Targeting BCMA in Multiple Myeloma

Abstract

Purpose of Review:

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a significant number of patients still progress on current available therapies. Here we review treatment modalities used to target BCMA in the treatment of MM, specifically antibody-drug conjugates (ADC), bispecific antibody constructs, and chimeric antigen receptor (CAR) modified T-cell therapies. We will provide an overview of therapies from these classes that have presented or published clinical data, as well as data on mechanisms of resistance to these novel agents.

Recent Findings:

Clinical trials exploring different BCMA-targeting modalities to treat multiple myeloma are underway and demonstrate promising results. In relapsed/refractory multiple myeloma, anti-BCMA ADCs and bispecific antibody constructs are showing impressive efficacy with manageable side effect profiles. In parallel, adoptive cellular therapy have induced dramatic durable responses in multiply relapsed and refractory myeloma patients.

Summary:

Therapeutic approaches targeting BCMA hold significant potential in the management of multiple myeloma and will soon be incorporated in combination with current standard therapies to improve outcomes for patients with multiple myeloma. In addition, novel approaches are being evaluated to overcome resistance mechanisms to anti-BCMA therapies.

Introduction

Multiple myeloma (MM) accounts for approximately 17% of all hematologic malignancies in the United States and in 2020, there were an estimated 12,830 myeloma-related deaths (1). MM remains incurable with estimated median overall survival (OS) of approximately 10 years with newer agents, such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAb) (2–5). Despite multiple effective treatments, most patients ultimately relapse or become refractory. A recent multicenter retrospective analysis of patients who have progressed on daratumumab-containing regimens demonstrated that survival for this patient population is poor with a median OS of 8.6 months (6). Patients with relapsed or refractory MM (RRMM) have progressively shorter durations of response with each subsequent line of standard salvage therapy (7). There remains an unmet need for novel approaches to provide durable responses and to evade resistance to prior therapies.

BCMA

B-cell maturation antigen (BCMA), also known as TNFRSF17 or CD269, is a member of the tumor necrosis factor receptor family (8–10). Its expression is restricted to some B-cell lineage cells with fairly uniform expression on normal plasma cells and myeloma cells, making it an ideal target antigen (11–13). It is essential for the survival of long-lived bone marrow (BM) plasma cells (12).

Ligands for BCMA include B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Engagement of BCMA by its ligands results in activation of p38/NF-κB to upregulate B-cell maturation, proliferation, and survival (14). Membrane bound BCMA can undergo γ-secretase-mediated shedding from the cell surface, leading to circulation of soluble BCMA (sBCMA) and reduced activation of surface BCMA by BAFF and APRIL. The overexpression and activation of BCMA are associated with progression of myeloma (9, 14–16).

For these reasons, BCMA has emerged as a promising target for MM. Here we review treatment modalities targeting BCMA, specifically antibody-drug conjugates (ADCs), bispecific antibody constructs, and chimeric antigen receptor (CAR) modified T cell therapies and provide an overview of therapies from these classes that have presented or published clinical data (Figure 1).

Figure 1.

Recent anti-BCMA therapeutic approaches to treat multiple myeloma. CAR: chimeric antigen receptor; BCMA: B-cell maturation antigen; BiTE: bispecific T-cell engager

Antibody drug conjugates (ADCs)

ADCs are molecules composed of a tumor-associated antigen mAb linked to a biologically active cytotoxic drug or payload. Once bound to the antigen expressing target cells, ADCs are internalized, and the toxic payload is released to induce DNA damage and cell death (17, 18).

Belantamab mafodotin

Belantamab mafodotin (belamaf) is an afucosylated, humanized IgG1 anti-BCMA mAb conjugated to the tubulin polymerization inhibitor, monomethyl auristatin F (MMAF) (17, 19, 20). Upon binding to the cell surface, belamaf is rapidly internalized, and MMAF is released inside the cell, causing disruption of the microtubule network which leads to cell cycle arrest and apoptosis. The afucosylated Fc region also facilitates the binding of effector cells to promote cell lysis of BCMA-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular-mediated phagocytosis (17).

Belamaf is the first BCMA-directed therapy to be FDA approved for RRMM patients who have received at least 4 prior lines, including an anti-CD38 mAb, a PI, and an IMiD in 2020. The multicenter, first-in-human phase 1 study comprised of dose escalation and expansion phases involving patients with progressive MM after stem cell transplant, alkylators, PIs, and IMiDs (19). It was administered intravenously (IV) every 3 weeks. Overall median PFS (mPFS) was 12 months (21). Corneal events were common (69%); most were grade ≤2 (54%) and did not require treatment discontinuation. Corneal events led to dose reduction and interruption in 46% and 49% of patients, respectively (21).

DREAMM-2 was a phase 2, randomized study to investigate the efficacy and safety of 2 doses of belamaf in RRMM patients with ≥ 3 prior lines of therapy, including a PI, IMiD, and anti-CD38 mAb (20, 22). Patients were randomized to receive belamaf at 2.5 mg/kg (n=97) or 3.4 mg/kg (n=99) every 3 weeks. The ORR in the 2.5 mg/kg cohort was 31%, including 19% with a ≥ very good partial response (VGPR). In the 3.4 mg/kg cohort, ORR was 35%, including 24% with a ≥VGPR. The median duration of response (DOR) for the 2.5 and 3.4 mg/kg cohorts were 11 months and 6.2 months, respectively. Median PFS was 2.8 months and 3.9 months, respectively. The estimated 1-year OS was 57%. The most common grade ≥3 adverse events (AEs) were keratopathy (2.5: 29%; 3.4: 24%), thrombocytopenia (2.5: 21%; 3.4: 32%), anemia (2.5: 20%; 3.4: 27%), pneumonia (2.5: 6%; 3.4: 13%), and neutropenia (2.5: 11%; 3.4: 16%). Discontinuations due to AEs were relatively uncommon (2.5: 9%; 3.4: 12%). The median time to onset of first keratopathy event was 37 and 22.5 days in the 2.5 and 3.4 mg/kg cohorts, respectively, with the majority of patients experiencing their first event by dose 4 (22).

