Study to Evaluate the Safety and Efficacy of Anti-CD38 CAR-T in Relapsed or Refractory Multiple Myeloma Patients

The MTD is assessed according to a 3+3 dose-escalation design by the occurrence of treatment-emergent dose-limiting toxicities during the 28-day Treatment Period in the dose-escalation phase of the study

CAR2 Anti-CD38 A2 CAR-T cell blood concentrations will be measured at different time points during the 28-day treatment period to evaluate the maximum concentration (Cmax).

CAR2 Anti-CD38 A2 CAR-T cell blood concentrations will be measured at different time points during the 28-day treatment period to evaluate the area under the curve (AUC).

The evaluation of safety will be measured by an assessment of the incidence of treatment-emergent adverse events for each patient in the dose-escalation and expansion phases of the study.

As a measure of activity, overall response rate will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. Response will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol.

As a measure of activity, depth of response (ie, category of response) will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol.

As a measure of activity, duration of response will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol.

As a measure of activity, Progression-free survival (PFS) will be assessed. The events for the assessment of PFS are disease progression and death events. This time to event endpoint will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate.

As a measure of activity, Overall Survival (OS) will be assessed. The events for the assessment of OS are death events. Time to event endpoints will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate.

The RP2D will be assessed by the incidence of treatment-emergent adverse events during the Treatment and Observation Periods.

The rate of response as a determination factor for the RP2D will be assessed by the incidence of responses of at least partial response according to the IMWG criteria during the Treatment and Observation Periods.

The depth of response as a determination factor for the RP2D will be assessed by the IMWG categories for response according to changes from baseline in M-protein levels in serum and urine, per cent plasma cells in the bone marrow, and size (area) of soft tissue extramedullary plasmacytomas (if applicable). This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol.

The duration of response as a determination factor for the RP2D will be assessed by the IMWG criteria for disease progression following the achievement of a response of at least a partial response according to changes in M-protein levels in serum and urine, per cent plasma cells in the bone marrow, the appearance of new lytic bone lesions, and/or the development of new soft tissue extramedullary plasmacytomas during the Treatment and Observation periods.

Progression-free survival as a determination factor for the RP2D will be assessed by the IMWG criteria for disease progression events and death events. This time to event endpoint will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate. Progression-free survival will be evaluated during the Treatment and Observation Periods of the study.

Overall survival as a determination factor for the RP2D will be assessed by death events that occur during the Treatment and Observation Periods. Time- to-event endpoints will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate.

The Cmax of the concentration of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The achievement of at least a partial response for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis to determine if a specific level of Cmax for the circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period is required for patients to achieve at least a partial response during the Treatment and Observation Periods.

The AUC of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The achievement of at least a partial response for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis to determine if a specific value for the AUC of circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period is required for patients to achieve at least a partial response during the Treatment and Observation Periods.

The Cmax of the concentration of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The incidence of CRS adverse events for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis will be conducted to determine if there is a level of Cmax for circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period above which is associated with the development of at least Grade 3 CRS in patients during the Treatment and Observation Periods.

The AUC of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The incidence of at least Grade 3 CRS for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis to determine if there is a specific value for the AUC of circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period above which is associated with the development of at least Grade 3 CRS in patients during the Treatment and Observation Periods.

The Cmax of the concentration of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The incidence of neurotoxicity adverse events for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis will be conducted to determine if there is a level of Cmax for circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period above which is associated with the development of at least Grade 2 neurotoxicity adverse events in patients during the Treatment and Observation Periods.

The AUC of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The incidence of at least Grade 2 neurotoxicity adverse events for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis to determine if there is a specific value for the AUC of circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period above which is associated with the development of at least Grade 2 neurotoxicity adverse events in patients during the Treatment and Observation Periods.