bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety of subcutaneous daratumumab in the treatment of plasma-cell disorders: A single-center experience.
Authors: Kye Jung , Seyer Magdalena , Patel Samit , Kim Eun-Jeong , Hewitt Rhonda , Liedtke Michaela , Iberri David Joseph 
Published: June 2021

e20007 Background: Daratumumab (Dara) is a CD38-directed monoclonal antibody approved for the treatment of patients with multiple myeloma (MM) and light-chain amyloidosis (AL). Infusion-related reactions (IRRs) have been reported in 28-56% of individuals receiving the conventional intravenous (IV) formulation, necessitating slow infusions and frequent use of rescue medications to mitigate complications. Recently subcutaneous (SC) Dara received approval in MM, and randomized data suggests a lower rate of IRRs compared to IV Dara. Guidelines regarding post-injection monitoring with SC Dara are not well established. This retrospective study aims to evaluate the safety of SC Dara in patients with MM and AL, and to suggest guidelines for monitoring following SC Dara administration. Methods: This single-center retrospective study included patients treated with MM or AL receiving SC Dara between June 2020 and December 2020. The primary outcome of the study was incidence of IRRs. Secondary outcomes include timing and severity of IRRs based on CTCAE version 4.0. Results: A total of 82 patients received SC Dara during the study period. Of these 82, forty-nine (60%) had previously received Dara (Dara-exposed), and 33 patients (40%) were Dara-naïve. Eight of the 82 patients (9.8%) experienced an IRR. All were grade 1 (n=5, 63%) or grade 2 (n=3, 38%) in severity. Seven patients in the Dara-naïve group experienced an IRR (21%), and one patient in the Dara-exposed group (2%) experienced injection-site erythema with the second SC dose after transitioning from IV. Three patients experienced reactions immediately after SC Dara administration, and four patients experienced delayed reactions >4 hours after SC Dara administration (median 11.9 hours; range 5-24). Among those with delayed reactions, three experienced reactions after being discharged from the treatment area but symptoms resolved without any intervention. Conclusions: In this single-center study of patients receiving SC Dara, IRRs occurred in about 10% of patients, and were more likely with a patient’s first dose of SC Dara. All reactions were mild to moderate in severity and could be managed in the outpatient setting. We suggest that Dara-naïve patients receiving their 1st SC Dara dose be monitored for one hour after SC Dara administration. Monitoring does not appear necessary for patients transitioning from IV to SC Dara or receiving subsequent doses of SC Dara. [Table: see text]
Recent updates on bispecific T-cell engager (BiTE) antibodies in relapsed and refractory multiple myeloma.
Authors: Rafae Abdul , Wahab Ahsan , Ehsan Hamid , Christy Joshua , Saleem Tabinda , Kandah Emad , Ali Rabia , Malik Mustafa Nadeem , Ali Sundas , Saeed Sara , Anwer Faiz 
Published: June 2021

e20034 Background: Bispecific T-cell engager (BiTE) antibodies are currently being studied for various hematological malignancies including relapsed and refractory multiple myeloma (RRMM). BiTE antibodies that target CD3 on T cells and antigens GPRC5D, BCMA or FcRH5 on myeloma cells are being studied in RRMM patients (pts). Methods: A comprehensive literature search was done on Pubmed, Embase, and Cochrane. The data presented in various conferences (ASH, ASCO) were also included. Results: Six clinical trials are currently evaluating anti-BCMA, anti CD3 BiTE in RRMM. Madduri et al. reported ORR of 39% in 49 pts treated with REGN5458 an anti BCMA and CD3 BiTE antibody. Grafall et. al reported an ORR of 73% with Teclistamab at 1500µg/kg SC. Harrison et al. reported ORR of 83% in 9 pts treated with 9mg of AMG 701. Lesokhin et al. reported an ORR of 33% among 18 RRMM pts at all dose levels and ORR of 75%. at dose level of 215μg/kg weekly (n=4), and 360 μg/kg weekly (n=4). Rodriguez et al. reported