Proliferation Of Plasma Cells Research Articles

Multiple Myeloma

The second most common hematologic malignancy is the clonal proliferation of neoplastic plasma cells within the bone marrow. There is the presence of monoclonal immunoglobulins in the serum and/or urine. This results in anemia, myelosuppression, bone destruction, and clinical consequences of para-proteinemia on kidney function and other organ systems. The disease manifests through the acronym CRAB (hypercalcemia, renal impairment, anemia, and bone lesions). Less frequent manifestations of multiple myeloma are of extramedullary localizations. Myeloma cells can become independent of the bone marrow microenvironment, circulate freely in the blood, and infiltrate organs. This results in a high-risk state characterized by increased proliferation, evasion of apoptosis, and treatment resistance. It can affect any area of tissue. Most commonly it involves the pleura, lymph nodes, chest wall, liver, skin/soft tissue, lungs, CNS, genitourinary system, breast and pancreas. In patients with confirmed multiple myeloma, the diagnosis of extramedullary involvement is typically established by the presence of pathological soft tissue masses using radiological methods such as computed tomography (CT) scan, positron emission tomography/CT (PET/CT), magnetic resonance imaging (MRI), or ultrasound, along with biopsy or physical examination. The molecular mechanisms underlying the development of extramedullary multiple myeloma (EMM) have not been fully defined. Various cytogenetic abnormalities are observed, and some studies have generated genomic sequencing profiles that distinguish EMM from classic multiple myeloma. While plasma cell leukemia (PCL) and central nervous system (CNS) EMM indicate a poor prognosis, outcomes for other manifestations can be highly heterogeneous. Sensitive imaging modalities including PET/CT and MRI (Fig.1) are integral components of diagnosis and response assessment. Patients with extramedullary multiple myeloma (EMM) have a clear survival disadvantage.

Use of daratumumab in combination with lenalidomide and dexamethasone (D-Rd regimen) in therapy of elderly patients with newly diagnosed multiple myeloma with high-risk cytogenetics. Clinical observation

Multiple myeloma (MM) is a B cell lymphoproliferative disease characterized by clonal proliferation of plasma cells and heterogenous progression. Successes in MM therapy are in large part based on the study of molecular and genetic features of disease pathogenesis and identification of high-risk chromosomal abnormalities determining prognosis and antitumor response. Elderly patients with newly diagnosed MM with high-risk cytogenetics who are not candidates for autologous stem cell transplantation should receive programs of antitumor therapy which increase progression-free survival and overall survival with satisfactory tolerability and minimal toxicity. Use of monoclonal antibodies in triplets at early stages allow to achieve deeper antitumor response, the absence of minimal residual disease in a greater number of observations, and improve survival in all patient subgroups.A clinical observation of a 75-year-old female patient with newly diagnosed MM with high-risk cytogenetics and multiple bone plasmacytomas with massive extraosseous components is presented. During D-Rd regimen therapy, after 8 daratumumab administrations very good partial remission was achieved which has been maintained for 20 months. Significant improvement in quality of life with satisfactory treatment tolerability and absence of adverse events are observed

Abstract 2277: Understanding the impact of clonal hematopoiesis on multiple myeloma: Insights from exosomal RNA analysis and survival analysis

