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Clinical/translational cancer immunotherapy
Original research
Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma
  1. Xiaoyan Qu1,
  2. Gang An2,
  3. Weiwei Sui2,
  4. Tingyu Wang2,
  5. Xian Zhang3,
  6. Junfang Yang3,
  7. Yan Zhang4,
  8. Lu Zhang4,
  9. Dan Zhu5,
  10. Jiaqi Huang5,
  11. Shigui Zhu5,
  12. Xin Yao5,
  13. Jing Li5,
  14. Chengxiao Zheng5,
  15. Kevin Zhu6,
  16. Yutian Wei5,
  17. Xiaoteng Lv5,
  18. Liping Lan5,
  19. Yihong Yao5,
  20. Daobin Zhou4,
  21. Peihua Lu3,
  22. Lugui Qiu2 and
  23. Jianyong Li1
  1. 1Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, China
  2. 2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
  3. 3Department of hematology, Hebei Yanda Lu Daopei Hospital, Langfang, China
  4. 4Department of hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  5. 5Cellular Biomedicine Group Inc, Shanghai, China
  6. 6University of Maryland School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Dr Jianyong Li; lijianyonglm{at}126.com

Abstract

Background Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study developed C-CAR088, a novel second-generation humanized anti-BCMA CAR T-cell therapy, and assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM.

Methods Patients received lymphodepletion with three doses of cyclophosphamide (300 mg/m2) and three doses of fludarabine (30 mg/m2) on days –5, –4, and –3, followed by an infusion of C-CAR088 on day 0. Doses of 1.0×106, 3.0×106, and 6.0×106 CAR T cells/kg (±20%) were tested in the dose-escalation cohorts and expansion cohorts. The primary endpoint was treatment safety, including the rate of treatment-emergent adverse events after cell infusion. Secondary endpoints were the overall response rate and progression-free survival. The exploratory endpoints were the quantification of C-CAR088 CAR T cells, selection of cytokines and chemokines in blood, and measurement of tumor BCMA expression.

Results As of July 2, 2021, 31 patients had been infused with C-CAR088. Any grade cytokine release syndrome (CRS) occurred in 29 patients (93.5%), and grade 3 CRS occurred in 3 patients (9.7%). One patient from the high-dose group (4.5–6.0×106 CAR T cells/kg) developed grade 1 neurotoxicity. No dose-limiting toxicities were observed in any dose group, and all adverse events were reversible after proper management. The overall response, stringent complete response, complete response (CR), and very good partial response rates were 96.4%, 46.4%, 10.7%, and 32.1%, respectively. The CR rate in the medium-dose (3.0×106 CAR T cells/kg) and high-dose (4.5–6.0×106 CAR T cells/kg) groups was 54.5% and 71.4%, respectively. In the CR group, 15 (93.7%) patients achieved minimal residual disease (MRD) negativity (test sensitivity >1/10−5). All seven patients with double-hit or triple-hit multiple myeloma achieved MRD-negative CR.

Conclusions The present study demonstrated that C-CAR088 had a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM.

Trial registration number NCT03815383, NCT03751293, NCT04295018, and NCT04322292.

  • Antibodies, Neoplasm
  • Costimulatory and Inhibitory T-Cell Receptors
  • Hematologic Neoplasms

Data availability statement

Data are available upon reasonable request. Data are available upon reasonable request. Following publication de-identified individual patient data may be shared with qualifying researchers by request with a research proposal. Requests should be directed to the corresponding author. The corresponding author had full access to all data and had final responsibility for the decision to submit the results for publication.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2022-005145

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CAR T)-cell therapy has excellent results in clinical trials. Nevertheless, the overall response rate (range, 73.0–100%), complete response rate (range, 33.0–76.5%), and treatment-associated complications vary widely across trials, and a subset of patients experience relapse a short time after treatment, which may be due to clonal evolution, loss of subclones, immunosuppression in the tumor microenvironment, and CAR T-cell exhaustion. C-CAR088 cells are genetically-modified anti-BCMA autologous CAR T cells. This study assessed the safety and efficacy of C-CAR088 T cell therapy in patients with relapsed or refractory multiple myeloma (RRMM).

    WHAT THIS STUDY ADDS

    • This study provided evidence for the safety profile and high antitumor activity of C-CAR088 in patients with RRMM. No dose-limiting toxicities were observed in patients treated with different doses of C-CAR088, and this novel therapy had a manageable safety profile. The overall response rate in RRMM was 96.4%. Deep and durable responses were observed in the medium-dose and high-dose groups, and progression-free survival at 12 months in these two groups was 69.5% (95% CI: 51.6% to 93.6%).

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY

    • The present study demonstrated that C-CAR088 had a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM.

    Background

    Multiple myeloma (MM) is a common hematologic malignancy characterized by the clonal proliferation of abnormal plasma cells in the bone marrow (BM).1 MM accounts for approximately 15% of hematopoietic neoplasms, and its aberrantly expanded immunoglobulins can damage relevant tissues and organs as a result of hypercalcemia, renal failure, anemia, or lytic bone lesions.2 3 With the recent development of therapeutic agents, including proteasome inhibitors, immunomodulators, monoclonal antibodies, and epigenetic drugs, the survival of patients with MM has improved significantly. However, MM remains incurable because most patients ultimately relapse or become refractory to treatment; thus, treatment focuses on controlling disease progression, improving quality of life, and prolonging survival.4–6 Chimeric antigen receptor-modified T (CAR T) cell immunotherapy acts through mechanisms distinct from those of MM therapies because of its ability to target specific cell-surface antigens by modifying patient or donor T cells. B-cell maturation antigen (BCMA), a transmembrane glycoprotein from the tumor necrosis factor (TNF) receptor superfamily, is preferentially expressed in plasmacytes, and its overexpression and activation in malignant plasma cells make it a potential therapeutic target.7 8 Anti-BCMA CAR T-cell therapy has shown excellent results in clinical trials.9–14 A meta-analysis showed that the overall response rate (ORR) of this therapy in patients with relapsed or refractory MM (RRMM) was 85.2% (95% CI: 0.797 to 0.910), and the complete response (CR) rate was 47.0% (95% CI: 0.378 to 0.583).15

    C-CAR088 cells were genetically-modified anti-BCMA autologous CAR T cells. This study assessed the safety and efficacy of C-CAR088 T-cell therapy in patients with RRMM following lymphodepletion with fludarabine and cyclophosphamide.

