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Background: C-CAR088, an anti-BCMA CAR T-cell therapy, is a novel 2nd generation 4-1BB chimeric antigen receptor T (CAR-T) cell therapy targeting BCMA. Previously presented results from an ongoing study of C-CAR088 in R/R MM (NCT03751293, NCT03815383, NCT04322292, NCT04295018) included a 95.7% overall response rate (ORR) for the dose of 1.0~6.0x10 6 CAR-T cells/kg with a favorable safety profile (Lu, 2020 ASH Oral Presentation #182). Here we present the updated results of the study, with more patients and longer follow up time. Methods: Dose escalation and expansion studies were conducted at four medical centers in China to evaluate the safety and efficacy of C-CAR088 in patients with R/R MM who were previously treated with at least 2 lines of therapy, including proteasome inhibitors (PIs) and IMiDs. C-CAR088 was administered to patients as a single infusion after lymphodepletion with fludarabine (30 mg/m 2) and cyclophosphamide (300 mg/m 2) daily for 3 days. The primary endpoint was the incidence of adverse events (AEs), including dose-limiting toxicities (DLTs), and the secondary endpoints included overall response rate(ORR), duration of response (DOR), and progression-free survival (PFS) by IMWG Uniform Response Criteria. Results: As of July 2nd, 2021, 31 patients had been infused with C-CAR088. The median vein-to-vein time was 18 days. The manufacturing success rate was 100%. 4, 13 and 14 patients were infused with 1.0, 3.0 and 4.5~6.0 x10 6 CAR+ T cells/kg respectively. The median follow-up time for all patients was 8.0 months (0.1-24.2). The median age of patients was 61 years (45-74). The median number of prior lines of therapy was 4 (2-13). There were 25 (80.6%) patients with at least one high risk cytogenetic abnormality and 17 (54.8%) patients with at least two high risk cytogenetic abnormalities. 7 patients (22.6%) received bridging therapy before C-CAR088 therapy. Cytokine release syndrome (CRS) developed in 29/31 (93.5%) patients, grade 1 in 18/31 (58.1%), grade 2 in 8/31 (25.8%) and grade 3 in 3/31 (9.7%) respectively. The median time to the first onset of CRS was 6 days (1-11) and the median duration of CRS was 5 days (2-14). 9/31 (29%) patients used tocilizumab and 6/31 (19.4%) patients used corticosteroids to manage CRS. Only one patient developed a grade 1 neurotoxicity. No DLTs were observed and all adverse events were reversible. One patient died of septic shock on day 2 after receiving C-CAR088. Clinical efficacy was assessed in 28 patients with ≥ 1 month of follow up. Among the 28 patients, 3, 11 and 14 patients were infused with the dose of 1.0 x 10 6 CAR+ T cells/kg 3 x10 6 CAR+ T cells/kg, and 4.5~6x10 6 CAR+ T cells/kg respectively. The ORR was 27/28 (96.4%): 4 (14.3%) achieved CR, 12 (42.9%) achieved sCR and 9 (32.1%) achieved very good partial response (VGPR). At the dose level of 1.0 x10 6 CAR+ T cells/kg, 3(100%) patients achieved VGPR. The median DOR was 3.7 months (1.8-5.8), and the median PFS was 4.6 months (2.7-6.2). The CR rate was 54.5% (6/11) and 71.4% (10/14) in the 3.0 and 4.5~6.0 x10 6 CAR+ T cells/kg cohorts respectively. The median time to CR was 2.0 (0.5-9.5) months. Minimal residual disease (MRD) was testedbyEuroFlow-based flow cytometric analysis in 16 patients who had CR, 15/16 (93.7%) patients were MRD negative with the sensitivity of 10 -5. With a median follow-up of 9.5 months (1.9-24.2) in ≥ 3.0x10 6 CAR+ T cells/kg cohorts, the median DOR and PFS had not been reached. The Kaplan-Meier estimation of PFS at 6 and 12 months was 81.1% (95% CI:65.9% ~99.8%) and 69.5 % (95% CI:51.6 % ~93.6%) respectively. 8 patients in the ≥ 3.0x10 6 CAR+ T cells/kg cohorts discontinued the study. 7 discontinued due to disease progression (PD), and 1 discontinued for other anticancer therapy. 4 progressed within 6 months, 2 progressed within 6-12 months, and 1 progressed within 12-24 months. C-CAR088 proliferated and expanded well in patients' blood. The median C max was 734,868 copies/μg gDNA. The median AUC 0~28day was 7,468,779 day·copies/μg gDNA. The median T max was 14 days. The median T last was 84 days. 71% (95% CI: 42%~92%) of patients with C max equal to or greater than the median C max achieved CR/sCR. Conclusion: C-CAR088 has a manageable safety profile, which includes low neurotoxicity rates (with no gr ≥3 events). Deep and durable responses were observed in ≥ 3.0x10 6 CAR-T cells/kg cohorts. Doses of 3.0 and 6.0×10 6 CAR T cells/kg were selected for further study. Figure 1 Figure 1. Disclosures Zhu: CBMG: Current Employment. Huang: CBMG: Current Employment. Li: CBMG: Current Employment. Lan: CBMG: Current Employment. Chen: CBMG: Current Employment. Humphries: CBMG Ltd: Current Employment. Yao: CBMG: Current Employment, Current holder of stock options in a privately-held company.