Abstract Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a trait characterized by the accumulation of somatic mutations in hematopoietic stem cells in certain adults. It has been observed that the presence of CHIP can have significant implications for the development and prognosis of various blood cancers. Multiple myeloma (MM), a cancer involving the abnormal proliferation of malignant plasma cells in the bone marrow, is one such condition. Exosomes, a type of extracellular vesicles, play a role in cell communication by carrying information between cells. Analysis of UK Biobank data confirmed the poor prognosis of multiple myeloma patients with CHIP and identified a potential of paracrine effect on plasma cancer cells. To gain deeper insights into this paracrine effect on plasma cells, we attempted to analyze cell-to-cell interaction, such as the expression of miRNAs in exosomes, through exosome RNA sequencing. In our research, exosomes were extracted from bone marrow samples of 30 multiple myeloma patients, and exosome RNA sequencing was performed. Differential expression of miRNAs was identified. A total of 14 down-regulated miRNAs were identified based on adjusted p value < 0.05, log2 fold change < -1. We found that hsa-let-7f-5p, hsa-let-7a-5p, and hsa-miR-148a-3p, which are mainly miRNAs targeting MAP kinase, were significantly down-regulated in the CHIP cases. A computational tool was used to predict and integrate the target genes and pathways regulated by these DE miRNAs. The results suggested that certain inflammatory and oncogenic pathways including the MAPK signaling pathways, were not effectively suppressed in cases with CHIP (KEGG, p < 0.005). In addition, the chemokine signaling pathway and cytokine-cytokine receptor interaction (KEGG, p < 0.005) related to the paracrine effect, integrins in angiogenesis (PID, p < 0.005) related to poor prognosis and metastasis of cancer were also not adequately inhibited in the CHIP cases. Using UK Biobank data, we called somatic CHIP variants excluding those with VAF < 0.02 and analyzed them against ICD-10 codes. Hazard ratios (HR) were computed through Cox proportional regression with covariates. CHIP presence significantly correlated with MM diagnosis (HR: 1.64, CI: 1.35-2, p < 0.001), notably in TET2 mutation carriers (HR: 2.35, CI: 1.63-3.4, p < 0.001). TET2 mutations intensified MGUS to MM progression (HR: 5.0, CI: 2.27-11.0, p < 0.001). CHIP in MM impacted EFS (HR: 1.61, CI: 1.25-2.1, p < 0.001), with TET2 mutation carriers facing higher hazards (HR: 1.66, CI: 1.05-2.6, p = 0.031). CHIP, especially TET2 mutations, significantly contribute to adverse MM outcomes and MGUS to MM evolution. Our findings provide insight into how CHIP influences the tumorigenesis and cancer progression of MM. Citation Format: Jeongmin Park, GangPyo Ryu, Daniel Nachun, Maggie Maurer, Siddhartha Jaiswal, Dong-Yeop Shin, Ja Min Byun, Junshik Hong, Youngil Koh, Sung-Soo Yoon. Understanding the impact of clonal hematopoiesis on multiple myeloma: Insights from exosomal RNA analysis and survival analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2277.

Abstract 364: Targeting LILRB1 to sensitize human myeloma to ferroptosis through disrupting cholesterol homeostasis

Abstract Multiple myeloma (MM) is a hematologic malignancy characterized by the uncontrolled clonal proliferation of plasma cells in the bone marrow (BM). Despite the demonstrated benefits of novel therapies, relapses are frequent, and acquired resistance to MM treatment eventually emerges in most, if not all, patients. MM patients who suffer more aggressive progression usually result in poorer survival. The genes driving such unfavored outcomes in MM have not been fully understood. Therefore, there is an urgent need to identify the genes and mechanisms that contribute to the aggressive behaviors of MM in order to develop improved therapeutic strategies for the disease. To discover new potential therapeutic targets for MM patients, we analyzed gene-profiling data of MM patients and identified leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, as one of the top-ranked genes associated with poor prognosis. LILRB1 on immune cells was reported to bind to its ligand, b2-microglobulin, on tumor cells. This interaction leads to immune suppression responses in various immune cells. However, the function of tumor-derived LILRB1 in tumor biology remains unclear and the role of LILRB1 in MM has been poorly studied. Our further analysis of the patient data demonstrated that MM patients with high expression of LILRB1 are closely related to higher MM recurrence rates, advanced stages, and lower survival rates, indicating that LILRB1 is an important player in MM pathogenesis and thus a promising target for MM therapy. Interestingly, RNA-seq data of human MM cells from the BM of MM-bearing mice showed that knockdown (KD) of LILRB1 activated cholesterol metabolism- and ferroptosis-related pathways in murine BM. Moreover, KD of LILRB1 significantly impaired tumor progression in murine models. Consistently, in vitro experiments also demonstrated that LILRB1 protected MM cells from ferroptosis inducer-caused lipid ROS and ferroptotic cell death, indicating that LILRB1 promotes the progression of MM cells by protecting them from ferroptosis. Further study were then conducted to reveal the underlying mechanism. LC-MS/MS analysis followed by co-IP demonstrated that LDLRAP1, an adaptor protein that interacts with LDLR, bound with LILRB1 and formed a complex together with LDLR. KD of LILRB1 inhibited LDL uptake by disrupting the interaction between LDLR and LDLRAP1 and triggering the compensatory cholesterol synthesis by upregulating the expression of SQLE that converted squalene to (S)-2,3-epoxysqualene. With less squalene to protect MM cells from lipid peroxidation, MM cells were more susceptible to the induction of ferroptosis. Thus, this study uncovers a novel function of LILRB1 in regulating cholesterol metabolism and protecting MM cells from ferroptosis during MM progression and implicates LILRB1 as a promising therapeutic target for MM patients. Citation Format: Miao Xian, Qing Yi, Qiang Wang, Liuling Xiao, Ling Zhong, chuanchao zhang, yabo Li, Jianfei Qian. Targeting LILRB1 to sensitize human myeloma to ferroptosis through disrupting cholesterol homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 364.