    Methods

    C-CAR088

    The structure of the second-generation CAR targeting the BCMA was shown in figure 1A. The single-chain variable fragment (scFv) of C-CAR088 was derived from a human IgG1 antibody and had a high binding affinity (KD=0.08 nM) for epitome cluster E3 in the BCMA extracellular domain using a surface plasmon resonance sensor (online supplemental table 1 and figure 1; Biacore, Uppsala, Sweden). The specificity of scFv to human BCMA was validated by protein microarrays and tissue cross-reactivity assays under good laboratory practice conditions (online supplemental table 2, figures 2 and 3) and was further confirmed by C-CAR088 preclinical study (online supplemental figures 4–6). In a preclinical study, human T cells transduced with the lentiviral vector encoding C-CAR088 exhibited unique functions in vitro, including CAR T-cell proliferation, cytokine production, and toxicity to BCMA-positive tumor cells (online supplemental figures 7–9). C-CAR088 cells were not activated by soluble BCMA (online supplemental figure 10) and patient with MM’s sera. In addition, C-CAR088 showed a strong dose-dependent tumor inhibition effect and survival benefit in animal studies (online supplemental figures 11–13).

    Figure 1
    Figure 1

    Trial contents and curative effect. (A) Schematic diagram of C-CAR088 CAR, a second-generation anti-BCMA CAR. The scFv of C-CAR088 is derived from a human IgG1 antibody targeting the BCMA extracellular domain. (B) Flowchart of this trial. *Died of progressive disease before C-CAR088. #Died of septic shock on day 3 after C-CAR088. (C) Best overall response at each dose level. BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; CR, complete response; ORR, overall response rate; PD, disease progression; PR, partial response; scFv, single-chain variable fragment; SD, stable disease; VGPR, very good partial response.

    C-CAR088 design

    C-CAR088 was designed by Shanghai Cellular Biomedical Group using autologous CAR T cells in a serum-free, automated, and closed system according to good manufacturing practices.

    Ethics approval

    The study protocols conformed to the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice (ICH E6).

    Study design

    This first-in-human, single-arm, open-label, phase 1, dose-escalation and expansion study evaluated the safety and efficacy of C-CAR088 in patients with RRMM admitted to four clinical centers in China. Eligible patients were aged 18–75 years and were diagnosed with MM according to International Myeloma Working Group (IMWG) diagnostic criteria for MM and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. The positivity of BM malignant plasma cells to BCMA was confirmed by flow cytometry (FC) or immunohistochemistry. Patients received at least two lines of treatment for MM, including immunomodulatory agents and proteasome inhibitors, and disease progression during or after the last treatment cycle was assessed according to IMWG criteria. Patients with one or more measurable MM lesions and one of the following conditions were included in the study: (1) serum M-protein ≥1 g/dL (10 g/L), (2) urine M-protein ≥200 mg/24 hours, (3) serum-free light chain (sFLC) ≥10 mg/dL, and abnormal κ/λ ratio. Patients received lymphodepletion with three doses of cyclophosphamide (300 mg/m2) and three doses of fludarabine (30 mg/m2) on days –5,–4, and –3, followed by an infusion of C-CAR088 on day 0. Doses of 1.0×106, 3.0×106, and 6.0×106 CAR T cells/kg (±20%) were tested in the dose-escalation cohorts and expansion cohorts.

    Treatment safety

    The primary endpoint was treatment safety, including the rate of treatment-emergent adverse events (TEAEs) after cell infusion. The rate of TEAEs was assessed using the National Cancer Institute’s Common Terminology Criteria for Adverse Events V.5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy consensus grading system. Dose-limiting toxicities (DLTs) were defined according to pre-established criteria.16

    Clinical response

    Secondary endpoints were the ORR and progression-free survival (PFS). Clinical response and disease progression were assessed according to IMWG Uniform Response Criteria for MM. The ORR was defined as the percentage of patients who achieved partial response (PR) or better. PFS was defined as the time from C-CAR088 infusion to first disease progression or death from any cause. Patients were closely followed by serum and urine protein electrophoresis, serum and urine immunofixation electrophoresis, sFLC assay, bone radiography, MRI, or positron emission tomography/CT. Minimal residual disease (MRD) in BM followed EuroFlow Consortium criteria using two eight-color FC panels. The first panel included antibodies against CD81, CD27, CD138, CD56, CD19, CD20, CD38, and CD45, and the second panel included antibodies against CD138, CD56, CD19, CD20, CD38, and CD45. B-cell clonality was assessed by the FC analysis of cytoplasmic kappa and lambda antibodies. Samples were analyzed on a Canto II flow cytometer (Becton Dickinson). The sensitivity of MRD assessment was up to 1×10−5. Plasma cell myeloma BCMA expression was assessed by FC as described previously.17 All antibodies were recommended by EuroFlow.

    The explore study

    The endpoints were the quantification of C-CAR088 CAR T cells, selection of cytokines and chemokines in blood, and measurement of tumor BCMA expression. The expansion and persistence of C-CAR088 were monitored in peripheral blood at baseline and follow-up. C-CAR088 transgene copies were measured by quantitative PCR. The area under the receiver operating characteristic curve (AUC0-28 days) was calculated using non-compartmental analysis.18 Maximum transgene level (Cmax), time to reach Cmax (Tmax), and time of last measurable transgene level (Tlast) were also measured.

    Cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, TNF-α, and interferon (IFN)-γ were monitored in peripheral blood at baseline and follow-up (within 28 days after C-CAR088 infusion) by FC using a BD Cytometric Bead Array kit.

    Statistical analysis

    Continuous variables were expressed as means and SD or medians with minimum and maximum. Categorical variables were expressed as numbers and percentages, and 95% CIs were calculated using the Clopper-Pearson exact method. Duration of response (DOR), overall survival (OS), PFS, and associated 95% CIs were estimated using the Kaplan-Meier method. Censoring of data for PFS and DOR was based on Food and Drug Administration (FDA) rules. DOR was defined as the time from the first evaluation of stringent CR (sCR), CR, very good partial response (VGPR), or PR to the first evaluation of relapse or death from any cause.