Belamaf is currently being investigated in combination with various active agents. Trudel and colleagues presented the part 1 results of the phase 1 dose-escalation study of the combination of belamaf, pomalidomide, and dexamethasone in RRMM patients. Thirty-five patients were enrolled and the maximum tolerated dose (MTD) was established as 2.5 mg/kg single and 2.5 mg/kg split dose in combination with standard pomalidomide and dexamethasone dosing. At a median follow-up of 6 months, ORR for the 29 evaluable patients was 86%, including 15 VGPRs and 4 stringent complete responses (sCR) (23). Preliminary results from DREAMM-6 (NCT03544281) evaluating the safety and efficacy of the combination of belamaf, bortezomib and dexamethasone (Arm B) demonstrated an ORR of 78%, (50% with VGPR) (24). Keratopathy occurred in all patients, including 10 with grade 3 keratopathy.

MEDI2228

MEDI2228 is an ADC that targets the extracellular domain of human BCMA with preferential binding to membrane-bound versus circulating sBCMA. It is comprised of a fully human antibody to BCMA conjugated to a pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker. After cell surface binding to BCMA, MEDI2228 is internalized and cleaved in the lysosomal compartment, releasing PBD, which cross-links DNA and leads to apoptosis. A phase 1, first-in-human, dose-escalation and expansion trial (NCT03489525) evaluated the safety, pharmacokinetics (PK), and clinical activity of MEDI2228 in patients with RRMM who had progressed on a PI, IMiD, and mAb (25). Eighty-two patients had received MEDI2228 during dose escalation and expansion; by October 2020, 0 patients remained on treatment. The MTD was determined at 0.14 mg/kg IV every 3 weeks. Treatment-related AEs (TRAEs) in ≥ 20% of patients at the 0.14 mg/kg dose included photophobia (59%), thrombocytopenia (32%), rash (32%), increased gamma-glutamyl transferase (24%), and pleural effusion (24%). In the 0.14 mg/kg cohort, ORR was 66%, including 24% VGPR. Median DOR was 5.9 months. MEDI2228 exhibited linear PK at doses of ≥0.05 mg/kg every 3 weeks that was minimally impacted by circulating levels of sBCMA at baseline. There was no difference in BM BCMA expression of responders compared with non-responders (25).

Bispecific antibody constructs/T-cell engagers

Bispecific antibody constructs are engineered to bind two distinct epitopes to facilitate cell-to-cell interactions between T cells and cancer cells expressing tumor-specific antigens (5, 26, 27). This approach allows for CD3⁺ T cell activation without regard for T-cell receptor specificity or reliance on major histocompatibility complex (MHC) Class 1 molecules on the surface of antigen-presenting cells for activation, circumventing one of the resistance mechanisms that tumors cells develop to T-cell based therapies by evading detection (downregulation of MHC class molecules). Several different constructs are currently under investigation for the treatment of MM, such as BiTE^® (bispecific T-cell engager) molecules and DuoBody^® technology (Table 1). BiTE^® molecules are fusion proteins consisting of single-chain variable fragments (scFv) connected by a linker (26). DuoBody^® bispecific antibody constructs are generated through controlled Fab-arm exchange, which uses single matching point mutations in the CH3 domain and recombination to combine heavy and light chain homodimers from two separate mAbs into a single heterodimeric, bispecific antibody structure (28–30).

Table 1.

Bispecific antibody constructs

Product	AMG 420 [31]	AMG 701 [32]	Elranatamab (PF-06863135) [34, 35]	CC-93269 [36]	Teclistamab (JNJ-64007957) [40, 41]	REGN5458 [42]	TNB-383B [43]
Structure	BCMA × CD3 BiTE® molecule	Half-life extended (HLE) BCMA × CD3 BiTE® with the addition of an Fc domain	• Full-length, humanized, bispecific mAb • Anti-CD3 and anti-BCMA targeting arms paired on an IgG2a backbone by hinge-mutation technology	• Humanized 2+1 IgG1-based TCE • Binds bivalently to BCMA on PCs and to the TCR CD3ε subunit. • Bivalent binding → superior potency, tumor targeting and retention	Humanized IgG4 bispecific DuoBody® antibody	Humanized BCMA × CD3 bispecific antibody	• Fully human triple chain BCMA × CD3 bispecific antibody with a unique construct: • A low activating αCD3 moiety • 2 αBCMA domains • Silenced IgG4 backbone
Administration/Dose	• Continuous IV • DLs: 0.2 – 800 mg/day as continuous infusion × 4 weeks followed by 2 weeks off • 6 wk cycles	• IV • DLs: 5–45 μg; 0.14–1.2 mg; 1.6–18 mg • Weekly • 4 wk cycle	• IV and SC • DLs: 80, 130, 215, 360, 600, and 1000 μg/kg • Weekly	• IV • DLs: 0.15–10 mg • Weekly for C1-3 → every other week for C4-6 → monthly for C7+ for up to 2 years • 4 wk cycle	• IV and SC • DLs: 0.3–720 μg/kg IV • Dose levels: 80–3000 μg/kg SC • Weekly	• IV • DLs: 3–96 mg • Split dose for wk 1 and 2 → weekly dosing wk 3–16 → every other wk	• IV • DLs: 0.025–60 mg (ongoing dose escalation) • Every 3 wk
Study Design Patient population	• Phase 1 dose escalation study (NCT03836053) • RRMM (≥2L)	• Phase 1/2 study (NCT03287908) • RRMM (≥3L PIs, IMiDs, anti-CD38 mAb) • 62% triple-refractory	• Phase 1 dose-escalation (NCT03269136) • RRMM • Allowed prior anti-BCMA therapy	• Phase 1 dose-finding study (NCT03486067) • RRMM (≥3L) • 2 stages for dose escalation phase: Stage 1, CC-93269 given in fixed doses; stage 2, fixed first dose on C1D1, followed by intra-patient dose escalation on C1D8	• Phase 1/2 study (NCT03145181) • RRMM or intolerant to established therapies • 32% HR cytogenetics • 39% penta-refractory	• Phase 1/2 study (NCT03761108) • RRMM (≥3L, PIs, IMiDs, anti-CD38 mAb) • Non-secretory myeloma with measurable plasmacytomas • 57% penta-refractory	• Phase 1 dose-escalation and expansion (NCT03933735) • RRMM (≥3L, PIs, IMiDs, anti-CD38 mAb) • 34% penta-refractory
Number of pts treated at data cutoff	N=42	N=85	N=30	N=19	N=84 (IV) N=65 (SC)	N=49	N=58
Median Age (years)	65	64	63	64	63	64	66
Median lines of prior therapy	3.5	6	8 (23% with prior anti-BCMA therapy)	5	6	5	6
ORR	• 70% (MTD 400 μg/day, 10 pts) • 5 sCR/CR, 1 VGPR, 1 PR	• 26% (82 pts, 17% ≥VGPR) • 36% (3–18 mg, 55 pts, 24% ≥VGPR)	80% (215–1000 μg/kg SC, 20 pts)	• 43% (30 pts, 17% sCR/CR) • 89% (10 mg dose, 9 pts, 44% sCR/CR) • Median time to response 4.1 wks	• 73% (22 pts at RP2D, 55% ≥VGPR) • RP2D 1500 μg/kg SC	• 39% (49 pts, 37% ≥VGPR) • 63% (96 mg, 8 pts, 63% ≥VGPR)	80% (40–60 mg, 15 pts, 13% sCR/CR, 60% VGPR)
MRD negativity	100%† (5 evaluable pts ≥ CR at MTD)	86%* (7 pts ≥ VGPR)		92%* (13 pts)	73%* (11 pts)	57%* (7 pts)	75%* (4 pts)
Most common adverse events	SAEs: Infection (70%) Polyneuropathy (10%)	G ≥ 3 AEs: CRS (65%) Anemia (42%) Diarrhea (31%) Hypophosphatemia (31%) Neutropenia (25%), Thrombocytopenia (21%)	TRAEs: CRS (73%) Injection site reaction (53%) Lymphopenia (53%) Neutropenia (33%) Thrombocytopenia (27%).	G ≥ 3 TEAEs: Neutropenia (43%) Anemia (37%) Infections (30%) Thrombocytopenia (17%) General health deterioration (10%) Pyrexia (7%)	Neutropenia (57%) CRS (55%) Anemia (55%) Thrombocytopenia (40%) Pyrexia (30%) Infections: 52% (G ≥ 3: 15%)	G ≥ 3 TRAEs: CRS (39%) Fatigue (35%) Nausea (31%) Pyrexia (31%), Back pain (27%) Infection (47%, G ≥ 3: 18%)	CRS (45%) Fatigue (24%) Headache (22%) Infection (21%) Nausea (21%)
CRS	38% (G ≥ 3: 2%)	65% (G ≥ 3: 9%)	73% (all G ≤ 2)	77% (G ≤ 2: 73%)	55% (all G ≤2) 64% at the RP2D	39% (all G ≤ 2)	45% (all G ≤ 2)
Median time of onset of CRS			2 days		2 days	18.7 hrs	<1 day
Median duration of CRS		2 days	2 days		2 days	11.7 hrs	1 day
Neurotoxicity		7% (all G ≤ 2)			5% (G ≥ 3: none with SC)	12% (all G ≤ 2)

