Table 1 BCMA CAR-T studies in Multiple Myeloma.

NCT02215967

Phase 1

First in human NIH study

Murine scFv (11D5-3)

CD28 co-stimulatory domain

Retroviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

0.3 × 10³ -9 × 10⁶ CAR-Ts (9 × 10⁶ dose expansion)

N = 24, n = 16 at the highest dose

RRMM, median 7.5 prior lines

At highest dose, ORR 81%

≥VGPR 63%

CRS 94% (≥ Grade 3 38%), ≥ Grade 3 neurotoxicity 25%

NCT02658929

Phase 1

CRB (bb2121/Ide-cel)

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

50-800 × 10⁶ CAR-Ts (150-450 × 10⁶ dose expansion)

N = 33

N = 62 (dose escalation n = 21, dose expansion n = 41), 45% >6 prior lines, 90% daratumumab-exposed

In the dose expansion phase: ORR 76%, ≥CR 65%

For all patients, median PFS 8.8 months, median OS 34.2 months

CRS 76% (≥ Grade 3 7%), neurotoxicity 44% (≥ Grade 3 3%)

NCT03361748

Phase 2

KarMMa

CRB (bb2121/Ide-cel)

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

150-450 ×10⁶ CAR-T

N = 128

≥ 3 Prior lines of therapy including PI/IMiD/anti-CD38, refractory to last agent

ORR 73%, ≥CR 33%

Of patients in sCR/CR, 76% MRD negative 10^-5, 59% of which had sustained MRD negativity after 12 months

Median PFS 8.8 months

CRS 84% (≥ Grade 3 5%), neurotoxicity 18% (14% grade 1-2)

NCT03601078

Phase 2 KarMMa-2

Bb2121/Ide-cel

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

150-450 ×10⁶ CAR-T

Cohort 1) RRMM ≥3 prior lines of therapy, Cohort 2b) PD < 18 months post start of therapy not including ASCT

Cohort 2a) PD < 18 months post ASCT

N = 37, 86% double class-refractory

Cohort 2c) inadequate response post ASCT

N = 31

Not reported

ORR 84%, 11/13 (85%) MRD negative at 6 months

Median PFS 11.4 months, median OS not reached

CRS 84% grade 3 3%), neurotoxicity 22% (all Grade 1/2)

ORR 87%, ≥CR 77%, median PFS and OS not reached

9/14 (64%) MRD negative at 36 months

CRS 58% (all Grade 1/2), neurotoxicity 7%

NCT035651128

Phase 3

KarMMa-3

Bb2121/Ide-cel

4-1BB co-stimulatory domain

Lentiviral vector

Ide-cel versus standard of care (DPd, DVd, Rd, Kd, EPd)

N = 386 (254 randomised to the Ide-cel arm, of which 225 treated)

Triple-exposed patients after 2-4 prior lines

Median 3 prior lines, 66% triple class refractory

ORR Ide-cel vs. SOC 71% vs 42%, ≥CR 39% vs 5%

Median PFS 13.3 vs 4.4 months (HR 0.49, p < 0.0001)

CRS 88% (≥ Grade 3 4%), neurotoxicity 15% (≥ Grade 3 3%)

NCT04196491

Phase 1

KarMMa-4

Bb2121/Ide-cel

4-1BB co-stimulatory domain

Lentiviral vector

4 cycles standard induction (KRd±Dara, VRd ±Dara, CyBorD), Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² lymphodepletion and Ide-cel

HR NDMM (R-ISS stage III)

Not reported

NCT04855136

Phase 1/2

KarMMa-7

Bb2121/Ide-cel

4-1BB co-stimulatory domain

Lentiviral vector

Tolerability and efficacy of Ide-cel in combination with other therapies in RRMM

Cohort A) CC-220 ±low dose dex, B) BMS- 986405, C) DPd/PVd

Not reported

NCT03274219

Phase 1

CRB402 (bb21217)

Murine scFv (11D5-3)

4-1BB

Lentiviral vector

Phosphoinositide 3 kinase inhibitor added during ex vivo culture to enrich memory-like T cells

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

150–450 × 10⁶ CAR-T

N = 72

≥ 3 Prior lines of therapy including PI/IMiD/±anti-CD38, refractory to last agent, median 6 prior lines, 68% triple refractory

ORR 69%, ≥sCR/CR 28%, ≥VGPR 58%, median DOR 17 months (11-35)

CRS 75% (71% grade 1-2), Neurotoxicity 15% (11% grade 1-2)

NCT03502577

Phase 1

CRB402 (bb21217)

Murine scFv (11D5-3)

4-1BB

Lentiviral vector

Phosphoinositide 3 kinase inhibitor

Gamma secretase inhibitor (GSI) JSMD194 ‘run in’, Fludarabine 30 mg/m², cyclophosphamide 300 mg/m², 5-45 ×10⁷ CAR-T cells with JSMD194 thrice weekly for 3 weeks

