Clonal Proliferation Of Plasma Cells Research Articles

P851: TARGETING GENE DEPENDENCIES IN MYC OVEREXPRESSING MULTIPLE MYELOMA

Background: Multiple myeloma (MM) is an incurable hematological malignancy characterized by a proliferation of clonal plasma cells in bone marrow. MM progresses from precursor stages, named monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to the symptomatic myeloma, MM. MYC abnormalities play a critical role in the disease progression. However, MYC is not therapeutically targetable due to its nuclear localization and the short half-life of the protein. Aims: To overcome this, we hypothesized that the proliferative advantage promoted by MYC overexpression induces differential genomic dependencies on other signaling pathways thus creates vulnerabilities that can be exploited therapeutically. Methods: We searched for genetic vulnerabilities associated with MYC overexpression by leveraging genome-scale pooled short hairpin RNA screening data for 236 cancer cell lines from Project Achilles. We generated an isogenic model of MYC overexpression (OE) in U266 cell line using EF1A-C-MYC lentiviral vector. Then, we performed RNA-seq, quantitative proteomics by Tandem Mass Tag mass spectrometry (TMT-MS) and a drug screening with ~2000 compounds. For validation, we performed pharmacological inhibition of glutamine catabolism as well as shRNA-mediated GLS1 knockdown. To determine the functional mechanisms, we used capillary electrophoresis-mass spectrometry (CE-MS) and Agilent Seahorse XF analyzer. Results: Achilles analysis revealed main dependencies associated with MYC overexpression on glutamine metabolism and specifically GLS1 (glutaminase) and SLC1A1 (glutamine transporter). Using a screening of 2000 small molecules, we further observed that inhibitors of NAD synthesis and mTORC1, which rely on the intracellular glutamine pool, had preferential effect on the proliferation of U266/MYC. Both RNA-seq and quantitative proteomics showed no significant upregulation of glutaminolysis related genes, suggesting a non-oncogenic dependency. Our validation tests confirmed this metabolic dependency, MYC OE cell lines failed to proliferate in the context of glutamine starvation and showed higher sensitivity to CB-839 and V-9302 inhibiting GLS1 and SLC1A5, respectively. Using the Seahorse analyzer, we measured the oxygen consumption rate (OCR) induced by glutamine. U266/MYC cells possess the ability to oxidize glutamine at a higher rate compared to U266/Ctrl. Additionally, higher sensitivity of U266/MYC to CB-839 was observed on both baseline and FCCP-induced OCR highlighting the role of glutamine in controlling mitochondrial OXPHOS in MYC OE cells. To understand the differential metabolic rewiring in MYC OE cells, we performed metabolomic analysis and observed higher GLS1 activity in U266/MYC presented by elevated glutamine to glutamate flux. We also identified the enriched metabolic pathways under GLS1 inhibition. Notably, CB-839 in U266/MYC results in more pronounced changes in TCA cycle and energy debt. This effect was blunted by the co-incubation with a-ketoglutarate, in a rescue experiment. Interestingly GLS1 inhibition was not limited to this effect, but extended to redox balance. CB839 significantly decreased glutathione level in U266/MYC. Furthermore, the intracellular concentrations of the glutamate-dependent amino acids were more depleted under GLS1 inhibition in U266/MYC compared to U266/Ctrl. Summary/Conclusion: Combining these observations, we were able to identify vulnerabilities to glutamine metabolism in MYC overexpressing cells. These results may lead to developing new therapeutic strategies to target MYC in clinical practice.

P868: A CIRCULATING SERUM MIRNAS-BASED MODEL TO PREDICT EARLY MORTALITY IN MULTIPLE MYELOMA PATIENTS TREATED WITH BORTEZOMIB-BASED REGIMENS.