    Results

    Efficacy of C-CAR088 in vitro and in vivo

    Human T cells transduced with the lentiviral vector encoding C-CAR088 exhibited unique functions in vitro, including 4-1BB expression, cytokine production, and toxicity to BCMA-positive tumor cells (online supplemental figures 7–9). C-CAR088 cells were not activated by soluble BCMA (online supplemental figure 10) and patients with MM’s sera. However, these cells killed BCMA-positive tumor cells in vivo, including RPMI-8226 MM cells. In addition, C-CAR088 showed a high dose-dependent tumor inhibition effect and survival benefit in animal studies (online supplemental figures 11–13).

    Patient enrollment and disease characteristics

    Between January 11, 2019, and July 2, 2021, 34 subjects were enrolled, and 33 underwent apheresis. One patient withdrew from the study because of fast disease progression, and one patient died of MM before lymphodepletion. Thirty-one patients were treated with C-CAR088 (figure 1B). Baseline patient and disease characteristics are shown in table 1.

    View this table:
    Table 1

    Baseline patient characteristics

    The median age of the cohort was 61 (range, 45–74) years. Seventeen (54.8%) patients were men, and 14 (45.2%) were women. Nineteen (61.3%) and 12 (38.7%) patients had ECOG-PS score of 0 and 1, respectively. Four (12.9%), 21 (67.7%), and 5 (16.2%) patients were classified as revised International Staging System stages I, II, and III, respectively. The most common types of MM were IgG (15, 48.4%), light chain (9, 29.0%), IgA (5, 16.1%), IgD (1, 3.2%), and non-secretory (1, 3.2%). Three (9%) patients had extramedullary disease, and 15 (48.4%) had double-hit or triple-hit MM, defined by the presence of two or three high-risk genetic abnormalities, including t(4;14), t(14;16), t(14;20), del(17p), and p53 mutation or 1q gain.

    The median number of prior lines of therapy was four (range, 2–13). All 31 (100%) patients were previously treated with immunomodulatory agents and protease inhibitors, 7 (22.6%) had undergone autologous stem cell transplantation (ASCT), and 7 (22.6%) had received anti-CD38 monoclonal antibodies (mAbs). Seven patients received bridge therapy before C-CAR088 infusion. BM aspirates were analyzed in 30 (96.8%) patients at baseline. Aspiration failed (dry tap) in one case. Twenty-eight patients had abnormal plasma cells in the BM at baseline, and one patient had extramedullary disease. The median proportion of BCMA-positive abnormal plasma cells was 49.12% (range, 0.44–99.13%). The median BCMA density in BCMA-positive malignant plasma cells in the BM was 836 (range, 61–8003) molecules/cell.

    Treatment safety

    As of July 2, 2021, 31 patients were treated with C-CAR088. The median follow-up was 9.4 (range, 1.9–24.2) months. No DLT was observed. Common adverse events (rate ≥20%) are shown in online supplemental table 3, and common grade 3 or higher adverse events are shown in table 2.

    View this table:
    Table 2

    Common grade 3 or higher adverse events (≥20%)

    The most common event was hematologic toxicity, including neutropenia (100% of cases), leukopenia (100%), thrombocytopenia (90.3%), and anemia (83.9%). These toxic effects of lymphodepleting chemotherapy were expected. The common grade ≥3 events were mostly hematologic toxicity. Sixteen (51.6%) patients had prolonged cytopenia, defined as grade ≥3 neutropenia or thrombocytopenia within 28 days after C-CAR088 therapy. CRS occurred in 29 (93.5%) patients with a median time to onset of 6 days (range, 1–11) and a median duration of 5 days (range, 2–14). Most cases of CRS (26/31, 83.9%) were grade 1 or 2, three cases (9.7%) were grade 3, and no cases were grade 4. The most frequent (≥20%) symptoms of CRS were fever (29/29, 100%), hypoxemia (8/29, 27.6%), increased D-dimer (7/29, 24.1%), tachycardia (7/29, 24.1%), hypotension (6/29, 20.7%), and increased transaminase (6/29, 20.7%). One patient in the high-dose group had grade 1 ICANS for 24 hours on day 8 of treatment and recovered after treatment with glucocorticoids. Three (9.7%) patients used tocilizumab alone, and six (19.4%) patients used tocilizumab and corticosteroids. Twenty-one patients (67.7%) had infections after infusion. Safety data are shown in table 3.

    View this table:
    Table 3

    Adverse events of special interest after C-CAR088 T cell infusion (N=31)

    Clinical efficacy

    Response to treatment was assessed on day 28 with ≥1 month of follow-up. One patient discontinued treatment on week 2, one patient died of septic shock caused by Vibrio cholerae infection on day 3 after C-CAR088 infusion, and one patient was not evaluable. Among 28 evaluable patients, the ORR was 96.4% (13 sCR, 3 CR, 9 VGPR). The CR rate increased to 71.4% as the dose increased (figure 1C, table 4). In the low-dose group, the best response in three (100%) patients was VGPR. The rate of CR/sCR in the medium-dose group (N=11) and high-dose group (N=14) was 54.5% and 71.4%, respectively, and the ORR in these groups was 100% and 92.9%, respectively. The median time to CR was 2.0 (0.5–9.5) months. In the intent-to-treat population (n=31), the ORR was 87.1% (13 sCR, 3 CR, 9 VGPR) (table 5).

    View this table:
    Table 4

    Response to C-CAR088 T cell therapy in response-evaluable population

    View this table:
    Table 5

    Response to C-CAR088 T cell therapy in ITT population

    Among 15 evaluable patients with at least two high-risk genetic abnormalities, the ORR was 93.3% (sCR, CR, and VGPR of 33.3%, 13.3%, and 46.7%, respectively). Of these, 13 patients received a medium-dose or a high dose, and the ORR was 92.3% (sCR, CR, and VGPR of 38.5%, 15.4%, and 38.5%, respectively). The two patients with triple-hit MM achieved CR.

