This is an open label, abbreviated (3+3) dose escalation study in subjects with RRMM, followed by an extension phase at the selected safe dose. The dose escalation stage will involve recruitment of 3 RRMM patients for 'low' dose (6 x 106 CAR-T cells/kg) CAR-T therapy. After 14 days of follow-up for each of the 3 subjects, the DSC will determine whether the next subject can be recruited.
After 14 days follow-up for the 3rd subject, DSC will review data for the 3rd subject and consider the data for the first 3 subjects. In the absence of dose limiting toxicities (DLTs), the DSC may recommend recruitment of 3 subjects to be treated with the 'high' dose (9x106 CAR-T cells/kg) CAR-T therapy, with similar staggering. In case of DLTs in one of the 3 low dose subjects, the DSC may recommend to recruit an additional 3 low dose subjects (6 in total). If there are no additional DLTs in these 3 patients the low dose may be recommended by the DSC for the extension stage. However, further DLTs may prompt the DSC to recommend to modify the protocol, or to stop the study. In case of DLTs in one of the first 3 high dose subjects, the DSC may recommend to recruit an additional 3 high dose subjects.If there are no additional DLTs in these 3 patients, the high dose may be recommended by the DSC for the study extension stage. However, further DLTs may prompt the DSC to recommend continuation to the extension stage with the low dose, or to modify the protocol, or to stop the study.
After completion of two months follow-up for the 6th subject in the low or high dose cohort (as applicable), and review of all the data for all subjects, following DSC recommendations, the Stage 2 extension phase of the study may recruit additional subjects, up to a maximum of 75 subjects for Stages 1 and 2, combined.
DSC will review study data during the extension stage follow-up after 5 years to determine if additional safety follow-up is required.
Bone marrow plasma cells must be at least 10% of total bone marrow cells based on a bone marrow biopsy/aspiration performed within 30 days of the start of protocol treatment.
Documented diagnosis of multiple myeloma according to IMWG diagnostic criteria.
Subjects must have measurable MM as defined by at least one of the criteria below.
Serum M-protein equal or greater than 0.4 g/dl (10 g/l).
Subjects with second malignancies in addition to multiple myeloma are not eligible if the second malignancy has required treatment within the past 3 years or is not in complete remission. There are two exceptions to this criterion: successfully treated non-metastatic basal cell or squamous cell skin carcinoma.
Women who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
Active systemic infections (defined as infections causing fevers or requiring antimicrobial treatment), or other major uncontrolled medical illnesses.
Active HBV and HCV infection which is identified by positive PCR to viral nucleotides in blood.
Sequential
CAR-BCMA
Biological/VaccineCAR-BCMA T-cells are genetically modified autologous T-cells directed to the B-cell maturation antigen (BCMA). CAR-BCMA T-cells identify and eliminate BCMA-expressing malignant plasma cells. Upon binding to BCMA-expressing cells, the CAR transmits a signal to promote T cell expansion, activation, persistence and elimination of malignant plasma cells.
Overall response rate
Overall response rate, two months after CAR-BCMA T-cell infusion determined in accordance with the International Myeloma Working Group (IMWG) guidance.
CAR BCMA related toxicity
Frequency of CAR-BCMA related toxicities: CRS and ICANS, according to ASTCT consensus grading (Lee 2019).
CAR BCMA related toxicity
Any AEs according to common Terminology Criteria for Adverse Events (CTCAE) version 5.0
progression free survival
PFS is defined as the time CAR T -cell infusion to the date of either first documented relapse, progression or death due to any cause.
overalll free survival
OS was defined as the time from CART-cell infusion to death of any cause
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