Recent Advances in Multiple myeloma

Multiple myeloma (MM) represents a malignant proliferation of plasma cells originating from a single clone. The tumour causes bone pain, fracture, anaemia, and other infections. Patients present with MM are symptomatic and need cytotoxic chemotherapy. Previously, melphalan and glucocorticoid were accepted as first-line treatments. Recently, immunomodulatory drugs and proteasome inhibitors have become the treatment of choice. There are several new drugs approved for multiple myeloma: monoclonal antibodies, nuclear export inhibitors, B-cell maturation antigen (BCMA)-directed antibody, CAR T-cell therapy, histone-deacetylase inhibitor, and stem cell mobilizer. Drugs like cobemetinib are being evaluated for potential role in the treatment of MM. Pharmacogenomics and precision medicine also play a crucial role in the treatment of multiple myeloma.

The role of pentraxin 3 and oxidative status in the prognosis of multiple myeloma.

Multiple myeloma (MM) is a bone marrow malignancy characterized by plasma cell proliferation. It was aimed to investigate pentraxin 3 (PTX3) levels, oxidative/antioxidative status, and their correlation in MM. In the study, four groups were established, including newly diagnosed MM (NDMM), MM in remission (Rem-MM), relapsed/refractory MM (RRMM) patients, and a healthy control group. PTX3 levels were measured using enzyme-linked immunosorbent assay, and the total antioxidant status (TAS) and total oxidant status (TOS) were assessed with an autoanalyzer. The oxidative stress index (OSI) was calculated using the formula: OSI (arbitrary unit) = TOS (µmol H2O2 Eq/L)/TAS (mmol Trolox Eq/L) × 100. The study involved comparing PTX3, TAS, TOS, and OSI levels among these four groups. PTX3 levels were significantly elevated in NDMM and RRMM groups compared to controls and the Rem-MM group (NDMM vs control; p < 0.001, NDMM vs Rem-MM; p < 0.001, RRMM vs control; p < 0.001, and RRMM vs Rem-MM; p = 0.006). TAS was higher in NDMM and RRMM groups versus controls (p = 0.009 and p < 0.001, respectively), and TOS was higher in rem-MM group versus NDMM and control groups (p < 0.001 and p = 0.016, respectively). OSI was higher in the Rem-MM group than in NDMM and RRMM groups (p < 0.001 and p = 0.009, respectively). Multivariate analysis confirmed associations between MM groups and PTX3 levels. Receiver operating characteristic analysis revealed high specificity (90%) and sensitivity (79%) for PTX3 in NDMM at a >0.56 ng/mL cut-off value. This study suggests that PTX3 levels may have diagnostic and prognostic potential in MM and its relationship with oxidative stress requires further exploration.

Multiple Myeloma and Occupational Risk Factors: A Narrative Review.

