Efficacy and safety of VRD regimen of autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma / 中华内科杂志

Objective: To explore the stem cell collection rate and efficacy and safety of patients aged 70 and below with newly diagnosed multiple myeloma (MM) treated with the VRD (bortezomib, lenalidomide and dexamethasone) regimen followed by autologous stem cell transplantation (ASCT). Methods: Retrospective case series study. The clinical data of 123 patients with newly diagnosed MM from August 1, 2018, to June 30, 2020, at the First Affiliated Hospital of Soochow University and Suzhou Hopes Hematology Hospital, who were eligible for VRD regimen sequential ASCT, were collected. The clinical characteristics, efficacy after induction therapy, mobilization regimen of autologous stem cells, autologous stem cell collection rate, and side effects and efficacy of ASCT were retrospectively analyzed. Results: Of the 123 patients, 67 were males. The median patient age was 56 (range: 31-70) years. Patients with IgG, IgA, IgD, and light-chain types accounted for 47.2% (58/123), 23.6% (29/123), 3.2% (4/123), and 26.0% (32/123) of patients, respectively. In addition, 25.2% (31/123) of patients had renal insufficiency (creatinine clearance rate<40 ml/min). Patients with Revised-International Staging System (R-ISS) Ⅲ accounted for 18.2% (22/121) of patients. After induction therapy, the rates of partial response and above, very-good partial response (VGPR) and above, and complete response (CR)+stringent CR were 82.1% (101/123), 75.6% (93/123), and 45.5% (56/123), respectively. Overall, 90.3% (84/93) of patients were mobilized with cyclophosphamide+granulocyte colony-stimulating factor (G-CSF) and 8 patients with G-CSF or G-CSF+plerixafor due to creatinine clearance rate<30 ml/min and one of them was mobilized with DECP (cisplatin, etoposide, cyclophosphamide and dexamethasone)+G-CSF for progressive disease. The rate of autologous stem cell collection (CD34+cells≥2×106/kg) after four courses of VRD regimen was 89.1% (82/92), and the rate of collection (CD34+cells≥5×106/kg) was 56.5% (52/92). Seventy-seven patients treated with the VRD regimen sequential ASCT. All patients had grade 4 neutropenia and thrombocytopenia. Among the nonhematologic adverse events during ASCT, the highest incidence was observed for gastrointestinal reactions (76.6%, 59/77), followed by oral mucositis (46.8%, 36/77), elevated aminotransferases (44.2%, 34/77), fever (37.7%, 29/77), infection (16.9%, 13/77) and heart-related adverse events (11.7%, 9/77). Among the adverse events, grade 3 adverse events included nausea (6.5%, 5/77), oral mucositis (5.2%, 4/77), vomiting (3.9%, 3/77), infection (2.6%, 2/77), elevated blood pressure after infusion (2.6%, 2/77), elevated alanine transaminase (1.3%, 1/77), and perianal mucositis (1.3%, 1/77); there were no grade 4 or above nonhematologic adverse events. The proportion of patients who achieved VGPR and above after VRD sequential ASCT was 100% (75/75), and the proportion of patients who were minimal residual disease-negative (<10-4 level) was 82.7% (62/75). Conclusion: In patients aged 70 and below with newly diagnosed MM treated with VRD induction therapy, the collection rate of autologous stem cells was good, and good efficacy and tolerability were noted after follow-up ASCT.

Regulatory Mechanism of Mangiferin Combined with Bortezomib on Malignant Biological Behavior of Burkitt Lymphoma and Its Effect on Expression of CXC Chemokine Receptors / 中国实验血液学杂志

