Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma

A Phase 2, Multicenter Study to Determine the Efficacy and Safety of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03361748

Acronym

KarMMa

Enrollment

149

Registered

2017-12-05

Start date

2017-12-13

Completion date

2023-12-20

Last updated

2025-05-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma, Efficacy and Safety, BB2121, CAR T Cell, BCMA, Relapsed and Refractory

Brief summary

This is an open label, single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of bb2121 in subjects with relapsed and refractory multiple myeloma. A leukapheresis procedure will be performed to manufacture bb2121 chimeric antigen receptor (CAR) modified T cells. Prior to bb2121 infusion subjects will receive lymphodepleting therapy with fludarabine and cyclophosphamide.

Detailed description

Anti-myeloma bridging treatment is allowed for disease control while bb2121 is being manufactured.

Interventions

BIOLOGICALbb2121

: bb2121 consists of autologous T lymphocytes transduced with an anti-BCMA02 CAR lentiviral vector to express a chimeric antigen receptor targeting the human B cell maturation antigen (anti-BCMA CAR).

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Eligibility is determined prior to leukapheresis. Subjects must satisfy the following criteria to be enrolled in the study: 1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF). 2. Documented diagnosis of multiple myeloma * Must have received at least 3 prior MM treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen. * Must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen. * Must have received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody. * Must be refractory to the last treatment regimen. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 4. Subjects must have measurable disease, including at least one of the criteria below: * Serum M-protein greater or equal to 1.0 g/dL * Urine M-protein greater or equal to 200 mg/24 h * Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal 5. Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy.

Exclusion criteria

The presence of any of the following will exclude a subject from enrollment: 1. Subjects with known central nervous system involvement with myeloma. 2. History or presence of clinically relevant central nervous system (CNS) pathology. 3. Subjects with active or history of plasma cell leukemia. 4. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease 5. Inadequate organ function 6. Ongoing treatment with chronic immunosuppressants 7. Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy 8. Evidence of human immunodeficiency virus (HIV) infection. 9. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) 10. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) and Hepatitis C virus (HCV) 11. Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months. 12. Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission 13. Pregnant or lactating women. 14. Subject with known hypersensitivity to any component of bb2121 productThe presence of any of the following will exclude a subject from enrollment: 1\. Subjects with known central nervous system involvement with myeloma. 2. History or presence of clinically relevant central nervous system (CNS) pathology. 3\. Subjects with active or history of plasma cell leukemia. 4. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease 5. Inadequate organ function 6. Ongoing treatment with chronic immunosuppressants 7. Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy 8. Evidence of human immunodeficiency virus (HIV) infection. 9. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) and Hepatitis C virus (HCV) 10. Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months. 11. Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission 12. Pregnant or lactating women. 13 Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, or tocilizumab.

Design outcomes

Primary

Measure	Time frame	Description
Overall Response Rate	From first dose to 24 Months	Number of participants who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an independent response committee (IRC).

