Objective:Multiple myeloma(MM)is a hematologically malignant clonal plasma cell disease.This study aims to explore the association between immunophenotypes and prognosis in patients with MM,to determine whether the ex...Objective:Multiple myeloma(MM)is a hematologically malignant clonal plasma cell disease.This study aims to explore the association between immunophenotypes and prognosis in patients with MM,to determine whether the expression of CD45 and CD200 is related to the prognosis of newly diagnosed MM(NDMM)patients,and to evaluate the significance of the combined expression of CD45 and CD200 in NDMM.Methods:A total of 123 NDMM patients admitted to Shengjing Hospital of China Medical University from July 2015 to August 2019 were enrolled.Five key immunophenotypic markers(including CD38,CD138,CD45,CD56,and CD200)were screened through flow cytometry and identified using random forest analysis and univariate Cox regression analysis.Patients were divided into 3 groups:Group A,CD45 and CD200 double-positive;Group B,CD45 or CD200 single-positive;Group C,CD45 and CD200 double-negative.Kaplan-Meier curves were used to analyze overall survival(OS)and progression-free survival(PFS)across groups.Multivariate Cox regression was performed to evaluate prognostic factors,and a nomogram was constructed based on these results.Results:The OS and PFS of single-positive groups for CD38,CD138,CD45,CD56,and CD200 were all shorter than those of their respective single-negative groups(all P<0.05).Significant differences were observed in OS(P<0.001)and PFS(P=0.001)among Groups A,B,and C.Group A had shorter OS and PFS(all P=0.001)compared to the Group B+C(cases from Group B and Group C were combined).CD45 and CD200 double-positive was an independent prognostic factor for NDMM[hazard ratio(HR)=2.178,95%confidence interval(CI)1.048 to 4.529;P=0.037].The nomogram and calibration curves constructed from multivariate Cox regression analysis demonstrated good concordance(concordance index=0.706;95%CI 0.661 to 0.751).Conclusion:NDMM patients with double-positive expression of CD45 and CD200 have significantly shorter OS and PFS.Compared with the use of either marker alone,the combined assessment of CD45 and CD200 may provide better prognostic stratification for MM patients.展开更多
Multiple myeloma(MM),one of the most common hemato logical neoplasms worldwide,originates from malignant plasma cells in the bone marrow.MM remains an incurable disease,although continued treatment advancements have m...Multiple myeloma(MM),one of the most common hemato logical neoplasms worldwide,originates from malignant plasma cells in the bone marrow.MM remains an incurable disease,although continued treatment advancements have markedly increased overall survival.Many patients with MM eventually experience relapse or become treatment-refractory1.Patients with relapsed or refractory multiple myeloma(RRMM)become progressively more challenging to manage and have poor prognosis2.展开更多
Objective:To investigate factors influencing vaccine hesitancy and its effects on SARS-CoV-2 infection in multiple myeloma(MM)patients during the Omicron BA.4/5 subvariant outbreak.Methods:This cross-sectional study w...Objective:To investigate factors influencing vaccine hesitancy and its effects on SARS-CoV-2 infection in multiple myeloma(MM)patients during the Omicron BA.4/5 subvariant outbreak.Methods:This cross-sectional study was conducted in China'Mainland from December 26,2022,to April 20,2023.An expert-developed anonymous online questionnaire was distributed via WeChat mini-program to several groups of 500 MM patients,each comprising of 500 patients.The questionnaire covered demographic characteristics,MM medical attributes,COVID-19 vaccine status,and clinical manifestations of COVID-19.Data were analyzed to assess the impact of vaccination on COVID-19 infection rates and the disease severity among MM patients.Results:Among 508 valid responses from 30 provinces,only 34.1%(n=173)of MM patients reported receiving COVID-19 vaccination,and the proportions were lower among patients who had undergone autologous stem cell transplantation(20.2%vs.48.4%,P<0.001).Vaccine hesitancy was primarily attributed to physician recommendations(52.0%),conflicts with MM treatment(37.8%),and concerns about MM progression(31.3%).Hospitalization due to severe SARS-CoV-2 infections was significantly reduced in the vaccinated group(4.8%vs.12.3%,P=0.038).Conclusions:The lower infection rate in MM patients may be attributed to stringent quarantine measures and self-imposed social restrictions.While vaccination did not directly correlate with fewer SARS-CoV-2 infections,it did afford protection to vulnerable populations.Clinicians are encouraged to recommend vaccines to MM patients to mitigate severe infections and associated mortality during recurrent COVID-19 waves.展开更多
Multiple myeloma is a complex and challenging blood cancer,particularly in cases where the disease has relapsed or become resistant to treatment.These situations often have a significant impact on both patient surviva...Multiple myeloma is a complex and challenging blood cancer,particularly in cases where the disease has relapsed or become resistant to treatment.These situations often have a significant impact on both patient survival and quality of life.Over recent years,advances in precision medicine and translational medicine have brought about a shift in treatment strategies,moving toward more personalized and targeted approaches.This review highlights the latest developments in the management of refractory and relapsed multiple myeloma,focusing on the current state of precision diagnosis and treatment,the role of translational medicine,and potential future directions in research.By reviewing key studies and clinical trial data,we aim to offer fresh perspectives and strategies that could improve clinical outcomes.展开更多