Background: C-CAR088, an anti-BCMA CAR T-cell therapy is a novel 2nd generation 4-1BB chimeric antigen receptor T (CAR-T) cell therapy targeting BCMA which is specifically and highly expressed on multiple myeloma (MM) cells. C-CAR088 is manufactured in a serum-free, automated and digital, closed system. Initial, early clinical trial results in patients with R/R MM supported preclinical findings and showed promising efficacy and manageable safety profile (Yao, Blood (2019) 134 (Supplement_1): 50.) Methods: The dose escalation and expansion studies have been conducted at four medical centers in China to evaluate the safety and efficacy of C-CAR088 in patients with R/R MM who were previously treated with at least 2 lines of therapy including proteasome inhibitors (PIs) and IMiDs. C-CAR088 is administered to patients as a single intravenous dose after a standard 3-day cyclophosphamide/fludarabine conditioning regimen. Results: As of July 15, 2020, 24 patients were infused and 21 patients had evaluable data for safety and clinical response at dose levels of 1.0 x 106 CAR-T cells/kg (n=3), 3 x106 CAR-T cells/kg (n=11) and 4.5~6x106 CAR-T cells/kg (n=7). The median vein to vein time was 16 days. The manufacturing success rate was 100%. The median age of patients dosed was 60 years (range: 45-74 years).The median number of prior lines of therapy was 4 (range: 2-12 prior therapies). There were 17 (81%) patients with at least one and 12 (57.1%) patients with at least two high risk cytogenetic tumor changes. Five patients (23.8%) had bridging therapy. C-CAR088 treatment was well tolerated. 20 of 21 (95%) patients had Grade 1-2 CRS and one patient experienced Grade 3 CRS. Median time to CRS was 6.5 days (range: 1-11 days) and median duration of CRS was 5 days (range: 2-10 days). Four patients (19%) received tocilizumab for CRS treatment. Only one patient experienced a Grade 1 neurotoxicity event. No dose-limiting toxicities were observed and all adverse events were reversible. The best overall response (BOR) included 6 complete responses (CRs), 10 very good partial responses (VGPRs) and 4 partial responses (PRs). Median follow-up was 182 days (range: 30-375 days). The median duration of response has not been reached. In the 3 x106 CAR-T cells/kg dose group, 5/11(45%) patients achieved a CR. The C-CAR088 PK profile in peripheral blood showed a trend of a dose dependent profile. AUC0~28day and Cmax increased and Tmax decreased with dose (P Conclusion: The clinical trial results in patients with R/R MM treated with C-CAR088 show a favorable safety profile and promising signs of efficacy. We will continue to evaluate these patients to understand the long-term effect of C-CAR088 in multiple myeloma patients. Clinical trial information: NCT04322292、NCT03815383、NCT03751293、NCT04295018 Research Sponsor: Cellular Biomedicine Group, Inc. Disclosures Zhu: Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Zheng:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Yan:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Lv:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Lan:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Yang:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Huo:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Han:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhao:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Qin:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Wu:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Yao:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhu:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Ren:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhang:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Huang:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Humphries:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Yao:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company.