    Seven (22.6%) patients from dose 3.0–6.0×106/kg cohort received anti-CD38 mAb prior to C-CAR088 therapy, all of them were responsive to C-CAR088, and four (57.1%) achieved sCR. PFS (HR: 1.39 (0.26, 7.38), p=0.7) and DOR (HR: 1.56 (0.28, 8.67), p=0.6) did not have significant differences between patients with or without prior anti-CD38 mAb treatment in these dose cohorts. Only one death was reported as of the cut-off date so it did not have enough data points to run the Cox proportional hazards regression model for OS. However, the trends of the curve in all three graphs indicated that C-CAR088 demonstrated similar efficacy in both patient groups (online supplemental figure 14).

    In cohorts receiving a medium or a high dose, the median follow-up was 9.5 months (range, 1.9–24.2). In these groups, PFS and OS at 12 months was 69.5% (95% CI: 51.6% to 93.6%) and 94.4% (95% CI: 84.4% to 100%), respectively, and the median PFS, OS, and DOR were not reached (figure 2A–C).

    Figure 2
    Figure 2

    Evaluation index. (A) Progression-free survival in the treatment groups. (B) Overall survival in the medium-dose and high-dose groups. (C) Duration of response in the medium-dose and high-dose groups. (D) Effect of baseline characteristics on CR and sCR to C-CAR088 T-cell therapy. BM, bone marrow; BCMA, B-cell maturation antigen; CR, complete response; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; MM, multiple myeloma; R-ISS, Revised International Staging System; sCR, stringent CR; UK, unknown.

    Subgroup analysis was performed to assess the effect of several factors, including baseline clinical and therapeutic characteristics, on CR and sCR (figure 2D). Patients in the medium-dose and high-dose groups were more likely to achieve CR/sCR.

    MRD

    MRD was determined in CR patients. None of the patients in the low-dose group achieved CR or better. In the medium-dose and high-dose groups, 15 (93.7%) patients achieved MRD negativity among 13 patients with sCR and 3 patients with CR. The seven patients with at least two high-risk genetic abnormalities achieved MRD-negative CR. Nonetheless, after a median follow-up of 9.4 months, two patients relapsed at 200 and 255 days after CR, respectively.

    Pharmacokinetic and pharmacodynamic profile of C-CAR088

    The pharmacokinetic profile of C-CAR088 was assessed by measuring the number of C-CAR088 transgene copies in the peripheral blood. Thirty patients had evaluable data. C-CAR088 pharmacokinetic parameters, including Cmax, Tmax, AUC0 -28 days, and Tlast, were shown in figure 3A.

    Figure 3
    Figure 3

    Pharmacokinetics of CAR T cells and changes after C-CAR088 infusion. (A) Number of CAR copies at serial time points up to the most recent visit at the cut-off date; (B) Cmax of CAR T-cell levels; (C) Area under the curve of CAR T-cell levels; (D) Tlast of CAR T-cell levels; (E) Tmax of CAR T-cell levels. (F) Changes in the levels of M-protein or serum-free light chain in the blood/urine of patients; (G) Changes in the serum levels of IL-6 and IFN-γ in the first month after C-CAR088 CAR T-cell infusion. The horizontal line within each box is the median. The lower and upper limits of each box represent the 25th and the 75th percentiles, respectively, and the error bars are 95% CIs. AUC0-28 days, area under the receiver operating characteristic curve; CAR, chimeric antigen receptor; Cmax, maximum transgene level; CRS, cytokine release syndrome; gDNA, genomic DNA; IFN, interferon; IL, interleukin; Tlast, time of last measurable transgene level; Tmax, time to reach Cmax.

    The median Tmax was 14 (range: 9–23) days. The median Cmax was 750,061 (range: 21,860–1,772,476) copies/µg genomic DNA (gDNA). The median AUC0-28days was 7,558,634 (range: 286,934–21,326,789) copies/µg gDNA/day. Tlast varied from 14+ to 566+ days. There were significant differences in these parameters between the groups. The pharmacokinetics of C-CAR088 between the groups was analyzed using Tukey’s honestly significant difference test. Tmax was significantly shorter in the medium-dose and high-dose groups (p<0.05). There were no significant intergroup differences in the other kinetic parameters (figure 3B–E).

    Changes in blood/urine M-protein and sFLC levels were used as a pharmacodynamic biomarker of CAR088. Blood/urine M-protein and sFLC levels after C-CAR088 infusion were compared with baseline. In the low-dose group, the average blood/urine M-protein or sFLC levels decreased to 68±39%, 41±44%, 30±54%, 13±15%, and 5±7% of baseline at 2, 4, 8, 12, and 16 weeks after infusion, respectively. Blood/urine M-protein or sFLC levels were 12±16% and 55±12% of baseline at 20 weeks and 6 months after infusion. These results suggested that the lowest dose did not completely inhibit tumor cells.

    In 12 patients from the medium-dose group, the average blood/urine M-protein or sFLC level decreased to 43±35%, 18±17%, 3±7%, 7±12%, 7±14%, 9±20%, 6±16%, and 3±8% of baseline at 2, 4, 8, 12, 16, and 20 weeks, 6 months, and 9 months, respectively. At 12 and 18 months, blood/urine M-protein or sFLC levels were undetectable.

    In 14 patients from the high-dose group, the average blood/urine M-protein or sFLC levels decreased to 27%±29%, 19%±33%, 16%±43%, 4%±5%, 3%±4%, 2%±3%, 0%±0%, 1%±3% at 2, 4, 8, 12, 16, 20 weeks, 6 months and 9 months, respectively. At 12 months after infusion, blood/urine M-protein or sFLC levels were undetectable. The decrease in M-protein or sFLC levels in blood/urine was inversely correlated with C-CAR088 expansion (figure 3F).

    The serum levels of IL-6 and IFN-γ increased transiently within 30 days after infusion. The peak levels of IL-6 and IFN-γ tended to correlate with CRS severity (figure 3G).