^*MRD status at ≥10⁻⁵ sensitivity

^†MRD status at 10⁻⁴ sensitivity

L: line

DL: dose level

ORR: overall response rate

MRD: minimal residual disease

CRS: cytokine release syndrome

sCR: stringent complete response

CR: complete response

VGPR: very good partial response

PR: partial response

G: grade

SAE: serious adverse event

TRAE: treatment-related adverse event

TEAE: treatment-emergent adverse event

AMG 420

AMG 420 (BI 836909) is a BCMA × CD3 BiTE^® molecule that has a very short half-life requiring continuous infusion to maintain efficacy. The phase 1 study reported an ORR of 70% at the MTD of 400 μg/day, including five minimal residual disease (MRD)-negative CRs, and one VGPR (31). Treatment-related serious AEs (SAEs) included two grade 3 polyneuropathies and one grade 3 edema. There was no grade ≥3 neurotoxicity, and the majority of cytokine release syndrome (CRS) events were grade ≤2. Although this drug has promising efficacy, the continuous IV infusions present logistical challenges, which has led to the development of AMG 701, a half-life extended (HLE) version of AMG 420.

AMG 701

AMG 701 is an HLE anti-BCMA BiTE^® (by the addition of an Fc domain) that is being investigated as a once weekly IV infusion. In the phase 1 first-in-human study, RRMM patients received AMG 701 weekly in a 4-week cycle (32). A 0.8 mg step-up dose was added prior to target doses ≥1.2 mg to prevent CRS. The most common AEs were CRS (65%), anemia (42%), diarrhea (31%), hypophosphatemia (31%), neutropenia (25%), and thrombocytopenia (21%). The majority of CRS events were grade ≤2. SAEs occurred in 38% of patients, including infections (17%) and CRS (9%). Reversible treatment-related neurotoxicity (all grade ≤2) was seen in 6 patients with a median duration of 1 day. ORR was 36% at doses 3–18 mg. Six out of 7 patients were MRD-negative with ongoing responses. The study is ongoing with continued dose escalation followed by a phase 2 dose expansion cohort. In addition, a sequential dose exploration cohort is planned to identify the recommended phase 2 dose (RP2D) of AMG 701 in combination with pomalidomide +/− dexamethasone (NCT03287908).

Elranatamab

Elranatamab (PF-06863135) is full-length, humanized, bispecific mAb with anti-CD3 and anti-BCMA targeting arms paired on an IgG2a backbone by hinge-mutation technology (33). The phase 1 study in RRMM demonstrated that IV dosing at 0.1–50 μg/kg weekly had anti-myeloma activity without reaching the MTD. Raje and colleagues reported on 17 patients who received elranatamab IV once weekly (34). Ten (59%) patients had a TRAE including CRS (24%), thrombocytopenia (24%), anemia (18%), and pyrexia (18%). Sixteen patients were evaluable for response: one with a minimal response and 6 with stable disease.

Subcutaneous (SC) dose escalation of elranatamab was then explored to reduce the maximum concentration (C_max), to achieve a more favorable therapeutic window and reduce the risk of CRS (35). Thirty patients received elranatamab at 80, 130, 215, 360, 600, and 1000 μg/kg weekly. Dose escalation is ongoing, and MTD has not been reached. The most common TRAEs were CRS (73%; all grade [G] ≤2), injection site reaction (53%), lymphopenia (53%), neutropenia (33%), and thrombocytopenia (27%). The ORR was 80% at 215–1000 μg/kg. Compared to IV, SC dosing did modulate the C_max allowing for higher doses to be administered without increased severity of CRS. SC dose escalation is ongoing and combination with standard therapies is being investigated. The phase 2 MagnetisMM-3 study is also ongoing (NCT04649359).

