Cardiovascular disease in patients with multiple myeloma may derive from factors unrelated to the disease (age, diabetes, dyslipidemia, obesity, prior cardiovascular diseases), related to the disease ...(cardiac AL-amyloidosis, hyperviscosity, high-output failure, arteriovenous shunting, anemia, renal dysfunction) and/or related to anti-myeloma treatment (anthracyclines, corticosteroids, alkylating agents, immunomodulatory drugs, proteasome inhibitors). Good knowledge of cardiovascular events, effective dose reductions, prevention and management of early and late cardiovascular side effects of chemotherapeutic agents are essential in current clinical practice. Myeloma experts are obliged to carefully balance the efficacy and toxicity of drugs for each individual patient. This review summarizes current data and novel insights into cardiovascular adverse events of today's anti-myeloma treatment, focusing on carfilzomib, as a starting point for developing consensus recommendations on preventing and managing cardiovascular side effects in patients with multiple myeloma.
The discovery of new antigens specific to multiple myeloma that could be targeted by novel immunotherapeutic approaches is currently of great interest. To this end, it is important to increase the ...number of proteins identified in the sample by combining different separation strategies. A capillary zone electrophoresis (CZE) method, coupled with drift tube ion mobility (DTIMS) and quadrupole time-of-flight mass spectrometry (QTOF), was developed for antigen discovery using the human myeloma cell line LP-1. This method was first optimized to obtain a maximum number of identifications. Then, its performance in terms of uniqueness of identifications was compared to data acquired by a microfluidic reverse phase liquid chromatography (RPLC) method. The orthogonality of these two approaches and the physicochemical properties of the entities identified by CZE and RPLC were evaluated. In addition, the contribution of DTIMS to CZE was investigated in terms of orthogonality as well as the ability to provide unique information. In conclusion, we believe that the combination of CZE-DTIMS-QTOF and microfluidic RPLC provides unique information in the context of antigen discovery.
Multiple myeloma (MM) is a plasma cell malignancy that affects an increasing number of patients worldwide. Despite all the efforts to understand its pathogenesis and develop new treatment modalities, ...MM remains an incurable disease. Novel immunotherapies, such as CAR T cell therapy (CAR) and bispecific T cell engagers (BiTE), are intensively targeting different surface antigens, such as BMCA, SLAMF7 (CS1), GPRC5D, FCRH5 or CD38. However, stem cell transplantation is still indispensable in transplant-eligible patients. Studies suggest that the early use of immunotherapy may improve outcomes significantly. In this review, we summarize the currently available clinical literature on CAR and BiTE in MM. Furthermore, we will compare these two T cell-based immunotherapies and discuss potential therapeutic approaches to promote development of new clinical trials, using T cell-based immunotherapies, even as bridging therapies to a transplant.
Elevated aerobic glycolysis rate is a biochemical alteration associated with malignant transformation and cancer progression. This metabolic shift unavoidably generates methylglyoxal (MG), a potent ...inducer of dicarbonyl stress through the formation of advanced glycation end products (AGEs). We have previously shown that the silencing of glyoxalase 1 (GLO1), the main MG detoxifying enzyme, generates endogenous dicarbonyl stress resulting in enhanced growth and metastasis in vivo. However, the molecular mechanisms through which MG stress promotes metastasis development remain to be unveiled.
In this study, we used RNA sequencing analysis to investigate gene-expression profiling of GLO1-depleted breast cancer cells and we validated the regulated expression of selected genes of interest by RT-qPCR. Using in vitro and in vivo assays, we demonstrated the acquisition of a pro-metastatic phenotype related to dicarbonyl stress in MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cellular models. Hyperactivation of MEK/ERK/SMAD1 pathway was evidenced using western blotting upon endogenous MG stress and exogenous MG treatment conditions. MEK and SMAD1 regulation of MG pro-metastatic signature genes in breast cancer cells was demonstrated by RT-qPCR.
High-throughput transcriptome profiling of GLO1-depleted breast cancer cells highlighted a pro-metastatic signature that establishes novel connections between MG dicarbonyl stress, extracellular matrix (ECM) remodeling by neoplastic cells and enhanced cell migration. Mechanistically, we showed that these metastasis-related processes are functionally linked to MEK/ERK/SMAD1 cascade activation in breast cancer cells. We showed that sustained MEK/ERK activation in GLO1-depleted cells notably occurred through the down-regulation of the expression of dual specificity phosphatases in MG-stressed breast cancer cells. The use of carnosine and aminoguanidine, two potent MG scavengers, reversed MG stress effects in in vitro and in vivo experimental settings.
These results uncover for the first time the key role of MG dicarbonyl stress in the induction of ECM remodeling and the activation of migratory signaling pathways, both in favor of enhanced metastatic dissemination of breast cancer cells. Importantly, the efficient inhibition of mitogen-activated protein kinase (MAPK) signaling using MG scavengers further emphasizes the need to investigate their therapeutic potential across different malignancies.