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. Despite the progress made in the treatment of MM, some patients die within the first year of diagnosis. Numerous studies underline the role of miRNAs in the pathogenesis of MM and their potential role in prognosis. Aims: The aim of this study was to analyze the expression of selected miRNAs in the serum of MM patients treated with bortezomib-based regimens and determine their potential to predict early mortality. Methods: The study was conducted in prospectively-recruited patients with newly-diagnosed MM who were qualified for bortezomib-based treatment regimens. All were admitted to the Department of Hematology, Medical University of Lodz between 2017 and 2021. Venous blood samples were collected from the patients before treatment initiation, processed, and stored for further use. Total RNA, including miRNA, was isolated from serum, and reverse-transcribed to cDNA. The expression of 31 selected miRNAs was determined using a miRCURY LNA miRNA Custom PCR Panel. The miRNA selection was based on the results of our previous study (Robak et al., Cancers Cancers (Basel) 2020; 12(9): 2569). Three miRNAs were used for expression normalization: hsa-miR-23b-3p, hsa-miR-151a-5p and hsa-miR-152-3p. Clinical data, including patient characteristics on diagnosis, treatment regimen, response to treatment and follow-up were obtained from hospital records. Differential expression analysis, univariate and multivariate logistic regression models were performed using R version 3.6.3. Results: A total of 69 MM patients were included in the study with a mean age at diagnosis of 64.9 ± 11.0 years. Among them, 17 patients experienced death within 12 months of diagnosis. Patients with early mortality were significantly older (72.6 vs. 62.3 years, p=0.0005), and more frequently men (70.6% vs. 42.3%, p=0.0429). No differences were observed in R-ISS distribution or CRAB symptoms between the groups, nor were any significant differences between percentage myeloma infiltration in the bone marrow and various laboratory findings, including LDH, serum M protein, albumin, CRP, and uric acid. In the differential expression analysis, two miRNAs were significantly downregulated in early mortality group- hsa-miR-328-3p (fold change- FC: 0.72, p=0.0342) and hsa-miR-409-3p (FC: 0.49, p=0.0357). Similarly, hsa-miR-328-3p (OR 0.44, 95%CI: 0.20-0.97, p=0.0415) and hsa-miR-409-3p (OR 0.69, 95%CI: 0.48-0.98, p=0.0400) were found to have a protective effect against early mortality in univariate analyses. The multivariate logistic regression analysis found that miRNAs retained their significance when established clinical prognostic factors were included. The final model consisted of hsa-miR-409-3p (OR 0.61, 95%CI: 0.37-0.99, p=0.0480), hsa-miR-328-3p (OR 0.33, 95%CI: 0.13-0.87, p=0.0254), age (OR 1.13, 95%CI: 1.03-1.23, p=0.0096) and R-ISS 3 (OR 2.91, 95%CI: 0.63-13.47, p=0.1723). A receiver operating characteristics (ROC) analysis for the model yielded an area under the curve (AUC) of 0.863 (95%CI: 0.761-0.965). At the optimal cut-off value of 0.28, the sensitivity and specificity reached 88.2% and 77.5%, respectively. Image:Summary/Conclusion: hsa-miR-409-3p and hsa-miR-328-3p are independent factors related to early mortality in MM patients. Our results were used to generate a multiple regression model that may have the potential to predict early mortality. Further external validation of our model is necessary to confirm its clinical value.

