Topical Collection "The Role of the Microenvironment in Multiple Myeloma: From Biology to Clinical Practice"
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Department of Hematology, Theagenion Cancer Hospital, A. Symeonidi 2, 54639 Thessaloniki, Greece
Interests: multiple myeloma and other plasma cell dyscrasias
Topical Collection Information
Dear Colleagues,
Multiple myeloma (MM) is an incurable hematological malignancy characterized by bone marrow (BM) infiltration by clonal plasma cells. Myeloma pathophysiology depends on several oncogenic events occurring in MM cells, and on extracellular factors, such as dynamic interactions between MM cells and the BM microenvironment, which are attributed to the clinical presentation of MM as well as to the progression of the precursor state of monoclonal gammopathy of undetermined significance (MGUS) to overt MM. Bone marrow microenvironment can be functionally divided into a cellular and non-cellular compartment, each of which have components playing distinct but interacting roles in the progression of MM. In this Special Issue, we will discuss the role of the BM microenvironment in MM cell growth and disease progression, as well as how this knowledge could be incorporated into the therapeutic design, to prevent MM progression, improve survival, and offer to our patients in the clinical setting a probability of cure.
Dr. Eirini Katodritou
Collection Editor
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Keywords
- multiple myeloma
- biology
- bone marrow microenvironment
- therapy
Published Papers (9 papers)
Open AccessArticle
Genetic and Functional Evidence of Complement Dysregulation in Multiple Myeloma Patients with Carfilzomib-Induced Thrombotic Microangiopathy Compared to Controls
by
, , , , , , , , , , , , , , , , , and | Viewed by 1082
Abstract
Background: Carfilzomib, an irreversible proteasome inhibitor approved for the treatment of relapsed/refractory Multiple Myeloma (MM) has been associated with Thrombotic Microangiopathy (TMA). Several pathogenetic mechanisms of carfilzomib-induced TMA have been proposed; however, recently, there has been a shift of focus on the potential
[...] Read more.
Background: Carfilzomib, an irreversible proteasome inhibitor approved for the treatment of relapsed/refractory Multiple Myeloma (MM) has been associated with Thrombotic Microangiopathy (TMA). Several pathogenetic mechanisms of carfilzomib-induced TMA have been proposed; however, recently, there has been a shift of focus on the potential contribution of complement dysregulation. Our aim was to explore whether patients with carfilzomib-induced TMA harbor germline variants of complement-related genes, which have been characterized as risk factors for TMA. Methods: We retrospectively recruited consecutive MM patients with carfilzomib-induced TMA and compared them to MM patients who received ≥4 cycles of carfilzomib and did not develop signs/symptoms of TMA, in a 1:2 ratio. Genomic DNA from peripheral blood was analyzed using next generation sequencing (NGS) with a complement-related gene panel; ADAMTS13 activity and soluble C5b-9 were measured using ELISA. Results: Complement-related variants were more common in patients with carfilzomib-induced TMA compared to non-TMA controls, regardless of patient and treatment characteristics; ADAMTS13 activity and C5b-9 were compatible with the phenotype of complement-related TMA. Conclusions: We confirmed the previous findings that implicated complement-related genes in the pathogenesis of carfilzomib-induced TMA. Most importantly, by incorporating a control group of non-TMA MM patients treated with carfilzomib-based regimens and functional complement assays, we enhanced the credibility of our findings.
Full article
Open AccessArticle
Newly Diagnosed Multiple Myeloma Patients with Skeletal-Related Events and Abnormal MRI Pattern Have Poor Survival Outcomes: A Prospective Study on 370 Patients
by
, , , , , , , , , , , , , and | Viewed by 1211
Abstract
Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among
[...] Read more.
Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most common reported SREs (48%). The incidence of SREs at diagnosis was higher in patients with osteolytic lesions, abnormal MRI pattern, hypercalcemia, and at least 60% bone marrow infiltration by plasma cells. Importantly, the patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median OS in comparison with the patients who had abnormal MRI patterns and/or the presence of SREs at diagnosis (9.3 vs. 6.6 years,
p = 0.048). Our data, which represent one of a few systematic reports on the incidence and characteristics of SREs in the era of novel agents, was indicative of a high incidence of SREs at the time of MM diagnosis. Early detection of myeloma bone disease and tailored patient management are essential to optimize patient outcomes.
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Open AccessArticle
CD24 Is a Prognostic Marker for Multiple Myeloma Progression and Survival
Cited by 6 | Viewed by 1317
Abstract
Surface antigens are commonly used in flow cytometry assays for the diagnosis of multiple myeloma (MM). Some of these are directly involved in MM pathogenesis or interactions with the microenvironment, but most are used for either diagnostic or prognostic purposes. In a previous
[...] Read more.
Surface antigens are commonly used in flow cytometry assays for the diagnosis of multiple myeloma (MM). Some of these are directly involved in MM pathogenesis or interactions with the microenvironment, but most are used for either diagnostic or prognostic purposes. In a previous study, we showed that in-vitro, CD24-positive plasma cells exhibit a less tumorigenic phenotype. Here, we assessed the prognostic importance of CD24 expression in patients newly diagnosed with MM as it correlates to their clinical course. Immunophenotyping by flow cytometry of 124 patients uniformly treated by a bortezomib-based protocol was performed. The expression of CD24, CD117, CD19, CD45, and CD56 in bone marrow PCs was tested for correlations to clinical parameters. None of the CD markers correlated with the response rates to first-line therapy. However, patients with elevated CD24+ expression on their PCs at diagnosis had a significantly longer PFS (
p = 0.002) and OS (
p = 0.044). In contrast, the expression of CD117, CD56, or CD45 was found to have no prognostic value; CD19 expression was inversely correlated with PFS alone (
p < 0.001) and not with OS. Thus, elevated CD24 expression on PCs appears to be strongly correlated with survival and can be used as a single-surface antigenic prognostic factor in MM.
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Open AccessReview
Understanding the Bioactivity and Prognostic Implication of Commonly Used Surface Antigens in Multiple Myeloma
Cited by 4 | Viewed by 1720
Abstract
Multiple myeloma (MM) progression is dependent on its interaction with the bone marrow microenvironment and the immune system and is mediated by key surface antigens. Some antigens promote adhesion to the bone marrow matrix and stromal cells, while others are involved in intercellular
[...] Read more.
Multiple myeloma (MM) progression is dependent on its interaction with the bone marrow microenvironment and the immune system and is mediated by key surface antigens. Some antigens promote adhesion to the bone marrow matrix and stromal cells, while others are involved in intercellular interactions that result in differentiation of B-cells to plasma cells (PC). These interactions are also involved in malignant transformation of the normal PC to MM PC as well as disease progression. Here, we review selected surface antigens that are commonly used in the flow cytometry analysis of MM for identification of plasma cells (PC) and the discrimination between normal and malignant PC as well as prognostication. These include the markers: CD38, CD138, CD45, CD19, CD117, CD56, CD81, CD27, and CD28. Furthermore, we will discuss the novel marker CD24 and its involvement in MM. The bioactivity of each antigen is reviewed, as well as its expression on normal vs. malignant PC, prognostic implications, and therapeutic utility. Understanding the role of these specific surface antigens, as well as complex co-expressions of combinations of antigens, may allow for a more personalized prognostic monitoring and treatment of MM patients.
Full article
Open AccessReview
Regulatory T-Cells and Multiple Myeloma: Implications in Tumor Immune Biology and Treatment
Cited by 9 | Viewed by 2092
Abstract
Multiple myeloma (MM) is associated with both cellular and humoral immune deficiencies and, despite significant advances in treatment, remains an incurable disease. Regulatory T-cells (Tregs) represent a critical subset of CD4 T-cells, characterized by CD4 + CD25+ Forkhead box P3+ (FoxP3+) phenotype, able
[...] Read more.