    Discussion

    Anti-BCMA CAR T-cell therapy is considered one of the most promising therapeutic strategies for RRMM. In the past 5 years, many clinical trials of anti-BCMA CAR T cells have been registered at https://clinicaltrials.gov. Nevertheless, the ORR (range, 73.0–100%), CR rate (range, 33.0–76.5%), and treatment-associated complications vary widely across trials, and a subset of patients experience relapse a short time after treatment,12 19–23 which may be due to clonal evolution, loss of subclones, immunosuppression in the tumor microenvironment, and CAR T-cell exhaustion.24 25 Increasing the efficacy of anti-BCMA CAR T-cell therapy depends largely on improving the structure and function of these cells.26 In this study, we used an scFv from a humanized BCMA antibody, maintaining the high affinity of the antibody and potentially reducing immunogenicity. This scFv also recognized macaque and mouse BCMA, suggesting that C-CAR088 might be effective to patients with RRMM with mutations in the BCMA gene. In this respect, one patient with MM treated with anti-BCMA CAR T cells developed biallelic loss of the BCMA gene due to the deletion of one allele and a point mutation that created an early stop codon on the other allele, resulting in relapse.27 In addition, C-CAR088 showed no cross-reactivity to other tissue parenchymal cells, despite its degeneracy for the BCMA epitope. It has been reported that most of the amino acid residues in the extracellular domain involved in ligand binding are located in the E2 domain of BCMA.28 The E2 domain could be blocked by natural ligands of BCMA. The epitope of scFv of C-CAR088 is located in the E3 domain, which is different from the E2 domain, increasing the binding affinity of C-CAR088 to BCMA, providing clinical benefit to patients.

    In the present trial, the overall median manufacturing time of C-CAR088 was 7 days (range, 5–11 days), with a median time of 7, 6, and 7.5 days in the low-dose, medium-dose, and high-dose groups, respectively. The median vein-to-vein time was 18 days (range, 14–84 days), obviating the need for bridging therapy for some of our patients. The median turnaround time (time from receipt to release of product) for ciltacabtagene autoleucel (Cilta-cel) was 29 days,23 and the median time from leukapheresis to Abecma availability was 33 days (range: 26–49 days).29 This characteristic of our product partially contributes to its uniqueness and superiority over other BCMA-directed CAR T products in the market or under investigation.

    In this phase 1 study, C-CAR088 was infused as a single dose of 1.0–6.0×106 cells/kg. Among 28 evaluable patients, the ORR was 96.4% (sCR, 46.4% and CR, 10.7%). Of these, three patients belonged to the low-dose group. The lower dose was ineffective given the lack of CR, inevitable disease progression (3/3), and significant prolongation of time when the number of C-CAR088 transgene copies peaked. In patients treated with 3.0–6.0×106 cells/kg, the ORR was 96.0% (sCR, 52.0% and VGPR, 12.0%) and 1-year PFS was 69.5%. sCR was 71.4% using ≥4.5×106 cells/kg. There was no clinical evidence of DLT; thus, the maximum tolerated dose has not been determined.

    Idecabtagene vicleucel (Idel-cel; bb2121) has recently received FDA approval for RRMM based on a phase 2 study involving 128 patients with RRMM; of these, 73% responded to therapy, and 33% had CR or better.12 Nonetheless, a phase 1 trial showed that 6 of 15 patients treated with Idel-cel who achieved CR experienced a relapse at 6 months of follow-up.30 Cilta-cel has FDA approval, with an ORR of 94.8%, sCR of 55.7%, VGPR of 32.0%, 1-year PFS of 77%, and 1-year OS of 89%.23 LCAR-B38M, a non-humanized CAR T-cell therapy targeting two BCMA epitopes, had an ORR of 88.2% (sCR, 76.5% and VGPR, 11.8%) in 17 patients with RRMM, and 1-year PFS and OS were 52.9% and 82.3%, respectively.31 The humanized anti-BCMA CT103A achieved an ORR of 100% and a CR rate of 72% in a phase 1 trial involving 18 patients with RRMM, and PFS and OS at 12 months were 58.3% and 75%, respectively.22 However, the utility of CT103A in patients with genetic mutations was not assessed. Several clinical trials on anti-BCMA CAR T-cell therapy for RRMM are underway; however, patient populations cannot be compared across studies. Our results showed that the short-term and long-term efficacy of C-CAR088 for patients with RRMM was similar to that of other anti-BCMA CAR T-cell therapies.

    The rate of CR was high in our cohort. In addition, MRD negativity increased to 60% (15/25) as the C-CAR088 dosage increased. Although MRD negativity did not translate into continuous remission for all patients, and two patients relapsed at 6–8 months after treatment, the rate of MRD-negative CR was lower than that of bb2121 (13.3% vs 37.5%),12 which might be attributed to the refractory nature of this patient population.

    Disease burden was high in our cohort. Based on the Mayo Stratification of Myeloma and Risk-Adapted Therapy (www.msmart.org), 25 (89.3%) patients presented at least one high-risk genetic abnormality, of which 13 and 2 patients were classified into the double-hit and triple-hit group, respectively. Nonetheless, response rates were high (ORR, 93.3% and sCR/CR rate, 46.7%) in this high-risk cohort, suggesting the wide applicability of C-CAR088 in patients with RRMM.

    In addition to high-risk cytogenetics, prior treatment with more than three therapeutic lines, extramedullary disease, and light-chain MM are associated with poor PFS.32 33 The median number of prior lines of therapy in our cohort was 4 (range, 2–13), consistent with previous trials.22 31 Given the limited supply of some pharmaceutical drugs in China, the median number of previous antimyeloma regimens was less than that in the Idel-cel trial (median, 6; range, 3–16).12 Moreover, patients with less than four therapeutic lines were more likely to achieve sCR or CR than those receiving four or more lines (81.8% vs 41.2%, p=0.054). Thus, a more frontline C-CAR088 should be used in patients with RRMM. The three (9.7%) patients with extramedullary lesions achieved CR, PR, or PD (one patient each); median PFS was 4.8 months, and 1-year PFS was 50.0%, similar to previous studies. The proportion of patients with light-chain MM (n=9, 29.0%) was slightly higher than that reported in a previous study (15–20%). The group with light-chain MM achieved sCR (four patients), PR (one patient), or PD (one patient). There were no significant differences in treatment efficacy between patients with extramedullary disease and patients with light-chain MM; however, these results should be interpreted with caution because of the small sample size.