OBJECTIVE@#To analyze the effects of mangiferin combined with bortezomib on the proliferation, invasion, apoptosis and autophagy of human Burkitt lymphoma Raji cells, as well as the expression of CXC chemokine receptors (CXCRs) family, and explore the molecular mechanism between them to provide scientific basis for basic research and clinical work of Burkitt lymphoma.@*METHODS@#Raji cells were intervened with different concentrations of mangiferin and bortezomib alone or in combination, then cell proliferation was detected by CCK-8 assay, cell invasion ability was detected by Transwell chamber method, cell apoptosis was detected by Annexin V/PI double-staining flow cytometry, apoptosis, autophagy and Akt/mTOR pathway protein expression were detected by Western blot, and the expression changes of CXCR family was detected by real-time quantitative PCR (RT-qPCR).@*RESULTS@#Different concentrations of mangiferin intervened Raji cells for different time could inhibit cell viability in a concentration- and time-dependent manner (r =-0.682, r =-0.836). When Raji cells were intervened by combination of mangiferin and bortezomib, compared with single drug group, the proliferation and invasion abilities were significantly decreased, while the apoptosis level was significantly increased (P <0.01). Mangiferin combined with bortezomib could significantly up-regulate the expression of pro-apoptotic protein Bax and down-regulate the expression of anti-apoptotic protein Bcl-2 after intervention in Raji cells. Caspase-3 was also hydrolyzed and activated, and then induced the apoptosis of Raji cells. Mangiferin combined with bortezomib could up-regulate the expression of LC3Ⅱ protein in Raji cells, and the ratio of LC3Ⅱ/LC3Ⅰ in cells was significantly up-regulated compared with single drug or control group (P <0.01). Mangiferin combined with bortezomib could significantly inhibit the phosphorylation levels of Akt and mTOR, inhibit the proliferation and invasion of Raji cells by inhibiting Akt/mTOR pathway, and induce cell autophagy and apoptosis. Mangiferin and bortezomib could down-regulate the expressions of CXCR4 and CXCR7 mRNA after single-agent intervention in Raji cells, and the down-regulations of CXCR4 and CXCR7 mRNA expression were more significant when the two drugs were combined (P <0.01). Mangiferin alone or combined with bortezomib had no significant effect on CXCR5 mRNA expression in Raji cells (P >0.05), while the combination of the two drugs could down-regulate the expression of CXCR3 (P <0.05).@*CONCLUSION@#Mangiferin combined with bortezomib can synergistically inhibit the proliferation and invasion of Raji cells, and induce autophagy and apoptosis. The mechanism may be related to the inhibition of Akt/mTOR signaling pathway, down-regulation of anti-apoptotic protein Bcl-2 and up-regulation of pro-apoptotic protein Bax, and the inhibition of the expression of CXCR family.

Research Progress on Mechanism of Bortezomib Resistance in Multiple Myeloma / 中国实验血液学杂志

Multiple myeloma (MM) is a common plasma cell malignancy, accounting for the second largest hematological malignancy. Proteasome inhibitors represented by bortezomib (BTZ) have been the main treatment for patients with newly diagnosed and relapsed or refractory myeloma in nearly two decades. Although BTZ has improved the prognosis of MM patients, MM remains incurable in most patients, mainly because MM cells become resistant to BTZ. This review is to better understand the mechanism of MM resistance to BTZ and explore possible new therapeutic strategies.

Establishment of Patient-Derived Xenograft (PDX) Zebrafish Model of Multiple Myeloma and Its Application in Drug Screening / 中国实验血液学杂志

OBJECTIVE@#To establish a MM patient-derived tumor xenograft model (MM-PDX) in zebrafish, and to evaluate the anti-myeloma activity of indirubin-3'-monoxime(I3MO) using this model.@*METHODS@#Zebrafish embryos 2 days after fertilization were transplanted with fluorescence labeled myeloma primary tumor cells, the survival of primary tumor cells in zebrafish was observed at 0,16 and 24 hours after cell injection. The zebrafish embryos after tumor cell transplantation were randomly divided into control group, BTZ treatment and I3MO treatment group. Before and 24 hours after treatment with BTZ and I3MO, the positive area with calcein or Dil in zebrafish were observed under fluorescence microscope to reflect the survival of tumor cells, and it was verified.@*RESULTS@#MM patient derived tumor cells survived in zebrafish. The construction of MM-PDX was successful. Compared with control group, the fluo- rescence area of the BTZ and I3MO treatment groups in zebrafish were significantly decreased(P<0.05), and BTZ and I3MO significantly inhibited the survival of MM cells in zebrafish.@*CONCLUSION@#MM-PDX model was successfully established. Zebrafish model derived from tumor cells of MM patients can be used as a tool for drug screening of MM.