an ORR of 80% among 15 RRMM pts treated with TNB-383B at the dose of 40-60mg IV every 3 weeks. Topp et al reported an ORR of 70% among 10 pts treated with AMG420/BI-836909 at MTD of 400µg/d. Chari et al reported results of Talquetamab which targets GPRC5D which showed an ORR of 66% in 55 evaluable pts. ORR at RP2D (405 µg/kg SC) was 69% in 19 pts treated at this dose. Cohen et al reported results on BFCR4350A, an anti FcRH5 BiTE which showed an ORR of 53% at dose ≥3.6/20mg Q3W. Cytokine release syndrome (CRS) is a serious side effect of BiTE antibodies and was reported in 39%, 64%, 65%, 61%, 45%, 38%, 54% and 76% in studies by Madduri et al, Grafall et al., Harrison et al., Lesokhin et al., Rodriguez et al., Topp et al., Chari et al., and Cohen et al., respectively. Most of the CRS cases were grade 1-2 and resolved either by themselves or required treatment with tocilizumab and steroids. Other most common side effects are reported in table. Conclusions: The most recent data on BiTE antibodies in RRMM has shown promising results with good tolerability. However, the trials are ongoing and a longer follow up is needed.[Table: see text]
Choosing optimal therapy for relapsed refractory multiple myeloma: A systematic review and network meta-analysis.
Authors: Nadeem Mahum , Gupta Samiksha , Naqvi Syed Arsalan Ahmed , Riaz Irbaz Bin , Chakraborty Rajshekhar , Aljama Mohammed A. , Husnain Muhammad 
Published: June 2021

e20037 Background: Several treatment options are available for relapsed refractory multiple myeloma(RRMM). However, in the absence of direct-comparative trials, it is unclear how to choose optimal therapy in RRMM. We conducted a network meta-analysis (NMA) to assess the comparative efficacy of different treatment options in RRMM. Methods: Standard electronic databases were searched for abstract and full-text publications of phase 2/3 randomized controlled trials (RCTs) assessing treatment regimens in RRMM. Progression free survival (PFS) , overall survival (OS), complete response (CR), and very good partial response (VGPR) were analyzed. Mixed treatment comparisons were made using fixed-effect network meta-analysis (NMA) within the frequentist framework due to sparse direct evidence. Sensitivity analyses were conducted using the Bayesian approach. Publication bias was assessed by visual inspection of comparison-adjusted funnel plots. P-score plots were used to assess relative rankings of the treatments. R statistical software v 4.0.3 was used to conduct the analyses. Results: After a review of 1137 citations, A total of 37 relevant studies were included in systematic review and 30 studies were analyzed in the network meta-analysis (29 contributed for PFS; 18 for OS; 23 for CR; 25 for VGPR). Mixed treatment comparisons showed high likelihood of PFS benefit with triplet regimens; Isatuximab-Carfilzomib-Dexamethasone (Isa-Kd; P-score: 0.98), followed by Daratumumab-Carfilzomib-Dexamethasone (DKd; P-score: 0.93), Daratumumab-Bortezomib-Dexamethasone (DVd P-score: 0.92), Elotuzumab-Pomalidomide-Dexamethasone (EPd); P-score: 0.84), and Isatuximab-Pomalidomide-Dexamethasone (Isa-Pd; P-score: 0.80) when compared to monotherapy and different doublet regimens. Isa-Kd and DKd continued to show significant PFS advantage when compared to Kd doublet. High likelihood of OS benefit was observed with Carfilzomib-Lenalidomide-Dexamethasone (KRd); P-score: 0.86) followed by Kd (P-score: 0.83), and DVd (P-score: 0.82). However, trials did not consistently report data for OS and most of the mixed treatment comparisons were statistically insignificant. Similar results were observed for CR and VGPR with triplet regimens showing better likelihood for achieving CR and VGPR. Conclusions: This NMA provide most updated evidence on different treatment options in RRMM and can serve as a contemporary guidance in the absence of head-to-head trials. The weight of current evidence favors the use of triplet regimens. Isa-Kd, DKd, DVd, EPd and Isa-Pd showed no statistically significant difference in terms of PFS in RRMM.