Secondary

Measure	Time frame	Description
Time to Response	From first dose to initial response (approximately on average 1.2 months, max of 8.8 months)	Time from first bb2121 infusion to first documentation of response of PR or better.
Duration of Response	From first dose to 24 months after first dose	Time from first documentation of response or PR or better to first documentation of disease progression or death from any cause, whichever occurs first.
Progression Free Survival (PFS)	From first dose to 24 months after first dose	Time from first bb2121 infusion to first documentation of progressive disease (PD), or death due to any cause, whichever occurs first.
Time to Progression (TTP)	From first dose to 24 months after first dose	Time from first bb2121 infusion to first documentation of progressive disease (PD), or death due to any cause, whichever occurs first.
Overall Survival	From screening to the end of follow up (approximately 5 years and 2 months)	Time from first bb2121 infusion to time of death due to any cause.
Number of Participants With Safety Related Events	From screening to the end of follow up (approximately 5 years and 2 months)	Number of participants with adverse events (AEs), adverse events of special interest (AESI), serious adverse events (SAEs), cytokine release syndrome, neurotoxicity, infection and clinically signifcant laboratory abnormalities.
Cmax	From first dose to the end of follow up (Approximately 5 years)	Cmax is defined as the maximum transgene level at Tmax Tmax: The time of maximum observed transgene level, obtained directly from the observed transgene level - time.
AUC 0-9M	at 9 months post first dose (Approximtately 9 Months)	The AUC of the transgene level from the time of dosing to 9 months
Tmax	From first dose to the end of follow up (Approximately 5 years)	Tmax: The time of maximum observed transgene level, obtained directly from the observed transgene level - time.
Complete Response Rate	From first dose to 24 Months	Percentage of participants who achieved CR or sCR according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC.
Percentage of Participants Who Achieved >= VGPR and MRD Negative Status	From screening to the end of follow up (Approximately 5 years and 2 months)	Percentage of participants who achieved ≥ VGPR and MRD negative status at a sensitivity of 10-⁵ at any time point within 3 months prior to achieving at least VGPR until the time of PD/death. MRD in the bone marrow will be measured using both next generation sequencing (NGS) techniques measuring immunoglobulin gene rearrangements of the malignant clone. MRD will be reported with a sensitivity of 10-⁴, 10-⁵, and 10-⁶ nucleated cells. The primary analysis for MRD negative response will use the sensitivity of 10-⁵. MRD = Minimal Residual Disease PD = Progressive Disease VGPR = Very good partial response.
Mean Change From Baseline on the EORTC QLQ-C30 - Fatigue.	At Day 1 and at specific time points up to month 24	Mean change from baseline on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100. The average of the scores will represent the symptoms score. A high score for a symptom scale/item represents a high level of symptomatic problem.
Mean Change From Baseline on the EORTC QLQ-C30 - Pain	At Day 1 and at specific time points up to month 24	Mean change from baseline on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100. The average of the scores will represent the symptoms score. A high score for a symptom scale/item represents a high level of symptomatic problem.
Mean Change From Baseline on the EORTC QLQ-C30 - Physical Functioning	At Day 1 and at specific time points up to month 24	The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100 and an average will be taken. This average is the overall score. A higher scale score represents a higher level of well-being and better ability of daily functioning. Thus, a high score for a functional scale represents a high/healthy level of functioning.
Mean Change From Baseline on the EORTC QLQ-C30 - Cognitive Functioning	At Day 1 and at specific time points up to month 24	The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100 and an average will be taken. This average is the overall score. A higher scale score represents a higher level of well-being and better ability of daily functioning. Thus, a high score for a functional scale represents a high/healthy level of functioning.
Mean Change From Baseline on the EORTC QLQ-C30 - Global Heath/QoL	At Day 1 and at specific time points up to month 24	Mean change from baseline on the EORTC QLQ-C30 The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A higher scale score represents a higher level of well-being and better ability of daily functioning. Thus, a high score for a functional scale represents a high/healthy level of functioning; a high score for the global health status/HRQoL represents a high HRQoL.
Mean Change From Baseline on the EORTC QLQ-MY20 - Disease Symptoms	At Day 1 and at specific time points up to month 24	Mean change from baseline on the EORTC QLQ-MY20 The EORTC has developed a myeloma module referred to as QLQ- MY20, to be administered alongside the core QLQ-C30. The QLQ-MY20 is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality. All items will be scored from 0 to 100. The average of the scores will represent the symptoms score. A high score for a symptom scale/item represents a high level of symptomatic problem.
Mean Change From Baseline on the EORTC QLQ-MY20 - Side Effects	At Day 1 and at specific time points up to month 24	Mean change from baseline on the EORTC QLQ-MY20 The EORTC has developed a myeloma module referred to as QLQ- MY20, to be administered alongside the core QLQ-C30. The QLQ-MY20 is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality. All items will be scored from 0 to 100. The average of the scores will represent the symptoms score. A high score for a symptom scale/item represents a high level of symptomatic problem.
Mean Change From Baseline on the EQ-5D-5L Index	At Day 1 and at specific time points up to month 24	The European Quality of Life 5D-5L Scale (EQ-5D-5L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses are coded so that a '1' indicates no problem, and '5' indicates the most serious problem. The responses for the 5 dimensions are combined in a 5-digit number. The EQ-5D-5L health utility index (HUI) is assessed using the Crosswalk algorithm for France based on the individual responses to the 5 EQ-5D-5L domains ranging from -0.530 to 1.000. The smallest change considered clinically meaningful, is defined as a score difference of 0.08 points.
Number of Participants With Anti-CAR-Antibodies	From first dose to the end of follow up (Approximately 5 years)	Number of Participants with Anti-CAR-Antibodies. Pre-postive is defined by last value before or on bb2121 infusion date is positive Post-positve is defined by at least one positive value post bb2121 infusion.