PB2015: YOUNG ADULTS WITH MULTIPLE MYELOMA – A SINGLE CENTER EXPERIENCE

Background: Multiple myeloma (MM) is a plasma-cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow with monoclonal protein in the serum and/or urine, and associated organ dysfunction. It mainly affects the elderly population and is uncommon in younger than 40 years and extremely rare before 30 years. Since this is an incurable disease, it is important to understand its behavior in young adult patients for a better therapeutic decision and surveillance. Aims: Description of presenting features and outcomes of MM patients ≤45 years. Methods: Retrospective review of MM patients, aged ≤45 years followed up in a tertiary hospital, between 2008 and 2021. Data analysis was performed using the statistical program IBM SPSS Statistics 26®. The overall survival (OS) and progression-free survival (PFS) was estimated by the Kaplan‐Meier method. Results: It was included 28 patients [71,4% male (n=20), 28,6% female (n=8)], with a median age at diagnosis of 41 years (36-45). M-proteins consisted of IgG (n=12, 45%), IgA (n=9, 31,1%), light-chain (n=4, 14,3%) and non-secretory disease (n=1, 3,6%). According to the International Staging System (ISS), 35,7%, 35,7%, and 17,9% of the patients had stage I, II, and III disease at the time of diagnosis, respectively. The most common ‘CRAB’ symptom was bone disease (n=17, 60,4%), followed by anemia (n=10, 35,7%), hypercalcemia (n=5, 17,9%) and kidney failure (n=3, 10,7%); 12 patients (42,9%) had two or more ‘CRAB’ symptoms. Fluorescence in situ hybridization (FISH) was done in 57,1% patient specimens, and cytogenetic high-risk abnormalities [del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation] were detected in 6 cases. Other chromosomal abnormalities, namely del(13q) and t(11;14) were found in 2 and 3 patients, respectively. Patients received induction treatment according local protocols [Vd (n=11), VTd (n10), CBd (n=3), VAd (n=2), TD (n=1), VTd-PACE (n=1)] followed by autologous stem cell transplant (ASCT). No patients had allogeneic stem cell transplant. Median follow-up time 68 months (7-165) with relapse was seen in 16 patients (57,1%) and the estimated median time until progression was 52 months. OS was not reached. Using univariate logistic regression analysis no association was found between overall survival or response to therapy, and disease staging, CRAB symptoms, cytogenetic abnormalities, immunophenotypic features or treatment strategy. Summary/Conclusion: Most data regarding the impact of age on survival mainly come from clinical trials developed before the current therapy choices were in use. However, some real-life studies evaluating young population of MM patients has been conducted to identify patient and disease features may have impact on this group of patients. The results of these studies are heterogeneous. On the other hand, in our population, ISS, CRAB symptoms, cytogenetic data, immunophenotypic features and treatment was not shown to have an impact on clinical course of the disease or survival. This study has limitations, particularly attributable to its retrospective nature, small number of patients within a single institution and lack of detailed information regarding imaging techniques, and comorbidities.

Abstract 6354: Using imaging mass cytometry to visualize the multiple myeloma tumor microenvironment post immune priming

Abstract Background: Multiple myeloma (MM) is an incurable cancer characterized by clonal plasma cell proliferation in the bone marrow, accounting for approximately 10% of all hematologic malignancies. Recently, patients with relapsed or refractory disease have been treated with a combination of the oncolytic reovirus Pelareorep, bortezomib, and dexamethasone, which was well-tolerated and led to prolonged progression free survival of over 3 years in a subset of patients. To understand the complex tumor immune microenvironment (TiME) and immune responses in patients before and after this treatment, we used imaging mass cytometry (IMC) to perform single cell, highly multiplexed, analysis of these patients’ bone marrow samples. Methods: We comprehensively characterized the changes in the MM TIME in pre and post bone marrow biopsy specimens taken from patients treated on a Phase 1b study with a combination of Pelareorep, bortezomib, and dexamethasone. For analysis with IMC, a marker panel of 35 antibodies was assembled to interrogate the various immune subsets of the bone marrow biopsies; each of these antibodies were conjugated to a unique metal isotope. After validation, the antibody cocktail was used to stain the biopsies. Pixel-based classification was performed in Ilastik to generate cell probability masks and processed in Cellprofiler. PhenoGraph was run in HistoCAT to identify the unique phenotypes. Rstudio was used for t-stochastic neighborhood embedding (tSNE) plot generation, and nearest neighbor analyses. ImaCytE was used for image visualization and spatial analysis. Results: Initial visualization of the raw, unsegmented data showed increased infiltration of natural killer cells and T cells in the post-treatment samples when compared against the pre-treatment samples. These changes correlated with immunohistochemical findings, clinical response to treatment, and changes in T cell clonality. After segmentation, the marker expression heatmaps for each of the clusters identified by PhenoGraph and the further subphenotyping in Rstudio showed complex ecosystems of cell-cell interactions. Nearest neighbor spatial analysis of the post-treatment samples revealed that NK cells (NKG2D+ and NKG2A+ subsets), monocytes (CD14+), macrophages (CD68+), cytotoxic T cells (CD3+, CD8+), and T helper cells (CD3+, CD4+) were significantly closer to the Pelareorep-primed MM than the non-primed MM. Further analysis in ImaCytE highlighted specific instances of these immune neighborhoods. Conclusions: IMC allows us to analyze the potent immune response and cellular interactions in the tumor microenvironment in multiple myeloma treated with Pelareorep and Bortezomib. Characterization of these complex interactions allows for a deeper understanding of the key mechanisms of action of these treatments and planning of future combination studies. Citation Format: Julian Olea, Kaijin Wu, Anthony Colombo, Claudia Villa Celi, Thomas Heineman, Matt Coffey, Steffan T. Nawrocki, Akil Merchant, Kevin R. Kelly. Using imaging mass cytometry to visualize the multiple myeloma tumor microenvironment post immune priming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6354.

