ABSTRACT
@#In recent years,considerable progress has been made in the treatment of multiple myeloma(MM).However,despite the current improved prognosis of this malignancy,it always ends in relapse and therefore new therapeutic approaches are urgently needed to overcome it.The chimeric antigen receptor(CAR)-T cells targeting B cell maturation antigen(BCMA),cluster of differentiation 19(CD19),cluster of differentiation 38(CD38) and kappa light chains have been evaluated,and have achieved remarkable results in clinical trials.However,even when MM is treated with CAR-T cell therapy,most patients eventually relapse,which is the greatest limitation of this therapy.This paperreviewedthe research progress,limitations and optimization of CAR-T cell immunotherapy in the treatment of MM.
ABSTRACT
Multiple myeloma (MM) is a malignant clonal disease of the plasma cells in bone marrow. Despite the progress of MM treatment, almost all patients will relapse or become resistant to the prescribed drugs. As such, new treatment targets are urgently needed. As well as genetic defects and bone marrow microenvironment disorders, increasing evidence shows that epigenetic regulation plays an important role in MM. Studies have shown that mutations in epigenetic factors are often related to genomic instability, drug resistance and disease progression. These mutations have been found to increase after treatment, particularly histone methylation and DNA methylation modifying enzymes. Here, we reviewed the progress in histone methylation modification in MM, in particular the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) in the development of MM.
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Myeloma bone disease (MBD) is one of the most common complications of multiple myeloma (MM). MBD is considered to be caused by the activation of osteoclasts and suppression of osteoblasts resulting from the involvement of neoplastic plasma cells and the change of bone marrow microenvironment. It may be a feasible way to improve the treatment of MBD by promoting osteogenic differentiation of bone marrow mesenchymal stem cell (BMSC), from which the osteoblasts mainly originate. Resveratrol (RES), a naturally occurring polyphenolic flavonoid compound, was reported to function in the modulation of bone metabolism. But the effects of RES on osteogenic differentiation of MM derived BMSC (MM-BMSC) and its underlying mechanism remains unknown. Totally 10 cases of MM-BMSCs were isolated, cultured and identified successfully in the present study. RES was found to promote osteogenic differentiation of MM-BMSC by alkaline phosphatase activity assay, qRT-PCR and alizarin red staining. SIRT1 was predicted to be the target gene of RES in promoting osteogenic differentiation with bioinformatic analysis. RES upregulated the expression of silent information regulator 1 (SIRT1) in MM-BMSC (P<0. 001) and its osteogenic differentiation was inhibited in the SIRT1 small interfering RNA (si-SIRT1) transfected group. Furthermore, the mRNA (P<0. 001) and protein (P<0. 01) expression of runt related transcription factor 2 (RUNX2) was increased in the RES treated group and decreased (mRNA P < 0. 01, protein P < 0. 05) in si-SIRT1 transfected group, respectively. In conclusion, resveratrol promotes osteogenic differentiation of MM-BMSCs via upregulating SIRT1/RUNX2 and seems to be a potential therapeutic agent to counteract bone disease in MM patients.
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Multiple myeloma (MM) is a kind of plasma cell tumor, characterized by clonal expansion of malignant plasma cells in the micro-environment of bone marrow, production of monoclonal immunoglobulins and dysfunction of related organs. In recent years, with the introduction of autologous stem cell transplantation and the application of Lenalidomide and Bortezomib, the traditional treatment of myeloma had been changed and the overall survival of the patients was prolonged. Although significant progresses have been made in treatment, multiple myeloma is still incurable, mainly due to primary drug resistance and disease recurrence. Signal transducers and activators of transcription 3 (STAT3) is a kind of signal transcription factor, which is involved in diverse cellular processes including the differentiation, proliferation and angiogenesis in normal cells. Recently, it had been found that the high expression of STAT3 in tumors was closely related to the occurrence, development, invasion and metastasis of malignant tumors. STAT3 also played a key role in the occurrence and progression of multiple myeloma. In this paper, we reviewed the molecular structure, signal pathway, activation, regulation and basic biological functions of STAT3, and found that non coding RNA, heat shock protein 90 (Hsp90), heme oxygenase-1 (HO-1) and other factors play important roles in the occurrence, survival and immune escape of multiple myeloma through STAT3 pathway whose activation is related to the resistance of multiple myeloma cells to Bortezomib, Lenalidomide and other conventional drugs. Therefore, STAT3 can be used as a potential target for multiple myeloma. This review provides a basis for accurate diagnosis and treatment of MM and a reference for STAT3 as a potential prognostic marker.