Cereblon (CRBN), Ikaros (IKZF1), Aialos (IKZF3) and multiple myeloma oncogene 1 (MUM1) are important component of CRBN signaling pathway when treat MM cells with IMiDs. CRBN interacts with the DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B) and regulator of Cullins 1 (ROC1) to form the functional E3 ubiquitin ligase complex (E3ULC). CRBN increases the interaction between E3ULC and IKZF1/3, leading to increased ubiquitination degradation of IKZF1/3, and then induce cytotoxicity in myeloma cells. Subsequently, degradation of IKZF1/3 induce depression of multiple myeloma oncogene 1 (MUM1), which is also called interferon regulatory factors (IRF4) and proved to be involved in the anti-MM activity of IMIDs in previous studies. Immunohistochemical (IHC) staining may be a convenient approach for researchers to differentiate the myeloma cells and non-myeloma cells in BM samples. In this study, we evaluated CRBN, IKZF1/3 and MUM1 expression level in bone marrow (BM) by immunohistochemical (IHC) staining and investigated the relationship between expression level and treatment outcome after IMiDs-based or bortezomib-based therapy in 123 newly diagnosed multiple myeloma (NDMM) patients. H-score method was applied according to both intensity and extent of staining. The intensity was graded from 0 to 3("0"for absent staining, "1" for weak expression, "2" for intermediate expression, and "3" for strong expression of the protein). The extent was graded from "0" to "100" to represent the percentage of MM cells with positive staining of any intensity. H-score was obtained by multiplying the intensity and extent score, ranging from 0 to 300, which reflected protein expression level in MM cells. The median H-score of CRBN, IKZF1, IKZF3 and MUM1 were 200, 0, 180 and 180, respectively. According to the median H-score, we classified the patients into high or low expression group. One hundred and twenty-three NDMM patients were enrolled in this study, including 64 males (52.0%) and 59 females (48.0%). The median age was 60 years (range 34-84). Fifty-one patients (41.5%) received IMiDs-containing regimen as the first-line therapy. The median follow-up time was 24.0 months (range, 10-76 months). After treated with IMiDs, patients with high level of CRBN and MUM1 achieved better overall response rate (ORR) than those expressed low level (CRBN, 88.0% vs. 42.3%, P=0.001; MUM1, 83.3% vs. 48.1%, P=0.009). Besides, patients with CRBN and MUM1 overexpression also had better overall survival (median OS, CRBN, not reached vs. 21.0 months, P=0.004; MUM1, not reached vs. not reached, P=0.021) and progression free survival (median PFS, CRBN, 28.0 vs. 12.0 months, P=0.002; MUM1, 32.0 vs. 12.0 months, P Disclosures No relevant conflicts of interest to declare.