Abstract 6374: BMP6 overcomes multiple myeloma-induced bone disease by inducing the expression of small leucine-rich proteoglycans

Abstract Multiple myeloma (MM), the second most common hematologic malignancy in adults, is characterized by clonal proliferation of malignant plasma cells and tumor-induced complications, including MM-induced bone disease (MBD). Up to 90% of MM patients develop MBD during the course of their disease, which is a major cause of morbidity and mortality. MM therapy focuses primarily on agents that seek to eradicate the tumor cells and others which inhibit bone resorption. In contrast, no drugs are currently available to promote bone formation in MM patients and reverse MBD. Towards addressing this unmet therapeutic need, we applied a modified version of our “humanized” bone marrow (BM)-like scaffold (huBMsc)-based xenograft model, where MM cells and bone marrow mesenchymal stromal cells (BMMSCs) are co-implanted. In this system, we investigated the impact of MM cells on BMMSCs to identify markers that can be targeted with the intent to reverse MBD. After confirming that MM cells indeed inhibit bone formation in vivo, we performed transcriptional analysis of ex vivo expanded “unexposed” control BMMSCs vs. “MM-exposed” BMMSCs and found 332 differentially expressed genes. Next, we compared these data with transcriptional profiles of BMMSCs after in vitro differentiation towards osteoblasts, as well as publicly available data of transcriptional profiles of BMMSCs obtained from MM, ALL, and AML patients. Combined, this analysis identified 8, MM-specific, differentially expressed genes, including the small leucine-rich proteoglycans (SLRPs), ASPN, OGN and OMD, that are 1) suppressed in the presence of MM (xenograft model and patient-derived BMMSCs); 2) induced during in vitro osteogenic differentiation; and 3) not dysregulated in BMMSCs in other hematological malignancies. As reported previously, we observed that bone morphogenetic protein (BMP)6 can upregulate the expression of these SLRPs in BMMSCs, while inducing osteogenic differentiation. Moreover, incubation of MM cells with BMP6 in either mono- or co-cultures with stromal cell lines, resulted in reduced MM cell viability. In addition, pretreatment of BMMSCs with BMP6 completely abolished their support of MM proliferation. Interestingly, BMP6, in contrast to BMP2 and BMP4, did not induce, but inhibited receptor activator of nuclear kappa-B ligand (RANKL)-dependent osteoclast generation. Collectively, our analyses identify BMP6 as a master regulator that promotes osteogenic differentiation, inhibits RANKL-dependent osteoclastogenesis and can directly induce MM cell death. Therefore, by reshaping the BM microenvironment to become less tumor-supportive, BMP6 represents an attractive candidate for MM treatment. Citation Format: Jiaxian Wang, Thomas Baardemans, Ricardo de Matos Simoes, Olga Dashevsky, Huipin Yuan, Joost D. de Bruijn, Anton C. Martens, Constantine S. Mitsiades, Richard W. Groen. BMP6 overcomes multiple myeloma-induced bone disease by inducing the expression of small leucine-rich proteoglycans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6374.

The concentration and type of monoclonal protein and their impact on clinical severity in patients with symptomatic myeloma

Background and objectives: Multiple Myeloma is a clonal plasma cell proliferation in the bone marrow that produces abnormal monoclonal proteins in serum and /or urine that leads to end-organ damage. We aimed to evaluate concentration, type of monoclonal protein, and their impact on the severity of symptomatic multiple myeloma patients. Methods: The study was conducted on 124 patients with symptomatic myeloma who were registered in the three centers in Kurdistan-Iraq from January–June 2019. Out of the 74 were males, and 50 were females. Demographic details, laboratory investigations, imaging study were reviewed, and informed consent was obtained for all patients; smoldering myeloma was excluded. Results: The most prevalent subtypes were IgG followed by IgA (61.3%, 18.5% respectively), whereas free light chain and non-secretory myeloma forming the rest, 12.1% and 6.45% for each subtype. There is a statistically positive association found between the concentration of monoclonal protein and the level of hemoglobin, ß2-microglobulin, and lactic acid dehydrogenase. There is no association for the concentration of monoclonal protein with each of calcium, albumin, creatinine, and erythrocyte sedimentation rate. Conclusions: We found a higher percentage of IgG/Kappa, high rates of non-secretory myeloma, low rates of light chain myeloma and younger age at presentation in comparison to western reports. The association between monoclonal protein concentration and some parameter of prognostic value in patients studied underscores its relevance to severity of disease in our locality.

