Anti-BCMA CAR-T cell-based therapies and bispecific antibodies in the immunotherapy era: are we ready for this?

Figures & data

Table 1. Anti-BCMA CAR-T cell clinical trials.

CAR-T product	Clinical trial	Phase	Therapy	MM population	Status of the trial
Idecabtagene Vicleucel (bb2121)	NCT02658929 (CRB-401)	1	bb2121 (150–450 × 10^6 CAR+ T cells)	RRMM ≥3 lines	Completed
	NCT03361748 (KarMMa)	2	bb2121	RRMM ≥3 lines	Active, not recruiting
	NCT03601078 (KarMMa-2)	2	bb2121	HR*-RRMM	Active, not recruiting
	NCT03651128 (KarMMa-3)	3	Bb2121 vs standard regimen (DPd, DVd, Ixa-Rd, Kd, or EloPd)	RRMM 2–4 lines	Active, not recruiting
	NCT04196491 (KarMMa-4)	1	bb2121	HR*-NDMM	Active, not recruiting
	NCT06045806 (KarMMa-9)		ide-cel + lena vs lena	NDMM	Recruiting
	KarMMa-8°			RRMM 1–3 Lines	Upcoming
bb21217	CRB-402 (NCT03274219)	1	bb21217	RRMM ≥3 lines	Active, not recruiting
Ciltacabtagene Autoleucel (JNJ-68284528, LCAR-B38M)	NCT03090659 (LEGEND-2)	1/2	LCAR-B38M CAR-T	RRMM ≥3 lines	Active, not recruiting
	NCT03548207 (CARTITUDE-1)	1b/2	JNJ-68284528	RRMM ≥3 lines	Active, not recruiting
	NCT03758417 (CARTIFAN-1)	2	LCAR-B38M CAR-T	RRMM ≥3 lines	Recruiting
	NCT04133636 (CARTITUDE-2)	2	Various cohorts administering cilta cel ± others (lena in D and E; D-VRd in E)	A: PD after 1–3 LOT B: Early relapse after 1^st line C: TCE and anti-BCMA RRMM D: suboptimal responders after ASCT E: HR-NDMM TNP F: SR-NDMM	Active, not recruiting
	NCT05201781 (CARTINUE)	4	Cilta-cel	long-term study of CARTITUDE-1 enrolled pts	Recruiting
	NCT04181827 (CARTITUDE-4)	3	Cilta-cel vs Dara-VD/PD	RRMM 1–3 lines	Active, not recruiting
	NCT04923893 (CARTITUDE-5)	3	VRD + Cilta-cel vs VRD + RD	TNP MM Unfit patients	Recruiting
	NCT05257083 (CARTITUDE-6)	3	Dara-VRD + Cilta-cel vs Dara-VRD + ASCT	TNP MM	Recruiting
PHE885	CADPT07A12101 (NCT04318327)	1	PHE885	RRMM ≥3 lines	Recruiting
	NCT05172596	2	PHE885	RRMM ≥3 lines	Recruiting
CT053	NCT03975907 (LUMMICAR)	1/2	Zevor-cel (CT053)	RRMM ≥3 lines	Recruiting
	NCT03915184 (LUMMICAR-2)	1/2	Zevor-cel (CT053)	RRMM ≥3 lines	Active, not recruiting
JCARH125	NCT03430011 (EVOLVE)	1/2	JCARH125 ± anakinra	RRMM ≥3 lines	Active, not recruiting
CART-BCMA	NCT02546167	1	CART-BCMA	RRMM ≥3 lines	Completed
p-BCMA-101 (PRIME)	NCT03288493	1/2	p-BCMA-101	RRMM	Terminated (Phase 1 completed; Phase 2 early terminated)
CT103	ChiCTR1800018137	1	CT103A	RRMM	Active, not recruiting
	NCT05066646 (FUMANBA-1)	1/2	CT103A	RRMM ≥3 lines	Recruiting
	NCT05181501 (FUMANBA-2)	1	CT103A	HR-TNP MM	Not yet recruiting
MCARH171	NCT03070327	1	EGFRt/BCMA-41BBz ± Lena	RRMM ≥2 lines	Active, not recruiting
KITE-585	NCT03318861	1	KITE-585	RRMM ≥3 lines	Active, not recruiting
CART-ddBCMA	NCT04155749	1	A: CART-ddBCMA B: ARC-T + SPRX00	RRMM ≥3 lines	Recruiting
FasT CAR-T GC012F	NCT04236011	1	GC012F	RRMM ≥3 lines	Unknown
	NCT04182581	1	GC012F	RRMM ≥3 lines	Unknown
ALLO-715	NCT04093596 (UNIVERSAL)	1	ALLO-715 ± Nirogacestat	RRMM ≥3 lines	Active, not recruiting
BMS-986354	NCT04394650	1	CC-98633	RRMM ≥3 lines	Active, not recruiting
ARI0002h	NCT04309981	1/2	ARI0002h	RRMM ≥2 lines	Active, not recruiting

*High-risk defined as R-ISS Stage III per IMWG criteria.

