Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Multiple myeloma survival in New South Wales, Australia, by treatment era to 2020

Objective: Australia has relatively high multiple myeloma(MM) incidence and mortality rates. Advancements in MM treatment over recent decades have driven improvements in MM survival in high-income countries;however, reporting in Australia is limited. We investigated temporal trends in population-wide MM survival across 3 periods of treatment advancements in New South Wales(NSW), Australia.Methods: Individuals with an MM diagnosis in the NSW Cancer Registry between 1985 and 2015 with vital follow-up to 2020, were categorized into 3 previously defined treatment eras according to their diagnosis date(1985±1995, chemotherapy only;1996±2007, autologous stem cell transplantation;and 2008±2015, novel agents including proteasome inhibitors and immunomodulatory drugs). Both relative survival and cause-specific survival according to Fine and Gray's competing risks cumulative incidence function were calculated by treatment era and age at diagnosis.Results: Overall, 11,591 individuals were included in the study, with a median age of 70 years at diagnosis. Five-year relative survival improved over the 36-year(1985±2020) study period(31.0% in 1985±1995;41.9% in 1996±2007;and 56.1% in 2008±2015). For individuals diagnosed before 70 years of age, the 5-year relative survival nearly doubled, from 36.5% in 1985±1995 to 68.5% in 2008±2015. Improvements for those > 70 years of age were less pronounced between 1985±1995 and 1996±2007;however, significant improvements were observed for those diagnosed in 2008±2015. Similar overall and age-specific patterns were observed for causespecific survival. After adjustment for gender and age at diagnosis, treatment era was strongly associated with both relative and cause-specific survival(P < 0.0001).Conclusions: Survival of individuals with MM is improving in Australia with treatment advances. However, older age groups continue to experience poor survival outcomes with only modest improvements over time. Given the increasing prevalence of MM in Australia, the effects of MM treatment on quality of life, particularly in older age, warrant further attention.

Development of a cell adhesion-based prognostic model for multiple myeloma:Insights into chemotherapy response and potential reversal of adhesion effects

Multiple myeloma(MM)is a hematologic malignancy notorious for its high relapse rate and development of drug resistance,in which cell adhesion-mediated drug resistance plays a critical role.This study integrated four RNA sequencing datasets(CoMMpass,GSE136337,GSE9782,and GSE2658)and focused on analyzing 1706 adhesionrelated genes.Rigorous univariate Cox regression analysis identified 18 key prognosis-related genes,including KIF14,TROAP,FLNA,MSN,LGALS1,PECAM1,and ALCAM,which demonstrated the strongest associations with poor overall survival(OS)in MM patients.To comprehensively evaluate the impact of cell adhesion on MM prognosis,an adhesion-related risk score(ARRS)model was constructed using Lasso Cox regression analysis.The ARRS model emerged as an independent prognostic factor for predicting OS.Furthermore,our findings revealed that a heightened cell adhesion effect correlated with tumor resistance to DNA-damaging drugs,protein kinase inhibitors,and drugs targeting the PI3K/Akt/mTOR signaling pathway.Nevertheless,we identified promising drug candidates,such as tirofiban,pirenzepine,erlotinib,and bosutinib,which exhibit potential in reversing this resistance.In vitro,experiments employing NCIH929,RPMI8226,and AMO1 cell lines confirmed that MM cell lines with high ARRS exhibited poor sensitivity to the aforementioned candidate drugs.By employing siRNA-mediated knockdown of the key ARRS model gene KIF14,we observed suppressed proliferation of NCIH929 cells,along with decreased adhesion to BMSCs and fibronectin.This study presents compelling evidence establishing cell adhesion as a significant prognostic factor in MM.Additionally,potential molecular mechanisms underlying adhesion-related resistance are proposed,along with viable strategies to overcome such resistance.These findings provide a solid scientific foundation for facilitating clinically stratified treatment of MM.