OBJECTIVE:To explore the therapeutic potential of the Dujieqing(DJQ)decoction(毒结清复方)for multiple myeloma(MM)and elucidate its mechanism of action.METHODS:RPMI8226 cells were treated with DJQcontaining serum(DJQ-C...OBJECTIVE:To explore the therapeutic potential of the Dujieqing(DJQ)decoction(毒结清复方)for multiple myeloma(MM)and elucidate its mechanism of action.METHODS:RPMI8226 cells were treated with DJQcontaining serum(DJQ-CS)and a Wnt/β-catenin pathway inhibitor,XAV-939.Cell counting kit-8 assay was used to examine cell viability,and flow cytometry was performed to examine apoptosis.Real-time polymerase chain reaction and Western blotting were used to evaluate the Wnt/β-catenin pathway family members in the cells.Subsequently,the RPMI8226 cells were subcutaneously injected into the left flank of none obesity disease and server combined immune-deficiency mice to replicate the xenograft tumor mouse models,which were treated with the DJQ decoction for 14 d.Hematoxylin and eosin staining was used to examine the pathological changes of the liver and kidney tissues,and to detect xenograft tumors.Wnt/β-catenin pathway family members were evaluated via Western blotting.RESULTS:DJQ-CS significantly reduced the m RNA and protein expression levels ofβ-catenin,c-myc,cyclin D1,and lymphoid enhancer binding factor 1(LEF1)while inhibiting the proliferation of RPMI8226 cells and inducing their apoptosis.Similar results were observed when the Wnt/β-catenin pathway was suppressed by inhibitors.Moreover,in the mouse model of xenograft tumors,DJQ decoction not only reduced the tumor volume but also inhibited the protein levels ofβ-catenin,c-myc,cyclin D1,and LEF1.The histopathology of the mice also showed increased apoptosis in tumor tissues,while the DJQ decoction treatment did not cause any pathological damage to the kidneys or liver.CONCLUSION:Our results indicate that the DJQ decoction suppresses tumor progression by inhibiting the Wnt/β-catenin pathway,offering a promising treatment approach for MM.展开更多
Background:Long non-coding RNAs are implicated in metabolic diseases and malignancies,but their role in multiple myeloma(MM)with type 2 diabetes mellitus(T2DM)remains unclear.This study evaluated Long non-coding RNA M...Background:Long non-coding RNAs are implicated in metabolic diseases and malignancies,but their role in multiple myeloma(MM)with type 2 diabetes mellitus(T2DM)remains unclear.This study evaluated Long non-coding RNA Morrbid expression in MM patients with/without T2DM.Methods:The study enrolled 107 MM patients(48 with T2DM,59 without)and 72 non-MM controls(23 with T2DM,49 without).Peripheral blood mononuclear cells(PBMCs)were isolated from whole blood samples using red blood cell lysis.Total RNA was extracted from PBMCs,followed by reverse transcription,and the expression levels of Morrbid were detected by Reverse transcription-quantitative PCR.Results:We found that the expression of Morrbid was upregulated in the MM group compared to the non-MM patients.Within the MM group,the expression of Morrbid was significantly higher in patients with T2DM than in those without T2DM.In contrast,no significant difference in Morrbid expression was observed between T2DM and non-T2DM patients in the non-MM patients.Furthermore,we discovered a positive correlation between Morrbid expression and fasting blood sugar levels in MM patients.Operating characteristic curve analysis revealed an area under the curve of 0.822(sensitivity 77.1%,specificity 79.7%)for diagnosing T2DM in MM,suggesting that Morrbid may serve as a novel diagnostic biomarker for T2DM in MM patients.Conclusions:The high expression of Morrbid in MM patients with T2DM may indicate its critical role in tumor-related glucose metabolism.Additionally,Morrbid may potentially serve as a diagnostic biomarker for T2DM in MM patients.展开更多
BACKGROUND The purpose of this paper is to demonstrate a practical stem cell collection method that provides sufficient stem cells for autologous stem cell transplantation(ASCT)in multiple myeloma(MM)patients despite ...BACKGROUND The purpose of this paper is to demonstrate a practical stem cell collection method that provides sufficient stem cells for autologous stem cell transplantation(ASCT)in multiple myeloma(MM)patients despite low peripheral CD34(pCD34)counts and to describe the benefits of this method for MM patients with limited resources.AIM To demonstrate a practical method for stem cell collection.METHODS Stem cell collection data on the last 300 patients at a community cancer center in Washington were reviewed.We report on the methods of collection,including medi-cations used and timing,used by the blood blank as well as their outcomes.The three MM patients with initially very low pCD34 counts all successfully underwent stem cell collection in a single trip to the transplant center for their ASCT.RESULTS Three patients whose pre-collection pCD34 counts were the lowest and less than 2.5 cells/μL were identified.These patients had the commonality of having multiple barriers to transportation and likely would have been able to make only one trip for the stem cell collections.CONCLUSION Despite particularly low pre-collection peripheral blood CD34 counts,successful autologous stem cell collection in MM patients is feasible by routinely adding plerixafor to granulocyte-colony stimulating factor on day 4 of mobilization.There is limited analysis demonstrating that sufficient stem cells for one or more transplants can be collected using this method.This practical and novel approach may benefit the high number of MM patients who face limited resources,finances,long travel times,and social support.These results are highly relevant to physicians treating similar patients.展开更多
Precise risk stratification is crucial for selecting the optimal risk-adapted treatment for newly diagnosed multiple myeloma (NDMM) patients. Various prognostic factors and staging systems have been developed to predi...Precise risk stratification is crucial for selecting the optimal risk-adapted treatment for newly diagnosed multiple myeloma (NDMM) patients. Various prognostic factors and staging systems have been developed to predict NDMM patient outcomes. The Durie-Salmon (D-S) staging system reflects tumor burden and clinical progression staging with prognostic value.展开更多
Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular ...Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular energy metabolism,has been implicated in various cancers.but its role in MM remains unclear.Methods:ERRγexpres-sion was assessed using bioinformatics and RT-qPCR.Functional studies were conducted through siRNA-mediated ERRγknockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.Results:ERRγwas significantly upregulated in the bone marrow of MM patients,correlating with advanced clinical stages and pathological fractures.Inhibition of ERRγreduced MM cell expansion both in vitro and in vivo,while promoting mitochondrial-dependent apoptosis.Co-immunoprecipitation assays demonstrated a physical association between ERRγand P65.Inhibition of ERRγattenuated canonical nuclear factor-kappa B(NF-κB)signaling by blocking the nuclear translocation of its key effector p65.Additionally,modulation of ERRγaltered receptor activator of nuclear factor-κB ligand(RANKL)levels,implying a potential role in bone degradation observed in MM cases.Conclusion:Collectively,the data broaden understanding of ERRγ’s contribution to MM development and propose it as a viable target for therapeutic intervention.展开更多