Multiple myeloma (MM) is associated with both cellular and humoral immune deficiencies and, despite significant advances in treatment, remains an incurable disease. Regulatory T-cells (Tregs) represent a critical subset of CD4 T-cells, characterized by CD4 + CD25+ Forkhead box P3+ (FoxP3+) phenotype, able to control peripheral tolerance and responses to foreign and tumor antigens. Tregs are elevated in various types of cancer, including hematological malignancies; in MM, data regarding Tregs function and numbers and their correlation with survival parameters are controversial. Advances in cancer biology have shown that the tumor microenvironment plays an important role in tumor progression. In MM, the highly immunosuppressive nature of the bone marrow microenvironment has been significantly elucidated in the past decade and it is now well acknowledged that targeting only the tumor clone may not be able to cure MM. Tregs within the tumor microenvironment might play a significant role in the suppression of antitumor immune responses against cancer cells and are considered to predict poor outcome in cancer patients; nonetheless the exact prognostic significance of this cell subpopulation in malignancies is still a matter of debate. In this review, we discuss the role of Tregs as an essential cell population of the MM immune microenvironment.
Full article
Open AccessArticle
The Potential Role of Proinflammatory Cytokines and Complement Components in the Development of Drug-Induced Neuropathy in Patients with Multiple Myeloma
by
, , , , , , , , , , , , , , , and | Viewed by 1544
Abstract
The launch of novel chemotherapeutic agents—in particular, proteasome inhibitors and immunomodulatory drugs—dramatically changed multiple myeloma (MM) therapy, improving the response rate and prolonging progression-free survival. However, none of the anti-MM drugs are deprived of side effects. Peripheral neuropathy (PN) seems to be one
[...] Read more.
The launch of novel chemotherapeutic agents—in particular, proteasome inhibitors and immunomodulatory drugs—dramatically changed multiple myeloma (MM) therapy, improving the response rate and prolonging progression-free survival. However, none of the anti-MM drugs are deprived of side effects. Peripheral neuropathy (PN) seems to be one of the most pressing problems. Despite extensive research in this area, the pathogenesis of drug-induced peripheral neuropathy (DiPN) has not yet been fully elucidated. In the present study, we aimed to assess the potential relationship between proinflammatory factors and the development of PN in MM patients with particular emphasis on the application of VTD (bortezomib, thalidomide, dexamethasone) regimen. Our analysis identified increased concentrations of CCL2, IL-1β, and IFN-γ in plasma of MM patients during treatment, both with and without symptoms of PN, compared with untreated neuropathy-free MM patients. At the same time, the plasma concentration of IL-1β in patients with neuropathy was significantly increased compared with patients without PN before and during treatment. Moreover, the results were enhanced at the transcript level by performing global mRNA expression analysis using microarray technology. The most significant changes were observed in the expression of genes responsible for regulating immunological and apoptotic processes. An in-depth understanding of the mechanisms responsible for the development of DiPN might in the future reduce the incidence of PN and accelerate diagnosis, allowing the choice of neuropathy-free treatment strategies for MM.
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Open AccessReview
Myeloma Bone Disease: The Osteoblast in the Spotlight
Cited by 6 | Viewed by 2468
Abstract
Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity)
[...] Read more.
Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity) and a downregulation of bone formation (via reduced osteoblast (OB) activity), leading to phenotypic osteolysis. Treatments are limited, and currently exclusively target OCs. Despite existing bone targeting therapies, patients successfully achieving remission from their cancer can still be left with chronic pain, poor mobility, and reduced quality of life as a result of bone disease. As such, the field is desperately in need of new and improved bone-modulating therapeutic agents. One such option is the use of bone anabolics, drugs that are gaining traction in the osteoporosis field following successful clinical trials. The prospect of using these therapies in relation to myeloma is an attractive option, as they aim to stimulate OBs, as opposed to existing therapeutics that do little to orchestrate new bone formation. The preclinical application of bone anabolics in myeloma mouse models has demonstrated positive outcomes for bone repair and fracture resistance. Here, we review the role of the OB in the pathophysiology of myeloma-induced bone disease and explore whether novel OB targeted therapies could improve outcomes for patients.