Multiple Myeloma (MM) is a neoplastic hematologic disorder caused by the excessive proliferation of plasma cells and leads to bone lesions, anemia, and kidney failure. No definite etiology has been proposed for MM, but several environmental and genetic risk factors have been implicated so far. Exposure to pesticides, benzene, and organic solvents like methyl chloride have been considered a potential risk factor. Asbestos, ionizing radiation, and wood dust exposure have also been associated with MM. As MM is a relatively rare condition, the number of studies is insufficient, and in many studies, only a few study participants recall exposure to any agents. Therefore, establishing a definite risk factor is cumbersome and further studies with large study samples are needed. By recognizing these occupational risk factors, clinicians can encourage employees to reduce their exposure as more as possible and implement precautionary measures. In this review, we highlighted the current research on the potential association between occupational exposures and MM. Because of these studies, new regulations with the goal of occupational exposure reduction are anticipated in the future.

Evaluation of different types of adjuvants in a malaria transmission-blocking vaccine

Adjuvants are critical components for vaccines, which enhance the strength and longevity of the antibody response and influence the types of immune response. Limited research has been conducted on the immunogenicity and protective efficacy of various adjuvants in malaria transmission-blocking vaccines (TBVs). In this study, we formulated a promising TBV candidate antigen, the P. berghei ookinete surface antigen PSOP25, with different types of adjuvants, including the TLR4 agonist monophosphoryl lipid A (MPLA), the TLR9 agonist cytosine phosphoguanosine oligodeoxynucleotides (CpG ODN 1826) (CpG), a saponin adjuvant QS-21, aluminum hydroxide (Alum), and two combination adjuvants MPLA + QS-21 and QS-21 + CpG. We demonstrated that adjuvanted vaccines results in elevated elicited antibody levels, increased proliferation of plasma cells, and efficient formation of germinal centers (GCs), leading to enhanced long-term protective immune responses. Furthermore, CpG group exhibited the most potent inhibition of ookinete formation and transmission-blocking activity. We found that the rPSOP25 with CpG adjuvant was more effective than MPLA, QS-21, MPLA + QS-21, QS-21 + CpG adjuvants in dendritic cells (DCs) activation and differentiation. Additionally, the CpG adjuvant elicited more rubust immune memory response than Alum adjuvant. CpG and QS-21 adjuvants could activate the Th1 response and promote the secretion of IFN-γ and TNF-α. PSOP25 induced a higher number of Tfh cells in splenocytes when combined with MPLA, CpG, and QS-21 + CpG; and there was no increase in these cell populations when PSOP25 was administered with Alum. In conclusion, CpG may confer enhanced efficacy for the rPSOP25 vaccine, as evidenced by the ability of the elicited antisera to induce protective immune responses and improved transmission-blocking activity.

Current Approaches in the Management of Monoclonal Gammopathies: an approach to Waldenström Macroglobulinemia

Monoclonal gammopathies encompass a spectrum of disorders characterized by the abnormal proliferation of plasma cells, leading to the production of monoclonal immunoglobulins. Waldenström macroglobulinemia (WM) is a rare, indolent lymphoproliferative disorder characterized by the presence of an IgM monoclonal gammopathy, bone marrow infiltration by lymphoplasmacytic cells, and clinical features such as hyperviscosity, lymphadenopathy, and hepatosplenomegaly. Recent advances in understanding the pathogenesis of WM have led to the development of novel therapeutic strategies, including targeted therapies and immunomodulatory agents, which have significantly improved outcomes for patients. This article provides an overview of the current understanding of WM pathophysiology, clinical presentation, diagnostic approach, and recent advancements in its management.

LARYNGEAL PLASMACYTOMA IN KAHLERS DISEASE: A CASE REPORT

Multiple myeloma or Kahlers disease is a malignant hematological disorder due to a monoclonal plasma cell proliferation primarily invading the hematopoietic bone marrow. Extra-medullar involvement occurs in 18% of patients with multiple myeloma. Laryngeal Localization remains rare and has been described in a few cases after a literature review.We report the case of a 44-year-old woman who presented an inspiratory dyspnea caused by a laryngeal tumor. The pathological study and bone marrow examination confirmed the laryngeal localization of multiple myeloma. Treatment consisted of chemotherapy with good clinical outcomes over a 2-year follow-up period.