Carfilzomib has become a new choice for patients with multiple myeloma（MM）.However, the use of carfilzomib single-agent or in combination with other agents in MM patients is not explicitly clarified in clinical prac...Carfilzomib has become a new choice for patients with multiple myeloma（MM）.However, the use of carfilzomib single-agent or in combination with other agents in MM patients is not explicitly clarified in clinical practice. Therefore, we analyzed the effects of carfilzomib and its safety and effectiveness using available clinical trial reports in order to find out the best therapy of carfilzomib. We searched MEDLINE, Embase, Pub Med and Cochrane databases as well as Chinese databases of carfilzomib trials（Jan. 2012 to Sep. 2016） for the MM treatment. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as the overall response rate（ORR） and performed by R software. A fixed-effects model or random-effects model was applied based on the heterogeneity among studies. Based on our research standard, we identified 17 prospective studies enrolling 1960 patients.A total of 594 MM patients were enrolled in carfilzomib single-agent clinical trials, and the ORR was 32%（I^2 = 84.9%, P〈0.0001）.A total of 1366 MM patients were enrolled in clinical trials of 10 groups of carfilzomib combination regimens, 1081 patients had a therapeutic effect, and the ORR was79%（I^2 = 91.0%, P〈0.0001）. The most frequent adverse events were fever, nausea, vomiting and other non-hematologic events. Carfilzomib was better tolerated than bortezomib, with a lower incidence of peripheral neuropathy and better therapeutic effects compared with other drugs. In this analysis, the highest ORR was achieved from combination of carfilzomib, lenalidomide and dexamethasone, which had a lower incidence of adverse events and a greater ORR compared with carfilzomib single-agent. Therefore, the combination of carfilzomib, lenalidomide and dexamethasone could be a good therapeutic agent with strong clinical effect. However, this conclusion needs to be validated in future study.展开更多
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 char...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.展开更多
Medical imaging is of crucial importance for diagnosis and initial staging as well as for differentiation of multiple myeloma(MM)from other monoclonal plasma cell diseases.Conventional radiography represents the refer...Medical imaging is of crucial importance for diagnosis and initial staging as well as for differentiation of multiple myeloma(MM)from other monoclonal plasma cell diseases.Conventional radiography represents the reference standard for diagnosis of MM due to its wide availability and low costs despite its known limitations such as low sensitivity,limited specificity and its inability to detect extraosseous lesions.Besides conventional radiography,newer cross-sectional imaging modalities such as whole-body low-dose computed tomography(CT),whole-body magnetic resonance imaging(MRI)and18F-fluorodeoxyglucose(FDG)positron emission tomography(PET)/CT are available for the diagnosis of osseous and extraosseous manifestations of MM.Whole-body low-dose CT is used increasingly,replacing conventional radiography at selected centers,due to its higher sensitivity for the detection of osseous lesions and its ability to diagnose extraosseous lesions.The highest sensitivity for both detection of bone marrow disease and extraosseous lesions can be achieved with whole-body MRI and18F-FDG PET/CT.According to current evidence,MRI is the most sensitive method for initial staging while18F-FDG PET/CT allows monitoring of treatment of MM.There is an evolving role for assessment of treatment response using newer MR imagingtechniques.Future studies are needed to further define the exact role of the different imaging modalities for individual risk stratification and therapy monitoring.展开更多
Multiple myeloma is a hematological malignancy inwhich clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic le-sions due to increased osteoclast(OC) activity and sup-presse...Multiple myeloma is a hematological malignancy inwhich clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic le-sions due to increased osteoclast(OC) activity and sup-pressed osteoblast(OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells(MSCs) play a critical role in multiple myeloma patho-physiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of my-eloma bone disease(MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients(pMSCs) and their healthy counterparts(dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibi-tory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and ac-tivity at various levels(i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncou-pling ephrinB2-EphB4 signaling, and through augment-ed production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents(at preclinical or clinical stage) targeting those signaling pathways is commented.展开更多
This study was designed to determine the impact of chrysoeriol on proliferation and cell cycle progression in the human multiple myeloma cell lines RPMI 8226 and KM3,and its related molecular mechanisms.Chryseoriol wa...This study was designed to determine the impact of chrysoeriol on proliferation and cell cycle progression in the human multiple myeloma cell lines RPMI 8226 and KM3,and its related molecular mechanisms.Chryseoriol was identified by using the phosphorylated AKT-specific cytoblot high throughput assay.CCK-8 assay was employed to examine the growth inhibition rate and IC 50 (48 h) in peripheral blood mononuclear cells (PBMNCs),RPMI 8226 and KM3 cells treated with chrysoeriol at various concentrations.Cells were labeled with 5-6-carboxyfluorescein diacetate succinimidyl ester (CFSE),and the proliferation dynamics was detected by flow cytometry and analyzed with ModFit software.The cell cycles of RPMI 8226 and KM3 cells were measured by flow cytometry when the IC 50 concentration of chrysoeriol was adopted.The alterations in cell-cycle related proteins (Cyclin B1,Cyclin D1,p21) and proteins in PI3K-AKT-mTOR pathway were determined by Western blot analysis.The results showed the proliferation of multiple myeloma cells was significantly inhibited by chrysoeriol,resulting in cell cycle arrest in G 2 /M phase.Chrysoeriol could significantly reduce the expression of p-AKT (s473) and p-4eBP1 (t37/46) protein,meanwhile enhanced Cyclin B1 and p21 protein expression.Similar effects were not observed in PBMNCs from normal donors.It was concluded that chrysoeriol was a selective PI3K-AKT-mTOR pathway inhibitor.It restrained the proliferation of human multiple myeloma cells,but didn’t affect proliferation of PBMNCs from normal donors.It might exhibit the cell cycle regulatory effect via the inhibition of PI3K-AKT-mTOR signal pathway.展开更多