Preliminary Study on the Relationship between the Developmental Stage of Multiple Myeloma Disease and the Results of Bone Marrow Whole Exome Sequencing / 中国实验血液学杂志

OBJECTIVE@#To investigate the genetic results of whole exome sequencing of bone marrow from new onset multiple myeloma (MM) patients to analyze the process of genetic clonal evolution in MM patients.@*METHODS@#Genomic DNA was extracted from bone marrow samples of 15 MM patients and the whole exomes sequencing was performed using next generation sequencing technology. Using own buccal cells as germline controls, combinated with clinical information, the mutation profile of genes from high-risk asymptomatic myeloma to symptomatic myeloma were analyzed, and genes that may be associated with the efficacy and side effects of bortezomib were screened.@*RESULTS@#Except for two patients in whom no peripheral neuropathy was observed after a short treatment period, other patients peripheral neuropathy developed of various degrees during treatment with bortezomib containing chemotherapy, and the vast majority of patients achieved remission after receiving this bortezomib-related chemotherapy regimen. All patients had comparable levels of the inherited mutations number, but the somatic mutations was correlated with disease evolution.@*CONCLUSION@#different gene "mutational spectra" exist in myeloma patients at different stages and are associated with progression through all stages of the disease.

The influencing factors of renal response in newly diagnosed multiple myeloma patients with renal impairment / 中华血液学杂志

Objective: To investigate the causative factors of renal function in newly diagnosed multiple myeloma (MM) patients with renal inadequacy. Methods: 181 MM patients with renal impairment from August 2007 to October 2021 at Peking Union Medical College Hospital were recruited, whose baseline chronic kidney disease (CKD) stage was 3-5. Statistical analysis was performed based on laboratory tests, treatment regimens, hematological responses, and survival among various renal function efficacy groups. A logistic regression model was employed in multivariate analysis. Results: A total of 181 patients were recruited, and 277 patients with CKD stages 1-2 were chosen as controls. The majority choose the BCD and VRD regimens. The progression-free survival (PFS) (14.0 months vs 24.8 months, P<0.001) and overall survival (OS) (49.2 months vs 79.7 months, P<0.001) of patients with renal impairment was considerably shorter. Hypercalcemia (P=0.013, OR=5.654) , 1q21 amplification (P=0.018, OR=2.876) , and hematological response over a partial response (P=0.001, OR=4.999) were independent predictive factors for renal function response. After treatment, those with improvement in renal function had a longer PFS than those without (15.6 months vs 10.2 months, P=0.074) , but there was no disparity in OS (56.5 months vs 47.3 months, P=0.665) . Conclusion: Hypercalcemia, 1q21 amplification, and hematologic response were independent predictors of the response of renal function in NDMM patients with renal impairment. MM patients with CKD 3-5 at baseline still have worse survival. Improvement in renal function after treatment is attributed to the improvement in PFS.

The Efficacy and Safety of Daratumumab-Based Regimen in Treatment of Multiple Myeloma Patients with Renal Impairment / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy and safety of daratumumab in treatment of multiple myeloma (MM) patients with renal impairment (RI).@*METHODS@#The clinical data of 15 MM patients with RI who received daratumumab-based regimen from January 2021 to March 2022 in three centers were retrospectively analyzed. Patients were treated with daratumumab or daratumumab combined with dexamethasone or daratumumab combined with bortezomib and dexamethasone and the curative effect and survival were analyzed.@*RESULTS@#The median age of 15 patients was 64 (ranged 54-82) years old. Six patients were IgG-MM, 2 were IgA-MM,1 was IgD-MM and 6 were light chain MM. Median estinated glomerular filtration rate (eGFR) was 22.48 ml/(min·1.73 M2). Overall response rate of 11 patients with MM was 91% (≥MR), including 1 case of stringent complete response (sCR), 2 cases of very good partial response (VGPR), 3 cases of partial response (PR) and 4 cases of minor response (MR). The rate of renal response was 60%(9/15), including 4 cases of complete response (CR), 1 case of PR and 4 cases of MR. A median time of optimal renal response was 21 (ranged 7-56) days. With a median follow-up of 3 months, the median progression-free survival and overall survival of all patients were not reached. After treatment with daratumumab-based regimen, grade 1-2 neutropenia was the most common hematological adverse reaction. Non-hematological adverse reactions were mainly infusion-related adverse reactions and infections.@*CONCLUSION@#Daratumumab-based regimens have good short-term efficacy and safety in the treatment of multiple myeloma patients with renal impairment.