°Registrational.

Abbreviations: ASCT: autologous stem cell transplantation; BCMA: B-cell maturation antigen; HR: high-risk; IMWG: International Myeloma Working Group; LOT: lines of therapy; MM: multiple myeloma; NDMM: newly diagnosed MM; PD: progressive disease; pts: patients; RRMM: relasped or refractory MM; SR: standard-risk; TCE: triple-class-exposed (including PI, IMiD and anti-CD38 agents); TNP: transplant not planned.

Table 2. Bispecific antibodies targeting T-cell and BCMA currently under investigation to treat MM.

BsAb name	Clinical trials	Phase	Therapy	MM population	Status of the trial
Teclistamab	NCT04557098 (MajesTEC-1)	1/2	Teclistamab SC/IV	RRMM ≥3 LOT	Recruiting
	NCT03145181 (MajesTEC-1)	1/2	Teclistamab SC/IV	RRMM ≥3 LOT	Recruiting
	NCT04696809(Japanese cohort)	1/2	Teclistamab SC	RRMM	Recruiting
	NCT04722146 (MajesTEC-2)	1	Tec + other tp: A: Tec-DP B: Tec-DRV (21-day) C: Tec-Niro D: Tec-lena E: Tec-DR F: Tec-DRV (28-day)	RRMM/NDMM	Active, not recruiting
	NCT05083169 (MajesTEC-3)	3	Tec-Dara vs DPd/DVd	RRMM	Active, not recruiting
	NCT05243797 (MajesTEC-4)	3	Tec vs lena Tec-lena vs lena	Maint in NDMM post ASCT	Recruiting
	NCT05695508 (MajesTEC-5)	2	A: Tec-DRd + Tec-DR (maint) B: Tec-DVRd + Tec-DR (maint) C: Tec-DR (maint)	NDMM TE	Recruiting
	NCT05552222 (MajesTEC-7)	3	Tec-DR/Tal-DR vs DRd	NDMM TNE	Recruiting
	NCT05572515 (MajesTEC-9)	3	Tec vs PVd/Kd	RRMM	Recruiting
	NCT05932680	2	Teclistamab (limited-duration regimen)	Pts ≥VGPR upon 6–9 mos teclistamab	Recruiting
	NCT05231629 (MASTER-2)	2	MRD-Guided Sequential Therapy	NDMM	Recruiting
	NCT05572229 (IFM 2021–01)	2	Tec-dara vs Tec-lena	NDMM (elderly MM, TNE)	Not yet recruiting
	NCT05469893 (Imuno-PRISM)	2	Tec vs lena-dex	SMM	Recruting
	NCT05338775 (TRIMM-3)*	1	Teclistamab + talquetamab (± PD-1 inhibitor)	RRMM	Recruiting
	NCT04586426 (RedirecTT-1)*	1b/2	Teclistamab + talquetamab (± dara)	RRMM	Recruiting
	NCT04108195* (TRIMM-2)	1b	Dara-Tec Dara-Tal Dara-Tec-poma Dara-Tal-poma	RRMM ≥3 LOT	Active, not recruiting
	NCT05849610 (GEM-TECTAL)*	2	Dara-VRD (ind) + Tec-dara (int) + Tec-dara (maint) + ERI Tal-dara	HR-NDMM	Recruting
Elranatamab	NCT03269136 (MagnetisMM-1)	1	Elranatamab IV vs SC	RRMM ≥3 LOT	Active, not recruiting
	NCT04798586 (MagnetisMM-2)	1	Elranatamab	RRMM ≥3 LOT	Active, not recruiting
	NCT04649359 (MagnetisMM-3)	2	Elranatamab	RRMM ≥3 LOT	Active, not recruiting
	NCT05090566 (MagnetisMM-4)	2	Elranatamab + Niro	RRMM ≥3 LOT	Recruiting
	NCT05020236 (MagnetisMM-5)	3	Elranatamab ± Dara vs Dara-Pd	RRMM 1–3 LOT (PI and lena based, no anti-CD38 refractory)	Recruiting
	NCT05623020 (MagnetisMM-6)	3	Elranatamab + DR ± dex	Part1: RRMM 1–2 LOT Part2: NDMM TNE	Recruiting
	NCT05317416 (MagnetisMM-7)	3	Elranatamab vs lena	NDMM (MRD+ after ASCT)	Recruiting
	NCT05228470 (MagnetisMM-8)	2	Elranatamab	RRMM ≥3 LOT	Active, not recruiting
	NCT05014412 (MagnetisMM-9)	2	Elranatamab ± dex	RRMM TCR	Active, not recruiting
	NCT05675449(MagnetisMM-20)	1	Elranatamab + Kd/Maplirpacept	RRMM ≥3 LOT	Recruiting
	NCT05927571 (GO43979)	1b	Cevostamab + Elranatamab	RRMM	Recruiting
Linvoseltamab (REGN 5458)	NCT03761108 (LINKER-MM1)	1/2	REGN 5458	RRMM ≥3 LOT	Recruiting
	NCT05137054	1	REGN5458+dara/K/lena/bort/poma/isa/REGN3767/cemiplimab/Niro	RRMM ≥2 LOT	Recruiting
	NCT05730036 (R5458-ONC-2245, LINKER-MM3)	3	REGN 5458 vs EloPd	RRMM 1–4 LOT	Recruiting
	NCT05828511 (LINKER-MM4)	1/2	REGN 5458	NDMM TE/TNE	Recruiting
REGN 5459	NCT04083534	1/2	REGN 5459	RRMM ≥3 LOT	Active, not recruiting
Pacanalotamab (AMG 420)	NCT02514239	1	AMG 420	RRMM ≥2 LOT	Recruitment completed
	NCT03836053	1	AMG 420	RRMM ≥3 LOT	Recruitment completed
Pavuratamab (AMG 701)	NCT03287908 (ParadigMM-1B)	1	AMG 701 ± poma ± dex	RRMM ≥3 LOT	Early termination°
TNB-383B	NCT03933735	1/2	TNB-383B	RRMM ≥3 LOT	Active, not recruiting
Alnuctamab (CC-93269)	NCT03486067	1	CC-93269	RRMM	Recruiting
ABBV-383	NCT05650632	1	ABBV-383	RRMM ≥3 LOT	Recruiting
	NCT05286229	1	ABBV-383	RRMM ≥3 LOT	Active, not recruiting
	NCT05259839 (M22–947)	1	ABBV-383 + Pd/Rd/Dd/Niro	RRMM	Recruiting
	NCT05650632	1b	ABBV-383	RRMM	Recruiting
RO729089	NCT04434469	1	RO7297089	RRMM	Recruitment Completed
WVT078	NCT04123418	1	WVT078 ± WHG626	RRMM ≥2 LOT	Active, not recruiting