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Open AccessReview
Bone Marrow Microenvironment Interplay and Current Clinical Practice in Multiple Myeloma: A Review of the Balkan Myeloma Study Group
by
, , , , , , , , , , , and | Viewed by 2327
Abstract
The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the interplay of treatment modalities used in the current clinical practice and
[...] Read more.
The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the interplay of treatment modalities used in the current clinical practice and TME. Bortezomib-based triplets are the standard for MM first-line treatment. Bortezomib is a proteasome inhibitor (PI) which inhibits the nuclear factor kappa B (NF-κB) pathway. However, bortezomib is decreasing the expression of chemokine receptor CXCR4 as well, possibly leading to the escape of extramedullary disease. Immunomodulatory drugs (IMiDs), lenalidomide, and pomalidomide downregulate regulatory T cells (Tregs). Daratumumab, anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody (MoAb), downregulates Tregs CD38+. Bisphosphonates inhibit osteoclasts and angiogenesis. Sustained suppression of bone resorption characterises the activity of MoAb denosumab. The plerixafor, used in the process of stem cell mobilisation and harvesting, block the interaction of chemokine receptors CXCR4-CXCL12, leading to disruption of MM cells’ interaction with the TME, and mobilisation into the circulation. The introduction of several T-cell-based immunotherapeutic modalities, such as chimeric-antigen-receptor-transduced T cells (CAR T cells) and bispecific antibodies, represents a new perspective in MM treatment affecting TME immune evasion. The optimal treatment approach to MM patients should be adjusted to all aspects of the individual profile including the TME niche.
Full article
Open AccessArticle
Plasmacytoid Dendritic Cells in Patients with MGUS and Multiple Myeloma
Cited by 5 | Viewed by 1548
Abstract
Background: Plasmacytoid dendritic cells (pDCs) play prominent roles in mediating innate and adaptive immune responses. However, it is unclear how pDCs contribute to the immunosuppressive tumor microenvironment described in multiple myeloma (MM). Methods: Newly diagnosed myeloma patients (MM,
n = 37) were analyzed
[...] Read more.
Background: Plasmacytoid dendritic cells (pDCs) play prominent roles in mediating innate and adaptive immune responses. However, it is unclear how pDCs contribute to the immunosuppressive tumor microenvironment described in multiple myeloma (MM). Methods: Newly diagnosed myeloma patients (MM,
n = 37) were analyzed to determine the pDC counts in comparison to peripheral blood (PB,
n = 53) and bone marrow (BM,
n = 10) samples of age-matched healthy donors (HD) using flow cytometry. Second, proliferation of myeloma tumor cells in the presence of freshly isolated pDCs was examined. Third, production of IFNα by pDCs co-cultured with MM cells was determined by intracellular staining. Results: We found a highly significant reduction of circulating pDCs (
p < 0.0001) and in bone marrow (
p < 0.0001) of MM patients compared to HD. We also observed a significant decrease of pDCs (
p = 0.004) in BM in patients with monoclonal gammopathy of undetermined significance (MGUS,
n = 12). Importantly, we determined that pDCs promote proliferation specifically of MM cells and not the stromal cells and that pDCs secrete IFNα upon co-culture with MM tumor cells. Conclusions: Our results show altered pDC frequencies in the BM microenvironment in MGUS and MM patients at diagnosis. We showed the tumor-promoting function of pDCs that may mediate immune deficiencies affecting long-term disease control and treatment outcome.
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