Clinical Characteristics and Survival Analysis of Patients with Plasma Cell Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical characteristics, therapeutic response and prognosis of patients with plasma cell leukemia (PCL) and improve the understanding of this disease.@*METHODS@#The clinical manifestations, laboratory tests and treatment response of 27 patients with plasma cell leukemia treated in The Second Hospital of Shanxi Medical University from December 2010 to August 2019 were analyzed retrospectively, and their clinical characteristics were summarized. Kaplan-Meier method was used for survival analysis.@*RESULTS@#There were 18 cases of primary plasma cell leukemia (pPCL) and 9 cases of secondary plasma cell leukemia (sPCL). The male to female ratio was 1.7∶1. The median age was 62 years old. The first manifestations were bone pain, fatigue, fever, splenomegaly and bleeding, and a large number of plasma cell infiltration was observed in the morphological examination of peripheral blood and bone marrow cells. 13 cases were detected by immunotyping and all of them expressed CD38/CD138. 8 cases underwent karyotype analysis, and 3 cases were normal, clonal abnormalities occurred in 5 cases. FISH detection was performed in 12 cases, of which 8 cases were abnormal. In 17 cases of bortezomib based chemotherapy, the ovevall response rate was 52.9%, which was higher than that in the non-bortezomib group, but there was no significant difference between the two groups (P =0.242). The overall median survival time of 27 patients was 6.4 months, the median progression-free survival time was 3.5 months, and the median survival time of patients with pPCL and sPCL was 8.2 months and 2.4 months, respectively, the difference between the two groups was statistically significant (P =0.031).@*CONCLUSION@#PCL is highly invasive and has diverse clinical manifestations, and is not sensitive to traditional chemotherapy. The median survival time of patients with pPCL is relatively longer than that of patients with sPCL. The chemotherapy regimen based on bortezomib improves the treatment effectiveness and prolongs the survival time of PCL patients.

CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

CUDC-101, an effective and multi-target inhibitor of epidermal growth factor receptor (EGFR), histone deacetylase (HDAC), and human epidermal growth factor receptor 2 (HER2), has been reported to inhibit many kinds of cancers, such as acute promyelocytic leukemia and non-Hodgkin's lymphoma. However, no studies have yet investigated whether CUDC-101 is effective against myeloma. Herein, we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma (MM) cell lines and induces cell apoptosis in a time- and dose-dependent manner. Moreover, CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase (PI3K) and HDAC, and regulated the cell cycle G2/M arrest. Moreover, we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug. Bortezomib is one of the important drugs in MM treatment, and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib. The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade. Collectively, our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib, which provides insights into exploring new strategies for MM treatment.

A combined regimen based on bortezomib and glucocorticoids for 6 patients with recurrent/refractory immune thrombotic thrombocytopenic purpura / 中华血液学杂志

Objective: To observe the efficacy and adverse reactions of a combination therapy regimen based on bortezomib and glucocorticoids in recurrent/refractory immune thrombocytopenic purpura (iTTP) . Methods: Six patients with recurrent/refractory TTP were included and treated with a glucocorticoid and two courses of bortezomib-based regimen. The clinical remission status of patients, changes in ADAMTS13 activity/ADAMTS13 inhibitor, and the occurrence of treatment-related adverse reactions were observed. Results: Of the 6 patients, 2 were males and 4 were females, with a median age of 21.5 (18-68) years. Refractory TTP was found in 1 case and recurrent TTP in 5 cases. Glucocorticoids were administered with reference to prednisone at 1 mg·kg(-1)·d(-1), and gradually reduced in dosage after achieving clinical remission. Bortezomib is subcutaneously administered at 1.3 mg/m(2) on days 1, 4, 8, and 11 with a 28-day treatment course consisting of 2 courses. Six patients achieved clinical remission after receiving bortezomib as the main treatment. ADMATS13 activity returned to normal in all patients with TTP after treatment, and the ADAMTS13 inhibitor turned negative. Thrombocytopenia is the most common adverse reaction after treatment, with other adverse reactions, including peripheral neuritis and abdominal pain, but ultimately all patients returned to normal. In a median follow-up of 26 (9-41) months, 5 patients maintained sustained remission, and 1 patient relapsed after 16 months of bortezomib treatment. Conclusion: Combination therapy of bortezomib and glucocorticoids has a satisfactory therapeutic effect and controllable adverse reactions for recurrent/refractory iTTP.