CC-93269

CC-93269 is a humanized 2+1 IgG1-based T-cell engager (TCE) that binds bivalently to BCMA on myeloma labs and to the T-cell receptor CD3ε subunit. The bivalent binding is thought to lead to superior potency, tumor targeting and retention (36). A phase 1 study in RRMM evaluated the safety and tolerability of CC-93269 administered IV weekly for cycles (C) 1–3, every other week for C4–6, and monthly for C7+ in a 28-day cycle for up to 2 years (37). The dose-escalation phase involved 2 stages: stage 1, CC-93269 given in fixed doses; stage 2, patients received a fixed first dose on C1D1, followed by intra-patient dose escalation on C1D8. For the 30 patients who had received CC-93269 from 0.15–10 mg, ORR was 43%. For the highest dose cohort (10 mg), ORR was 89%, including 44% sCR/CR (37). The most common grade ≥3 TRAEs were neutropenia (43%), anemia (37%), infections (30%), thrombocytopenia (17%), general physical health deterioration (10%), and pyrexia (7%). CRS was seen in 77% of patients with the majority being grade ≤2 and occurred most frequently with the first or second dose.

Teclistamab

Teclismatab (JNJ-64007957) is a humanized IgG4 bispecific DuoBody^® antibody that recruits CD3-expressing T cells to BCMA-expressing myeloma cells, which leads to the activation of T cells and subsequent target cell lysis mediated by secreted perforin and various granzymes stored in cytotoxic T cells (38, 39). A phase 1 study of teclistamab in RRMM explored various SC and IV doses +/− step-up doses. Interim results of teclistamab IV (0.3 – 270 μg/kg) included 78 patients and found that the most common TRAEs were CRS (56%), anemia (58%), neutropenia (45%), and thrombocytopenia (40%) (40). CRS events were all grade 1–2 and generally confined to the initial doses. Six patients had neurotoxicity, including 3% grade ≥3. Infection-related AEs were reported in 65% of patients. PK results indicated that the half-life of teclistamab supported weekly dosing. At the 270 μg/kg dose (n=12), the ORR was 67%. Updated results presented by Garfall and colleagues included 65 patients who received teclistamab SC (80–3000 μg/kg) and 84 who received IV (0.3–720 μg/kg) (41). RP2D for SC teclistimab was 1500 μg/kg. The most common TRAEs with the combined IV and SC cohorts included CRS (55%), neutropenia (57%), and anemia (55%). At the RP2D of 1500 μg/kg, ORR was 73% (55% ≥VGPR). Two of 107 patients had antidrug antibodies at low titer. From preliminary population PK analysis, sBCMA does not appear to impact teclistamab exposure. The phase 1 study is ongoing, and the phase 2 expansion study has started. Various combination studies are planned for teclistimab with daratumumab (NCT04108195; NCT04722146), talquetamab (GPRC5D x CD3 DuoBody^® antibody; NCT04586426), IMiDs, PIs, and nirogacestat, a γ-secretase inhibitor (GSI) (NCT04722146).

REGN5458

REGN5458 is a humanized BCMA × CD3 bispecific antibody. In a phase 1/2 study, REGN5458 was given to RRMM patients (included non-secretory myeloma with measurable plasmacytomas) as a split dose for week 1 and week 2 followed by weekly dosing from week 3–16, then transitioned to every other week (42). The most common TRAEs included CRS (39%), fatigue (35%), nausea (31%), pyrexia (31%), and back pain (27%). CRS occurred primarily during the initial doses and were all grade ≤2. ORR was 39% across all dose levels. At the 96 mg dose (n=8), the ORR was 62.5%. Responses occurred early (most by 4 weeks) and deepened with time. The observed median DOR was 6.0 months (1.0–13.1 months). Tumor responses were not impacted by the level of BM BCMA expression. Enrollment in the phase 1 dose-escalation portion is ongoing, and the phase 2 portion is actively recruiting.

TNB-383B

TNB-383B is fully human triple chain BCMA × CD3 bispecific antibody with a unique construct including a low activating αCD3 moiety that preferentially activates effector T cells over regulatory T cells (targeting lysis with minimal cytokine release), 2 αBCMA domains to favor cell surface BCMA binding, and a silenced IgG4 backbone to prevent non-specific T-cell activation and confer a longer half-life. In a phase 1 study, RRMM patients received TNB-383B (0.025–60 mg) IV every 3 weeks at fixed doses (43). The most common AEs were CRS (45%), fatigue (24%), headache (22%), infection (21%), and nausea (21%). Thus far, 2 DLTs were observed, including grade 3 confusion (not ICANS-related) and grade 4 thrombocytopenia, which both resolved without sequelae. All CRS cases were limited to grade ≤ 2. ORR for cohorts receiving 40–60 mg was 80%, including 73% ≥VGPR. Dose escalation and expansion portions of the study are ongoing.

Chimeric antigen receptor (CAR)-modified therapy

CAR T cells are genetically modified T cells that express a chimeric antigen receptor (CAR) against a specific tumor antigen, which upon binding to the antigen initiates T cell activation (44–46). These CAR constructs consist of an extracellular non-MHC restricted targeting domain usually derived from a scFv, a spacer region, a transmembrane domain, an intracellular signaling domain (CD3ζ), and a co-stimulatory domain (e.g., CD28, OX40, 4–1BB)(45–47). CAR T cells are typically obtained from patients (autologous CAR T cells) or healthy donors (allogeneic CAR T cells) via leukapheresis, modified to express the CAR, and expanded ex vivo. While the CAR T cells are being manufactured, patients may receive bridging therapy to maintain disease control prior to CAR T infusion. Before infusion of the expanded CAR T cells, most patients receive a lymphodepleting chemotherapy regimen which reduces endogenous levels of lymphocytes to create a favorable environment for CAR T cell expansion, persistence, and activity. These cells combine the target specificity of a mAb with the enhanced cytotoxicity of T cells without requiring HLA presentation of the target antigen (5, 47).

Several BCMA-targeted CAR T-cell therapies have demonstrated promising efficacy in clinical trials for RRMM (Table 2).

Table 2.

