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  • 1
    In: EMBO Molecular Medicine, EMBO, Vol. 14, No. 1 ( 2022-01-11)
    Type of Medium: Online Resource
    ISSN: 1757-4676 , 1757-4684
    Language: English
    Publisher: EMBO
    Publication Date: 2022
    detail.hit.zdb_id: 2485479-7
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  • 2
    Online Resource
    Online Resource
    American Society of Hematology ; 2022
    In:  Blood Vol. 140, No. Supplement 1 ( 2022-11-15), p. 12589-12590
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 12589-12590
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Molecular Cancer, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2022-09-22)
    Abstract: Multiple myeloma (MM) is a heterogeneous disease with different patterns of clonal evolution and a complex tumor microenvironment, representing a challenge for clinicians and pathologists to understand and dissect the contribution and impact of polyclonality on tumor progression. Methods In this study, we established a global cell ecological landscape of the bone marrow (BM) from MM patients, combining single-cell RNA sequencing and single-molecule long-read genome sequencing data. Results The malignant mutation event was localized to the tumor cell clusters with shared mutation of ANK1 and IFITM2 in all malignant subpopulations of all MM patients. Therefore, these two variants occur in the early stage of malignant clonal origin to mediate the malignant transformation of proplasmacytes or plasmacytes to MM cells. Tumor cell stemness index score and pseudo-sequential clonal evolution analysis can be used to divide the evolution model of MM into two clonal origins: types I and IX. Notably, clonal evolution and the tumor microenvironment showed an interactive relationship, in which the evolution process is not only selected by but also reacts to the microenvironment; thus, vesicle secretion enriches immune cells with malignant-labeled mRNA for depletion. Interestingly, microenvironmental modification exhibited significant heterogeneity among patients. Conclusions This characterization of the malignant clonal evolution pattern of MM at the single-cell level provides a theoretical basis and scientific evidence for a personalized precision therapy strategy and further development of a potential new adjuvant strategy combining epigenetic agent and immune checkpoint blockade.
    Type of Medium: Online Resource
    ISSN: 1476-4598
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2091373-4
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 37-37
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 37-37
    Abstract: PURPOSE: Kinesin spindle protein is an attractive target for cancer treatment since it plays an important role in mitosis without directly affecting microtubules. LH031 is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity.. This phase 1 study was conducted to evaluated dose limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for LH031 in Chinese patients with Refractory/Resistance Multiple Myeloma (RRMM).The pharmacokinetics (PK) and preliminary efficacy of LH031 were also evaluated. METHODS: A non-randomized, single-center, open-label, dose-escalation phase 1 trial was conducted to evaluate the safety, tolerability, pharmacokinetics and efficacy of single or multiple escalation dose (20 mg, 30 mg, 40 mg, 50 mg) of LH031 given as schedule of oral once a day. LH031 was administered on Day 1~5 of each week for 3 weeks (21 days) per cycle. A standard 3+3 dose escalation design was employed. An expansion cohort was conducted at the MTD. Pharmacokinetics was evaluated in plasma. A major efficacy evaluation was performed at the end of each treatment cycle. RESULTS: The study is still on going, at present there are 6 patients received LH031 and completion of all visits, divided equally into 20mg and 30mg cohort. Patients in each cohort had received a median of 6 prior therapies. DLTs reported in two patients dosed at 30mg. Both of the DLTs were neutropenia. The most commonly reported treatment-related AEs were hematological toxicity (e.g. neutropenia, lymphocytopenia, leukocytopenia) that were similar to other Eg5 inhibitors. The main severe adverse events (CTCAE grade 3 or 4) in the 20mg and 30 mg dose groups were leukocytopenia and neutropenia, and they were all reversible. Neurotoxicity related to LH031 was not observed. Efficacy data demonstrated that the best response was Stable Disease(SD) and Disease Control Rate (DCR, ≥SD[≥8 weeks]) was 50%. The longest treatment time was 177 days, even though PFS was determined according to the last tumor evaluation before the COVID period (D88). The PK data shows that T1/2 are approximately 20h in Chinese patients, which is longer than Caucasian (10h); Chinese AUC for 20mg is also higher than that of Caucasian (1996 h*ng/ml vs. 476 h*ng/ml) ; the exposure at 20mg dose group is close to that at 50 mg dose in Caucasian. These PK parameter indicates that the elimination of LH031 is slower in Chinese patients compared with Caucasian. CONCLUSIONS: The current phase 1 study showed that LH031 was an accepted safety profile at 20mg. DLTs was expected and reversible. MTD is to be determined by recruiting 3 more subjects at 20mg dose. It demonstrated that the elimination rate of LH031 in Chinese patients was slower than Caucasian. The monotherapy showed some benefit to RRMM, Phase 2 clinical trials are being planned to include various combination therapies with existing treatments (e.g. lenalidomide, dexamethasone, bortezomib) for MM to benefit more potential refractory/resistance MM patients. Disclosures Song: Link Health Group: Current Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 29-30