Multiple myeloma is the second most common hematologic malignancy and occurs most commonly in elderly patients. Almost all multiple myeloma patients develop bone lesions in the course of their ...disease or have evidence of bone loss at initial diagnosis. Whole-body conventional radiography remains the gold standard in the diagnostic evaluation, but computed tomography, magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography are increasingly used as complementary techniques in the detection of bone lesions. Moreover, the number of lesions detected and the presence of extramedullary disease give strong prognostic information. These new techniques may help to assess treatment response in solitary plasmacytoma or in multiple myeloma. In this article, we review recent data on the different imaging techniques used at diagnosis and in the assessment of treatment response, and discuss some current issues.
We aimed to compare fatigue of newly diagnosed patients with myelodysplastic syndromes (MDS) with that of the general population (GP). We also investigated the ability of the IPSS and IPSS-R to ...capture severity of patient-reported fatigue at diagnostic workup. A sample of 927 newly diagnosed patients with MDS was consecutively enrolled in a large international observational study and all patients completed the FACIT-Fatigue questionnaire at baseline. Fatigue was compared with that of the GP (N = 1075) and a 3-point difference in mean scores was considered as clinically meaningful. Fatigue of MDS patients was on average 4.6 points below the mean of the GP (95% CI, -5.9 to -3.2, p < 0.001), reflecting clinically meaningful worse fatigue. Unlike the IPSS, the IPSS-R identified clearly distinct subgroups with regard to burden of fatigue. Mean scores differences compared with GP ranged from nonclinically relevant for very low risk (Δ = -1.8, 95% CI, -4.0 to 0.5, p = 0.119) to large clinically meaningful differences for very high-risk IPSS-R patients (Δ = -8.2, 95% CI, -10.3 to -6.2, p < 0.001). At diagnostic workup, fatigue of MDS is clinically meaningful worse than that reported by the GP. Compared with the IPSS classification, the IPSS-R provides a better stratification of patients with regard to fatigue severity.
Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene expression profiling-defined proliferation subgroup. Although ...recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified in order to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analyzed the activity of the MELK inhibitor OTSSP167 both
and
was found to be significantly overexpressed in the proliferative subgroup of myeloma. This finding translated into poor overall survival in patients with high
low
expression. Enrichment analysis of upregulated genes in myeloma cells of
patients confirmed the strong implications in myeloma cell proliferation. Targeting MELK with OTSSP167 impaired the growth and survival of myeloma cells, thereby affecting central survival factors such as
and
This activity was also observed in the 5TGM.1 murine model of myeloma. OTSSP167 reduced bone marrow infiltration and serum paraprotein levels in a dose-dependent manner. In addition, we revealed a strong link between MELK and other proliferation-associated high-risk genes (
) and MELK inhibition also impaired the expression of those genes. We therefore conclude that MELK is an essential component of a proliferative gene signature and that pharmacological inhibition of MELK represents an attractive novel approach to overcome the poor prognosis of high-risk patients with a proliferative expression pattern.
According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow ...plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of "monoclonal gammopathy of undetermined significance-like", in which patients never progress during their lifetimes, to "early multiple myeloma", in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a "split personality" makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.
Antibody-based therapies targeting CD38 are currently used as single agents as well as in combination regimens for multiple myeloma, a malignant plasma cell disorder. In this study, we aimed to ...develop anti-CD38 single-domain antibodies (sdAbs) that can be used to trace CD38
tumour cells and subsequently used for targeted radionuclide therapy. SdAbs are derived from Camelidae heavy-chain antibodies and have emerged as promising theranostic agents due to their favourable pharmacological properties.
Four different anti-CD38 sdAbs were produced, and their binding affinities and potential competition with the monoclonal antibody daratumumab were tested using biolayer interferometry. Their binding kinetics and potential cell internalisation were further studied after radiolabelling with the diagnostic radioisotope Indium-111. The resulting radiotracers were evaluated in vivo for their tumour-targeting potential and biodistribution through single-photon emission computed tomography (SPECT/CT) imaging and serial dissections. Finally, therapeutic efficacy of a lead anti-CD38 sdAb, radiolabelled with the therapeutic radioisotope Lutetium-177, was evaluated in a CD38
MM xenograft model. RESULTS : We retained anti-CD38 sdAb #2F8 as lead based on its excellent affinity and superior stability, the absence of competition with daratumumab and the lack of receptor-mediated internalisation. When intravenously administered to tumour-xenografted mice, radiolabelled sdAb #2F8 revealed specific and sustained tumour retention with low accumulation in other tissues, except kidneys, resulting in high tumour-to-normal tissue ratios. In a therapeutic setting, myeloma-bearing mice received three consecutive intravenous administrations of a high (18.5 MBq) or a low radioactive dose (9.3 MBq) of
Lu-DTPA-2F8 or an equal volume of vehicle solution. A dose-dependent tumour regression was observed, which translated into a prolonged median survival from 43 days for vehicle-treated mice, to 62 days (p = 0.027) in mice receiving the low and 65 days in mice receiving the high (p = 0.0007) radioactive dose regimen, respectively.
These results highlight the theranostic potential of radiolabelled anti-CD38 sdAbs for the monitoring and treatment of multiple myeloma.
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