CAR T cell therapies

Product	Structure/Manufacturing	Study design	Efficacy	Safety
Idecabtagene vicleucel (ide-cel; bb2121) [48, 49, 50]	• Murine scFv • 4-1BB costimulatory domain • CD8α hinge and transmembrane domains • Culture/activation medium: anti-CD3 and anti-CD28, OKT3 • Transduction: lentiviral vector	• CRB-401: Phase 1 two-part trial (NCT02658929) • Dose escalation: RRMM, ≥3L, ≥50% BCMA expression on PCs • Dose expansion: exposed to daratumumab, refractory to last line, no BCMA expression required • Lymphodepletion regimen^ before ide-cel infusion • DL: 50, 150, 450, 800 × 106 cells • Median age: 61 years • Median prior lines: 6 • 27.4% HR cytogenetics • 32 pts (51.6%) received bridging therapy	• ORR (62 pts): 76% (39% sCR/CR, 26% VGPR, 11% PR) • MRD-† (15 evaluable pts ≥ CR): 100% • mDOR: 10.3 months • mPFS: 8.8 months • mOS: 34.2 months • Target dose ≥ 150 × 106CAR+ T cells • 96%, 86%, 57%, and 20% of pts had detectable CAR+ T cells at 1, 3, 6, and 12 months, respectively	• Most common G ≥ 3 AE: neutropenia (85%), leukopenia (58%), anemia (45%), thrombocytopenia (45%) • CRS: 76% (G ≥ 3: 7%) • Median time to CRS onset: 2 days • Median duration of CRS: 5 days • NT: 35% (G ≥ 3: 2%) • Median time to NT onset: 5 days • Median duration of NT: 3 days
		• KarMMa: multicenter phase 2 (NCT03361748) • RRMM (≥3L, PI, IMiD, anti-CD38 mAb, refractory to last line) • Lymphodepletion regimen^followed by 150–450 × 106CAR+ T cells • N=128 received ide-cel, 140 enrolled • Median age: 61 years • Median prior lines: 6 • 26% penta-refractory • 88% had bridging therapy (4% with response)	• ORR (128 pts): 73% (33% sCR/CR) • MRD-* and s≥ CR: 26% • MRD-* and ≥ VGPR: 39% • mDOR: 10.7 months • mPFS: 8.8 months • mOS: 19.4 months • Median peak CAR+ T expansion 11 days • 59% (of 49 pts) and 36% (of 11 pts) had detectable CAR+ T cells at 6 and 12 months, respectively	• Most common AEs: cytopenia (97%), CRS (84%) • CRS: 84% (G ≥ 3: 5%, including 1 G5 at 300 × 106dose) • Median time to CRS onset: 1 days • Median duration of CRS: 5 days • NT: 18% (G ≥ 3: 3%) • Median time to NT onset: 2 days • Median duration of NT: 3 days
bb21217 [51]	bb2121 structure with ex vivo culture with addition of PI3K inhibitor, bb007, to increase memory-like T-cell phenotype	• CRB-402: Phase 1 two-part trial (NCT03274219) • RRMM (≥3L, ≥50% BCMA expression on PCs for escalation phase, prior CD38 mAb exposure and refractory to last line for expansion phase) • Lymphodepletion regimen^ before bb21217 infusion • Dose escalation levels: 150, 300, or 450 × 106 CAR+ T cells • Dose expansion: 300 and 450 × 106 CAR+ T cells • N=69 • Median age: 62 years • Median prior lines: 6 • 23% HR cytogenetics • 44% triple-refractory	• ORR (59 pts): 68% (17 sCR/CR, 15 VGPR, 8 PR) • MRD-* (28 responders ≥ PR): 89% • mDOR: 17 months • Enrichment of memory-like T-cells associated with peak CAR T expansion and response • CAR T cell persistence observed in 6/11 and 3/6 pts at month 12 and 18, respectively • Phase 1 CRB-402 has completed enrollment; follow-up is ongoing.	• Most common G ≥ 3 AE: lymphopenia, leukopenia, anemia, thrombocytopenia, neutropenia • CRS: 70% (G ≥ 3: 4%, including 2 G5) • Median time to CRS onset: 2 days • Median duration of CRS: 4 days • NT: 16% (G ≥ 3: 4%) • Median time to NT onset: 7 days • Median duration of NT: 2 days • 2 deaths within 8 wks of bb21217 infusion due to CRS
Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528 in the US, LCAR-B38M in China) [52, 53, 54]	• 2 bispecific anti-BCMA epitopes • scFv: variable heavy-chain only, llama derived • 4-1BB signaling domain • CD8α hinge and transmembrane region • Culture/Activation medium: IL-2 • Transduction: lentiviral vector	• Phase 1 LEGEND-2 (NCT03090659) • RRMM in China • Lymphodepletion with cyclophosphamide followed by 3 infusions of cilta-cel over 7 days. • Median cilta-cel dose: 0.5 × 106 cells/kg • N=57 • Median age: 54 years • Median prior lines: 3	• ORR (57 pts): 88% (39 CR, 3 VPGR, 8 PR) • MRD-† (57 evaluable pts): 63% • mDOR: 22 months • mPFS: 20 months • mOS: NR	• Most common G ≥ 3 AE: leukopenia (30%), thrombocytopenia (23%), AST increased (21%) • CRS: 90% (G ≥ 3: 7%) • Median time to CRS onset: 9 days • Median duration of CRS: 9 days • NT: 1 pt (G1)
		• Phase 1b/2 CARTITUDE-1 (NCT03548207) • RRMM (≥3L or double refractory to PI and IMiD and received anti-CD38 mAb) • Lymphodepletion regimen^ before single cilta-cel infusion • Target dose 0.75 × 106 CAR+ T cells/kg • N=97 (29 phase 1b, 68 phase 2) • Median age: 61 years • Median prior lines: 6 • 23.7% HR cytogenetics • 42.3% penta-refractory • 73 pts received bridging therapy • Median production time: 29 days	• ORR (97 pts): 96.9% (67% sCR/CR, 25.8% VGPR, 4.1% PR) • MRD-* (53 evaluable pts): 93% • mPFS: NR • 12-month PFS rate: 76.6% • 12-month OS rate: 88.5%	• Most common AE: CRS (95%), neutropenia (91%), anemia (81%), thrombocytopenia (79%). • Grade ≥ 3 infection: 20% • CRS: 95% (G ≥ 3: 4.1%) • Median time to CRS onset: 7 days • Median duration of CRS: 4 days • ICANS: 16.5% (G ≥ 3: 2.1%) • Median time to ICANS: 8 days • Median duration of ICANS: 4 days • 14 deaths (9 due to AEs, 5 due to PD)