In this study,we administered a modified schedule of weekly intravenous Bortezomib at 1.6 mg/m 2 with dexamethasone(BD) and compared it to the standard 1.3 mg/m 2 twice-weekly BD regimen in Chinese patients with newly...In this study,we administered a modified schedule of weekly intravenous Bortezomib at 1.6 mg/m 2 with dexamethasone(BD) and compared it to the standard 1.3 mg/m 2 twice-weekly BD regimen in Chinese patients with newly diagnosed multiple myeloma(MM).We assessed the difference in efficacy,safety profile and survival between the once-weekly and twice-weekly cohorts(13 vs.24 patients).The over response rate was similar with both arms of the study,being 77% in the once-weekly schedule and 74.9% in the twice-weekly schedule(P=0.690).The median overall survival was not reached in either schedule.Also,the median progression-free survival and duration of response of the once-weekly schedule did not significantly differ from those of the twice-weekly schedule(8 months vs.10 months,P=0.545 and 6 months vs.7 months,P=0.467 respectively).Peripheral sensory neuropathy and grade 3/4 hematologic toxic effects were more frequently reported in the twice-weekly schedule than the once-weekly schedule,but there was no statistically significant difference.This preliminary experience in Chinese patients with newly diagnosed MM indicated that once-weekly infusion of Bortezomib plus dexamethasone may improve safety without affecting outcome.展开更多
Background: Despite the recent development of new therapies, multiple myeloma(MM) remains an incurable disease. Thus, new, efective treatments are urgently needed, particularly for relapsed or refractory MM(RRMM). In ...Background: Despite the recent development of new therapies, multiple myeloma(MM) remains an incurable disease. Thus, new, efective treatments are urgently needed, particularly for relapsed or refractory MM(RRMM). In an earlier phase I study, a novel form of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) that is currently in clinical development for the treatment of hematologic malignancies, i.e., circularly permuted TRAIL(CPT), was well tolerated at a dose of 2.5 mg/kg per day and showed promising preliminary activity in patients with RRMM. This phase II, open-label, multicenter study further investigated the eicacy and safety of 2.5-mg/kg per day CPT as single-agent therapy for patients with RRMM.Methods: Patients with RRMM were treated once daily with CPT(2.5 mg/kg, intravenously) for 14 consecutive days for each 21-day cycle. Clinical response and toxicity were assessed after each treatment cycle.Results: Twenty-seven patients received CPT. Using the European Group for Blood and Marrow Transplantation criteria, we calculated the overall response rate of 33.3% with 1 near-complete response(n CR) and 8 partial responses(PRs). The clinical beneit rate(48.1%) included 1 nCR, 8 PRs, and 4 minimal responses. The most common treatmentrelated adverse events(TRAEs) were fever, aspartate aminotransferase elevation, alanine aminotransferase elevation, leucopenia, rash, neutropenia, and thrombocytopenia. We graded toxicity using the Common Toxicity Criteria for Adverse Events, version 3.0, and determined that 37.0% of patients had at least 1 grade 3–4 TRAE.Conclusions: CPT as a single agent can elicit a response in patients with RRMM and is well tolerated. Further clinical investigation is warranted.展开更多
Multiple myeloma(MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells(CSCs) has been demonstrated in many solid and...Multiple myeloma(MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells(CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activate stemness signaling(Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.展开更多
Objective： To investigate the effects of triptolide（TPL） on cell growth, cell cycle and the expressions of p21wapl/cipl and p27kipl. Methods： MTT assay was used to determine the cell viability after triptolide tr...Objective： To investigate the effects of triptolide（TPL） on cell growth, cell cycle and the expressions of p21wapl/cipl and p27kipl. Methods： MTT assay was used to determine the cell viability after triptolide treatment in human multiple myeloma RPMI-8226 cells. The effect on cell cycle distribution was determined by flow cytometry. Semi-quantitative reverse transcription-PCR was used to examine the mRNA expressions of p21wapl/cipl and p27kipl. The protein expressions of p21 wapl/cipl and p27kipl were determined by Western blot. Results： Triptolide of varying concentrations induced cell viability inhibition in dose- and time-related fashion and caused Go- G1 phase arrest of cell cycle progression in RPMI-8226 cells. These effects accompanied with up-modulation of the expressions of p21 wapl/cipl and p27kipl. Conclusion： These results suggest that triptolide inhibit cell proliferation and cell cycle progression via up-regulating p21wapl/cipl and p27kipl and triptolide may exert its anti-cancer activity through this pathway.展开更多
The effect of triptolide on proliferation and apoptosis of human multiple myeloma RPMI-8226 cells in vitro,as well as the roles of nuclear factor-kappa B（NF-κB） and IκBα was investigated.The effect of tritptolide...The effect of triptolide on proliferation and apoptosis of human multiple myeloma RPMI-8226 cells in vitro,as well as the roles of nuclear factor-kappa B（NF-κB） and IκBα was investigated.The effect of tritptolide on the growth of RPMI-8226 cells was studied by MTT assay.Apoptosis was detected by Hoechest 33258 staining and Annexin V/PI double staining assay.The expression of NF-κB and IκBα was observed by Western blot and confocal microscopy.The results showed that triptolide inactivated NF-κB apoptotic pathway in human multiple myeloma RPMI-8226 cells.Triptolide at nM range induced proliferation inhibition in a dose-and time-dependent manner and apoptosis in a dose-dependent fashion in RPMI-8226 cells.Besides,we observed the inhibition of NF-κB /p65 in the nuclear fraction was correlated with the increase in the protein expression of IκBα in the cytosol.These results suggested that triptolide might exhibit its strong anti-tumor effects via inactivation of NF-κB/p65 and IκBα.展开更多
基金supported by the National Natural Science Foundation,China(81870166).