Vasculitis crioglobulinémica por hiperviscosidad y formación de criogel como debut de mieloma múltiple. Caso clínico / Cryoglobulinemic vasculitis due to hyperviscosity and cryogel formation as the onset of multiple myeloma. Report of one case

Multiple Myeloma (MM) is characterized by a clonal expansion of plasma cells in the bone marrow. These cells typically produce a monoclonal immunoglobulin, and its symptoms arise either from plasma cell infiltration in several organs, or secondary to the presence of a monoclonal protein peak. Symptoms can be summarized by the acronym CRAB (hypercalcemia, renal failure, anemia and bone lesions). Sometimes, in the setting of a protein secreting monoclonal gammopathy, formation of cryoglobulins develops. Cryoglobulins are plasma proteins that precipitate at low temperatures, forming a cold - induced precipitate at small vessels, causing a wide range of clinical manifestations. We report a female consulting for ulcers lasting 2 months in the left foot associated with purpuric lesions in both lower limbs. Protein electrophoresis showed a monoclonal peak in the gamma region. Bone marrow aspirate showed 27% of plasma cells with kappa chain restriction by cytometry. The presence of cryoglobulins was confirmed. The patient was treated with dexamethasone and bortezomib, with a progressive healing of lower limb lesions and disappearance of cryoglobulins. She was discharged in good conditions.

Recomendaciones para el tratamiento de la Amiloidosis AL / Recommendations for the treatment of AL amyloidosis

Immunoglobulin light chain (AL) amyloidosis is a rare disease. Treatment is challenging, justified in part by systemic compromise and limited scientific evidence. Develop evidencebased recommendations that allow adequate treatment of patients with amyloidosis AL. A list of PICO format questions focused on the effectiveness and safety of amyloidosis AL treatment was generated. PubMed, Cochrane and Epistemonikos were searched. The levels of evidence and grades of recommendation were based on the GRADE system.11 recommendations were generated. In selected patients with amyloidosis AL, autologous hematopoietic stem cell transplantation (ASCT) is recommended after induction with bortezomibbased regimens and conditioning with melphalan, since it could deepen the hematological and organ response, its durability and improve survival. In patients not eligible for ASCT, first-line treatment with bortezomib-based regimens is recommended, since it is likely to achieve a higher rate of hematological and organ response and improve survival. In patients with a contraindication or inaccessibility to bortezomib, treatment with alkylating agents and corticosteroids is recommended, since they are likely to achieve haematological and organ response and improve survival. These treatment recommendations are based on the available evidence and the experience of the panel of experts, in a scenario of limited available resources, according to developing countries.

La amiloidosis por cadenas livianas de inmunoglobulinas (AL) es una enfermedad poco frecuente. El tratamiento implica un desafío, justificado en parte por el compromiso sistémico y la evidencia científica escasa. Objetivos: Elaborar recomendaciones basadas en la evidencia que permitan realizar un adecuado tratamiento de pacientes con amiloidosis AL. Métodos: Se generó un listado de preguntas con formato PICO centradas en la efectividad y seguridad del tratamiento de la amiloidosis AL. Se realizó la búsqueda en PubMed, Cochrane y Epistemonikos. Los niveles de evidencia y los grados de recomendación se basaron en el sistema GRADE. Resultados: Se generaron 11 recomendaciones. En pacientes con amiloidosis AL seleccionados, se recomienda el trasplante autólogo de células progenitoras hematopoyéticas (TCPH) posterior a una inducción con esquemas basados en bortezomib y el acondicionamiento con melfalán, ya que podría profundizar la respuesta hematológica, de órgano, su durabilidad y mejorar la supervivencia. En pacientes no elegibles para TCPH, se recomienda el tratamiento de primera línea con esquemas basados en bortezomib, dado que es probable que logre mayor tasa de respuesta hematológica, de órgano y mejore la supervivencia. En pacientes con contraindicación o inaccesibilidad al bortezomib, se recomienda el tratamiento con agentes alquilantes y corticoides, dado que es probable que logren la respuesta hematológica, de órgano y mejoren la supervivencia. Discusión: Estas recomendaciones de tratamiento se basan en la evidencia disponible y la experiencia del panel de expertos, en un escenario de recursos disponibles limitados, acorde a los países en vías de desarrollo.

Mieloma múltiple en Chile. Uso de drogas noveles en dos centros nacionales / The impact of novel drugs on the survival of patients with multiple myeloma in two chilean centers