Orvacabtagene autoleucel (orva-cel; JCARH125) [55, 56]	• Fully human anti-BCMA scFV, modified spacer • CD28 transmembrane domain • 4-1BB costimulatory domain • Transduction: lentiviral vector • Optimized manufacturing to deliver a product comprising purified CD4+ and CD8+ CAR T cells enriched for central memory phenotype	• Phase 1/2 EVOLVE (NCT03430011) • Lymphodepletion regimen^ followed by orva-cel infusion • DLs: 50, 150, 300, 450, 600 × 106 CAR+ T cells • RRMM (≥3L, refractory to last line; BCMA cohort – relapsed after prior anti-BCMA therapy) • Median age: 61 years • Median prior lines: 6 • 41% HR cytogenetics (include 1q21 abnormality) • 48% penta-refractory • 63% had bridging therapy	• ORR (62 pts): 92% (36% sCR/CR, 32% VGPR, 24% PR) • MRD-* (25 evaluable pts): 84% at month 3 • Persistence of CAR+ T cells detected in 69% (20/29) pts at month 6 • High baseline sBCMA did not impact orva-cel activity • 12/12 pts with high baseline sBCMA achieved ≥ PR. • Enrollment at RP2D of 600 × 106 CAR+ T cells is ongoing	• Most common AEs: neutropenia (90%), CRS (89%), thrombocytopenia (52%), anemia (50%) • Grade ≥ 3 infection: 13% • CRS: 89% (G ≥ 3: 3%) • Median time to onset of CRS: 2 days • Median duration of CRS: 4 days • NT (G ≥ 3): 3% • Median onset of NT: 4 days • Median duration of NT: 4 days • MAS/HLH (G ≥ 3): 5%
CT053 [57, 58]	• Human anti-BCMA scFv • 4-1BB costimulatory domain	• Multicenter phase 1 investigator-initiated study in eastern China • RRMM (≥2L, ≥ 50% BCMA expression on PCs) • Lymphodepletion regimen^ followed by a single infusion of CT053 • DL: 0.5, 1.0, 1.5, 1.8 × 108 CAR+ T cells • 24 pts treated (21 pts at 1.5 × 108 CAR+ T cells) • Median age: 60 years • Median prior lines: 5 • 71% HR cytogenetics	• ORR: 87.5% (79% sCR/CR) • mDOR: 21.8 months • mPFS: 18.8 months • Median CAR+ T cell persistence: 161 days	• Most common G ≥ 3 AE: leukopenia (83%), neutropenia (85%), lymphopenia (79%), thrombocytopenia (21%) • CRS: 63% (all G ≤ 2) • CRS occurred 1–4 days after infusion • Median duration of CRS: 6 days • NT: 1 pt G ≥ 3 (seizure)
		• Phase 1b/2 LUMMICAR-2 study (NCT03915184) • RRMM in North America (≥3L, refractory to last line) • Lymphodepletion regimen^ followed by single infusion of 1.5–3.0 × 108 CAR+ T cells. • N=20 (14 pts 1.5–1.8 × 108 and 6 pts 2.5–3.0 × 108) • Median age: 62 years • Median prior lines: 5 • 55% HR cytogenetics (including 1q gain) • 50% penta-refractory • 25% had extramedullary disease • 85% had bridging therapy	• ORR (18 pts): 94% (5 sCR/CR, 5 VGPR, 7 PR) • Responses were independent of baseline BM BCMA expression • CT053 transgene levels showed expansion and persistence with peak expansion at 7–14 days. • Phase 2 portion of LUMMICAR-2 is ongoing	• Most common G ≥ 3 AE: neutropenia (100%), leukopenia (100%), thrombocytopenia (36%) • CRS: 78% (all G ≤ 2) • Median time of CRS onset: 2 days • Median duration of CRS: 4 days • ICANS: 3 pts (1 pt G3 ICANS)
P-BCMA-101 [60]	• Anti-BCMA Centyrin™ fused to a CD3ζ/4-1BB signaling domain, safety switch and selection gene • piggyBac® (PB) DNA Modification System • Modified manufacturing process now uses Nanoplasmid (NP) to improve transposition of P-BCMA-101 • Manufacturing system produces cells with a high percentage of TSCM phenotype	• Phase 1/2 PRIME study (NCT03288493) • RRMM (≥3L if exposed to PI + IMiD, ≥2L if refractory to PI + IMiD, allows for prior anti-BCMA or CAR T cell therapy) • Lymphodepletion regimen^ followed by P-BCMA-101 infusion • Multiple cohorts:  • single administration (0.75 to 15 × 106 CAR+ T cells/kg)  • cyclic administration (1/3 + 2/3 dose vs 1/3 + 1/3 + 1/3)  • combination (with lenalidomide after apheresis, with lenalidomide before apheresis, and with rituximab) • Median age: 60 years • Median prior lines: 8 • 4 pts were refractory to anti-BCMA therapy	• ORR (34 pts with original manufacturing process): 57% • ORR (6 pts with modified manufacturing using NP at 0.75 × 106dose): 67% (50% ≥ VGPR) • Circulating P-BCMA-101 cells peaked at 2–3 weeks after infusion and remained detectable for up to 1.5 years. • Dose escalation is continuing in the Nanoplasmid group	• Most common AEs: neutropenia (77%), thrombocytopenia (42%), anemia (40%), leukopenia (40%), and infection (45%) • CRS: 17% (all G ≤ 2) • NT: 2 pts (both G3)
ALLO-715 [61]	• Allogeneic CAR T therapy • Human anti-BCMA scFv • 4-1BB costimulatory domain • TALEN-mediated CD52 KO allows for selective lymphodepletion with ALLO-547 • TALEN-mediated TRAC KO eliminates TCRα to minimize risk of GvHD	• Phase 1 UNIVERSAL (NCT04093596) • RRMM (≥3L, refractory to last line, no donor-specific antibodies) • No bridging therapy allowed • DLs: 40, 160, 320, and 480 × 106 CAR+ T cells • Lymphodepleting regimens: fludarabine (30 mg/m2/day × 3 days; F), cyclophosphamide (300 mg/m2/day × 3 days; C), ALLO-647 (13–30 mg × 3 days; A)  • FCA, CA • Median age: 65 years • Median prior lines: 5 • 48% HR cytogenetics • 94% penta-exposed	• ORR (26 pts): 42% (6 ≥ VGPR) • ORR at 320M cell dose (10 pts): 60% (4 ≥ VGPR) • MRD-* (5 evaluable pts): 100% • Median time to response: 16 days • Improved expansion at higher cell doses • Expansion and persistence observed through month 4	• Most common G ≥ 3 AE: anemia (42%), neutropenia (42%), lymphopenia (29%) • CRS: 45% (all G ≤ 2) • No GVHD • No ICANS