A Rare Extramedullary Involvement Site in Patients With Multiple Myeloma: Stomach.

Multiple myeloma (MM) is a hematologic malignancy associated with uncontrolled clonal proliferation of plasma cells. Extramedullary disease in MM is an aggressive entity with a poor prognosis. Moreover, involvement of the gastrointestinal tract is a rare aggressive biological sign. 18 F-FDG PET/CT is an irreplaceable modality in the assessment of extramedullary disease. We present 2 cases with gastric involvement of MM that were shown by 18 F-FDG PET/CT and confirmed as plasma cell infiltration pathologically. 18 F-FDG PET/CT studies of MM patients should be interpreted carefully for gastrointestinal involvement, and it should be kept in mind that it can mimic other malignancies.

Identification of Immune-Related Genes for Risk Stratification in Multiple Myeloma Based on Whole Bone Marrow Gene Expression Profiling.

Background: Multiple myeloma (MM) is characterized by abnormal proliferation of bone marrow clonal plasma cells. Tumor immunotherapy, a new therapy that has emerged in recent years, offers hope to patients, and studying the expression characteristics of immune-related genes (IRGs) based on whole bone marrow gene expression profiling (GEP) in MM patients can help guide personalized immunotherapy. Methods: In this study, we explored the potential prognostic value of IRGs in MM by combining GEP and clinical data from the GEO database. We identified hub IRGs and transcription factors (TFs) associated with disease progression by Weighted Gene Co-expression Network Analysis (WGCNA), and modeled immune-related prognostic signature by univariate and multivariate Cox and least absolute shrinkage and selection operator (LASSO) regression analysis. Subsequently, the prognostic ability of signature was verified by multiple statistical methods. Moreover, ssGSEA and GSEA algorithm reveled different immunological characteristics and biological function variation in different risk groups. We mapped the hub IRGs by protein-protein interaction network (PPI) and extracted the top 10 ranked genes. Finally, we conducted vitro assays on two alternative IRGs. Results: Our study identified a total of 14 TFs and 88 IRGs associated with International Staging System (ISS). Ten IRGs were identified by Cox -LASSO regression analysis, and used to develop optimal prognostic signature for overall survival (OS) in MM patients. The 10-IRGs were BDNF, CETP, CD70, LMBR, LTBP1, NENF, NR1D1, NR1H2, PTK2B and SEMA4. In different groups, risk signatures showed excellent survival prediction ability, and MM patients also could be stratified at survival risk. In addition, IRF7 and SHC1 were hub IRGs in PPI network, and the vitro assays proved that they could promote tumor progression. Notably, ssGSEA and GSEA results confirmed that different risk groups could accurately indicate the status of tumor microenvironment (TME) and activation of biological pathways. Conclusion: Our study suggested that immune-related signature could be used as prognostic markers in MM patients.

Relationship between first-line treatment response and bone marrow fibrosis in newly diagnosed multiple myeloma