Analysis of the role of dihydromyricetin derived from vine tea(Ampelopsis grossedentata)on multiple myeloma by activating STAT1/RIG-I axis

Multiple myeloma(MM)is a plasma cell malignancy and remains incurable as it lacks effective curative approaches;thus,novel therapeutic strategies are desperately needed.The study aimed to explore the therapeutic role of dihydromyricetin(DHM)in MM and explore its mechanisms.Human MM and normal plasma samples,human MM cell lines,and normal plasma cells were used for in vitro experiments.Cell counting kit-8(CCK-8),flow cytometry,and trans-well assays were performed for the assessment of cell viability,apoptosis,migration,and invasion,respectively.Quantitative real-time polymerase chain reaction(qRT-PCR)was employed to assess the mRNA expression of signal transducer and activator of transcription 1(STAT1)and retinoic acid-inducible gene I(RIG-I).Western blotting was employed to assess E-cadherin,N-cadherin,signal transducer,STAT1,p-STAT1,and RIG-I protein expression.A tumor xenograft model was used for in vivo experiments.Here,dihydromyricetin(DHM)dose-dependently restrained viability,apoptosis,migration,and invasion,and facilitated apoptosis of U266 cells.After DHM treatment,the Ecadherin level was increased and the N-cadherin level was decreased in U266 and RPMI-8226 cells,suggesting the inhibitory effects of DHM on epithelial-mesenchymal transition(EMT)in MM.Besides,the levels of p-STAT1/STAT1 and RIG-I were down-regulated in MM.However,the STAT1 inhibitor fludarabine undid the suppressive effect of DMH on the malignant characteristics of U266 cells.Also,DHM inhibited MM tumor growth and EMT,and activated STAT1/RIG-I pathway in vivo.Collectively,this study first revealed that DHM can restrain EMT and tumor growth in MM by activating STAT1/RIG-I signaling,which provides a novel drug for the treatment of MM.

Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

A genetic variant study of bortezomib-induced peripheral neuropathy in Chinese multiple myeloma patients

Background:Bortezomib results in peripheral neuropathy(PN)in approximately 50%of patients,during multiple myeloma(MM)treatment,a complication known as Bortezomib-induced peripheral neuropathy(BIPN).The drug response varies among individuals.Genetic factor may play an important role in BIPN.Methods:A nextgeneration sequencing(NGS)panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy.mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR(RT-qPCR).Serum homocysteine(Hcy)levels were detected in 40 samples by chemiluminescent microparticle immunoassay(CMIA).Results:Compared with the non-BIPN group(n=89),a total of 8 significantly associated single nucleotide polymorphisms(SNPs)were identified in the BIPN group(n=115):MTHFR(rs1801131,rs1801133,rs17421511),EPHX1(rs1051740),MME(rs2016848),ALDH1A1(rs6151031),HTR7(rs1935349)and CYP2A6(rs8192720).The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment(NP group)was lower than that of newly diagnosed patients without peripheral neuritis after treatment(NnP group)(1.70±0.77 vs.2.81±0.97,p=0.009).Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group(11.66±1.79μmol/L vs.8.52±3.29μmol/L,p=0.016)and healthy controls(11.66±1.79μmol/L vs.8.55±2.13μmol/L,p≤0.001).Conclusion:CYP2A6,EPHX1,MTHFR,ALDH1A1,HTR7,MME and BIPN are linked in Chinese MM patients.BIPN is more likely to occur in patients with lower MTHFR mRNA expression,which might result in higher serum Hcy levels.

Plasmacytosis mimicking multiple myeloma in angioimmunoblastic T-cell lymphoma:A case report and review of literature

BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL)is a common subtype of peripheral T-cell lymphoma.Approximately half of patients with AITL may concurrently present with hypergammaglobulinemia.Increased numbers of plasma cells in the bone marrow are commonly observed at diagnosis.These tumors mimic plasma cell myelomas,hindering a conundrum of clinical diagnoses and potentially delaying appropriate treatment.CASE SUMMARY A 78-year-old woman experienced poor appetite,weight loss of 5 kg,fatigue 2 months before presentation,and shortness of breath 2 d before presentation,but no fever or night sweats.Physical examination revealed splenomegaly and many palpable masses over the bilateral axillary regions,approximately>2 cm in size,with rubbery consistency and no tenderness.Blood tests revealed anemia and thrombocytopenia,lactate dehydrogenase level of 153 U/L,total protein level of 10.9 g/dL,albumin to globulin ratio of 0.2,and immunoglobulin G level more than the upper limit of 3000 mg/dL.The free kappa and lambda light chain concentrations were 451 and 614 mg/L,respectively.A pathological examination confirmed the diagnosis of AITL.The initial treatment was the cyclophosphamide,epirubicin,vincristine,and prednisolone regimen.Following this treatment,pleural effusion was controlled,and the patient was discharged in a stable condition and followed up in our outpatient department.CONCLUSION This report highlights the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia.A precise diagnosis of AITL requires a comprehensive evaluation,involving clinical,immunophenotypic,and histological findings conducted by a multidisciplinary team to ensure appropriate treatment.