BACKGROUND: The incorporation of novel drugs, such as proteasome inhibitors and immunomodulators, improved considerably the survival of patients with multiple myeloma. Aim: To evaluate the effect on survival of proteasome inhibitors and immunomodulators in patients with multiple myeloma in two national hospitals. MATERIAL AND METHODS: Review of clinical records from two hospitals of Santiago. Epidemiological, clinical, laboratory and therapeutic data was obtained from 144 patients with multiple myeloma diagnosed between 2002 and 2016. Results: Information was retrieved from 78 patients at one center and from 66 at the other center. The mean age at diagnosis was 58 and 62 years, the proportion of males was 53% and 52%, and presentation at stage III was 34% and 46%, respectively. The use of novel drugs, mainly bortezomib, was 90% in one of the centers and 3% in the other one. The use of autologous stem-cell transplantation was 47% and 3% respectively. The median overall survival of patients from the centers with and without access to novel drugs was 117 and 71 months respectively (p < 0.05). The five-year overall survival was 93 and 43% respectively (p < 0.05). CONCLUSIONS: The use of novel drugs, especially bortezomib, and autologous stem-cell transplantation significantly improved the survival of multiple myeloma patients treated in national hospitals. It is necessary to include them as a first line treatment.

Impact of quality of response on survival outcomes among multiple myeloma patients treated with novel agents - a retrospective analysis

Abstract BACKGROUND: In this era of target therapies, novel data on the correlation between response endpoints and survival outcomes in multiple myeloma have arisen. OBJECTIVE: To determine the impact of quality of response on clinical outcomes, using first-line treatment, and identify risk factors influencing progression-free survival (PFS) and overall survival (OS) among myeloma patients. DESIGN AND SETTING: Retrospective analysis on myeloma patients who were treated at the Clinic of Hematology and Clinical Immunology, University Clinical Centre, Niš, Serbia, over a four-year period. METHODS: A total of 108 newly diagnosed patients who received first-line therapy consisting of conventional chemotherapy or novel agent-based regimens were included in this analysis. RESULTS: The quality of response to first-line therapy for the whole cohort was classified as follows: complete response (CR) in 19%; very good partial response (VGPR) in 23%; partial response (PR) in 38%; and less than PR for the remaining patients. After a median follow-up of 25.4 months, the three-year PFS and OS for the entire study population were 47% and 70%, respectively. Achievement of CR was the main factor associated with significantly prolonged PFS and OS, in comparison with patients who reached VGPR and PR. Likewise, addition of the new drugs bortezomib and thalidomide to standard chemotherapy led to considerably extended PFS and OS, compared with conventional therapy alone. CONCLUSIONS: This analysis demonstrated that the quality of response after application of first-line treatment using novel agent-based regimens among multiple myeloma patients was a prognostic factor for PFS and OS, which are the most clinically relevant outcomes.

Establishment and comparison of three human multiple myeloma cell line transplantation models in mice / 中华血液学杂志

Objective: To establish three types of xenotransplantation models using human myeloma cell lines ARP1, MM.1S, and NCI-H929 and to compare the proliferation, tumor load, and biological characteristics of the three types of cells after transplantation. Methods: Suspensions of human myeloma cell lines ARP1, MM.1S, and NCI-H929 were implanted into NOD/SCID mice by subcutaneous injection or tail vein injection. The survival of the mice was observed weekly, and the tumor load was measured. Flow cytometry was used to detect the proportion of CD138(+) cells in tumor tissue or the mouse bone marrow. CD138(+) cells and light chains were detected by immunofluorescence. Light chains in bone marow and peipheral blood were measured by ELISA, and bone disease was assessed by micro-CT. Results: Mice injected with ARP1, MM.1S, and NCI-H929 cells all formed tumors subcutaneously in about 2 weeks. Immunofluorescence detection supported plasma cell tumors. Kappa light chains were detected in the peripheral blood of ARP1 mice on day 20 after tail vein transplantation (8.2±1.0 ng/ml) . After 6 weeks of tail vein transplantation, mice in the ARP1 group showed signs of weight loss, mental depression, and dragging legs, and human CD138(+)CD38(+) cells were detected in the bone marrow (BM) . Furthermore, bortezomib (BTZ) treatment given once the tumor was established significantly reduced the tumor burden[ (5.7±0.2) % vs (21.3±2.1) %, P<0.01]. Human CD138(+)CD38(+) cells were not detected in the BM of the MM.1S or NCI-H929 groups. Conclusion: The results of this study suggest that the mouse models constructed by the three cell lines (ARP1, MM.1S, and NCI-H929) can be used as models for the pathogenesis and clinical research of MM.