Objectives: Multiple myeloma (MM) occurs with uncontrolled and clonal increase proliferation of plasma cells in the bone marrow. Myelofibrosis can be primary or can be secondary when associated with other malignant or non-malignant diseases. MM is a malignant disease in which both collagen and reticulin fibrosis can be detected together at the time of diagnosis.The aim of this study is to investigate the relationship between bone marrow fibrosis at diagnosis and response to after first-line treatment in newly diagnosed MM. Material and Methods: In this study, 95 newly diagnosed MM patients were analyzed retrospectively. Demographic characteristics, complete blood count, biochemical examinations, bone marrow fibrosis grades, and first-line treatment response of the patients were retrieved from records as it is a retrospective study. Patients were divided into 2 groups according to their response to first- line treatment. Patients who have a strict complete response (sCR), complete response (CR) or a very good partial response (VGPR) responses to first-line therapy were included in the first group. Patients who gave partial response (PR), minimal response (MR) or progressive disease (PD) responses to the first-line therapy were included in the second group. Results: There were 72 patients in the Group I (good response group) and 23 patients in Group II (poor response group). Between the good response group and poor response group myeloma type, platelet count at diagnosis, β2 microglobulin, lactate dehydrogenase, erythrocyte sedimentation rate, bone marrow plasma cell ratio, R-ISS, and first-line treatment were not statistically significant (P > 0.05 ). Age was statistically significantly lower in the good response group (P = 0.04). In male gender, a better response was obtained (P = 0.02). At the time of diagnosis, hemoglobin levels in the good response group were found high compared to the poor response group (P = 0.02). Bone marrow fibrosis was found to be lower at the time of diagnosis in the group that responded good response to first-line treatment (P = 0.01). Conclusion: In this study, it was shown that bone marrow fibrosis at diagnosis is an important factor affecting the response to first-line treatment.The degree of bone marrow fibrosis detected at the time of diagnosis in MM may guide the selection of targeted therapy in first-line treatment.

Gene Expression Profiling in Multiple Myeloma: Redefining the Paradigm of Risk-Adapted Treatment.

Multiple myeloma is a blood cancer characterized by clonal proliferation of plasma cells in the bone marrow. In recent years, several new drugs have been added to the therapeutic landscape of multiple myeloma, which have contributed to increased survival rates. However, while the use of therapeutics has evolved, there is still a group of high-risk patients who do not benefit from current treatment strategies. Risk stratification and risk-adapted treatment are crucial to identify the group of patients with urgent need for novel therapies. Gene expression profiling has been introduced as a tool for risk stratification in multiple myeloma based on the genetic make-up of myeloma cells. In this review we discuss the challenge of defining the high-risk multiple myeloma patient. We focus on the standardized analysis of myeloma cancer cells by gene expression profiling and describe how gene expression profiling provides additional insights for optimal risk-adapted treatment of patients suffering from multiple myeloma.

Multiple Myeloma: Challenges Encountered and Future Options for Better Treatment.

Multiple myeloma (MM) is a malignant hematological disease. The disease is characterized by the clonal proliferation of malignant plasma cells in the bone marrow. MM accounts for 1.3% of all malignancies and has been increasing in incidence all over the world. Various genetic abnormalities, mutations, and translocation, including epigenetic modifications, are known to contribute to the disease’s pathophysiology. The prognosis is good if detected early, or else the outcome is very bad if distant metastasis has already occurred. Conventional treatment with drugs poses a challenge when there is drug resistance. In the present review, we discuss multiple myeloma and its treatment, drug resistance, the molecular basis of epigenetic regulation, the role of natural products in epigenetic regulators, diet, physical activity, addiction, and environmental pollutants, which may be beneficial for clinicians and researchers.

Cancer-Cell-Biomimetic Nanoparticles for Targeted Therapy of Multiple Myeloma Based on Bone Marrow Homing.

Multiple myeloma (MM) is the second most common hematological malignancy. It is characterized by abnormal transformation and uncontrolled clonal proliferation of malignant plasma cells in the bone marrow (BM), which can destroy bone structure and inhibit hematopoiesis. Although there are new therapeutic methods, they are not curative, mainly because it is difficult to deliver an effective amount of drug to BM, leading to a failure to eradicate MM cells inside the BM. BM homing is an important and unique characteristic of MM cells and it is mainly affected by surface molecules on the tumor cell membrane. Inspired by this mechanism, an MM-mimicking nanocarrier is developed by coating bortezomib (BTZ)-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) nanoparticles with the MM cell membrane. The MM-mimicking nanoparticles can enter the BM based on BM homing as a "Trojan horse" and target the tumor cells through homologous targeting. In this way, drug availability at the myeloma site is enhanced so as to inhibit MM growth. In addition, these MM-mimicking nanoparticles can escape phagocytosis by the MPS and have a long circulation effect. The in vivo therapeutic results demonstrate an excellent treatment efficacy for MM. Accordingly, this strategy may be a promising platform for the treatment of MM.

Identification of the Cysteine Protease Legumain as a Potential Chronic Hypoxia-Specific Multiple Myeloma Target Gene.

