6·8; P < 0·001, CMG) and 81·3% (95% CI 47·1-98·8; HR 38·63; P < 0·001, Heidelberg). Serum parameters in the CMG model allow identification of patients with SMM with an 80% risk of progression to symptomatic MM within 2 years.
Asunto(s)
Mieloma Múltiple Quiescente/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , República Checa , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Mieloma Múltiple Quiescente/patologíaRESUMEN
Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014-0.096), 0.102 (80% CI, 0.044-0.160), and 0.206 (80% CI, 0.118-0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025-0.092), 0.107 (80% CI, 0.058-0.155), and 0.150 (80% CI, 0.089-0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four-month PFS rates were 89.9% (90% CI, 78.5-95.4%), 82.0% (90% CI, 69.0-89.9%), and 75.3% (90% CI, 61.1-85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.