Evaluation of the Efficacy and Safety of Chemotherapy in Elderly Patients with Multiple Myeloma under Different Frailty Scores / 中国实验血液学杂志

OBJECTIVE@#To compare the efficacy and safety of different chemotherapy regimens in elderly multiple myeloma (MM) patients with different Frailty scores.@*METHODS@#The clinical data of elderly patients with MM were retrospectively analyzed, including age, treatment regimen, efficacy, adverse reactions, and the Frailty score included in the activity of daily living score, the instrumental activity of daily living scale and the Charlson comorbidity index. The patients were divided into fit group, mediate fit group and frail group according to the scoring standard. The treatment efficiency and adverse reaction rates of elderly MM with different physical conditions treated by different chemotherapy regimens were analyzed.@*RESULTS@#Among the 70 patients, the effective rates of the patients in fit group, the mediate fit group, and the frail group were 79.5%, 81%, and 40%, and the effective rates of the fit patients in double and triple groups were 54.5% and 89.3%, 70% and 90.9% for mediate fit patients, 42.9% and 33.3% for frail patients, the triple regimen in fit patients showed obvious advantages, and the difference showed statistically significant (P<0.05), while the efficacy for mediate patients and frail patients showed no significant difference. During the induction of bortezomib, the incidence of adverse reactions for the patients in the triple group (78.6%) was higher than 67.9% in the double group, and the difference showed no statistically significant (P>0.05).There was no significant difference in the 1-year overall survival rate of the patients and with molecular genetic abnormalities among each groups.@*CONCLUSION@#The therapeutic effect is related to the patient's physical condition. For patients with healthy physique, the triple regimen should be used first. For patients with weak physical constitution, the chemotherapy regimen with low drug toxicity should be selected for safety.

Effect of Celastrol Based on IRAK4/ERK/p38 Signaling Pathway on Proliferation and Apoptosis of Multiple Myeloma Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of celastrol on the proliferation and apoptosis of human multiple myeloma (MM) cell lines, reveal the relationship between IRAK4/ERK/p38 signaling pathway and celastrol regulating the proliferation and apoptosis of H929 and ARP-1 cells, and explore whether celastrol combined with bortezomib has synergistic effect. @*METHODS@#CCK-8 method was used to detect the viability of MM cell lines H929 and ARP-1 treated by different concentrations of celastrol, bortezomib, and their combination, and the synergistic effect was determined by Kim's formula. The apoptosis rate of H929 cells and necrosis rate of ARP-1 were detected by Annexin V/PI method. The expression of key proteins and apoptosis proteins in IRAK4/ERK/p38 signaling pathway were detected by Western blot. @*RESULTS@#Celastrol could significantly inhibit the proliferation of H929 and ARP-1 cells (r=0.9018, r=0.9244) and induce apoptosis in a time-dependent manner. Compared with the control group, celastrol could significantly up-regulate the expression of PARP and cleaved caspase-3 while down-regulate the expression of p-IRAK4, p-ERK, and p-p38 in H929 and ARP-1 cells. Celastrol and bortezomib alone inhibited the proliferation of H929 and ARP-1 cells. Compared with celastrol and bortezomib alone, their combination had lower cell survival rate and higher apoptosis rate (P<0.05). @*CONCLUSION@#Celastrol can inhibit the proliferation and promote the apoptosis of H929 and ARP-1 cells, which may be related to inhibiting the phosphorylation of IRAK4 and blocking the activation of IRAK4/ERK/p38 signaling pathway. Celastrol combined with bortezomib has synergistic effect, which can more effectively inhibit the proliferation and induce apoptosis of H929 and ARP-1 cells.

The Relationship between Hematopoietic Scoring System Composed of HB，PLT and MCV and Prognosis and Curative Effect of Multiple Myeloma Patients / 中国实验血液学杂志

OBJECTIVE@#To investigate the prognostic value of hemopoietic scoring system composed of hemoglobin (HB), platelet count (PLT) and mean corpuscular volume (MCV) in MM patients and its correlation with curative effect.@*METHODS@#The clinical data of 172 newly diagnosed MM patients treated by bortezomib as the first-line regimen in our hospital from May 2014 to December 2019 were collected, three variables (HB≤100 g/L, PLT≤150×109/L, MCV≥96 fl) were introduced, each variable was distributed 1 score, the patients were divided into four groups (0, 1, 2 and 3 points in group 1, 2, 3 and 4, respectively), and the clinical characteristics and prognosis of the patients in the four groups were analyzed. The initial efficacy evaluation after 3-4 courses of treatment was carried out, and the curative effect of the patients in the different hematopoiesis score groups were compared.@*RESULTS@#The median OS time of the patients in group 1, 2, 3 and 4 was 27.0, 22.5, 20.7 and 18.1 months, while the median PFS time were 23.0, 19.0, 18.0 and 14.0 months, respectively. The OS and PFS of the patients in low score group were significantly better than those in high score group (P=0.045, P=0.048). There was no significant difference in the curative effect of the patients treated by bortezomib after 3-4 courses (P>0.05).@*CONCLUSION@#Hematopoiesis score can preliminarily predict the overall survival of newly diagnosed MM patients, but there is no significant difference between different scoring groups in the initial curative effect.