Deletions of the 13q14 chromosome region are associated with B-cell chronic lymphocytic leukemia (B-CLL) and several other types of cancer, suggesting the presence of a tumor suppressor gene. In previous studies the minimal region of deletion (MDR) was mapped to a less than 300-kilobase (kb) interval bordered by the markers 173a12-82 and 138G4/1.3R. For the identification of the putative tumor suppressor gene, the entire MDR (approximately 347 kb) has been sequenced, and transcribed regions have been identified by exon trapping, EST-based full-length complementary DNA cloning, database homology searches, and computer-assisted gene prediction analyses. The MDR contains 2 pseudogenes and 3 transcribed genes: CAR, encoding a putative RING-finger containing protein; 1B4/Leu2, generating noncoding transcripts; and EST70/Leu1, probably representing another noncoding gene (longest open reading frame of 78 codons). These genes have been sequenced in 20 B-CLL cases with 13q14 hemizygous deletion, and no mutations were found. Moreover, no somatic variants were found in the entire MDR analyzed for nucleotide substitutions by a combination of direct sequencing and fluorescence-assisted mismatch analysis in 5 B-CLL cases displaying 13q14-monoallelic deletion. The nondeleted allele of theCAR and EST70/Leu1 genes was expressed in B-CLL specimens, including those with monoallelic loss, whereas no expression of 1B4/Leu2 was detectable in B-CLL, regardless of the 13q14 status. These results indicate that allelic loss and mutation of a gene within the MDR is an unlikely pathogenetic mechanism for B-CLL. However, haplo-insufficiency of one of the identified genes may contribute to tumorigenesis.

【Abstract】 Objective Multiple myeloma (MM) is a kind of plasma cell malignancy tumor with larger heterogeneity. Patient's survival varies greatly. This study retrospectively analyzed serum lactate dehydrogenase (LDH) in 107 cases of elderly MM patients, to discuss its correlation with other clinical indicators of MM and the prognostic significance. Methods 107 cases of elderly MM patients were selected from our hospital from July 2008 to January 2016 as the research objects, all of whom were above 60 years and were newly diagnosed. OLIPAS AU5400 fully automatic biochemical analyzer was used to assay serum LDH concentration, and prognosis analysis was carried out combined with patients' clinical data. On this basis, 73 cases of MM patients were given R-ISS staging. Results At primary diagnosis, about 9.4% patients had increased LDH (10/107), with the median follow-up time of 15 (1-88.5) months. Median overall survival (OS) was 52.5±6.9 months in normal LDH group, while 15.5±5.2 (months) in elevated LDH group, and there were statistically significant differences (p Disclosures No relevant conflicts of interest to declare.

Objective: To investigate and analyze the incidence, risk factors, prophylaxis and treatment of thromboembolism associated with lenalidomide-based regimens for multiple myeloma (MM) patients. Methods: 22 newly diagnosed / relapsed MM patients received lenalidomide-based regimes from May 2013 to May 2015 in our department. All diagnosis of thromboembolism were based on objective clinical symptoms, and confirmed by imaging (lower extremity vascular ultrasound, chest CT angiography (CTA), and two-dimensional echocardiography). Investigatethe incidence of thethromboembolism, and analyze the prophylaxis and treatment for the thromboembolism according to risk factors such as patients' characteristics, disease status, and therapy regimes. Results: Aspirin was used as thromboprophylaxis in 16 patients, low molecular weight heparin (LMWH) in 2 patients, and warfarin in 1 patient, while 3 patients received no thromboprophylaxis. There were 4 cases were diagnosedas thromboembolism with the incident of 18.2%. Threeof them were deep vein thrombosis (DVT), while 1 patient was combined withpulmonary embolism (PE), andthe rest one was found thromboembolism in the left atria. The chemotherapy regimes were lenalidomide plus dexamethasone (≤40mg qw). Other risk factors include: old age, male, immobility, central venous catheter (CVC), surgical history, hypertension, cardiovascularevent, IgG/IgA and light chain type, newly diagnosis, and erythropoietin (EPO). The management of thromboembolism included LMWH, warfarin, venous filter placement, adjustment of chemotherapy regimes and maintenance therapy of antithromboembolism. All the 4 patients were well managedat the last follow-up. Conclusion: Thromboembolism was one of the most common non-hematologic adverse events of lenalidomide-based therapy. Aspirin was an effective option for thromboprophylaxis. More cases will be observed for longer time to optimize further evaluations forantithromboticprophylaxes, which include risk stratification-based prophylacticstrategies, new predictors and specific assessment of all thromboprophylaxis options. Disclosures No relevant conflicts of interest to declare.