Circulating clonotypic B cells in multiple myeloma and monoclonal gammopathy of undetermined significance

Thiago, Leandro S.; Pérez-Andrés, Martín; Balanzategui, Ana; Sarasquete, María Eugenia; Jara‐Acevedo, María; Bárcena, Paloma; Sánchez, María Luz; Almeida, Júlia; González, Marcos; Miguel, Jesús F. San; Órfão, Alberto

doi:10.3324/haematol.2013.092817

Cited by 22 publications

(14 citation statements)

References 38 publications

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“…However, recent investigations conducted with optimized molecular assessment of clonal variable, joining, and diversity (VDJ) sequences among FACS-sorted peripheral blood B-cell subsets revealed that such clonotypic cells are either absent or present below the detection limits (10 À6 ; ref. 37). Regarding the potential impact of genetic heterogeneity and clonal tiding after treatment on the feasibility of MFC to detect MRD, it should be highlighted that the multidimensional approach of current flow cytometry immunophenotyping not only allows detection of clonal heterogeneity in approximately 30% of newly diagnosed patients, but also makes it possible to monitor all the different phenotypic subclones throughout a patient's treatment, thereby assessing potential (phenotypical) clonal selection upon therapy.…”

Section: Advantages and Disadvantages Of Mrd Techniquesmentioning

confidence: 99%

Is This the Time to Introduce Minimal Residual Disease in Multiple Myeloma Clinical Practice?

Paiva

Puig

García‐Sanz

et al. 2015

Clinical Cancer Research

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Increasing therapeutic options and prolonged survival in multiple myeloma have raised interest in the concept of depth of response and its importance to predict patients' outcomes. Although the efficacy of current treatment approaches has greatly improved in the past decade, the definition of complete response (CR) remains unaltered and continues to use conventional serological and morphologic techniques. That notwithstanding, there is growing interest in minimal residual disease (MRD) monitoring, which has emerged in recent years as one of the most relevant prognostic factors in multiple myeloma. MRD can be assessed both inside (e.g., immunophenotypic and molecular techniques) and outside the bone marrow (e.g., PET/CT). Here, we focus on flow- and molecular-based assays by which different cooperative groups have demonstrated the efficacy of MRD assessment to predict outcomes even among patients in CR, and irrespectively of disease risk. Although further standardization is still required, the time has come to implement MRD monitoring in prospective clinical trials as a sensitive tool to evaluate treatment efficacy and for risk-adapted treatment, particularly in the consolidation and maintenance settings. Here, we present a comprehensive and critical review on the methodologic aspects, specific characteristics, and clinical significance of MRD monitoring by flow cytometry, PCR, and next-generation sequencing. Clin Cancer Res; 21(9); 2001–8. ©2015 AACR.

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Section: Advantages and Disadvantages Of Mrd Techniquesmentioning

confidence: 99%

Is This the Time to Introduce Minimal Residual Disease in Multiple Myeloma Clinical Practice?

Paiva

Puig

García‐Sanz

et al. 2015

Clinical Cancer Research

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“…55 Nevertheless, recent investigations conducted with sensitive ASO-PCR assessment of clonal Ig heavy (IGH) myeloma sequences among fluorescenceactivated cell sorter-sorted peripheral blood (PB) B-cell subsets, revealed that such clonotypic cells are either absent or present below highly sensitive limits of detection. 56 Highly sensitive MFC-based MRD monitoring (down to 10 25 ) requires the availability of $8-color digital flow cytometers coupled to novel sample preparation procedures that allow fast and costeffective, routine evaluation of .5 million nucleated cells (for detailed protocols, see www.EuroFlow.org; Table 1). This contrasts with previous MFC studies that defined MRD as the presence of a discrete population of clonal PCs at the 0.01% (ie, 10 24 ) limit of detection.…”

mentioning

confidence: 99%

New criteria for response assessment: role of minimal residual disease in multiple myeloma

Paiva

Dongen

Órfão

2015

Blood

263

271

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Assessment of minimal residual disease (MRD) is becoming standard diagnostic care for potentially curable neoplasms such as acute lymphoblastic leukemia. In multiple myeloma (MM), the majority of patients will inevitably relapse despite achievement of progressively higher complete remission (CR) rates. Novel treatment protocols with inclusion of antibodies and small molecules might well be able to further increase remission rates and potentially also cure rates. Therefore, MRD diagnostics becomes essential to assess treatment effectiveness. This review summarizes reports from the past 2 decades, which demonstrate that persistent MRD by multiparameter flow cytometry, polymerase chain reaction, next-generation sequencing, and positron emission tomography/computed tomography, predicts significantly inferior survival among CR patients. We describe the specific features of currently available techniques for MRD monitoring and outline the arguments favoring new criteria for response assessment that incorporate MRD levels. Extensive data indicate that MRD information can potentially be used as biomarker to evaluate the efficacy of different treatment strategies, help on treatment decisions, and act as surrogate for overall survival. The time has come to address within clinical trials the exact role of baseline risk factors and MRD monitoring for tailored therapy in MM, which implies systematic usage of highly sensitive, cost-effective, readily available, and standardized MRD techniques.

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“…4). Yet, the existence and phenotype of clonotypic B cells in the peripheral blood of MM patients is still a matter of debate (33, 35–37). Taken into account the phenotype of CD24 lo CD38 + CD27 + B cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mass Cytometry Analysis Shows That a Novel Memory Phenotype B Cell Is Expanded in Multiple Myeloma

Hansmann

Blum

et al. 2015

Cancer Immunology Research

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It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals and thus high resolution technologies are likely required. We used cytometry by time-of-flight (CyTOF) and next generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related pre-cancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 pre-cancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T, B, and natural killer cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0±0.7% (mean±SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27+) and naïve (CD24loCD38+) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells.

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Circulating clonotypic B cells in multiple myeloma and monoclonal gammopathy of undetermined significance

Cited by 22 publications

References 38 publications

Is This the Time to Introduce Minimal Residual Disease in Multiple Myeloma Clinical Practice?

Is This the Time to Introduce Minimal Residual Disease in Multiple Myeloma Clinical Practice?

New criteria for response assessment: role of minimal residual disease in multiple myeloma

Mass Cytometry Analysis Shows That a Novel Memory Phenotype B Cell Is Expanded in Multiple Myeloma

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