Infection in Multiple Myeloma: Microbiological Profile and Prognosis in Senegalese Patients

Introduction: Infections are additional factors of morbidity and mortality in multiple myeloma (MM), and the current recommendation is antibiotic prophylaxis. In sub-Saharan Africa, few data on infectious complications of MM are available. We aim to describe the microbiological features of infections in MM, and their impact on survival in Senegalese patients. Methods: A retrospective (January 2005-January 2022), analytic, multicenter study on infections in patients followed for MM (IMWG criteria) in Senegalese clinical hematology services. The socio-epidemiological, diagnostic, microbiological, evolutionary and survival aspects were analyzed. Results: The study included 106 patients with multiple myeloma who had an infection at admission or during the treatment. Ten patients have the comorbidity (hypertension, lupus, type 2 diabetes). These patients had 136 infectious events identified at diagnosis (79.2%) or during chemotherapy (20.8%). The sites of infection are lung (42.6%), urinary (29.4%), dermatological (6.6%), digestive (5.2%), osteoarticular (4.4%), ear, nose and throat (3.7%), central nervous system (1.5%), or without site. We recorded 26.4% of patients with multi-site infections. The causal pathogens are bacteria (Gram-negative bacilli: 22.1%;Gram positive bacilli: 9.5%, Mycobacterium tuberculosis: 13.3%), parasitique (plasmodium falciparum 6.6%), viruses (SARS-COV2: 2.9%, VZV: 2.2%) and fungal (2.9%). Survival was reduced in patients who had an infection at the time of multiple myeloma diagnosis (p: 0.189) and those who had multiple infectious foci (p: 0.011). Conclusion: Infections in multiple myeloma are more frequent at diagnosis. The germs are varied and mostly bacteria, particularly gram-negative bacteria, and Kochs bacillus. Our study reveals that multiple infectious foci are a poor prognosis factor. It is necessary to evaluate the infectious risk early, and to adopt an antibiotic prophylaxis based on our tropical environment.

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

BACKGROUND 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.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS 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.RESULTS 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.CONCLUSION 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.

Treatment Efficacy and Safety of Bortezomib Combined with Dexamethasone and Lenalidomide Chemotherapy Regimen for Multiple Myeloma

Objective:To analyze the effect of bortezomib combined with dexamethasone and lenalidomide in the treatment of multiple myeloma.Methods:60 cases of multiple myeloma patients admitted to our hospital from January 2022 to December 2023 were selected randomly,with 30 cases in each group.Bortezomib combined with dexamethasone was administered in the control group,and bortezomib combined with dexamethasone and lenalidomide was given to the observation group,and the treatment effect was analyzed.Results:After treatment,CD^(3+)and CD^(4+)of the observation group were higher than that of the control group,CD^(8+)was lower than that of the control group,and the total treatment efficiency was higher,which was statistically significant(P<0.05),and there was no difference in the total incidence of adverse reactions between the two groups(P>0.05).Conclusion:Bortezomib combined with dexamethasone and lenalidomide is effective in the treatment of multiple myeloma as it regulates the immune function and is safe,thus it can be promoted in clinical practice.