^{^}lymphodepletion with cyclophosphamide and fludarabine (doses varied)

^*MRD status at ≥10⁻⁵ sensitivity

^†MRD status at 10⁻⁴ sensitivity

L: line

DL: dose level

PC: plasma cells

ORR: overall response rate

MRD: minimal residual disease

CRS: cytokine release syndrome

sCR: stringent complete response

CR: complete response

VGPR: very good partial response

PR: partial response

PD: progressive disease

mDOR: median duration of response

mPFS: median progression free survival

mOS: median overall survival

PI: proteasome inhibitor

IMiD: immunomodulatory agent

mAb: monoclonal antibody

G: grade

NT: neurotoxicity

NR: not reached

NP: nanoplasmid

MAS/HLH: macrophage activation syndrome/hemophagocytic lymphohistiocytosis

GVHD: graft-versus-host-disease

ICANS: immune effector cell-associated neurotoxicity syndrome

RP2D: recommended phase 2 dose

KO: knockout

scFv: single-chain variable fragments

RRMM: relapsed or refractory multiple myeloma

T_SCM: T stem cell memory

sBCMA: soluble B-cell maturation antigen

Idecabtagene vicleucel (ide-cel)

Ide-cel (bb2121) is an anti-BCMA CAR T cell therapy that utilizes a lentiviral vector for CAR insertion and includes a 4–1BB costimulatory domain and murine scFv. The phase 1 multicenter trial (CRB-401) for RRMM patients treated at various doses demonstrated an ORR of 85%, including 45% with sCR/CR (48, 49). The most common grade ≥ 3 AEs were hematologic including neutropenia (85%), leukopenia (58%), anemia (45%), and thrombocytopenia (45%). CRS occurred in 76% patients, of which 70% were grade ≤ 2 and 2 patients had grade 3 CRS. Neurotoxicity occurred in 14 (42%) patients and were grade ≤ 2 in 13 (39%) patients. The mPFS was 11.8 months; median DOR was 10.9 months. The dose of 150–450 × 10⁶ CAR T cells has been evaluated in the multicenter phase 2 KarMMa trial. The ORR of ide-cel was 73% with CR rate (CRR) of 33% and median DOR and PFS of 10.7 and 8.8 months, respectively (50). For the 54 patients treated at 450 × 10⁶ cells, the ORR was 82%, including 39% CRR with a median PFS of 12.1 months. The incidence of CRS increased with the dose, but the majority were grade ≤ 2. There were 5 deaths (4%) within 8 weeks of ide-cel infusion, including 2 for progression and 3 from AEs (CRS, aspergillus pneumonia, gastrointestinal bleed). Based on these findings, ide-cel was approved by the FDA for the treatment of advanced MM after at least 4 prior lines of therapies, including an IMiD, a PI, and an anti-CD38 mAb.

The use of ide-cel in various other settings is an area of active investigation: in triple-class exposed RRMM and high-risk MM patients in the phase 2 KarMMa-2 study (NCT03601078); in comparison to standard regimens in RRMM in the phase 3 KarMMa-3 study (NCT03651128); and in high risk NDMM in the phase 1 KarMMa-4 (NCT04196491).

bb21217

bb21217 is bb2121 that is cultured in the presence of the phosphoinositide-3 kinase inhibitor bb007 ex vivo to promote a memory-like phenotype, in order increase the persistence and potency of CAR T cells. CRB-402 is a phase 1 dose escalation study of bb21217 (150, 300, or 450 × 10⁶). Among the 69 RRMM patients treated, CRS developed in 70% (majority grade ≤ 2) and neurotoxicity developed in 16% (51). There were 2 deaths within 8 weeks of bb21217 infusion due to CRS. ORR was 68% including 29% with sCR/CR and 25% with VGPR. The median DOR was 17 months. The target dose of 450 × 10⁶ CAR T cells was selected as the RP2D and follow-up is ongoing. Long-term CAR T cell persistence was observed in 6/11 evaluable patients at month 12 and 3/6 patients at month 18 (51).

Ciltacabtagene autoleucel (cilta-cel)

Cilta-cel (JNJ-68284528) is a CAR T cell product with two BCMA-targeting llama-derived single-domain antibodies designed to confer avidity. This product was developed in the US based on data from LCAR-B38M in China. The multicenter phase 1 LEGEND-2 study in China treated 57 RRMM patients with 3 infusions of LCAR-B38M administered over 7 days and resulted in an ORR of 88% (68% CR, 5% VGPR, 14% PR), and an MRD negativity rate of 63% (52). At a median follow-up of 19 months, mPFS was 20 months (53). The most common grade ≥3 AEs were leukopenia (30%), thrombocytopenia (23%), and increased AST (21%). CRS occurred in 90% of patients including 7% with grade ≥3 CRS.

In the phase 1b/2 CARTITUDE-1 study RRMM patients in the United States received a single infusion of cilta-cel at a target dose of 0.75 × 10⁶ CAR+ T cells/kg. On a recent update with 97 patients treated, ORR was 97% with 67% with sCR and 26% with VGPR (54). Median time to first response was 1 month. Of the 53 evaluable patients, 93% were MRD negative. The 12-month PFS and OS rates were 76.6% and 88.5%, respectively. Although the response rates are unprecedented, the 14 deaths that occurred in the study is concerning but most were due to infection or progressive disease (PD) and not directly related to the product (9 were due to AEs, including CRS/ hemophagocytic lymphohistiocytosis [HLH], neurotoxicity, respiratory failure, sepsis, septic shock, pneumonia, lung abscess, and acute myeloid leukemia and 5 due to PD). The most common AEs were CRS (95%; grade [G] 3/4 4%), neutropenia (91%; G3/4 91%), anemia (81%; G3/4 68%), and thrombocytopenia (79%; G3/4 60%). Grade 3/4 infection occurred in 20% of patients. CAR T cell-related neurotoxicity was reported in 21% of patients (G3/4 10%) (54). Further investigations of cilta-cel in other myeloma populations are ongoing: CARTITUDE-2 (NCT04133636) will include different cohorts such as triple-class exposed RRMM (≤3 lines [L], high risk MM (1L with PD <12 months from ASCT), RRMM with prior BCMA-direct therapy, and NDMM; CARTITUDE-4 (NCT04181827) will compare cilta-cel with standard therapy in RRMM (≤3L).