Recent updates on three drug combination regimen for relapsed refractory multiple myeloma.
Authors: Saleem Tabinda , Rafae Abdul , Christy Joshua Jonathan , Kuriakose Kiran , Malik Mustafa Nadeem , Kandah Emad , Qurashi Hafiz , Ali Rabia , Anwer Faiz 
Published: June 2021

e20039 Background: Two drug regimens comprising proteasome inhibitors, immunomodulatory agents, or a monoclonal antibody are the standard of care for multiple myeloma. However, due to the increased relapse incidence, multiple different combination therapies are under study to treat relapsed and refractory multiple myeloma (RRMM). Methods: A comprehensive data search was done across various data sets, including PubMed, Cochrane, and Embase, using MeSH terms and keywords to include all phase III clinical trials involving three-drug regimens in the last five years. Results: We report eleven clinical trials evaluating three-drug combination regimens vs. two-drug regimens for RRMM. In 2015 Stewart et al. reported ORR of 87.1% vs. 66.7% in 396 patients treated with Carflizomib (K), Lenalidomide (R), and dexamethasone (d) compared to 396 patients treated with Rd alone. Lonial et al. reported ORR of 79% vs 66% for Eltozumab + Rd (n321) vs Rd (n=325). In 2016 San-Miguel et al. treated 387 patients with bortezomib, panobinostat + d, and 381 patients with bortezomib + d, with ORR of 40.3% vs. 35.8%. Shah J et al. compared Pembrolizumab, pomalidomide + d (n=125) to pomalidomide + d (n=124) with ORR of 34% vs 40% respectively. In 2018, Elotuzumab, pomalidomide (P) + d (n=60) vs. Pd (n=57) combination studied by Dimopoulos et al. resulted in an ORR of 53% vs. 26%. In 2019 Schjesvold et al. compared isatuximab, Pd (n=154), with Pd (n=153) with an ORR of 60% and 35%, respectively. Most recently, in 2020, Kumar et al. reported ORR of 82% with venetoclax, bortezomib (V) +d (n=194) compared to ORR of 68% with Vd (n=97). Mateos et al. reported ORR of 85% with VDd (n=251), vs 63% with Vd (n=247). Bahlis et al. reported ORR of 92.9% in 268, and Suzuki et al. reported ORR of 90.2% in 52 patients treated with DRd vs. ORR of 76.4% in 283 and ORR of 72.1% in 44 patients treated with Rd alone. In another trial, Dimopoulos et al. resulted in an ORR of 53% with KDd (n=312) compared to 75% with Kd (n=154). A summary of adverse effects is listed in table. Conclusions: Three drug regimen showed better results compared to two-drug regimens with a similar safety profile. A longer follow-up of these trials is needed to confirm this.[Table: see text]
Differences in disease characteristics and outcomes in older versus younger adults with multiple myeloma.