Current treatment paradigm and survival outcomes among patients with newly diagnosed multiple myeloma in China:a retrospective multicenter study

Objective:Evidence on the prognostic value of autologous stem cell transplantation(ASCT)and minimal residual disease(MRD)dynamics of patients with newly diagnosed multiple myeloma(NDMM)in China is limited.Our objective in the current study was to understand the current care paradigm and outcomes of these patients.Methods:This longitudinal cohort study used historical data from three top-tier hematologic disease care hospitals that contributed to the National Longitudinal Cohort of Hematological Diseases-Multiple Myeloma.Treatment regimens[proteasome inhibitor(PI)-,immunomodulatory drug(IMiD)-,PI+IMiD-based,and conventional],post-induction response,ASCT and MRD status,and survival outcomes[progression-free survival(PFS)and overall survival(OS)]were evaluated.Results:In total,454 patients with NDMM were included(median age,57 years;59.0%males)with a median follow-up of 58.7 months.The overall response rate was 91.0%,83.9%,90.6%,and 60.9%for PI-,IMiD-,PI+IMiD-based,and conventional regimens,respectively.Patients with ASCT during first-line therapy(26.2%)had a longer PFS and OS than patients who did not receive ASCT[median PFS,42.9 vs.21.2 months,P<0.001;median OS,not reached(NR)vs.65.8 months,P<0.001].The median OS was NR,71.5,and 56.6 months among patients with sustained MRD negativity,loss of MRD negativity,and persistent MRD,respectively(P<0.001).Multivariate analysis revealed that the lactic dehydrogenase level,International Staging System stage,extra-medullary disease,and upfront ASCT were independent factors in predicting OS among NDMM patients.Conclusions:Our study showed that novel agent-based regimens,first-line ASCT,and sustained MRD negativity were associated with a superior outcome for patients with NDMM in China(Identifier:NCT04645199).

Interaction between age and gender on survival outcomes in extramedullary multiple myeloma over the past two decades

BACKGROUND Extramedullary multiple myeloma(MM)(EMM)is a rare and aggressive subentity of MM that can be present at diagnosis or develop anytime during the disease course.There is a paucity of data on the clinical characteristics and overall epidemiology of EMM.Furthermore,there is a scarcity of data on how the interaction of age and gender influences the survival of EMM.AIM To evaluate the clinical characteristics of patients with EMM over the past 2 decades and to identify epidemiologic characteristics that may impact overall prognosis.METHODS A total of 858 patients diagnosed with EMM,between 2000 and 2017,were ultimately enrolled in our study by retrieving the Surveillance,Epidemiology,and End Results database.We analyzed demographics,clinical characteristics,and overall mortality(OM)as well as cancer-specific mortality(CSM)of EMM.Variables with a P value<0.1 in the univariate Cox regression were incorporated into the multivariate Cox model to determine the independent prognostic factors,with a hazard ratio(HR)of greater than 1 representing adverse prognostic factors.RESULTS From a sample of 858 EMM,the male gender(63.25%),age range 60-79 years(51.05%),and non-Hispanic whites(66.78%)were the most represented.Central Nervous System and the vertebral column was the most affected site(33.10%).Crude analysis revealed higher OM in the age group 80+[HR=6.951,95%confidence interval(95%CI):3.299-14.647,P=0],Non-Hispanic Black population(HR=1.339,95%CI:1.02-1.759,P=0.036),Bones not otherwise specified(NOS)(HR=1.74,95%CI:1.043-2.902,P=0.034),and widowed individuals(HR=2.107,95%CI:1.511-2.938,P=0).Skin involvement(HR=0.241,95%CI:0.06-0.974,P=0.046)and a yearly income of$75000+(HR=0.259,95%CI:0.125-0.538,P=0)had the lowest OM in the crude analysis.Crude analysis revealed higher CSM in the age group 80+,Non-Hispanic Black,Bones NOS,and widowed.Multivariate cox proportional hazard regression analyses only revealed higher OM in the age group 80+(HR=9.792,95%CI:4.403-21.774,P=0)and widowed individuals(HR=1.609,95%CI:1.101-2.35,P=0.014).Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups.Eyes,mouth,and ENT involvement had the lowest CSM in the multivariate analysis.There was no interaction between age and gender in the adjusted analysis for OM and CSM.CONCLUSION EMM is a rare entity.To our knowledge,there is a scarcity of data on the clinical characteristics and prognosis factors of patients with extramedullary multiple myeloma.In this retrospective cohort,using a United States-based population,we found that age,marital status,and tumor site were independent prognostic factors.Furthermore,we found that age and gender did not interact to influence the mortality of patients with EMM.