    Abstract: PurposeEarly infection was an important cause of mortality in patients with multiple myeloma (MM). The study aimed to assess factors affecting early infection and identify patients with high risk developing infection. MethodsDuring January 2010 to June 2019, patients with MM were analyzed, retrospectively. The data was divided into training and independent validation cohort. The least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction, feature selection, and model building. ResultsOf 745 confirmed MM patients, 540 eligible cases were included in final analyses. In total, 165 patients (30.6%) suffered infections, while 110 patients (20.4%) occurred early infections during the first 3 months after diagnosis. Bacteria and the respiratory tract were the most common pathogen and localization of infection, respectively. In training cohort, PS≥2, HGB & lt;100g/L, β2MG≥6.0mg/L and GLB≥80g/L were identified associated with early infections by LASSO regression. Based on the four factors, an early infection risk model of MM (IRMM) was established to define high- and low-risk groups, which showed significantly different rates of infection (35.3% vs. 9.4%,P & lt;0.001, HR=4.381 [95% CI, 2.802-7.221]). IRMM displayed good discrimination (AUC=0.756) and calibration (P=0.94). ConclusionWe determined risk factors for early infection and established a predictive model to help clinicians identify patients with high-risk infection. It can help clinicians to determine whether to adjust monitoring and treatment strategies, or apply prophylactic interventions to high-risk patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2718-2718
    Abstract: Background The Phase III TOURMALINE-MM4 Trial demonstrated that the oral proteasome inhibitor, Ixazomib maintenance significantly improved progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing ASCT. However, patient recruitment for clinical trials is highly selective so the extent to which study populations represent real-world patients is unclear. Currently, data validating the use of ixazomib maintenance in clinical practice in Chinese landscape is scarce. Methods we conducted a retrospective, observational study of NDMM patients meeting International Myeloma Working Group (IMWG) criteria, who received ixazomib-based maintenance therapy. Data was collected from 26 medical centers in southern China. Enrollment was stratified by risk stage, transplant status and maintenance regimens. The characteristics, toxicities and survival outcomes were recorded. Results We included 105 NDMM patients who received ixazomib-based maintenance treatment. Mean age at diagnosis was 59.82 ± 9.80 years, with 62.9% male patients. MM International Staging System (ISS), stage 3 was the most common with 49.04% of patients; 62.86% had an Eastern Cooperative Oncology Group performance score ≥2, and 81.9% with concomitant diseases. By the end of over 70 months follow-up since initial diagnosis, median PFS was 69.45 (95%CI: 31.42-107.48) months, and median OS was not achieved yet. We explored potential influencing factors of progression at the post-maintenance evaluation with a crude model using logistic regression. Difference in PFS was not statistically significant by status at pre-maintenance response, transplantation, maintenance therapy regimens (single/two/three-agent) and dexamethasone in maintenance regimens (p & gt;0.05). Eight patients (7.62%) had grade≥3 treatment-emergent adverse events (TEAEs); 5.7% discontinued treatment because of TEAEs. Common any-grade TEAEs included fatigue (18.1%), diarrhea (16.19%), and peripheral neuropathy (11.43%). Conclusion Although there are certain differences in maintenance treatment options for newly diagnosed multiple myeloma patients in real-world practice, the results of our retrospective study support that the ixazomib-based maintenance therapy was effective with acceptable toxicity and single-agent ixazomib maintenance provided enough clinical benefit compared to two or three agents. Keywords: multiple myeloma, ixazomib, maintenance therapy, real-world practice Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
    Online Resource
    Online Resource
    Frontiers Media SA ; 2022
    In:  Frontiers in Oncology Vol. 12 ( 2022-3-17)
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-3-17)
    Abstract: The study aimed to assess factors associated with early infection and identify patients at high risk of developing infection in multiple myeloma. Methods The study retrospectively analyzed patients with MM seen at two medical centers between January 2013 and June 2019. One medical center reported 745 cases, of which 540 of the cases were available for analysis and were further subdivided into training cohort and internal validation cohort. 169 cases from the other medical center served as an external validation cohort. The least absolute shrinkage and selection operator (Lasso) regression model was used for data dimension reduction, feature selection, and model building. Results Bacteria and the respiratory tract were the most common pathogen and localization of infection, respectively. In the training cohort, PS≥2, HGB & lt;35g/L of the lower limit of normal range, β2MG≥6.0mg/L, and GLB≥2.1 times the upper limit of normal range were identified as factors associated with early grade ≥ 3 infections by Lasso regression. An infection risk model of MM (IRMM) was established to define high-, moderate- and low-risk groups, which showed significantly different rates of infection in the training cohort (46.5% vs. 22.1% vs. 8.8%, p & lt;0.0001), internal validation cohort (37.9% vs. 24.1% vs. 13.0%, p =0.009) and external validation cohort (40.0% vs. 29.2% vs. 8.5%, p =0.0003). IRMM displayed good calibration ( p & lt;0.05) and discrimination with AUC values of 0.76, 0.67 and 0.71 in the three cohorts, respectively. Furthermore, IRMM still showed good classification ability in immunomodulatory (IMiD) based regimens, proteasome-inhibitors (PI) based regimens and combined IMiD and PI regimens. Conclusion In this study, we determined risk factors for early grade ≥ 3 infection and established a predictive model to help clinicians identify MM patients with high-risk infection.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2649216-7
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  • 8
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 99, No. 11 ( 2020-11), p. 2589-2598
    Abstract: The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients’ preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1–20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 1458429-3
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