    The proportion of patients treated with anti-CD38 mAb and ASCT was relatively low in our cohort, which could be explained by treatment landscape differences between China and western countries. Daratumumab was first approved in China in July 2019 for RRMM monotherapy, followed by the combination with lenalidomide and dexamethasone (Rd) / bortezomib and dexamethasone (Vd) for RRMM (≥1 lines of therapies), the combination with Rd or bortezomib, melphalan and predisone (VMP) for transplant-ineligible newly diagnosed MM, which were approved in 2021. The availability and higher cost of daratumumab relative to other classic antimyeloma drugs might explain the limited data on treatment with this drug. Other anti-CD38 antibodies have not been approved in China to date. In addition, the overall ASCT rate in Chinese patients with MM is much lower than in the USA and Europe. The limited access to melphalan (withdrawal from China in 2012 and re-launch in 2018), physicians’ concerns about patients’ age (usually restricted to patients younger than 65 years), and patients’ low willingness for transplantation contributes to the situation. The transplantation rate in China is increasing with the development of therapeutic drugs but is lower than that in other countries. The percentage of patients treated with daratumumab and ASCT in our cohort is similar to that of other CAR-T trials in China.22 34 35

    The expansion and persistence of C-CAR088 were notable. Expansion peaked within 9 days at doses of at least 3.0×106 cells/kg, which was earlier than that in previous trials, indicating that the onset of action of C-CAR088 might be faster.12 22 As of July 2021, CAR T cells persisted for more than 566 days. Durability will be assessed at follow-up.

    Whether there is a threshold or a range of BCMA expression on MM cells for optimal recognition and killing is unknown.9 36 Patients with any level of BCMA expression at baseline were enrolled. In line with a previous study, there was no significant association between baseline BCMA density on tumor plasma cells and response to C-CAR088 therapy.36

    CRS is one of the most common TEAEs, with a reported incidence of 76–100% (grade 3–4 AEs, 5–41%).12 19 20 30 31 36 Most CRS cases in our trial were mild (grade 1 or 2, 83.9%; grade 3, 9.7%) and easily managed or reversible. The rate of use of tocilizumab+corticosteroids in our cohort was 29%, slightly higher than that reported in a trial with Idel-cel (21%) but much lower than that of other treatments (LCAR-B38M, 52.9%; CT103A, 61.1%; Cilta-cel, 69%).12 22 23 31 CRS occurred at a median of 6 days post-infusion, which was later than that for Idel-cel (median, 1 day), CART-BCMA (median, 4 days), and CT103A (median, 2 days).12 22 36 The median duration of CRS was 5 days, slightly longer than that for Cilta-cel (4 days).23 Neurotoxicity (n=1, grade 1) and ICANS (n=1, grade 1) were mild. High-grade hematologic toxicity was notable and somewhat persistent, which might be due to lymphodepleting chemotherapy and the potential effect of C-CAR088 on hematopoietic progenitor cells. In addition, the need for lymphodepletion remains controversial.36

    The incidence of infectious events was consistent with that in an Idel-cel trial (67.7% vs 69%).12 The rate of grade ≥3 infections was lower than that of CT103A (38.7% vs 44.4%).22 One patient died of V. cholerae infection on day 3 after infusion. Deaths due to infection are common in patients undergoing anti-BCMA CAR T-cell therapy.12 20 22 23 31 36 BCMA is essential for maintaining humoral immunity.37 The ‘on-target, off-tumor’ activity of anti-BCMA CAR T-cell therapy eliminates normal plasma cells and causes immunosuppression, increasing the risk of infection.38 Additionally, CAR T-cell toxicity may be due to tumor-induced immune dysfunction, the effects of previous therapies, lymphodepletion, use of corticosteroids and tocilizumab for treating CRS, and prolonged cytopenia and hypogammaglobulinemia.39–41 One study showed that anti-BCMA CAR T cells caused a 7-month aplasia of normal BM plasma cells and a longer period of hypogammaglobulinemia.42 Thus, protecting this patient population from infections is essential.

    Conclusions

    The present study demonstrates that C-CAR088 has a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM. Nonetheless, large multicenter clinical trials are necessary to confirm our results.

    Data availability statement

    Data are available upon reasonable request. Data are available upon reasonable request. Following publication de-identified individual patient data may be shared with qualifying researchers by request with a research proposal. Requests should be directed to the corresponding author. The corresponding author had full access to all data and had final responsibility for the decision to submit the results for publication.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study has been approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (approval number: 2018-SR-322), Hebei Yanda Ludaopei Hospital (approval number: Daopei EC approval (2018) No.13), Peking Union Medical College Hospital (HS-1943) and Institute of Hematology & Blood Diseases Hospital (QT2019007-EC-2). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    The authors thank the patients who volunteered to participate in the study, and their families; physicians and nurses who cared for patients and supported this clinical trial; and all staff members at the study sites and staff members involved in data collection and analysis.