Countries

Belgium, Canada, France, Germany, Italy, Japan, Spain, United States

Participant flow

Pre-assignment details

137 participants treated

Participants by arm

Arm	Count
BB2121 BB2121	137
Total	137

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Death	77
Overall Study	Lost to Follow-up	4
Overall Study	Withdrawal by Subject	20

Baseline characteristics

Characteristic	BB2121
Age, Continuous	59.4 Years STANDARD_DEVIATION 9.53
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	112 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	14 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	12 Participants
Race (NIH/OMB) Black or African American	6 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	16 Participants
Race (NIH/OMB) White	103 Participants
Sex: Female, Male Female	54 Participants
Sex: Female, Male Male	83 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	82 / 137
other Total, other adverse events	137 / 137
serious Total, serious adverse events	108 / 137

Outcome results

Primary

Overall Response Rate

Number of participants who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an independent response committee (IRC).

Time frame: From first dose to 24 Months

Population: All Treated Participants

Arm	Measure	Value (NUMBER)
BB2121	Overall Response Rate	74.5 Percentage of Participants

Secondary

AUC 0-9M

The AUC of the transgene level from the time of dosing to 9 months

Time frame: at 9 months post first dose (Approximtately 9 Months)

Population: PK Evaluable Population for AUC at 9 Months

Arm	Measure	Group	Value (MEAN)	Dispersion
BB2121	AUC 0-9M	Total	8634034.70 copies*days/ug	Standard Deviation 9909488.82
BB2121	AUC 0-9M	450x10^6 cells	10599751.18 copies*days/ug	Standard Deviation 10833877.42
BB2121	AUC 0-9M	300x10^6 cells	6604279.35 copies*days/ug	Standard Deviation 8523928.48
BB2121	AUC 0-9M	150x10^6 cells	10555200.59 copies*days/ug	Standard Deviation 13555457.13

Secondary

Cmax

Cmax is defined as the maximum transgene level at Tmax Tmax: The time of maximum observed transgene level, obtained directly from the observed transgene level - time.

Time frame: From first dose to the end of follow up (Approximately 5 years)

Population: PK Evaluable Population

Arm	Measure	Group	Value (MEAN)	Dispersion
BB2121	Cmax	Total	388150.65 transgene copies/ug of genomic DNA	Standard Deviation 372280.64
BB2121	Cmax	450x10^6 cells	449826.92 transgene copies/ug of genomic DNA	Standard Deviation 375293.18
BB2121	Cmax	300x10^6 cells	335916.20 transgene copies/ug of genomic DNA	Standard Deviation 369546.39
BB2121	Cmax	150x10^6 cells	317793.50 transgene copies/ug of genomic DNA	Standard Deviation 284926.3

Secondary

Complete Response Rate

Percentage of participants who achieved CR or sCR according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC.

Time frame: From first dose to 24 Months

Population: All Treated Participants

Arm	Measure	Value (NUMBER)
BB2121	Complete Response Rate	34.3 Percentage of participants

Secondary

Duration of Response

Time from first documentation of response or PR or better to first documentation of disease progression or death from any cause, whichever occurs first.

Time frame: From first dose to 24 months after first dose

Population: All Treated Participants with a CR or PR as per IRC

Arm	Measure	Value (MEDIAN)
BB2121	Duration of Response	11.04 Months

Secondary

Mean Change From Baseline on the EORTC QLQ-C30 - Cognitive Functioning

The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100 and an average will be taken. This average is the overall score. A higher scale score represents a higher level of well-being and better ability of daily functioning. Thus, a high score for a functional scale represents a high/healthy level of functioning.