文摘Objective:Multiple myeloma(MM)is a hematologically malignant clonal plasma cell disease.This study aims to explore the association between immunophenotypes and prognosis in patients with MM,to determine whether the expression of CD45 and CD200 is related to the prognosis of newly diagnosed MM(NDMM)patients,and to evaluate the significance of the combined expression of CD45 and CD200 in NDMM.Methods:A total of 123 NDMM patients admitted to Shengjing Hospital of China Medical University from July 2015 to August 2019 were enrolled.Five key immunophenotypic markers(including CD38,CD138,CD45,CD56,and CD200)were screened through flow cytometry and identified using random forest analysis and univariate Cox regression analysis.Patients were divided into 3 groups:Group A,CD45 and CD200 double-positive;Group B,CD45 or CD200 single-positive;Group C,CD45 and CD200 double-negative.Kaplan-Meier curves were used to analyze overall survival(OS)and progression-free survival(PFS)across groups.Multivariate Cox regression was performed to evaluate prognostic factors,and a nomogram was constructed based on these results.Results:The OS and PFS of single-positive groups for CD38,CD138,CD45,CD56,and CD200 were all shorter than those of their respective single-negative groups(all P<0.05).Significant differences were observed in OS(P<0.001)and PFS(P=0.001)among Groups A,B,and C.Group A had shorter OS and PFS(all P=0.001)compared to the Group B+C(cases from Group B and Group C were combined).CD45 and CD200 double-positive was an independent prognostic factor for NDMM[hazard ratio(HR)=2.178,95%confidence interval(CI)1.048 to 4.529;P=0.037].The nomogram and calibration curves constructed from multivariate Cox regression analysis demonstrated good concordance(concordance index=0.706;95%CI 0.661 to 0.751).Conclusion:NDMM patients with double-positive expression of CD45 and CD200 have significantly shorter OS and PFS.Compared with the use of either marker alone,the combined assessment of CD45 and CD200 may provide better prognostic stratification for MM patients.
基金supported by grant from the National Natural Science Foundation of China(Grant No.82300231).
文摘Multiple myeloma(MM),one of the most common hemato logical neoplasms worldwide,originates from malignant plasma cells in the bone marrow.MM remains an incurable disease,although continued treatment advancements have markedly increased overall survival.Many patients with MM eventually experience relapse or become treatment-refractory1.Patients with relapsed or refractory multiple myeloma(RRMM)become progressively more challenging to manage and have poor prognosis2.
基金funded by the Capital Health Development Scientific Research Fund(Grant No.2022-2-4013)National High-Level Hospital Clinical Research Funding(2022-PUMCH-B-048).
文摘Objective:To investigate factors influencing vaccine hesitancy and its effects on SARS-CoV-2 infection in multiple myeloma(MM)patients during the Omicron BA.4/5 subvariant outbreak.Methods:This cross-sectional study was conducted in China'Mainland from December 26,2022,to April 20,2023.An expert-developed anonymous online questionnaire was distributed via WeChat mini-program to several groups of 500 MM patients,each comprising of 500 patients.The questionnaire covered demographic characteristics,MM medical attributes,COVID-19 vaccine status,and clinical manifestations of COVID-19.Data were analyzed to assess the impact of vaccination on COVID-19 infection rates and the disease severity among MM patients.Results:Among 508 valid responses from 30 provinces,only 34.1%(n=173)of MM patients reported receiving COVID-19 vaccination,and the proportions were lower among patients who had undergone autologous stem cell transplantation(20.2%vs.48.4%,P<0.001).Vaccine hesitancy was primarily attributed to physician recommendations(52.0%),conflicts with MM treatment(37.8%),and concerns about MM progression(31.3%).Hospitalization due to severe SARS-CoV-2 infections was significantly reduced in the vaccinated group(4.8%vs.12.3%,P=0.038).Conclusions:The lower infection rate in MM patients may be attributed to stringent quarantine measures and self-imposed social restrictions.While vaccination did not directly correlate with fewer SARS-CoV-2 infections,it did afford protection to vulnerable populations.Clinicians are encouraged to recommend vaccines to MM patients to mitigate severe infections and associated mortality during recurrent COVID-19 waves.
基金supported by grants from the 925th Science Foundation(Grant Nos.2023-3 and 2024-2/3).
文摘Multiple myeloma is a complex and challenging blood cancer,particularly in cases where the disease has relapsed or become resistant to treatment.These situations often have a significant impact on both patient survival and quality of life.Over recent years,advances in precision medicine and translational medicine have brought about a shift in treatment strategies,moving toward more personalized and targeted approaches.This review highlights the latest developments in the management of refractory and relapsed multiple myeloma,focusing on the current state of precision diagnosis and treatment,the role of translational medicine,and potential future directions in research.By reviewing key studies and clinical trial data,we aim to offer fresh perspectives and strategies that could improve clinical outcomes.