*Trials including teclistamab (JNJ-64007957) and talquetamab (JNJ-64407564).

°Early termination of the study due to business decision, not safety reasons.

Abbreviations: ASCT: autologous stem cell transplantation; D, Dara: daratumumab; d, dex: dexamethasone; HR: high-risk; ind: induction; int: intensification; isa: isatuximab; elo: elotuzumab; IV: intravenously; K: carfilzomib; LOT: lines of therapy; maint: maintenance; MM: multiple myeloma; Mos: months; MRD: minimal residual disease; NDMM: newly diagnosed MM; Niro: nirogacestat; P, poma: pomalidomide; PD-1: Programmed cell death protein 1; Pts: patients; R, lena: lenalidomide; RRMM: relapsed/refractory MM; SC: subcutaneous; SMM: smoldering MM; Tal: talquetamab; TCR: triple-class refractory; TE: transplant-eligible; Tec: teclistamab; TNE: transplant-not eligible; tp: terapies; V, bort: bortezomib.

Table 3. Anti-BCMA comparing therapies: pros and cons of each treatment.

	CAR-T	BsAbs
Efficacy	ORR >80% (98% cilta-cel)	ORR 55–75%
Deep of response	≥CR 83% 92% MRD-negativity	≥CR < 40% Up to 90% MRD-negativity (elranatamab)
Disease-free and survival outcomes	mPFS 34.9 mos (cilta-cel) mOS 24.8 to NR	mPFS 12 mos mOS 18.3 mos (teclistamab)
Dosing frequency	One dose	Treat to progression
Health-related quality of life	Meaningful improvements in symptoms, physical functioning, overall health status, and HRQoL	Improved pain and overall HRQoL
Availability	Limited slots, cell therapy facility	Wider availability
Waiting time for the product	4–6 week turn-around time*	Off the shelf
Toxicity	Higher rates of CRS, ICANS Hypogamma lasting average 6 mos	CRS (mostly grade 1–2), very low ICANS Hypogamma long-lasting
Prolonged cytopenias	More common	Limited to neutropenia, usually decreasing with bi-weekly/monthly dosing
Infection risk	High (shorter duration)	High and prolonged (long-lasting)
Time off therapy	Yes, one time treatment	Continuous therapy
Hospitalization	Inpatient or outpatient Hospital proximity up to 30 days	Limited to step up dosing phase
Treatment logistics	Complex, only in specialized center Long time for production	Simple infusion, but frequent Requires hospital stay
Best Candidates	Fit, good PS, No rapid progression	Can travel frequently
Costs	> $400K One time, upfront	>$30k/month Pay as you go
Patient place in therapy	Later line, salvage fit, >3 LOT	Later line salvage unfit, >3 LOT

*Newer constructs require shorter time of manufacturing (down to 2 days manufacturing process).

Abbreviations: CR: complete remission; CRS: cytokines release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; LOT: lines of therapy; mos: months; MRD: minimal residual disease; PS: performance status.