Authors: Jacobs Michael , Langerman Spencer , Jakubowiak Andrzej J. , Chiu Brian C , Derman Benjamin Avi 
Published: June 2021

e20041 Background: Older adults are underrepresented in clinical trials in multiple myeloma (MM), as are the risk prognostication schema derived from them, which limits their generalizability to this age group. Despite appropriate fitness, older adults may not be offered the same therapies as their younger counterparts. In this study, we compared disease characteristics and their associations with outcomes in older and younger adults with MM. Methods: We obtained data for newly diagnosed MM patients from the MM Research Foundation CoMMpass registry (version IA16), a prospective observational study with highly annotated clinical data, cytogenetics, and longitudinal outcomes. Chi-square or Fisher’s exact test were used for comparisons of categorical variables. Progression free survival (PFS) and overall survival (OS) curves were constructed using the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazard models were computed to estimate hazard ratio (HR) and 95% confidence interval (CI) for association between pre-treatment variables and outcomes. Results: 1,143 patients were analyzed, including 853 patients (pts) under age 70 years (< SEV) and 290 pts age 70+ years (SEV+). SEV+ had a higher frequency of ISS score 3 (p < 0.001), lower estimated glomerular filtration rate (median 57.6 vs 74.7 mL/min/1.73m2, p < 0.001), and worse ECOG performance status (PS) (p = 0.01). Of the cytogenetic abnormalities analyzed [del17p, gain1q, t(4;14), t(8;14), t(14;16), t(14;20), and hyperdiploidy], SEV+ had higher frequency of gain1q (42% vs 33%, p = 0.02) and t(14;20) (3% vs 1%, p = 0.03) compared with younger adults. SEV+ received less proteasome inhibitor + immunomodulatory imide triplet induction therapy (27% vs 55%, p < 0.001) and less frontline autologous stem cell transplant (ASCT) (22% vs 59%, p < 0.001). SEV+ were less likely to achieve >complete response to induction therapy compared to < SEV (32% vs 18%, p < 0.001). SEV+ had worse PFS (HR 1.8, 1.6-2.2, p < 0.001) and OS (2.3, 1.8-2.9, p < 0.001) compared to < SEV. On multivariate analysis, increasing ISS, gain1q, high risk gene expression profiling (UAMS70), and lack of triplet induction with frontline ASCT were associated with both poorer PFS and OS in < SEV. For SEV+, multivariate analysis revealed that increasing ISS, t(14;16), and lack of triplet+ASCT were associated with inferior PFS, while age, male sex and increasing ISS were associated with inferior OS. Conclusions: Older adults have a greater prevalence of ISS 3, gain1q, and t(14;20) compared with younger adults but only ISS translates into inferior PFS or OS within this group. Increased access to triplet induction therapy and expanding access to frontline ASCT among older adults may help to improve outcomes in this growing subset of patients.
In-depth genomic characterization of programmed cell death ligand 1 (PD-L1) expression in Chinese lung adenocarcinoma patients.
Authors: Kang Li , Liu Jun , Li Jia , Wu Lin , Xiao Yajie , Du Haijian , Zhao Zhikun , Li Xiaoting , Wu Dongfang , Zhao Zhuxiang , chen bolin 
Published: June 2021

e20500 Background: Immune checkpoint blockades have revolutionized anticancer treatments for lung cancers, and PD-L1 expression has been served as crucial predictive biomarkers for immunotherapies. However, PD-L1 expression has been found to be influenced by some extrinsic or intrinsic factors in vitro or to be associated with other biomarkers in vivo. Methods: An amount of tumor tissues was taken from a biopsy or surgery for PD-L1 expression assay and genomic profiling in Chinese lung adenocarcinoma patients using extend targeted sequencing panel. In-depth retrospective analyses of clinical features, gene alternations, singling pathways and immune signatures was conducted in negative group (TPS < 1%), intermediate group (1% ≤ TPS < 50%), and high group (TPS ≥ 50%). Clinical responses to selected mutation were also evaluated from public database such as TCGA and MSKCC. Results: A total of 248 Chinese patients with lung adenocarcinoma was retrospectively identified and included in this study, consisting of negative group (n = 124, 50%), intermediate group (n = 93, 38%), and high group (n = 38, 12%). High tumor mutation burden was significantly as associated with high PD-L1 expression. In addition, PD-L1 expression was highly related with gene alternations such as PRKDC, KMT2D, ERBB2 and SETD2. Moreover, signaling pathways of DDR, TP53, cell cycles and NOTCH also obviously related with PD-L1 expression. Besides, most of patients in high PD-L1 group were determined as high-grade immune subtypes (C2-C4), showing significant higher levels of IFN-gamma, CD8+ T-cells, NK cells, NK CD56 dim cells, Th1 cells, Th2 cells (P < 0.0001). Moreover, the prognostic value of SETD2 mutation was slight positive with overall survival from MSKCC cohort (HR 1.92 [95%CI 0.90-4.10], P = 0.085), and the percentage of IFN-gamma was significantly higher in SETD2 mutant group than in wild-type subgroup ( P < 0.01). Conclusions: This study illustrated in-depth genomic profiles and immune signatures of PD-L1 expression in Chinese lung adenocarcinoma patients, which might interpret more potential molecular mechanisms for anti-cancer immunotherapy in NSCLC. In addition, SETD2 may be potential biomarkers for predicting patients’ prognosis.
