Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous “omas” throughout the skeleton, indicating that there is continuous trafficking of tumor cells ...to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic factors that mediate tumor invasiveness as well as factors present in the tumor microenvironment that are permissive to oncogenic proliferation. Therapeutic agents that target the different steps of cell dissemination and progression are discussed. Despite the significant advances in the treatment of MM, better therapeutic agents that target this metastatic cascade are urgently needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple myeloma (MM) is a genetically complex disease that evolves from pre-malignant stages, such as monoclonal gammaopathy of undetermined significance and smouldering multiple myeloma, and ...progresses to symptomatic MM; this continuum provides a unique framework to study the sequential genomic evolution of MM. In the past 5 years, results from large-scale whole-exome sequencing studies have provided new insights into the clonal heterogeneity and evolution of the disease. Moreover, the recurrent co-occurrence of genomic events helps to dissect the genomic complexity underlying tumour progression. According to the primary genetic events involved in tumorigenesis, MM tumours are hierarchically subdivided into hyperdiploid and non-hyperdiploid subtypes; subsequently, secondary genetic events lead to tumour progression. In this Review, we describe the 'driver' gene alterations involved in the development and progression of MM, with a focus on the sequential acquisition of the main genomic aberrations. We also provide valuable insight into the clonal heterogeneity and clonal evolution of the disease, as well as into the therapeutic implications of a comprehensive understanding of the genomic complexity of MM.
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NUK, OILJ, SBMB, UL, UM, UPUK
Treon et al provide early clinical data supporting a theoretical rationale for continuing ibrutinib in patients receiving the drug during COVID-19 illness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. The recent advances in our knowledge about MGUS and smoldering multiple myeloma (SMM) have helped us better ...understand the pathogenesis of myeloma. It seems that myeloma evolves from a precursor state in almost all cases. We do not completely understand the multistep process from the precursor state to myeloma, but studies like whole genome sequencing continue to improve our understanding of this process. The process of transformation may not be linear acquisition of changes, but rather a branched heterogeneous process. Clinical features that are prognostic of rapid transformation have been identified, but no specific molecular markers have been identified. Even with recent advances, multiple myeloma remains an incurable disease in the vast majority, and intervening at the precursor state provides a unique opportunity to alter the natural history of the disease. A limitation is that a vast majority of patients with precursor disease, especially low-risk MGUS, will never progress to myeloma in their lifetime, and treating these patients is not only unnecessary but may be potentially harmful. The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. As our understanding of the molecular and genetic processes improves, these studies will guide the selection of high-risk patients more appropriately and ultimately direct a tailored management strategy to either delay progression to symptomatic myeloma or even "cure" a person at this premalignant stage.
One of the great advances in the field of cancer therapy in recent years is the emergence of immune therapies. Immune therapies, especially immune checkpoint inhibitors, have shown promising results ...in pre-clinical models and clinical trials of solid tumors, such as melanoma, breast cancer and lung cancer. Therapeutic strategies targeting the immune microenvironment have also been applied to hematological malignancies such as multiple myeloma (MM), a plasma cell neoplasia characterized by clonal proliferation of malignant plasma cells mainly in the bone marrow (BM). MM is associated with both cellular and humoral immune deficiencies, indicating that the evolution of the disease from a precursor state (monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (sMM)) is associated with an immunosuppressive milieu that fosters immune escape and tumor growth. Despite significant advances in treatment, MM is mostly an incurable disease. Therefore, it is vital to develop novel therapeutic agents that not only target the MM clone itself but also the MM immune microenvironment. However, the complexity of the BM microenvironment and heterogeneity of tumor cell clones make it a difficult task for developing appropriate immune therapies of MM. In this article, we review the current knowledge of the interaction between malignant plasma cells and the bone marrow immune microenvironment during disease progression.