The importance of removing interference caused by Darzalex® (daratumumab) in pre-transfusion testing

Introduction: Multiple myeloma (MM) is a hematologic malignacy characterized by the uncontrolled proliferation of abnormal plasma cells in the bone marrow. Darzalex® (daratumumab) has emerged as a highly effective therapeutic agent for MM, offering an additional treatment option for patients who have developed resistance to other therapies. However, the use of Darzalex® poses challenges in pre-transfusion testing due to its strong binding affinity of the monoclonal anti-CD38 antibody to CD38 protein, resulting in panreactivity with test erythrocytes and complicating the detection of erythrocyte alloantibodies. The objective of this case report is to outline the procedures, significance, and methodologies for mitigating this interference using the DaraEx® reagent. Case Report: We present the cases of three patients diagnosed with MM and treated with Darzalex® at our institution in 2023. Following the administration of Darzalex®, all three patients exhibited positive results on indirect antiglobulin tests (IAT). Cross-matching tests conducted with red blood cell concentrates also yielded positive results, with strengths ranging from 2+ to 3+. To eliminate interference, we used a specific DaraEx® reagent that utilizes Fab fragments of anti-CD38 to mitigate interference by masking CD38 on the cell surface. Subsequent application of this reagent resulted in negative IAT results for all three patients. However, one patient still displayed a weakly positive cross-matching test (&lt;1+), suggesting that complete elimination of interference may not always be achievable with the DaraEx® method. Conclusion: Despite the availability of reliable methods such as dithiothreitol and the DaraEx® reagent for mitigating interference, complete success in eliminating interference remains elusive. This underscores the importance of implementing proactive measures to prevent interference. Patients undergoing Darzalex® therapy should undergo comprehensive immunohematological testing before medication administration. Given the increased need for blood transfusions in MM patients, ensuring the compatibility of blood products is essential for safe transfusion practices.

Different evasion strategies in multiple myeloma.

Multiple myeloma is the second most common malignant hematologic malignancy which evolved different strategies for immune escape from the host immune surveillance and drug resistance, including uncontrolled proliferation of malignant plasma cells in the bone marrow, genetic mutations, or deletion of tumor antigens to escape from special targets and so. Therefore, it is a big challenge to efficiently treat multiple myeloma patients. Despite recent applications of immunomodulatory drugs (IMiDS), protease inhibitors (PI), targeted monoclonal antibodies (mAb), and even hematopoietic stem cell transplantation (HSCT), it remains hardly curable. Summarizing the possible evasion strategies can help design specific drugs for multiple myeloma treatment. This review aims to provide an integrative overview of the intrinsic and extrinsic evasion mechanisms as well as recently discovered microbiota utilized by multiple myeloma for immune evasion and drug resistance, hopefully providing a theoretical basis for the rational design of specific immunotherapies or drug combinations to prevent the uncontrolled proliferation of MM, overcome drug resistance and improve patient survival.

Solitary plasmacytoma: A case report

Plasmacytoma is a discrete, unifocal, and monoclonal neoplastic proliferation of plasma cells. It may present as one of the three distinct clinical entities: multiple myeloma (MM), solitary plasmacytoma of the bone, and extramedullary plasmacytoma. Solitary plasmacytoma of the bone accounts for 3% of all plasma cell neoplasms. About 50% of the cases of solitary plasmacytoma of the bone transform into MM. The most commonly involved sites are vertebrae and long bones. It is extremely rare in jaws. We are presenting a case of solitary plasmacytoma of the maxilla in a 59-year-old female patient with comprehensive clinical, radiological, histological, and immunohistochemical features.

Clinical Profile and Treatment of Multiple Myeloma at a Tertiary Hospital in Kenya: A Five-Year Retrospective Review.