Longitudinal analysis of dynamic changes of T-lymphocytes during multimodal treatment of patients with inoperable stage III NSCLC.
Authors: Hofer Thomas Philipp , Käsmann Lukas , Pelikan Carolyn , Mathur Saloni , Eze Chukwuka , Taugner Julian , Tufman Amanda , Reinmuth Niels , Belka Claus , Noessner Elfriede , Manapov Farkhad 
Published: June 2021

e20503 Background: Acute lymphocytopenia is associated with poor survival in solid cancers treated with multimodal therapy. A prospective analysis of peripheral blood mononuclear cells (PBMCs) during multimodal treatment in inoperable stage III NSCLC patients was performed to assess a correlation of T-lymphocytes changes with 6-months progression-free survival rates (PFS6M). Methods: Twenty patients at median age of 65.5 years (range 33-77), 85% male, 55% with adenocarcinoma and 40% with squamous cell carcinoma, were prospectively enrolled in this study. Eighteen (90%) patients received platinum-based concurrent chemo-radiotherapy (cCRT); seven (35%) patients additional concurrent and/or sequential immune check-point inhibition (four patients nivolumab and three durvalumab); patients treated with nivolumab received induction chemotherapy. Thoracic irradiation (TRT) was applied in all patients with median cumulative dose in equivalent 2Gy fractions (EQD2) of 64Gy (range: 52-65Gy). Peripheral blood was collected 5-10 days before treatment begin (A1), on the last day of TRT (RTend), and during follow-up. Samples were analyzed using polychromatic flow cytometry. Results are reported for three time-points: A1, RTend, and 6 months after TRT (C3) or the last sample available before that time-point. Results: From A1 to RTend, 16 (80%) patients experienced severe T-cell (CD3+, CD3+CD4+, CD3+CD8+) depletion, including 3 (15%) patients who received two doses of concurrent nivolumab. T-lymphocyte nadir was independent of the absolute numbers of PBMCs before treatment begin. In two patients, T-cell count remained stable, and increased in two other patients. No correlation of dynamic changes from A1 to RTend with PFS6M was observed. From RTend to C3, T-lymphocytes recovered in 11 (55%) patients; in 6 (30%) T-cell count further decreased or remained at very low levels. For total CD3 T-cells, CD3+CD4+ and CD3+CD8+ subsets, progressive disease in the first six months after TRT was associated with a decrease of median values (P = 0.03 for total CD3+ and CD3+CD4+, P = 0.08 for CD3+CD8+ T-cells). In contrast, an increase of all medians was associated with PFS6M (P = 0.007 for total CD3+, P = 0.002 for CD3+CD4+, P = 0.06 for CD3+CD8+ T-cells). Conclusions: There is a significant difference between patients with regards to T-lymphocytes recovery after the end of TRT, which is predictive for PFS6M, with poor median recovery observed in patients with early progress.
Mutational landscape with a focus on KRAS mutations in non-small lung cancer in Taiwan.
Authors: Tran Nguyet , Bonner Joseph D. , Chen Wei-Ju , Lin Fang-Wei , Gruber Peter J. , Lange Jeff , Lauer Andrea , Gruber Stephen B. 