Communication between bone marrow mesenchymal stem cells and multiple myeloma cells:Impact on disease progression

Multiple myeloma(MM)is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow(BM).The interaction between MM cells and the BM microenvironment,and specifically BM mesenchymal stem cells(BM-MSCs),has a key role in the pathophysiology of this disease.Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs,aiding the progression of this hematological tumor.The relation of MM cells with the resident BM-MSCs is a two-way interaction.MM modulate the behavior of BM-MSCs altering their expression profile,proliferation rate,osteogenic potential,and expression of senescence markers.In turn,modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression.The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs,long non-coding RNAs or other molecules.However,the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes.Thus,understanding the way this communication works and developing strategies to interfere in the process,would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.

Lactate Decreases Bortezomib Sensitivity and Predicts Poor Clinical Outcomes of Multiple Myeloma

Objective:Metabolic disorders are regarded as hallmarks of multiple myeloma(MM)and are responsible for rapid cancer cell proliferation and tumor growth.However,the exact biological roles of metabolites in MM cells have not been fully explored.This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid(Lac)in the proliferation of myeloma cells and cell sensitivity to bortezomib(BTZ).Methods:Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients.The CCK8 assay and flow cytometry were used to detect cell proliferation,apoptosis,and cell cycle changes.Western blotting was used to detect the potential mechanism and apoptosis-and cycle-related protein changes.Results:Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients.It was significantly correlated with Durie-Salmon Staging(DS Staging)and the International Staging System(ISS Staging)and the serum and urinary involved/uninvolved free light chain ratios.Patients with relatively high lactate levels had a poor treatment response.Moreover,in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells,which was accompanied by an increased proportion of S-phase cells.In addition,Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2(NFκB2)and Re1B.Conclusion:Metabolic changes are important in MM cell proliferation and treatment response;lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.

PLAGL1 Is Identified as a Potential Diagnostic Marker for Co-Occurrence with Osteoporosis and Multiple Myeloma

Background: Osteoporosis (OP) is a common clinical manifestation of multiple myeloma (MM). The aim of this study was to investigate the possible molecular pathways and shared genes in the co-occurrence of OP and MM. Methods: The Gene Expression Omnibus database was used to retrieve gene expression information. Use WGCNA and differential analysis to screen out Hub genes. The GENEMANIA was used to build protein-protein interaction (PPI) networks. Enrichment analyses were performed to explore the functions. Validation datasets were selected to verify the diagnostic marker reliability of PLAGL1. The immune microenvironment of diseases was analyzed by immune infiltration analyses. Results: We confirmed a hub gene called PLAGL1, which is significantly under-expressed in both OP and MM. We found hub genes were associated with glucose and energy metabolism. Subsequently, the reliability of PLAGL1 for diagnosing OP and MM was verified using ROC curves, with all areas under the curve > 0.75. Moreover, PLAGL1 regulates t lymphocytes and may participate in the occurrence of OP in MM through immune pathways. Conclusions: PLAGL1 is a hub gene for the co-occurrence of OP and MM. It can regulate T-lymphocyte involvement in disease development. PLAGL1 may be a novel diagnostic marker for the co-occurrence of OP and MM.

Meta-analysis of the efficacy and safety of daratumumab in the treatment of multiple myeloma

BACKGROUND The treatment of multiple myeloma has significantly progressed over the past half-century.The purpose of this study was to perform a systematic review and meta-analysis in order to explore the efficacy and safety of daratumumab in treating multiple myeloma.AIM To explore the efficacy and safety of daratumumab in treating multiple myeloma.METHODS A systematic literature search was performed using Chinese and English databases,including the China National Knowledge Infrastructure,Wanfang,China Biology Medicine,VIP,the Cochrane Library,Embase,and PubMed.The search encompassed studies in treating multiple myeloma with daratumumab,spanning from the inception of the database to June 2023.Revman 5.1 software was used for analysis.RESULTS Our analysis included eight English articles and one Chinese article of high quality.The meta-analysis results indicated that compared to other therapies,daratumumab could improve the overall response rate(ORR)[odds ratio(OR)=2.67,95%confidence interval(CI)=2.01,3.53,Z=6.85,P<0.00001],complete remission(CR)(OR=2.87,95%CI=2.16,3.83,Z=7.23,P<0.00001)and progression-free survival(PFS)time(hazard ratio=0.48,95%CI=0.38,0.60,Z=6.54,P<0.00001)in patients with multiple myeloma.These differences were statistically significant.Additionally,these results suggested that daratumumab increases the risk of neutropenia and thrombocytopenia with minimal effect on the incidences of anemia and upper respiratory tract infections.CONCLUSION Daratumumab can improve ORR,CR rate,and PFS in patients with multiple myeloma.It also increases the risk of neutropenia and thrombocytopenia,necessitating careful monitoring during its clinical application.