Multiple myeloma (MM) is a chronic B-cell malignancy that involves proliferation of neoplastic clonal plasma cells in the bone marrow with circulating monoclonal immunoglobulins or constituent chains in serum or urine or both. It is a rare cancer with a lifetime risk of 0.76% and an age-adjusted incidence rate of 2.5-7.2 per 100,000 in high-income countries. There is a paucity of local data on the morbidity and treatment of MM. This was a single-centre descriptive retrospective study at the Kenyatta National Hospital (KNH). The study population included inpatients and outpatients with a documented diagnosis of MM managed between 1st January 2014 and 31st December 2018. Demographic data, pathology reports, laboratory results, and clinical findings were transcribed and uploaded to a database, and data analysis was done using Stata 16® software. A total of 207 patient files were reviewed. The median age at presentation was 60 years with a slight male preponderance. Bone pain was the predominant complaint in 59% (139/207) of patients, with 17% of patients presenting with paraparesis or paraplegia. For patients who underwent imaging, osteolytic bone lesions were identified in 90.6% (126/139). Anaemia was present in 71% (147/207) patients, hypercalcemia in 55.4%, and renal dysfunction in 38.2%. There were 25 different treatment regimens prescribed, with 13 patients (7%) being on bortezomib-based triplet therapy. MM in KNH is a disease of the middle aged, affecting men and women almost equally and presenting mainly with bone pain and anaemia. Although there seems to be a general improvement in diagnosis and care, access to novel and less toxic agents for treatment is still wanting.

Role of minimal residual disease assessment in multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. MM is a heterogeneous disease, featured by various molecular subtypes with different outcomes. With the advent of very efficient therapies including monoclonal antibodies, bispecific T-cell engagers and chimeric antigen receptor T cells (CAR T cells), most MM patients now have a prolonged survival. However, the disease remains incurable, and a subgroup of high-risk patients continue to have early relapse and short survival. Novel and highly sensitive methods have been developed allowing the detection of minimal residual disease (MRD) during or after treatment. Achievement of MRD negativity is a strong and independent prognostic factor in both prospective randomized clinical trials and in the real-world setting. While MRD assessment is now a validated endpoint in clinical trials, its incorporation in clinical practice is not yet established and its potential impact on guiding therapy remains under in-depth evaluation. Here we discuss the different methods available for MRD assessment and the role of MRD evaluation in MM management.

Multiple myeloma in a young patient

Multiple myeloma is a type B blood cancer characterized by clonal proliferation of malignant plasma cells. The median age at diagnosis is 70 years, however, it is rare among younger patients, and less than 0.5% are younger than 30 years. A 33-year-old man, who began with progressive acute kidney injury is presented, accompanied by a severe lower back pain and impossibility to walk. A dorso-lumbar spine CT scan showed an extensive process consisting of multiple osteolytic lesions at T12, L2, ribs, pelvic and proximal femur. Radiology, along with histology, bone marrow aspiration and protein electrophoresis analysis allowed to establish the diagnosis of stage III multiple myeloma, after which the patient received chemotherapy. Despite the rarity of multiple myeloma among young patients, this diagnosis should be evoked when clinical, biological and radiological signs are in favour. There appears to be no difference between younger and older patients in disease presentation, although longer survival was reported among younger patients.

Multiple myeloma in the mandible mimicking a radicular cyst: A case report and literature review

AbstractBackgroundMultiple myeloma (MM) is a hematopoietic malignancy characterized by monoclonal plasma cell proliferation. Mandibular involvement in patients with MM is rare, and its clinical and radiological characteristics remain unclear.Case PresentationA 78‐year‐old man presented with MM in the mandible, mimicking a radicular cyst. Chemotherapy yielded a poor prognosis, and the patient died 1.5 years post‐diagnosis. Literature suggests that jawbone involvement of MM is a poor prognostic factor.ConclusionThis report highlights the features of MM in the jawbone, and its variable manifestation, which may include non‐neoplastic findings, thus emphasizing the importance of a definitive biopsy‐based diagnosis.

Gene signatures to therapeutics: Assessing the potential of ivermectin against t(4;14) multiple myeloma.