Mieloma múltiple. Experiencia de 9 años en el Hospital Naval Almirante Nef / Multiple myeloma. Nine years' experience at the Hospital Naval Almirante Nef

Introducción: el mieloma múltiple (MM) continúa siendo una enfermedad incurable sin embargo, el trasplante autólogo de médula ósea (TAH), y las drogas antineoplásicas han permitido mejorar la sobrevida global (SG) de los pacientes. Materiales y métodos: estudio de cohorte retrospectivo de 50 pacientes con diagnóstico de MM en el hospital Naval Almirante Nef, desde 2005 a 2013. Los pacientes se dividieron en dos cohortes, según la eligibilidad a trasplante, y analizados acordes a la primera línea de tratamiento y la sobrevida global (SG) hasta abril de 2019. Resultados: mediana de edad 73 años (47-88 años), SG 49 meses, y 50% en etapa-II del Sistema de Etapificación Internacional. La SG de los 39 no candidatos a TAH fue 46 meses; con un mayor número de respuestas completas y sobrevida, con el esquema melfalán-prednisona-talidomida. La SG de los 11 candidatos a TAH fue 66 meses, siendo el esquema bortezomib-ciclofosfamida-dexame-tasona el que concentró un mayor número de respuestas completas libres de progresión. Se trasplantó el 45% de los candidatos, con una mediana de sobrevida de 79 meses versus a los 51 meses de aquellos no trasplantados. Tres casos de neuropatía asociada a talidomida y uno a bortezomib. La SG a los seis meses y a los cinco años de todos los pacientes fue 86% y 44%, respectivamente. Conclusión: la incorpo-ración de nuevos fármacos permitió obtener mejores resultados de sobrevida lo que se condice con estudios nacionales e internacionales.

Introduction: Multiple myeloma (MM) is still an incurable disease however, autologous stem cell transplantation (ASCT), and antineo-plastic drugs have allowed improving the overall survival (OS) of patients. Materials and methods: A retrospective cohort study of 50 patients diagnosed with MM at the Hospital Naval Almirante Nef, from 2005 to 2013. The patients were divided into two cohorts according to transplantation eligibility and analyzed about first-line treatment and overall survival (OS) up to April 2019. Results: Median age 73 years (47-88 years), OS 49 months, and 50% in stage-II International Staging System. OS of the 39 non-candidates for ASCT was 46 months: with a higher number of complete responses and survival, with the melphalan-prednisone-thalidomide scheme. The OS of the 11 candidates for ASCT was 66 months, with the bortezomib-cyclophosphamide-dexamethasone scheme being the one with the highest number of progression-free complete responses. Forty-five percent of the candidates were transplanted, with a median survival of 79 months versus 51 months for those not transplanted. Three cases of neuropathy were associated with thalidomide and one with bortezomib. OS at six months and five years for all patients was 86% and 44%, respectively. Conclusion: The incorporation of new drugs allowed to obtain better survival results, which is by national and international studies.

The Effects of Chidamide Combined with Anti-myeloma Drugs on the Proliferation and Apoptosis of Myeloma Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of chidamide combined with anti-myeloma drugs on the proliferation and apoptosis of myeloma cells.@*METHODS@#The proliferation inhibition of the cells was detected by CCK-8 method, and flow cytometry was used to detected the apoptosis of the cells.@*RESULTS@#Chidamide could inhibit the proliferation of myeloma cells and promote the apoptosis of primary myeloma plasma cells in a time- and dose-dependent manner (P<0.05). In NCI-H929 cell line, chidamide combined with low-dose bortezomib and lenalidomide showed synergistic effect, while combined with dexamethasone and pomalidomide showed additive effect. In MM.1s cell line, chidamide combined with bortezomib, dexamethasone, lenalidomide and pomalidomide all showed synergistic effects.@*CONCLUSION@#Chidamide inhibits proliferation of myeloma cells in a time- and dose-dependent manner and promotes apoptosis of primary myeloma plasma cells. Furthermore, it can enhance the inhibitory effect of anti-myeloma drugs.