Summary
Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow (BM). Despite the significant advances in treatment, MM is still a fatal malignancy. ...This is mainly due to the supportive role of the BM microenvironment in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM microenvironment is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a non‐cellular compartment. In this review, we discuss the interaction between the malignant plasma cell and the BM microenvironment and the strategy to target them.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Haematological malignancies were previously thought to be driven solely by genetic or epigenetic lesions within haematopoietic cells. However, the niches that maintain and regulate daily production ...of blood and immune cells are now increasingly being recognized as having an important role in the pathogenesis and chemoresistance of haematological malignancies. Within haematopoietic cells, the accumulation of a small number of recurrent mutations initiates malignancy. Concomitantly, specific alterations of the niches, which support haematopoietic stem cells and their progeny, can act as predisposition events, facilitating mutant haematopoietic cell survival and expansion as well as contributing to malignancy progression and providing protection of malignant cells from chemotherapy, ultimately leading to relapse. In this Perspective, we summarize our current understanding of the composition and function of the specialized haematopoietic niches of the bone marrow during health and disease. We discuss disease mechanisms (rather than malignancy subtypes) to provide a comprehensive description of key niche-associated pathways that are shared across multiple haematological malignancies. These mechanisms include primary driver mutations in bone marrow niche cells, changes associated with increased hypoxia, angiogenesis and inflammation as well as metabolic reprogramming by stromal niche cells. Consequently, remodelling of bone marrow niches can facilitate immune evasion and activation of survival pathways favouring malignant haematopoietic cell maintenance, defence against excessive reactive oxygen species and protection from chemotherapy. Lastly, we suggest guidelines for the handling and biobanking of patient samples and analysis of the niche to ensure that basic research identifying therapeutic targets can be more efficiently translated to the clinic. The hope is that integrating knowledge of how bone marrow niches contribute to haematological disease predisposition, initiation, progression and response to therapy into future clinical practice will likely improve the treatment of these disorders.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The microenvironment in myeloma Lomas, Oliver C; Tahri, Sabrin; Ghobrial, Irene M
Current opinion in oncology,
2020-March, 2020-03-00, 20200301, Volume:
32, Issue:
2
Journal Article
PURPOSE OF REVIEWThe aim of the review is to describe recent advances in our understanding of how multiple myeloma interacts with its cellular and molecular neighbours in the bone marrow ...microenvironment, and how this may provide targets for prognostication and prevention.
RECENT FINDINGSThe bone marrow microenvironment in myeloma is beginning to yield targets that are amenable to therapy. A number of trials demonstrate some clinical efficacy in heavily pretreated disease. The challenge remains for how and when these therapeutic interventions are of particular benefit early in disease progression.
SUMMARYMultiple myeloma is rarely curable and its interactions with the bone marrow microenvironment are evident. However, separating cause from effect remains a challenge. We propose that targeting specific niches within the bone marrow will yield therapies that have the potential for significant benefit in myeloma and may facilitate earlier intervention to disrupt an environment that is permissive for myeloma progression.
Exosomes, secreted by several cell types, including cancer cells, can be isolated from the peripheral blood and have been shown to be powerful markers of disease progression in cancer. In this study, ...we examined the prognostic significance of circulating exosomal microRNAs (miRNAs) in multiple myeloma (MM). A cohort of 156 patients with newly diagnosed MM, uniformly treated and followed, was studied. Circulating exosomal miRNAs were isolated and used to perform a small RNA sequencing analysis on 10 samples and a quantitative reverse transcription polymerase chain reaction (qRT-PCR) array on 156 samples. We studied the relationship between miRNA levels and patient outcomes, including progression-free survival (PFS) and overall survival (OS). We identified miRNAs as the most predominant small RNAs present in exosomes isolated from the serum of patients with MM and healthy controls by small RNA sequencing of circulating exosomes. We then analyzed exosomes isolated from serum samples of 156 patients using a qRT-PCR array for 22 miRNAs. Two of these miRNAs, let-7b and miR-18a, were significantly associated with both PFS and OS in the univariate analysis and were still statistically significant after adjusting for the International Staging System and adverse cytogenetics in the multivariate analysis. Our findings support the use of circulating exosomal miRNAs to improve the identification of patients with newly diagnosed MM with poor outcomes. The results require further validation in other independent prospective MM cohorts.
•Two circulating exosomal microRNAs, let-7b and miR-18a, improved survival prediction in patients with MM.•Circulating exosomal miRNAs enhanced the stratification of patients with high-risk factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hematologic malignancies rely heavily on support from host cells through a number of well-documented mechanisms. Host cells, specifically mesenchymal stem cells (MSC), support tumor cell growth, ...metastasis, survival, bone marrow colonization, and evasion of the immune system. In multiple myeloma, similar to solid tumors, supporting cells have typically been considered healthy host cells. However, recent evidence reveals that many MSCs derived from patients with multiple myeloma (MM-MSC) show significant defects compared with MSCs from nondiseased donors (ND-MSC). These abnormalities range from differences in gene and protein expression to allelic abnormalities and can initiate after less than 1 day of coculture with myeloma cells or persist for months, perhaps years, after removal from myeloma influence. Alterations in MM-MSC function contribute to disease progression and provide new therapeutic targets. However, before the scientific community can capitalize on the distinctions between MM-MSCs and ND-MSCs, a number of confusions must be clarified, as we have done in this review, including the origin(s) of MM-MSCs, identification and characterization of MM-MSCs, and downstream effects and feedback circuits that support cancer progression. Further advances require more genetic analysis of MM-MSCs and disease models that accurately represent MSC-MM cell interactions.
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