    References

    1. ↵
      1. Palumbo A,
      2. Anderson K
      . Multiple myeloma. N Engl J Med 2011;364:1046–60.doi:10.1056/NEJMra1011442pmid:http://www.ncbi.nlm.nih.gov/pubmed/21410373
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Liu J,
      2. Liu W,
      3. Mi L, et al
      . Incidence and mortality of multiple myeloma in China, 2006-2016: an analysis of the global burden of disease study 2016. J Hematol Oncol 2019;12:136.doi:10.1186/s13045-019-0807-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/31823802
      OpenUrlPubMed
    3. ↵
      1. Rajkumar SV
      . Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol 2020;95:548–67.doi:10.1002/ajh.25791pmid:http://www.ncbi.nlm.nih.gov/pubmed/32212178
      OpenUrlCrossRefPubMed
    4. ↵
      1. Abramson H
      . Monoclonal antibodies for the treatment of multiple myeloma: an update. Int J Mol Sci 2018;19:3924.doi:10.3390/ijms19123924
    5. ↵
      1. Jelinek T,
      2. Paiva B,
      3. Hajek R
      . Update on PD-1/PD-L1 inhibitors in multiple myeloma. Front Immunol 2018;9:2431.doi:10.3389/fimmu.2018.02431pmid:http://www.ncbi.nlm.nih.gov/pubmed/30505301
      OpenUrlPubMed
    6. ↵
      1. Lee JH,
      2. Kim S-H
      . Treatment of relapsed and refractory multiple myeloma. Blood Res 2020;55:S43–53.doi:10.5045/br.2020.S008pmid:http://www.ncbi.nlm.nih.gov/pubmed/32719176
      OpenUrlPubMed
    7. ↵
      1. Rickert RC,
      2. Jellusova J,
      3. Miletic AV
      . Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011;244:115–33.doi:10.1111/j.1600-065X.2011.01067.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/22017435
      OpenUrlCrossRefPubMed
    8. ↵
      1. Cho S-F,
      2. Anderson KC,
      3. Tai Y-T
      . Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-Based immunotherapy. Front Immunol 2018;9:9.doi:10.3389/fimmu.2018.01821pmid:http://www.ncbi.nlm.nih.gov/pubmed/30147690
      OpenUrlCrossRefPubMed
    9. ↵
      1. Ali SA,
      2. Shi V,
      3. Maric I, et al
      . T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016;128:1688–700.doi:10.1182/blood-2016-04-711903pmid:http://www.ncbi.nlm.nih.gov/pubmed/27412889
      OpenUrlAbstract/FREE Full Text
    10. ↵
      1. Brudno JN,
      2. Kochenderfer JN
      . Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 2016;127:3321–30.doi:10.1182/blood-2016-04-703751pmid:http://www.ncbi.nlm.nih.gov/pubmed/27207799
      OpenUrlAbstract/FREE Full Text
    11. ↵
      1. Gagelmann N,
      2. Riecken K,
      3. Wolschke C, et al
      . Development of CAR-T cell therapies for multiple myeloma. Leukemia 2020;34:2317–32.doi:10.1038/s41375-020-0930-xpmid:http://www.ncbi.nlm.nih.gov/pubmed/32572190
      OpenUrlPubMed
    12. ↵
      1. Munshi NC,
      2. Anderson LD,
      3. Shah N, et al
      . Idecabtagene Vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021;384:705–16.doi:10.1056/NEJMoa2024850pmid:http://www.ncbi.nlm.nih.gov/pubmed/33626253
      OpenUrlCrossRefPubMed
    13. ↵
      1. Neelapu SS,
      2. Tummala S,
      3. Kebriaei P, et al
      . Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol 2018;15:47–62.doi:10.1038/nrclinonc.2017.148pmid:http://www.ncbi.nlm.nih.gov/pubmed/28925994
      OpenUrlCrossRefPubMed
    14. ↵
      1. Rodríguez-Lobato LG,
      2. Ganzetti M,
      3. Fernández de Larrea C, et al
      . Car T-cells in multiple myeloma: state of the art and future directions. Front Oncol 2020;10:1243.doi:10.3389/fonc.2020.01243pmid:http://www.ncbi.nlm.nih.gov/pubmed/32850376
      OpenUrlPubMed
    15. ↵
      1. Gagelmann N,
      2. Ayuk F,
      3. Atanackovic D, et al
      . B cell maturation antigen-specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: a meta-analysis. Eur J Haematol 2020;104:318–27.doi:10.1111/ejh.13380pmid:http://www.ncbi.nlm.nih.gov/pubmed/31883150
      OpenUrlPubMed
    16. ↵
      1. Lee DW,
      2. Gardner R,
      3. Porter DL, et al
      . Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188–95.doi:10.1182/blood-2014-05-552729pmid:http://www.ncbi.nlm.nih.gov/pubmed/24876563
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Salem DA,
      2. Maric I,
      3. Yuan CM, et al
      . Quantification of B-cell maturation antigen, a target for novel chimeric antigen receptor T-cell therapy in myeloma. Leuk Res 2018;71:106–11.doi:10.1016/j.leukres.2018.07.015pmid:http://www.ncbi.nlm.nih.gov/pubmed/30053652
      OpenUrlPubMed
    18. ↵
      1. Denney WS,
      2. Duvvuri S,
      3. Buckeridge C
      . Abstracts accepted for American conference on Pharmacometrics 2015 (ACoP6). Journal of Pharmacokinetics and Pharmacodynamics 2015;42:11–107.
      OpenUrlCrossRef
    19. ↵
      1. Brudno JN,
      2. Maric I,
      3. Hartman SD, et al
      . T cells genetically modified to express an Anti-B-Cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol 2018;36:2267–80.doi:10.1200/JCO.2018.77.8084pmid:http://www.ncbi.nlm.nih.gov/pubmed/29812997
      OpenUrlCrossRefPubMed
    20. ↵
      1. Xu J,
      2. Chen L-J,
      3. Yang S-S, et al
      . Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci U S A 2019;116:9543–51.doi:10.1073/pnas.1819745116pmid:http://www.ncbi.nlm.nih.gov/pubmed/30988175
      OpenUrlAbstract/FREE Full Text
    21. ↵
      1. Li C,
      2. Cao W,
      3. Que Y, et al
      . A phase I study of anti-BCMA CAR T cell therapy in relapsed/refractory multiple myeloma and plasma cell leukemia. Clin Transl Med 2021;11:e346.doi:10.1002/ctm2.346pmid:http://www.ncbi.nlm.nih.gov/pubmed/33784005
      OpenUrlPubMed
    22. ↵
      1. Wang D,
      2. Wang J,
      3. Hu G, et al
      . A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Blood 2021;137:2890–901.doi:10.1182/blood.2020008936pmid:http://www.ncbi.nlm.nih.gov/pubmed/33512480
      OpenUrlPubMed
    23. ↵
      1. Berdeja JG,
      2. Madduri D,
      3. Usmani SZ, et al
      . Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 2021;398:314–24.doi:10.1016/S0140-6736(21)00933-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/34175021
      OpenUrlPubMed