Published: June 2021

e20513 Background: Lung cancer is the leading cause of cancer death in Taiwan. The poor prognosis of lung cancer patients with advanced disease and recent development of precision medicine motivates the investigation of molecular targets. The purpose of the study is to estimate the prevalence of KRAS gene mutations and 15 other gene targets among non-small cell lung cancer (NSCLC) patients in Taiwan. Methods: This retrospective study included 933 NSCLC patients diagnosed between January 1992 and July 2018 at six medical centers in Taiwan, including Taichung Veteran’s General Hospital, Chung San Medical University Hospital, China Medical University Hospital, Kaohsiung Veteran’s General Hospital, Tri-Service General Hospital and National Taiwan University Hospital. Patients ≥18 years, had primary histologically confirmed NSCLC diagnosis at time before any treatment, and availability of archival tumor tissue with >30% tumor cellularity. Mutational Analysis: The Formalin-Fixed Paraffin-Embedded (FFPE) tumor blocks were analyzed for the prevalence of somatic mutations. The entire coding sequence of 16 genes was analyzed by next generation sequencing of macrodissected DNA from FFPE recut slides at a depth of greater than 300x and interrogated for somatic pathogenic variants. RNA was not available; hence this limits sensitivity to detect fusions. Results: The mean age at diagnosis was 62 years, 498/933 (53%) were women, 411/843 (49%) were smokers or former smokers, and 829/933 (89%) of adenocarcinoma histopathology. Stage was available for 723 patients with a distribution of 328/723 (45%) Stage I, 120/723 (17%) Stage II, 210/723 (29%) Stage III, and 65/723 (9%) Stage IV. EGFR mutations were identified in 327/933 (35.1%) and TP53 mutations in 179/933 (19.2%). KRAS mutations were identified in 72/933 (7.7%) patients, with KRAS G12C mutations observed in 23/933 (2.5%), KRAS G12D in 16/933 (1.7%), and KRAS G12V in 14/933 (1.5%) (Table). In addition, co-occurring mutations with KRAS were observed and are highlighted, including 14 TP53, 4 PIK3CA, 2 EGFR, 2 CTNNB1, 1 STK11, 1 BRAF and 1 PTEN. Conclusions: EGFR and TP53 were the most frequent mutations identified among all stage NSCLC in Taiwanese populations, followed by KRAS. KRAS G12C and KRAS G12D, the two most frequent KRAS mutations, were identified in 32% and 22% of the KRAS-mutant tumors. Although the prevalence of any KRAS mutation or KRAS G12C mutation is lower than typically seen in Western countries, it is similar to observations among Asian populations. These findings broaden the understanding of the mutational landscape of NSCLC patients in Taiwan to inform development of new therapeutic approaches. [Table: see text]
Investigation of immune microenvironment in EGFR mutant NSCLC.
Authors: Hu Yi , Cui Longgang , Zhao Xiaochen , Bai Yuezong , Zhang Fan 
Published: June 2021

e20517 Background: Immune checkpoint inhibitor therapy has made great achievements in NSCLC, but patients with EGFR mutations have poor efficacy with immunotherapy. Previous studies have explored the expression of PD-L1, neo-antigen, co-mutation and regulatory pathways in EGFR mutate NSCLC. This work compared the immune microenvironment of EGFR mutant and wild-type NSCLC. Methods: Patients: NSCLC. Using multi-color immunohistochemistry (multi-IHC) to evaluate the expression of 2 indicators in tumors and tumor stroma, namely CD8+ T cell and macrophage. Shapiro-Wilk was used for normality test, and t-test or Mann-Whitney U test was used according to the results. Two-sided P < 0.05 was considered a significant difference. Results: The study included 119 NSCLC patients, including 59 women (49.6%) and 60 men (50.4%), with a median age of 57. There were 68 patients (57.1%) with EGFR mutations, 19 patients (16%) with KRAS mutations, and 58 patients (48.7%) with TP53 mutations. multi-IHC results showed that, EGFR mutation Vs EGFR wild type samples, (1) the number and proportion of CD8+ T cells in tumor were not statistically different. The median number of CD8+ T cells in tumor stroma was 231.5 vs 359, p = 0.05 and the proportion of CD8+ T cells was 3.92% vs 5.64%, p = 0.02; (2) The median number of macrophage in tumors was 1522 vs 110, p < 0.01, and the proportion of macrophage cells was 24.93% Vs 1.38%, p < 0.01. The median value of macrophages in tumor stroma was 617.5 Vs 208, p < 0.01, and the proportion of macrophages cells was 10.88% vs 3.03%, p < 0.01. Conclusions: Compared with EGFR wild-type patients, EGFR mutation patients have a lower proportion of CD8+ T cells and a higher proportion of macrophages in the immune microenvironment.