Reduction rate of monoclonal protein as a useful prognostic factor in standard-risk group of newly diagnosed multiple myeloma

BACKGROUND Multiple myeloma(MM)is a common hematologic malignancy that originates from a malignant clone of plasma cells.Solitary plasmacytoma,history of diabetes,and platelet count are considered as prognostic factors for MM.But some patients are still associated with much worse outcomes without any prognostic predictors.This study aimed to observe the reduction rate of monoclonal protein(M protein)after the first and fourth chemotherapy cycles,which is considered as a new prognostic factor for progression-free survival(PFS)in standard-risk group of newly diagnosed MM patients.AIM To investigate the reduction rate of M protein after first and fourth cycle chemotherapy as a useful prognostic factor.METHODS A total of 316 patients diagnosed with MM for the first time between 2010 and 2019 at the Lishui Municipal Central Hospital were included.All patients were diagnosed according to the National Comprehensive Cancer Network(NCCN)2020.V1 diagnostic criteria.The risk assessment was performed by the Mayo Stratification for Macroglobulinemia and Risk-Adapted Therapy guidelines.After diagnosis,164 patients were evaluated and underwent treatment with four to eight courses of continuous induction chemotherapy.The patients with no response after induction treatment were administered additional therapy following the NCCN 2020.V1 criteria.The following baseline data from the patients were collected:Gender,age at diagnosis,Durie-Salmon stage,glutamicpyruvic transaminase,glutamic-oxaloacetic transaminase,catabolite activator protein,albumin/globulin ratio,lactate dehydrogenase,translocation(t)(6;14),t(11;14),maintenance regimen,total cholesterol(TC),triglyceride,and phosphorous.All baseline data and the reduction rate of M protein after each chemotherapy cycle from the first to fourth were assessed by univariate analysis.The factors influencing the overall survival and PFS were then assessed by multivariate analysis.We found the first cycle(C1)reduction rate and the fourth cycle(C4)reduction rate as predictors of PFS.Then,PFS was compared between patients with a C1 reduction rate of M protein of≥25%vs<25%and≥50%vs<50%,and between patients with a C4 reduction rate of≥25%vs<25%,≥50%vs<50%,and≥75%vs<75%.RESULTS Multivariate analysis revealed age[hazard ratio(HR):1.059,95%confidence interval(95%CI):1.033-1.085,P≤0.001],International Staging System stage(HR:2.136,95%CI:1.500-3.041,P≤0.001),autotransplantion(HR:0.201,95%CI:0.069-0.583,P=0.019),TC(HR:0.689,95%CI:0.533-0.891,P=0.019),C1 reduction rate(HR:0474,95%CI:0.293-0.767,P=0.019),and C4 reduction rate(HR:0.254,95%CI:0.139-0.463,P=0.019)as predictors of PFS.The Kaplan-Meier survival analysis and the log-rank tests revealed that a higher reduction rate of M protein after first cycle(≥50%)and fourth cycle(≥75%)chemotherapy was associated with a longer PFS than the lower one.CONCLUSION Higher reduction rates of M protein after the first and fourth chemotherapy cycles can act as advantageous prognostic factors for PFS in standard-risk group of MM patients during initial diagnosis.