Multiple myeloma (MM) is the second most common hematologic malignancy, which is characterized by clonal proliferation of neoplastic plasma cells in the bone marrow. This microenvironment is characterized by low oxygen levels (1–6% O2), known as hypoxia. For MM cells, hypoxia is a physiologic feature that has been described to promote an aggressive phenotype and to confer drug resistance. However, studies on hypoxia are scarce and show little conformity. Here, we analyzed the mRNA expression of previously determined hypoxia markers to define the temporal adaptation of MM cells to chronic hypoxia. Subsequent analyses of the global proteome in MM cells and the stromal cell line HS-5 revealed hypoxia-dependent regulation of proteins, which directly or indirectly upregulate glycolysis. In addition, chronic hypoxia led to MM-specific regulation of nine distinct proteins. One of these proteins is the cysteine protease legumain (LGMN), the depletion of which led to a significant growth disadvantage of MM cell lines that is enhanced under hypoxia. Thus, herein, we report a methodologic strategy to examine MM cells under physiologic hypoxic conditions in vitro and to decipher and study previously masked hypoxia-specific therapeutic targets such as the cysteine protease LGMN.

The Mucolipin TRPML2 Channel Enhances the Sensitivity of Multiple Myeloma Cell Lines to Ibrutinib and/or Bortezomib Treatment.

Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow. The aim of the present study is the evaluation of biological effects of Ibrutinib in human MM cell lines alone or in combination with different doses of Bortezomib. In addition, the relationship between the expression of TRPML2 channels and chemosensitivity of different MM cell lines to Ibrutinib administered alone or in combination with Bortezomib has been evaluated. By RT-PCR and Western blot analysis, we found that the Ibrutinib-resistant U266 cells showed lower TRPML2 expression, whereas higher TRPML2 mRNA and protein levels were evidenced in RPMI cells. Moreover, TRPML2 gene silencing in RPMI cells markedly reverted the effects induced by Ibrutinib alone or in combination with Bortezomib suggesting that the sensitivity to Ibrutinib is TRPML2 mediated. In conclusion, this study suggests that the expression of TRPML2 in MM cells increases the sensitivity to Ibrutinib treatment, suggesting for a potential stratification of Ibrutinib sensitivity of MM patients on the basis of the TRPML2 expression. Furthermore, studies in vitro and in vivo should still be necessary to completely address the molecular mechanisms and the potential role of TRPML2 channels in therapy and prognosis of MM patients.

Monoclonal antibodies for the treatment of multiple myeloma

Multiple myeloma (MM) is the second most common haematological malignancy, accounting for 1–1.8% of all cancers in Europe, and is the most common plasma cell disorder (a group of related diseases that result from a clonal proliferation of plasma cells)​[1,2]​. Typically, the presence of monoclonal protein (M-protein) either in the serum or urine is important for […]

Imaging for Multiple Myeloma according to the Recent International Myeloma Working Group Guidelines: Analysis of Image Acquisition Techniques and Response Evaluation in Whole-Body MRI according to MY-RADS

Multiple myeloma (MM) is a malignant hematologic disease caused by the proliferation of clonal plasma cells in the bone marrow, and its incidence is increasing in Korea. With the development of treatments for MM, the need for early diagnosis and treatment has emerged. In recent years, the International Myeloma Working Group (IMWG) has been constantly revising the laboratory and radiological diagnostic criteria for MM. In addition, as whole-body MRI (WBMR) has been increasing used in the diagnosis and treatment response evaluation of patients with MM, the Myeloma Response Assessment and Diagnosis System (MY-RADS) was created to standardize WBMR image acquisition techniques, image interpretation, and response evaluation methods. Radiologists need to have a detailed knowledge of the features of MM for accurate diagnosis. Thus, in this review article, we describe the imaging method for MM according to the latest IMWG guidelines as well as the image acquisition and response evaluation technique for WBMR according to MY-RADS.