基金Supported by National Science Foundation-Funded Project:based on the Connection Sclerostin with Wnt/β-catenin Pathway to Explored the Effect Mechanism of Dujieqing Oral Liquid on the Inhibit Tumor and Promote Bone Formation in Multiple Myeloma(No.81960839)Innovation Project of Guangxi Graduate Education-Funded Project:Sclerostin Regulates Wnt/β-catenin Pathway to Explore the Mechanism of Dujieqing Decoction in Inhibiting Tumor Growth and Promoting Osteogenesis of Multiple Myeloma(No.YCSW2021224)To Investigate the Effect and Mechanism of Dujiangqing Oral Liquid on Osteogenic Differentiation of Mesenchymal Stem Cells in Multiple Myeloma Mice based on Wnt/β-catenin Signaling Pathway(No.YCSW2023386)。
文摘OBJECTIVE:To explore the therapeutic potential of the Dujieqing(DJQ)decoction(毒结清复方)for multiple myeloma(MM)and elucidate its mechanism of action.METHODS:RPMI8226 cells were treated with DJQcontaining serum(DJQ-CS)and a Wnt/β-catenin pathway inhibitor,XAV-939.Cell counting kit-8 assay was used to examine cell viability,and flow cytometry was performed to examine apoptosis.Real-time polymerase chain reaction and Western blotting were used to evaluate the Wnt/β-catenin pathway family members in the cells.Subsequently,the RPMI8226 cells were subcutaneously injected into the left flank of none obesity disease and server combined immune-deficiency mice to replicate the xenograft tumor mouse models,which were treated with the DJQ decoction for 14 d.Hematoxylin and eosin staining was used to examine the pathological changes of the liver and kidney tissues,and to detect xenograft tumors.Wnt/β-catenin pathway family members were evaluated via Western blotting.RESULTS:DJQ-CS significantly reduced the m RNA and protein expression levels ofβ-catenin,c-myc,cyclin D1,and lymphoid enhancer binding factor 1(LEF1)while inhibiting the proliferation of RPMI8226 cells and inducing their apoptosis.Similar results were observed when the Wnt/β-catenin pathway was suppressed by inhibitors.Moreover,in the mouse model of xenograft tumors,DJQ decoction not only reduced the tumor volume but also inhibited the protein levels ofβ-catenin,c-myc,cyclin D1,and LEF1.The histopathology of the mice also showed increased apoptosis in tumor tissues,while the DJQ decoction treatment did not cause any pathological damage to the kidneys or liver.CONCLUSION:Our results indicate that the DJQ decoction suppresses tumor progression by inhibiting the Wnt/β-catenin pathway,offering a promising treatment approach for MM.
基金Luzhou Municipal Government-Southwest Medical University Cooperation Application Foundation(Project No.:2023LZXNYDJ045)Luzhou Science and Technology Bureau,China(Project No.:2024JYJ064)Academic Research Projects of Southwest Medical University(Project No.:2023QN042&2024ZKY040)。
文摘Background:Long non-coding RNAs are implicated in metabolic diseases and malignancies,but their role in multiple myeloma(MM)with type 2 diabetes mellitus(T2DM)remains unclear.This study evaluated Long non-coding RNA Morrbid expression in MM patients with/without T2DM.Methods:The study enrolled 107 MM patients(48 with T2DM,59 without)and 72 non-MM controls(23 with T2DM,49 without).Peripheral blood mononuclear cells(PBMCs)were isolated from whole blood samples using red blood cell lysis.Total RNA was extracted from PBMCs,followed by reverse transcription,and the expression levels of Morrbid were detected by Reverse transcription-quantitative PCR.Results:We found that the expression of Morrbid was upregulated in the MM group compared to the non-MM patients.Within the MM group,the expression of Morrbid was significantly higher in patients with T2DM than in those without T2DM.In contrast,no significant difference in Morrbid expression was observed between T2DM and non-T2DM patients in the non-MM patients.Furthermore,we discovered a positive correlation between Morrbid expression and fasting blood sugar levels in MM patients.Operating characteristic curve analysis revealed an area under the curve of 0.822(sensitivity 77.1%,specificity 79.7%)for diagnosing T2DM in MM,suggesting that Morrbid may serve as a novel diagnostic biomarker for T2DM in MM patients.Conclusions:The high expression of Morrbid in MM patients with T2DM may indicate its critical role in tumor-related glucose metabolism.Additionally,Morrbid may potentially serve as a diagnostic biomarker for T2DM in MM patients.
文摘BACKGROUND The purpose of this paper is to demonstrate a practical stem cell collection method that provides sufficient stem cells for autologous stem cell transplantation(ASCT)in multiple myeloma(MM)patients despite low peripheral CD34(pCD34)counts and to describe the benefits of this method for MM patients with limited resources.AIM To demonstrate a practical method for stem cell collection.METHODS Stem cell collection data on the last 300 patients at a community cancer center in Washington were reviewed.We report on the methods of collection,including medi-cations used and timing,used by the blood blank as well as their outcomes.The three MM patients with initially very low pCD34 counts all successfully underwent stem cell collection in a single trip to the transplant center for their ASCT.RESULTS Three patients whose pre-collection pCD34 counts were the lowest and less than 2.5 cells/μL were identified.These patients had the commonality of having multiple barriers to transportation and likely would have been able to make only one trip for the stem cell collections.CONCLUSION Despite particularly low pre-collection peripheral blood CD34 counts,successful autologous stem cell collection in MM patients is feasible by routinely adding plerixafor to granulocyte-colony stimulating factor on day 4 of mobilization.There is limited analysis demonstrating that sufficient stem cells for one or more transplants can be collected using this method.This practical and novel approach may benefit the high number of MM patients who face limited resources,finances,long travel times,and social support.These results are highly relevant to physicians treating similar patients.
基金supported by the National Natural Science Foundation of China (Grant nos. 82470209 and 82170141)the Jiaxing Key Discipiline of Medcine-Nephrology (Grant no. 2023-ZC-011)。
文摘Precise risk stratification is crucial for selecting the optimal risk-adapted treatment for newly diagnosed multiple myeloma (NDMM) patients. Various prognostic factors and staging systems have been developed to predict NDMM patient outcomes. The Durie-Salmon (D-S) staging system reflects tumor burden and clinical progression staging with prognostic value.
文摘Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular energy metabolism,has been implicated in various cancers.but its role in MM remains unclear.Methods:ERRγexpres-sion was assessed using bioinformatics and RT-qPCR.Functional studies were conducted through siRNA-mediated ERRγknockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.Results:ERRγwas significantly upregulated in the bone marrow of MM patients,correlating with advanced clinical stages and pathological fractures.Inhibition of ERRγreduced MM cell expansion both in vitro and in vivo,while promoting mitochondrial-dependent apoptosis.Co-immunoprecipitation assays demonstrated a physical association between ERRγand P65.Inhibition of ERRγattenuated canonical nuclear factor-kappa B(NF-κB)signaling by blocking the nuclear translocation of its key effector p65.Additionally,modulation of ERRγaltered receptor activator of nuclear factor-κB ligand(RANKL)levels,implying a potential role in bone degradation observed in MM cases.Conclusion:Collectively,the data broaden understanding of ERRγ’s contribution to MM development and propose it as a viable target for therapeutic intervention.
