Utilizing next-generation sequencing in the management of multiple myeloma

Lionetti, Marta; Neri, Antonino

doi:10.1080/14737159.2017.1332996

Cited by 29 publications

(29 citation statements)

References 82 publications

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“…Cutting-edge next-generation sequencing (NGS) technology has now made it possible to acquire a more comprehensive view of genomic alterations in MM. NGS not only offers genome-scale data but can also detect very low-frequency mutations [ 29 ]. Not surprisingly, NGS-based methods substantially improved the sensitivity of MRD detection in MM [ 30 ].…”

Section: Multiple Myeloma—epidemiology and Aetiologymentioning

confidence: 99%

The NF-κB Activating Pathways in Multiple Myeloma

2018

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Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-κB) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal through the canonical as well as the non-canonical arms to activate the NF-κB system in myeloma cells. In fact, frequent engagement of both the NF-κB pathways constitutes a distinguishing characteristic of myeloma. In turn, NF-κB signaling promotes proliferation, survival and drug-resistance of myeloma cells. In this review article, we catalog NF-κB activating genetic mutations and microenvironmental cues associated with multiple myeloma. We then describe how the individual canonical and non-canonical pathways transduce signals and contribute towards NF-κB -driven gene-expressions in healthy and malignant cells. Furthermore, we discuss signaling crosstalk between concomitantly triggered NF-κB pathways, and its plausible implication for anomalous NF-κB activation and NF-κB driven pro-survival gene-expressions in multiple myeloma. Finally, we propose that mechanistic understanding of NF-κB deregulations may provide for improved therapeutic and prognostic tools in multiple myeloma.

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Section: Multiple Myeloma—epidemiology and Aetiologymentioning

confidence: 99%

The NF-κB Activating Pathways in Multiple Myeloma

2018

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“…Because MM evolves secondary to acquired genetic events 18 , efforts toward individualizing treatments have, until now, focused on sequencing strategies [19][20][21] . Such early efforts have, however, failed to stimulate an era of precision medicine since actionable mutations are rare, subclonal, and lack matched therapeutics.…”

Section: Introductionmentioning

confidence: 99%

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

et al. 2020

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Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

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“…Improved understanding of clonal dynamics is likely to have an impact on the prognostication and treatment of MM in the future. The field where NGS is closest to routine clinical application is in the detection of minimal residual disease (MRD) [ 43 ]. NGS-based quantification of clonotypic immunoglobulin gene rearrangements is the basis for this technique, which will be discussed in detail in the subsequent section [ 44 ].…”

Section: Genetic and Genomic Techniques In Multiple Myelomamentioning

confidence: 99%

Potential Clinical Application of Genomics in Multiple Myeloma

Soekojo

Mel

Ooi

et al. 2018

IJMS

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Multiple myeloma is a heterogeneous disease with different characteristics, and genetic aberrations play important roles in this heterogeneity. Studies have shown that these genetic aberrations are crucial in prognostication and response assessment; recent efforts have focused on their possible therapeutic implications. Despite many emerging studies being published, the best way to incorporate these results into clinical practice remains unclear. In this review paper we describe the different genomic techniques available, including the latest advancements, and discuss the potential clinical application of genomics in multiple myeloma.

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Utilizing next-generation sequencing in the management of multiple myeloma

Abstract: Introduction: Multiple myeloma (MM) is a bone marrow plasma cell malignancy characterized by

Cited by 29 publications

References 82 publications

The NF-κB Activating Pathways in Multiple Myeloma

The NF-κB Activating Pathways in Multiple Myeloma

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

Potential Clinical Application of Genomics in Multiple Myeloma

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