The Prognostic Value of Classical Immunoparesis in Multiple Myeloma

Multiple myeloma (MM) is a very heterogeneous hematological malignancy characterized by the proliferation of clonal plasma cells in bone marrow, leading to a decrease in normal plasma cells. The immune system plays a key role in both the pathogenesis and the prognosis of MM. A wide range of immune dysfunctions can be demonstrated in most patients at diagnosis. The presence of suppression of uninvolved immunoglobulins, also called classical immunoparesis (CIP), can be demonstrated in the majority of newly diagnosed MM (NDMM) patients, although its prognostic impact remains controversial in previous studies. Our population-based study confirms that CIP is present in most NDMM patients. It is associated with several well-known prognostic factors, including the International Staging System, being more frequent in late stages. Median overall survival in CIP+ patients was 62.4 months (CI 95%, 52.1-72.7), whereas it was not reached for those CIP- (p=0.150). Despite the absence of statistical significance, the multivariate Cox proportional hazards model endorses CIP as an independent and strong prognostic factor for overall survival in NDMM, besides age, performance status, total serum cholesterol, and the presence of 1q gain. More comprehensive studies, including complete immune profiling, are warranted to establish the role of CIP in the context of the current and emerging prognostic factors in NDMM.

Isatuximab in the Treatment of Multiple Myeloma: A Review and Comparison With Daratumumab.

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved survival outcomes for patients with MM, this disease is still considered incurable owing to its high incidence of relapse and refractoriness. Isatuximab is an anti-CD38 monoclonal antibody that can induce apoptosis in myeloma cells through a variety of mechanisms. Many clinical studies have demonstrated the efficacy and efficiency of isatuximab in both relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma, leading to its approval for the treatment of adults with RRMM in combination therapies. In this review, the structure, mechanisms of action, pharmacokinetics, pharmacogenetics, and safety profile of isatuximab in MM are summarized. Additionally, isatuximab is compared with daratumumab in terms of mechanism and efficacy.

Biochemical profile of multiple myeloma about 50 cases

Multiple myeloma (MM) is a clonal proliferation of plasma cells invading the bone marrow and secreting monoclonal immunoglobulin. In order to study the epidemiological and biological and biochemical characteristics of MM, we carried out a retrospective work on a cohort of 50 cases collected at the Avicenna Military Hospital in Marrakesh, during a period of 5 years (from January 2013 to December 2017). Our study included 32 men (64%) and 18 women (36%), with an average age of 60.6 years, with extremes at 44 and 87 years. The circumstances of discovery were dominated by bone pain and alteration in general condition, which are revealing in more than 65% of cases. Biologically: the sedimentation rate was accelerated in 86% of cases, a monoclonal peak appearance was revealed on serum proteins electrophoresis in 88%of cases, most often located in the γ zone (64%), a predominance of the Ig G isotype (64%), and kappa light chains in 60% of cases, Bence Jones protein (BJP) was found in 7 patients, i.e. 14% of cases, and plasmacytosis over 10% was found on the myelograms in 90 % of cases.

Checkpoint Inhibitors in Multiple Myeloma: Intriguing Potential and Unfulfilled Promises.

Simple SummaryMultiple myeloma (MM) is a hematological malignancy caused by aberrations in the plasma cell development, resulting in uncontrolled production of plasma cells and or monoclonal proteins. Currently, several treatments are centered around immune-based therapies including immunomodulatory agents, monoclonal antibodies, cellular therapies, and stem cell transplantation. We review the biologic rationale, efficacy, side effects, and limitations of immune-checkpoint inhibitors (ICIs), which have been successful in several solid organ malignancies such as melanoma, kidney, and lung cancers. Recent clinical trials evaluating ICIs as monotherapy and in combination with approved pharmaceutical drugs in MM, have thus far remained underwhelming due to excessive side effects and lack of efficacy in aggressive and advanced cases. There may be a role for ICIs in early forms of MM and preventing recurrence once achieving remission. Side effect mitigation and improved efficacy to combat resistance are needed prior to profoundly impacting the current MM landscape. Clinical studies to answer these questions are ongoing, and we eagerly await this data to determine if ICIs will become a permanent fixture in MM.Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum of malignancies, this aberration of myeloma development gives rise to the biological rationale for the use of immune checkpoint inhibitors (ICIs) in MM. However, the initial experience with these agents has been challenging with limited single agent efficacy, significant toxicity, and side effects. Herein, we review the biological and immunological aspects of MM and ICIs. We discuss the basic biology of immune checkpoint inhibitors, mechanisms of resistance, and drug failure patterns, review the published clinical trial data for ICIs in MM, and look towards the future of ICIs for MM treatment.