Multiple myeloma (MM) is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow. The translocation, (t)(4;14), results in high-risk MM with limited treatment alternatives. Thus, there is an urgent need for identification and validation of potential treatments for this MM subtype. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets. To elucidate the molecular basis and search for potential effective drugs of t(4;14) MM subtype by employing a comprehensive approach. The transcriptional signature of t(4;14) MM was sourced from the Gene Expression Omnibus. Two datasets, GSE16558 and GSE116294, which included 17 and 15 t(4;14) MM bone marrow samples, and five and four normal bone marrow samples, respectively. After the differentially expressed genes were identified, the Cytohubba tool was used to screen for hub genes. Then, the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Using the STRING database and Cytoscape, protein-protein interaction networks and core targets were identified. Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis, respectively. In this study, a total of 258 differentially expressed genes with enriched functions in cancer pathways, namely cytokine receptor interactions, nuclear factor (NF)-κB signaling pathway, lipid metabolism, atherosclerosis, and Hippo signaling pathway, were identified. Ten hub genes (cd45, vcam1, ccl3, cd56, app, cd48, btk, ccr2, cybb, and cxcl12) were identified. Nine drugs, including ivermectin, deforolimus, and isoliquiritigenin, were predicted by the Connectivity Map database to have potential therapeutic effects on t (4;14) MM. In molecular docking, ivermectin showed strong binding affinity to all 10 identified targets, especially cd45 and cybb. Ivermectin inhibited t(4;14) MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro. Furthermore, ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14) MM cells. Collectively, the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14) MM diagnosis and treatment, with ivermectin emerging as a potential therapeutic alternative.

CAR NK92 Cells Targeting BCMA Can Effectively Kill Multiple Myeloma Cells Both In Vitro and In Vivo.

Multiple myeloma (MM) is a hematological malignancy caused by malignant proliferation of plasma cells in bone marrow. Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents. However, MM remains an incurable neoplastic plasma cell disorder. In addition, almost all MM patients inevitably relapse due to drug resistance. Chimeric antigen receptor (CAR)-modified NK cells represent a promising immunotherapeutic modality for cancer treatment. In this study, NK92 cells were engineered to express the third generation of BCMA CAR. In vitro, BCMA CAR-engineered NK92 cells displayed higher cytotoxicity and produced more cytokines such as IFN-γ and granzyme B than NK92 cells when they were co-cultured with MM cell lines. Furthermore, BCMA CAR-engineered NK92 cells released significantly higher amounts of cytokines and showed higher cytotoxicity when they were exposed to primary cells isolated from MM patients. The cytotoxicity of BCMA CAR NK92 cells was enhanced after MM cells were treated with bortezomib. Additionally, BCMA CAR NK92 cells exhibited potent antitumor activities in subcutaneous tumor models of MM. These results demonstrate that regional administration of BCMA CAR NK92 cells is a potentially promising strategy for treating MM.

DNA Sequencing of CD138 Cell Population Reveals TP53 and RAS-MAPK Mutations in Multiple Myeloma at Diagnosis.

Multiple myeloma is a hematologic neoplasm caused by abnormal proliferation of plasma cells. Sequencing studies suggest that plasma cell disorders are caused by both cytogenetic abnormalities and oncogene mutations. Therefore, it is necessary to detect molecular abnormalities to improve the diagnosis and management of MM. The main purpose of this study is to determine whether NGS, in addition to cytogenetics, can influence risk stratification and management. Additionally, we aim to establish whether mutational analysis of the CD138 cell population is a suitable option for the characterization of MM compared to the bulk population. Following the separation of the plasma cells harvested from 35 patients newly diagnosed with MM, we performed a FISH analysis to detect the most common chromosomal abnormalities. Consecutively, we used NGS to evaluate NRAS, KRAS, BRAF, and TP53 mutations in plasma cell populations and in bone marrow samples. NGS data showed that sequencing CD138 cells provides a more sensitive approach. We identified several variants in BRAF, KRAS, and TP53 that were not previously associated with MM. Considering that the presence of somatic mutations could influence risk stratification and therapeutic approaches of patients with MM, sensitive detection of these mutations at diagnosis is essential for optimal management of MM.