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Objective: This study investigated the efficacy and safety of a combination of lenalidomide, bortezomib, and dexametha-sone (RVD) in patients with newly diagnosed multiple myeloma (NDMM). Methods: The clinical features and responses of 48 patients with NDMM who were treated with RVD from January 2015 to May 2019 in Beijing Chaoyang Hospital were retrospectively analyzed. Results: The median age of the 48 patients was 59 years (range: 34-79). Among these, 44 patients were Durie-Salmon stageⅢ, 15 were ISS stageⅡ, 19 were ISS stageⅢ, and 12 had plasmacytoma; 32.5% of all patients were cytogenetic high-risk. All patients re-ceived a median of four cycles (range: 1-9) of the RVD regimen as induction treatment. The overall response rate was 97.9%, with 35.4% of patients achieving complete response (CR) or better. The rate of very good partial remission (VGPR) or better was increased from 64.1% (after two cycles) to 84.6% (after four cycles). The mean collection of CD34+cells was 4.2 (± 2.6)×106/kg. Negative minimal residual disease (MRD), as indicated by next-generation flow (NGF), was achieved in 20.6% of patients after induction. Two patients with positive MRD after induction became MRD negative after transplantation. Two patients developed grade 3 or 4 hematologic toxic-ity. No nonhematologic toxicity of grade 3 or 4 was observed. Conclusions: In patients with NDMM, RVD treatment resulted in signifi-cantly improved response rates and exhibited an acceptable risk-benefit profile, with no adverse impact on stem cell collection. RVD combined with transplantation significantly improved the negative rate of MRD, as indicated by NGF.
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Multiple myeloma (MM) is a common malignant tumor of blood system, often manifested as bone destruction, hypercalcemia, and hyperviscosity syndrome. Electrolyte disturbance and hypertension caused by MM can induce posterior reversible encephalopathy syndrome (PRES). This case report reviews that a patient with osteodynia had several mental abnormalities, and was diagnosed as having κ light chain MM with PRES after thorough examination.
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Multiple myeloma(MM) was the second malignant hematological disease in many countries. There had continuing change in diagnostic criteria in MM, along with the more treatment methods and the understand of this disease. From 1975 to 2013, the change of diagnostic criteria experienced three stages. Firstly, we emphasized the numerical value in 1975, secondly, we emphasized the clonal characteristics of plasma cell and wakened the numerical value because of the FACS and immunofixation widespreadly used, thirdly, we emphasized the number again because of the differentiation of primary amyloidosis. Along with these changes, the target population had changed also, 20%patients cannot be diagonsed if using criteria of 1975, and some asymptomatic MM may be diag-nosed with MM in the future.
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BACKGROUND: M protein, as a marker for monoclonal gammopathy, has been evaluated by protein electrophoresis (PEP) and immunofixation electrophoresis (IFE). Recently a highly sensitive, automated immunonephelometric assay for measurement of free light chains (FLCs) in serum and urine has been developed for the identification and monitoring of patients with monoclonal gammopathy. METHODS: We measured the concentration of kappa and lambda FLCs in 120 healthy individuals aged 20 to 80 years to establish the reference range of kappa and lambda FLCs and kappa/lambda FLC ratio and in 61 serum and 14 urine samples from patients with multiple myeloma (MM) to examine the correlation between the amount of M protein indirectly calculated on PEP and the direct measurement of FLCs. RESULTS: The concentrations of kappa and lambda FLCs and the kappa/lambda FLC ratio in healthy individuals were not significantly related to age or sex. The 95 percentile reference ranges for kappa FLC, lambda FLC, and kappa/lambda FLC ratio were 8.5-23.7 mg/L, 9.5-23.5 mg/L, and 0.67-1.38, respectively. On the PEP performed with MM specimens, 18 cases did not show the evidence of M protein. But, they revealed abnormal FLC concentrations on FLC assay and a significant correlation was found between the amount of M protein and the concentration of kappa and lambda FLC. However, inconsistent results such as the concentra-tion of kappa+lambda FLCs being more than the total protein in urine or M protein in serum were found in 5 of the 14 urine and 1 of the 61 serum samples of MM patients. CONCLUSIONS: FLC assay showed a good correlation with PEP and was more sensitive and accurate than PEP. Therefore, FLC assay is useful for diagnosing and monitoring monoclonal gammopathy at an early stage of the disease and during a remission state after chemotherapy or peripheral blood stem cell transplantation.