N = 18

RRMM, median 10 prior lines of therapy, 67% penta-refractory, 39% prior- BCMA targeted therapy

ORR 89%, ≥CR 44%, ≥VGPR 78%, median PFS 11 months (2 months in BCMA-exposed)

CRS 95% (83% grade 1-2), 66% ICANS

NCT03090659

Phase 1/2

Legend-2

LCAR-B38M

2 camelid variable heavy chain only domains

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 25 mg/m², cyclophosphamide 250 mg/m² days -5 to -3, or cyclophosphamide 300 mg/m²

0.07-2.1 ×10⁶/kg CAR-T

≥ 3 Prior lines of therapy including bortezomib

N = 17 (3 sites) median 4 prior lines

N = 57 (4^th site) median 3 prior lines

ORR 88%, sCR 82%, median PFS 12 months

CRS 59% (grade 1-2), 35% (grade 3), no neurotoxicity

ORR 88%, ≥CR 74%, median PFS 20 months

CRS 82% (grade 1-2), 7% (grade 3)

5 year follow-up of overall cohort: ORR 89%, ≥CR 67%, median PFS 18 months

NCT03548207

Phase 1b

CARTITUDE-1

JNJ-4528 (Cilta-cel)

2 camelid variable heavy chain only domains

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

0.75 × 10⁶/kg CAR-T

N = 97

≥ 3 Prior lines of therapy, PI/IMiD/anti-CD38

Median 6 prior lines, 87.6% triple-refractory, 42.3% penta-refractory

ORR 98%, sCR 83%

Of 61 patients evaluable for MRD, 91.8% MRD negative to 10^-5

27 month PFS 55% and OS 70%, median PFS and OS not estimable

CRS 94.8% (≥Grade 3 3%) neurotoxicity 20.6% (≥Grade 3 9.3%), 8.2% ICANS, MNTs 5% ( < 1% following risk reduction strategies)

NCT04133636

Phase 1

CARTITUDE-2

COHORT A

JNJ-4528 (Cilta-cel)

2 camelid variable heavy chain only domains

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

0.75 × 10⁶/kg CAR-T

N = 20

PD after 1-3 prior lines of therapy including PI/IMiD, lenalidomide-refractory

Median 2 prior lines of therapy, 40% triple-refractory, 95% refractory to last line

ORR 95%, ≥CR 80%

24 month PFS and OS 75%

Sustained MRD negativity to 10^-5

After 6 months (40%) and 12 months (35%)

CRS 95% (≥Grade 3 10%), neurotoxicity 30% (≥Grade 3 5%), ICANS 15% (all Grade 1/2), no MNTs

NCT04133636

Phase 1

CARTITUDE-2

COHORT B

JNJ-4528 (Cilta-cel)

2 camelid variable heavy chain only domains

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

0.75 × 10⁶/kg CAR-T

Early relapse following frontline therapy including PI/IMiD ( < 12 months from ASCT or start of non-ASCT containing treatment)

N = 19

ORR 100%, ≥CR 74%

24 month PFS 74% and OS 82%

Sustained MRD negativity to 10^-5

After 6 months (53%) and 12 months (37%)

CRS 84% (≥Grade 3 5%), neurotoxicity 26% (≥Grade 3 5%), ICANS 15% (all Grade 1/2), MNTs 5% (≥Grade 3 5%, n = 1)

NCT04133636

Phase 1

CARTITUDE-2

COHORT C

JNJ-4528 (Cilta-cel)

2 camelid variable heavy chain only domains

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

0.75 × 10⁶/kg CAR-T

N = 20

PD post PI/IMiD/CD38 monoclonal antibody/non-cellular anti-BCMA immunotherapy

13 patients had received anti-BCMA drug conjugate, 7 prior BCMA bispecific antibody treatment, 80% refractory to prior anti-BCMA therapy

ORR 60%, 35% MRD negative at a median 11.3 months follow-up

Median PFS 9.1 months

CRS 60% (all Grade 1/2), ICANS 20% (≥Grade 3 10%), no MNTs

NCT04181827

Phase 3

CARTITUDE-4

JNJ-4528 (Cilta-cel)

2 camelid variable heavy chain only domains

4-1BB co-stimulatory domain

Lentiviral vector

Cilta-cel vs. PVd/DPd Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

0.75 × 10⁶/kg CAR-T

N = 419 (208 randomised to Cilta-cel, of which 176 treated)

1-3 prior lines of treatment, lenalidomide-refractory.