    24. ↵
      1. Shah N,
      2. Chari A,
      3. Scott E, et al
      . B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia 2020;34:985–1005.doi:10.1038/s41375-020-0734-zpmid:http://www.ncbi.nlm.nih.gov/pubmed/32055000
      OpenUrlCrossRefPubMed
    25. ↵
      1. Wang J,
      2. Hu Y,
      3. Huang H
      . Acute lymphoblastic leukemia relapse after CD19-targeted chimeric antigen receptor T cell therapy. J Leukoc Biol 2017;102:1347–56.doi:10.1189/jlb.5RU0817-315Rpmid:http://www.ncbi.nlm.nih.gov/pubmed/29018147
      OpenUrlCrossRefPubMed
    26. ↵
      1. Huang R,
      2. Li X,
      3. He Y, et al
      . Recent advances in CAR-T cell engineering. J Hematol Oncol 2020;13:86.doi:10.1186/s13045-020-00910-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/32616000
      OpenUrlCrossRefPubMed
    27. ↵
      1. Samur MK,
      2. Fulciniti M,
      3. Aktas Samur A, et al
      . Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun 2021;12:868.doi:10.1038/s41467-021-21177-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/33558511
      OpenUrlCrossRefPubMed
    28. ↵
      1. Liu Y,
      2. Hong X,
      3. Kappler J, et al
      . Ligand-receptor binding revealed by the TNF family member TALL-1. Nature 2003;423:49–56.doi:10.1038/nature01543pmid:http://www.ncbi.nlm.nih.gov/pubmed/12721620
      OpenUrlCrossRefPubMed
    29. ↵
      Abecama FDA package insert. Available: https://www.fda.gov/media/147055/download
    30. ↵
      1. Raje N,
      2. Berdeja J,
      3. Lin Y, et al
      . Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med 2019;380:1726–37.doi:10.1056/NEJMoa1817226pmid:http://www.ncbi.nlm.nih.gov/pubmed/31042825
      OpenUrlCrossRefPubMed
    31. ↵
      1. Zhao W-H,
      2. Liu J,
      3. Wang B-Y, et al
      . A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol 2018;11:141.doi:10.1186/s13045-018-0681-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/30572922
      OpenUrlCrossRefPubMed
    32. ↵
      1. Bhutani M,
      2. Foureau DM,
      3. Atrash S, et al
      . Extramedullary multiple myeloma. Leukemia 2020;34:1–20.doi:10.1038/s41375-019-0660-0pmid:http://www.ncbi.nlm.nih.gov/pubmed/31776467
      OpenUrlPubMed
    33. ↵
      1. Zhang M,
      2. Zhou L,
      3. Zhao H, et al
      . Risk factors associated with durable progression-free survival in patients with relapsed or refractory multiple myeloma treated with Anti-BCMA CAR T-cell therapy. Clin Cancer Res 2021;27:6384–92.doi:10.1158/1078-0432.CCR-21-2031pmid:http://www.ncbi.nlm.nih.gov/pubmed/34548316
      OpenUrlAbstract/FREE Full Text
    34. ↵
      1. Hao S,
      2. Jin J,
      3. Jiang S, et al
      . Two-Year follow-up of investigator-initiated phase 1 trials of the safety and efficacy of fully human Anti-Bcma CAR T cells (CT053) in relapsed/refractory multiple myeloma. Blood 2020;136:27–8.doi:10.1182/blood-2020-140156
      OpenUrl
    35. ↵
      1. Du J,
      2. Wei R,
      3. Jiang S, et al
      . Car-T cell therapy targeting B cell maturation antigen is effective for relapsed/refractory multiple myeloma, including cases with poor performance status. Am J Hematol 2022;97:933–41.doi:10.1002/ajh.26583pmid:http://www.ncbi.nlm.nih.gov/pubmed/35488407
      OpenUrlPubMed
    36. ↵
      1. Cohen AD,
      2. Garfall AL,
      3. Stadtmauer EA, et al
      . B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest 2019;129:2210–21.doi:10.1172/JCI126397pmid:http://www.ncbi.nlm.nih.gov/pubmed/30896447
      OpenUrlCrossRefPubMed
    37. ↵
      1. O'Connor BP,
      2. Raman VS,
      3. Erickson LD, et al
      . BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 2004;199:91–8.doi:10.1084/jem.20031330pmid:http://www.ncbi.nlm.nih.gov/pubmed/14707116
      OpenUrlAbstract/FREE Full Text
    38. ↵
      1. Sidana S,
      2. Shah N
      . Car T-cell therapy: is it prime time in myeloma? Blood Adv 2019;3:260–5.doi:10.1182/hematology.2019000370pmid:http://www.ncbi.nlm.nih.gov/pubmed/31714964
      OpenUrlPubMed
    39. ↵
      1. Park JH,
      2. Romero FA,
      3. Taur Y, et al
      . Cytokine release syndrome grade as a predictive marker for infections in patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with chimeric antigen receptor T cells. Clin Infect Dis 2018;67:533–40.doi:10.1093/cid/ciy152pmid:http://www.ncbi.nlm.nih.gov/pubmed/29481659
      OpenUrlCrossRefPubMed
    40. ↵
      1. Kochenderfer JN,
      2. Somerville RPT,
      3. Lu T, et al
      . Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy. Mol Ther 2017;25:2245–53.doi:10.1016/j.ymthe.2017.07.004pmid:http://www.ncbi.nlm.nih.gov/pubmed/28803861
      OpenUrlPubMed
    41. ↵
      1. Fried S,
      2. Avigdor A,
      3. Bielorai B, et al
      . Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant 2019;54:1643–50.doi:10.1038/s41409-019-0487-3pmid:http://www.ncbi.nlm.nih.gov/pubmed/30809033
      OpenUrlCrossRefPubMed
    42. ↵
      1. Wang Y,
      2. Li C,
      3. Xia J, et al
      . Humoral immune reconstitution after anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma. Blood Adv 2021;5:5290–9.doi:10.1182/bloodadvances.2021004603pmid:http://www.ncbi.nlm.nih.gov/pubmed/34587230
      OpenUrlPubMed

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • XQ and GA contributed equally.

    • Contributors XQ, GA, XZ, YZ, DZhu, DZhou, PL, LQ, and JL designed the study. WS, TW, JY, and LZ contributed to sample collection. JH, SZ, XY, JingL, CZ, KZ, YW, XL, LL, and YY contributed valuable ideas and input during the study. XQ, GA, and JL wrote the manuscript and all authors participated in editing the manuscript. XQ and GA contributed equally as first authors. JL is responsible for the overall content as the guarantor.

    • Funding This study was funded by Cellular Biomedicine Group Inc.

    • Competing interests XQ, GA, WS, TW, XZ, JY, YZ, LZ, DZhou, PL, LQ, JL and KZ declare that they have no competing interests. DZhu, JH, SZ, XY, JingL, CZ, YW, XL, LL and YY are employees of Cellular Biomedicine Group.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.