Advances in Biomarkers for Multiple Myeloma

Multiple myeloma(MM)is the second most common malignancy in hematology.MM is characterized by the malignant proliferation of plasma cells in the bone marrow,accompanied by the secretion of monoclonal immunoglobulin,mainly occurring in the elderly.The clinical manifestations of MM include renal dysfunction,bone destruction,infection,anemia,hemorrhage,hypercalcemia,and hyperviscosity syndrome.The recent discovery of biomarkers related to the diagnosis or prognosis of MM provides an important basis for the diagnosis and treatment of MM.This paper reviews the research progress of biomarkers expressed in tissues and peripheral blood at home and abroad.

Clinical Features of Renal Insufficiency due to Multiple Myeloma and Related Risk Factors

Objective: To study clinical features of the patients with multiple myeloma(MM) accompanied by renal insufficiency and investigate the related risk factors of renalimpairment. Methods: A control study of clinical characteristics was performed between 91 patientswith renal insufficiency due to MM and 165 patients with normal renal function in MM during the sameperiod. The data were statistically analyzed by chi-square test and logistic regression analysis.Results: Renal insufficiency was the initial presentation in 48 (52.7%) of the 91 patients, and 30(62.5%) of the 48 patients were misdiagnosed. The prognosis of group with renal insufficiency wassignificantly poorer than that of group with normal renal function: mortality in 3 months, 3months-1 year was 26/91 vs 14/165 (P 【 0.0001), 14/91 vs 12/165 (P 【 0.05) respectively, andpatients survived 】 1 year was 18/91 vs 95/165 (P 【 0.0001). The incidence of hypercalcemia,hyperuricemic, severe anemia, high serum M-protein concentration and lytic bone lesions weresignificantly higher in renal insufficiency group than those in control group (P 【 0.05). Logisticregression analysis identified 5 risk factors of renal impairment, including, severe anemia(Exp(β)=13.819, P 【 0.0001), use of nephrotoxic drugs (Exp(β)=6.217, P = 0.001), high serumM-protein concentration (Exp(β) = 5.026, P = 0.001), male (Exp(β)=3.745, P=0.006), andhypercalcemia (Exp(β)=3A72, P=0.006), but age, serum density of uric acid, type of serum M-protein,and Bence Jones proteinuria were not significantly associated with renal insufficiency. Conclusion:Renal insufficiency was a common early complication of MM, which often resulted in misdiagnosis.The status of these patients tended to be very bad, with many other complications, when MM wasdiagnosed, so their prognosis was poor. The occurrence of renal insufficiency in patients with MMand hypercalcemia, severe anemia, high serum M-protein concentration, especially use of nephrotoxicdrugs should be alert.

Gastrointestinal amyloidosis in a patient with smoldering multiple myeloma:A case report

BACKGROUND Smoldering multiple myeloma(SMM)is an asymptomatic plasma cell proliferative disorder that can progress to multiple myeloma(MM).Amyloidosis(light chain)(AL)is the most common form of systemic amyloidosis.There are few reports of SMM coexisting with AL involving the digestive tract.CASE SUMMARY A 63-year-old woman presented with lower limb edema,abdominal distension,abdominal pain,and hematochezia.Gastroscopy showed gastric retention,gastric angler mucosal coarseness,hyperemia,and mild oozing of blood.Colonoscopy showed hyperemic and edematous mucosa of the distal ascending colon and sigmoid colon with the presence of multiple round and irregular ulcers,submucosal ecchymosis,and hematoma.Gastric and colonic tissue biopsy confirmed the diagnosis of AL by positive Congo red staining.MM was confirmed by bone marrow biopsy and immunohistochemistry.The patient had no hypercalcemia,renal dysfunction,anemia,bone lesions or biomarkers of malignancy defined as plasma cells>60%in bone marrow.Additionally,no elevated serum free light chain ratio,or presence of bone marrow lesions by magnetic resonance imaging(SLiM criteria)were detected.The patient was finally diagnosed with SMM coexisting with AL.She received chemotherapy and was discharged when the symptoms were relieved.She is doing well at nearly five years of follow up.CONCLUSION This case highlights that high index of suspicion is required to diagnose gastrointestinal AL.It should be suspected in elderly patients with endoscopic findings of granular-appearing mucosa,ecchymosis,and submucosal hematoma.Timely diagnosis and appropriate therapy can help to improve the prognosis of these patients.