基金Zhejiang Public Welfare Technology Application Research Project(Grant No.2015C33285)Zhejiang Provincial Natural Science Foundation Project(Grant No.Y14H300005)
文摘Carfilzomib has become a new choice for patients with multiple myeloma（MM）.However, the use of carfilzomib single-agent or in combination with other agents in MM patients is not explicitly clarified in clinical practice. Therefore, we analyzed the effects of carfilzomib and its safety and effectiveness using available clinical trial reports in order to find out the best therapy of carfilzomib. We searched MEDLINE, Embase, Pub Med and Cochrane databases as well as Chinese databases of carfilzomib trials（Jan. 2012 to Sep. 2016） for the MM treatment. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as the overall response rate（ORR） and performed by R software. A fixed-effects model or random-effects model was applied based on the heterogeneity among studies. Based on our research standard, we identified 17 prospective studies enrolling 1960 patients.A total of 594 MM patients were enrolled in carfilzomib single-agent clinical trials, and the ORR was 32%（I^2 = 84.9%, P〈0.0001）.A total of 1366 MM patients were enrolled in clinical trials of 10 groups of carfilzomib combination regimens, 1081 patients had a therapeutic effect, and the ORR was79%（I^2 = 91.0%, P〈0.0001）. The most frequent adverse events were fever, nausea, vomiting and other non-hematologic events. Carfilzomib was better tolerated than bortezomib, with a lower incidence of peripheral neuropathy and better therapeutic effects compared with other drugs. In this analysis, the highest ORR was achieved from combination of carfilzomib, lenalidomide and dexamethasone, which had a lower incidence of adverse events and a greater ORR compared with carfilzomib single-agent. Therefore, the combination of carfilzomib, lenalidomide and dexamethasone could be a good therapeutic agent with strong clinical effect. However, this conclusion needs to be validated in future study.
文摘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.
文摘Medical imaging is of crucial importance for diagnosis and initial staging as well as for differentiation of multiple myeloma(MM)from other monoclonal plasma cell diseases.Conventional radiography represents the reference standard for diagnosis of MM due to its wide availability and low costs despite its known limitations such as low sensitivity,limited specificity and its inability to detect extraosseous lesions.Besides conventional radiography,newer cross-sectional imaging modalities such as whole-body low-dose computed tomography(CT),whole-body magnetic resonance imaging(MRI)and18F-fluorodeoxyglucose(FDG)positron emission tomography(PET)/CT are available for the diagnosis of osseous and extraosseous manifestations of MM.Whole-body low-dose CT is used increasingly,replacing conventional radiography at selected centers,due to its higher sensitivity for the detection of osseous lesions and its ability to diagnose extraosseous lesions.The highest sensitivity for both detection of bone marrow disease and extraosseous lesions can be achieved with whole-body MRI and18F-FDG PET/CT.According to current evidence,MRI is the most sensitive method for initial staging while18F-FDG PET/CT allows monitoring of treatment of MM.There is an evolving role for assessment of treatment response using newer MR imagingtechniques.Future studies are needed to further define the exact role of the different imaging modalities for individual risk stratification and therapy monitoring.
基金Supported by Grants from the Spanish Ministry of Economíay Competitividad-Instituto de Salud CarlosⅢ,No.PI12/02591European Funds for Regional Development+3 种基金the Spanish Health Thematic Networks of Cooperative Research in Cancer,No.RTICC RD12/0036/0058Cellular Therapy,No.TerCelRD12/0019/0001,group 8the Network of Centers for Regenera-tive Medicine and Cellular Therapy from Castilla y Leónthe Spanish Society of Hematology and Hemotherapy(to Garcia-Gomez A)
文摘Multiple myeloma is a hematological malignancy inwhich clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic le-sions due to increased osteoclast(OC) activity and sup-pressed osteoblast(OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells(MSCs) play a critical role in multiple myeloma patho-physiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of my-eloma bone disease(MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients(pMSCs) and their healthy counterparts(dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibi-tory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and ac-tivity at various levels(i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncou-pling ephrinB2-EphB4 signaling, and through augment-ed production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents(at preclinical or clinical stage) targeting those signaling pathways is commented.
基金supported by grants from the National Natural Sciences Foundation of China(No.30770914No.30901587)China State Key Basic Research Program(No.2002CB513100)
文摘This study was designed to determine the impact of chrysoeriol on proliferation and cell cycle progression in the human multiple myeloma cell lines RPMI 8226 and KM3,and its related molecular mechanisms.Chryseoriol was identified by using the phosphorylated AKT-specific cytoblot high throughput assay.CCK-8 assay was employed to examine the growth inhibition rate and IC 50 (48 h) in peripheral blood mononuclear cells (PBMNCs),RPMI 8226 and KM3 cells treated with chrysoeriol at various concentrations.Cells were labeled with 5-6-carboxyfluorescein diacetate succinimidyl ester (CFSE),and the proliferation dynamics was detected by flow cytometry and analyzed with ModFit software.The cell cycles of RPMI 8226 and KM3 cells were measured by flow cytometry when the IC 50 concentration of chrysoeriol was adopted.The alterations in cell-cycle related proteins (Cyclin B1,Cyclin D1,p21) and proteins in PI3K-AKT-mTOR pathway were determined by Western blot analysis.The results showed the proliferation of multiple myeloma cells was significantly inhibited by chrysoeriol,resulting in cell cycle arrest in G 2 /M phase.Chrysoeriol could significantly reduce the expression of p-AKT (s473) and p-4eBP1 (t37/46) protein,meanwhile enhanced Cyclin B1 and p21 protein expression.Similar effects were not observed in PBMNCs from normal donors.It was concluded that chrysoeriol was a selective PI3K-AKT-mTOR pathway inhibitor.It restrained the proliferation of human multiple myeloma cells,but didn’t affect proliferation of PBMNCs from normal donors.It might exhibit the cell cycle regulatory effect via the inhibition of PI3K-AKT-mTOR signal pathway.