ORR Cilta-cel vs SOC 85% vs 67%, ≥CR 73% vs 22%, MRD negativity 61% vs 16%

12 month PFS 76% vs 49%

CRS 76% (≥Grade 3 1%), ICANS 5% (all Grade 1/2), 9% cranial nerve palsy, 3% peripheral neuropathy, 1 patient MNT (grade 1)

NCT04923893

Phase 3

CARTITUDE-5

JNJ-4528 (Cilta-cel)

2 camelid variable heavy chain only domains

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

0.75 × 10⁶/kg CAR-T

NDMM, not eligible for transplant

VRd and Cilta-cel vs. VRd and Rd maintenance

Not reported

NCT05257083

Phase 3

CARTITUDE-6

JNJ-4528 (Cilta-cel)

2 camelid variable heavy chain only domains

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

0.75 × 10⁶/kg CAR-T

NDMM

D-RVd and Cilta-cel vs. D-VRd and ASCT

Not reported

NCT03318861

Phase 1

KITE-583

Human anti-BCMA scFv CD28 co-stimulatory domain

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

3 × 10⁷- 1 × 10⁹ CAR-T

N = 14

≥3 prior lines of therapy including PI/IMiD

median 5 prior lines

Best response is PR in 1 patient

Limited expansion

CRS 21%, neurotoxicity 21%

NCT04318327

Phase 1

PHE885

T-charge platform enables in vivo CAR-T expansion and manufacture <2 days

Human anti-BCMA scFv

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine and cyclophosphamide- regimen not stated, 5-14.3 × 10⁶ CAR-T

N = 46

≥ 2 Prior lines of therapy, IMiD/PI/anti-CD38

Median 4 prior lines, 96% triple class-refractory

4 evaluable after 3 months

2 sCR, 1 PR, 1 PD

CRS 100% (all grade 1-2), 33% neurotoxicity

ORR 98%, 60% of evaluable patients (n = 10) MRD negative

CRS 96% (≥Grade 3 11%), ICANS 22% (≥Grade 3 7%)

NCT03070327

Phase 1

MCARH171

Human scFv

4-1BB co-stimulatory domain

tEGFR safety switch

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3, or cyclophosphamide 3 g/m²

72-818 × 10⁶ CAR-T

N = 11

Triple class-exposed RRMM

Median 6 prior lines

ORR 64%, 100% at highest dose

AEs evaluable in 10 patients

CRS 60% (≥Grade 3 20%)

Grade 2 neurotoxicity 10% (n = 1)

NCT03430011

Phase 1/2

EVOLVE

JCARH125 (Orva-cel)

Human scFv

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

50–600 × 10⁶ CAR-T

N = 44 at higher doses

≥ 3 Prior lines of therapy including PI/IMiD/anti-CD38

median 6 prior lines, 92% penta-exposed

ORR 91%, sCR/CR 39%

≥ Grade 3 CRS 2%, ≥ Grade 3 neurotoxicity 4% (total numbers not reported)

ChiCTR1800018137

Phase 1/2 FUMANBA-1 study

CT103A

Human scFv

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 25 mg/m², cyclophosphamide 20 mg/kg for 3 days

1-6 × 10⁶ CAR-T

N = 103

≥ 3 Prior lines of therapy including PI/IMiD, refractory to last line, median 4 prior lines, 18.3% prior CAR-T

ORR 96%, ≥CR 74%

12-month PFS 79%

95% (n = 101 evaluable) MRD negative to 10^-5

95% CRS (≥ Grade 3 3%), ICANS in 2 patients (both grade 2)

NCT03602612

Phase 1

FHVH33-CD8BBZ

Human heavy chain variable domain (FHVH33)

4-1BB co-stimulatory domain

Gamma retroviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

N = 25

RRMM, median 6 prior lines

ORR 92%, sCR 52%

Median PFS 78 weeks

CRS 96% (Grade 3 25%)

Grade 3 neurotoxicity 8%

NCT03716856

NCT03302403

NCT03380039

Phase 1

CT053

Human scFv (25C2)

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

50–180 × 10⁶ CAR-T

N = 24

≥ 2 Prior lines of therapy

Median 5 prior lines, 42% extramedullary disease

ORR 88%, ≥CR 79%

CRS 63% (all Grade 1/2), 1 patient had grade 3 neurotoxicity

NCT03975907

Phase 1

Lummicar Study 1

CT053 (Zevor-cel)

Human scFv (25C2)

4-1BB co-stimulatory domain

Lentiviral vector

Fludarabine 30 mg/m², cyclophosphamide 300 mg/m² days -5 to -3

1 × 10⁸ CAR-T (n = 3), 1.5 × 10⁸ CAR-T (n = 11)

N = 14

≥ 3 Prior lines of therapy, including PI/IMiD

Median 6 prior lines

ORR 100%, sCR 79% (100% of patients in sCR were MRD negative to 10^-5)

12 month PFS 86%

CRS 93% (all Grade 1/2)