文摘In this study,we administered a modified schedule of weekly intravenous Bortezomib at 1.6 mg/m 2 with dexamethasone(BD) and compared it to the standard 1.3 mg/m 2 twice-weekly BD regimen in Chinese patients with newly diagnosed multiple myeloma(MM).We assessed the difference in efficacy,safety profile and survival between the once-weekly and twice-weekly cohorts(13 vs.24 patients).The over response rate was similar with both arms of the study,being 77% in the once-weekly schedule and 74.9% in the twice-weekly schedule(P=0.690).The median overall survival was not reached in either schedule.Also,the median progression-free survival and duration of response of the once-weekly schedule did not significantly differ from those of the twice-weekly schedule(8 months vs.10 months,P=0.545 and 6 months vs.7 months,P=0.467 respectively).Peripheral sensory neuropathy and grade 3/4 hematologic toxic effects were more frequently reported in the twice-weekly schedule than the once-weekly schedule,but there was no statistically significant difference.This preliminary experience in Chinese patients with newly diagnosed MM indicated that once-weekly infusion of Bortezomib plus dexamethasone may improve safety without affecting outcome.
文摘Background: Despite the recent development of new therapies, multiple myeloma(MM) remains an incurable disease. Thus, new, efective treatments are urgently needed, particularly for relapsed or refractory MM(RRMM). In an earlier phase I study, a novel form of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) that is currently in clinical development for the treatment of hematologic malignancies, i.e., circularly permuted TRAIL(CPT), was well tolerated at a dose of 2.5 mg/kg per day and showed promising preliminary activity in patients with RRMM. This phase II, open-label, multicenter study further investigated the eicacy and safety of 2.5-mg/kg per day CPT as single-agent therapy for patients with RRMM.Methods: Patients with RRMM were treated once daily with CPT(2.5 mg/kg, intravenously) for 14 consecutive days for each 21-day cycle. Clinical response and toxicity were assessed after each treatment cycle.Results: Twenty-seven patients received CPT. Using the European Group for Blood and Marrow Transplantation criteria, we calculated the overall response rate of 33.3% with 1 near-complete response(n CR) and 8 partial responses(PRs). The clinical beneit rate(48.1%) included 1 nCR, 8 PRs, and 4 minimal responses. The most common treatmentrelated adverse events(TRAEs) were fever, aspartate aminotransferase elevation, alanine aminotransferase elevation, leucopenia, rash, neutropenia, and thrombocytopenia. We graded toxicity using the Common Toxicity Criteria for Adverse Events, version 3.0, and determined that 37.0% of patients had at least 1 grade 3–4 TRAE.Conclusions: CPT as a single agent can elicit a response in patients with RRMM and is well tolerated. Further clinical investigation is warranted.
基金Associazione Italiana per la Ricerca sul Cancro,AIRC 5×1000 Molecular Clinical Oncology Special Program,Milan,IT,No.9965by the European Commission’s Seventh Framework Programme(EU FPT7)under grant agreement No.278706(OVERMy R)by MIUR PRIN 2010NECHBX
文摘Multiple myeloma(MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells(CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activate stemness signaling(Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.
基金supported by the National Natural Science Foundation of China(No.30700882)supported by a grant from the Department of Immunology,Tongji Medical College, Huazhong University of Science and Technology,Wuhan, China.
文摘Objective： To investigate the effects of triptolide（TPL） on cell growth, cell cycle and the expressions of p21wapl/cipl and p27kipl. Methods： MTT assay was used to determine the cell viability after triptolide treatment in human multiple myeloma RPMI-8226 cells. The effect on cell cycle distribution was determined by flow cytometry. Semi-quantitative reverse transcription-PCR was used to examine the mRNA expressions of p21wapl/cipl and p27kipl. The protein expressions of p21 wapl/cipl and p27kipl were determined by Western blot. Results： Triptolide of varying concentrations induced cell viability inhibition in dose- and time-related fashion and caused Go- G1 phase arrest of cell cycle progression in RPMI-8226 cells. These effects accompanied with up-modulation of the expressions of p21 wapl/cipl and p27kipl. Conclusion： These results suggest that triptolide inhibit cell proliferation and cell cycle progression via up-regulating p21wapl/cipl and p27kipl and triptolide may exert its anti-cancer activity through this pathway.
基金supported by a grant from National Natural Sciences Foundation of China (No. 30700882)
文摘The effect of triptolide on proliferation and apoptosis of human multiple myeloma RPMI-8226 cells in vitro,as well as the roles of nuclear factor-kappa B（NF-κB） and IκBα was investigated.The effect of tritptolide on the growth of RPMI-8226 cells was studied by MTT assay.Apoptosis was detected by Hoechest 33258 staining and Annexin V/PI double staining assay.The expression of NF-κB and IκBα was observed by Western blot and confocal microscopy.The results showed that triptolide inactivated NF-κB apoptotic pathway in human multiple myeloma RPMI-8226 cells.Triptolide at nM range induced proliferation inhibition in a dose-and time-dependent manner and apoptosis in a dose-dependent fashion in RPMI-8226 cells.Besides,we observed the inhibition of NF-κB /p65 in the nuclear fraction was correlated with the increase in the protein expression of IκBα in the cytosol.These results suggested that triptolide might exhibit its strong anti-tumor effects via inactivation of NF-κB/p65 and IκBα.