Orvacabtagene autoleucel (orva-cel)

Orva-cel (JCARH125) is a fully human CAR T cell product with low affinity for sBCMA, a 4–1BB costimulatory domain and optimized manufacturing to deliver a product comprising purified CD4+ and CD8+ CAR T cells enriched for central memory phenotype. The phase 1/2 EVOLVE study is evaluating the safety and efficacy of increasing doses of orva-cel in RRMM patients (55, 56). The ORR for patients treated with 50 and 150 × 10⁶ CAR+ T cells was 79% and 86% with CRR of 43% and 18%, respectively (55). For the 62 patients treated with 300, 450, and 600 × 10⁶ CAR+ T cells, ORR was 92%, including 68% with ≥VGPR (56). The incidence of grade ≥3 infection was 13%. CRS occurred in 89% of patients (3% with G≥3); neurologic events occurred in 13% of patients. Macrophage activation syndrome (MAS)/HLH G≥3 was reported in 3 patients. There were 2 deaths within 90 days of orva-cel infusion (1 due to G5 MAS/HLH). Persistence of CAR+ T cells was detected in 69% of the 29 evaluable patients at month 6. Enrollment at the RP2D of 600 × 10⁶ CAR+ T cells is ongoing and will include a cohort of patients who progressed after anti-BCMA directed therapies.

CT053

CT053 is a CAR T cell product comprised of a fully human BCMA-specific scFv (25C2) with high binding affinity with a 4–1BB costimulatory signal domain. It is manufactured in 8–10 days. A phase 1 study in China involved RRMM patients treated at various doses (0.5, 1.0, 1.5, 1.8 × 10⁸) (57). Of the 24 patients treated, 21 patients received 1.5 × 10⁸ cell dose. ORR was 87.5% (79% with sCR/CR). Median PFS was 18.8 months. The most common TRAEs grade ≥3 included leukopenia (83%), neutropenia (85%), lymphopenia (79%), and thrombocytopenia (21%). CRS occurred in 63% of patients and were grade ≤2. One patient experienced grade 3 neurotoxicity (seizure). CT053 expansion was detected 1–7 days after infusion and peaked between day 7–21. Median T cell persistence was 161 days.

LUMMICAR-2 is the phase 1b/2 study of CT053 in North America administered as a single infusion of 1.5–3.0 × 10⁸ CAR+ T cells. For the 20 patients treated, including 6 receiving 2.5–3.0 × 10⁸ cells, the most common grade ≥3 AEs were hematologic, including neutropenia (100%), leukopenia (100%), thrombocytopenia (36%) within 30 days of treatment (58). CRS occurred in 78% of patients (all G≤2). Three patients had immune effector cell-associated neurotoxicity syndrome (ICANS), including 1 grade 3. After a median follow-up of 6 months, 18 patients were evaluable for response, and ORR was 94% with 5 sCR/CR, 5 VGPR, and 7 PR. Responses were independent of the baseline BM BCMA expression. CT053 transgene levels showed expansion and persistence with peak expansion at 7–14 days (58). The phase 2 portion of LUMMICAR-2 is ongoing.

P-BCMA-101

P-BCMA-101 is a novel anti-BCMA CAR T cell product produced using the piggyBac (PB) DNA Modification System instead of a viral vector, requiring only plasmid DNA and mRNA (59, 60). This manufacturing system makes it less costly and produces cells with a high percentage of T stem cell memory (T_SCM) phenotype, which has been associated with better clinical responses, gradual tumor killing resulting in less toxicity, better DOR, and potential for re-response. Moreover, the higher cargo capacity of PB allows the incorporation of multiple genes in addition to the CAR, including a safety switch for rapid CAR T cell elimination or a selection gene allowing for enrichment of CAR+ cells. P-BCMA-101 has a Centyrin™ fused to a CD3ζ/4–1BB signaling domain. Centyrins are fully human fibronectin domain with high specificity and potentially less immunogenicity than traditional scFv. A modified manufacturing process using nanoplasmids was recently incorporated to improve transposition of P-BCMA-101 (60).

The phase 1/2 PRIME study enrolled patients with RRMM, allowing for prior BCMA or CAR T cell therapy, into multiple exploratory cohorts: single administration (0.75 to 15 × 10⁶ CAR T cells/kg), cyclic administration (1/3 dose + 2/3 dose vs 1/3 + 1/3 + 1/3), combination (with lenalidomide after apheresis, with lenalidomide before apheresis, and with rituximab) (60). The most common AEs were cytopenias and infection. CRS was seen in 17% of patients (all G≤2) and 4% with grade 3 neurotoxicity. The overall safety profile of P-BCMA-101 has allowed for 16 patients to date to receive all study-related treatments as an outpatient. ORR was 57% in 34 evaluable patients using the original manufacturing process. The current process with nanoplasmids at the 0.75 × 10⁶ dose resulted in an ORR of 67% for 6 patients. Consistent with having a high percentage of T_SCM, circulating P-BCMA-101 cells peaked at 2–3 weeks after infusion and remained detectable for up to 1.5 years. Response correlated with the C_max and AUC of cell expansion, both of which did not correlate with dose administered (60). The trial is ongoing in the nanoplasmid groups.

ALLO-715

ALLO-715 is a genetically modified anti-BCMA allogeneic CAR T cell product with a 4–1BB costimulatory domain in which the T-cell receptor (TCR)α constant gene is disrupted to reduce the risk of graft-versus-host-disease (GVHD) and the CD52 gene is disrupted with TALEN technology, a genome editing technology, to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion. It is manufactured from peripheral blood mononuclear cells obtained from healthy volunteer donors. The phase 1 UNIVERSAL study is evaluating ALLO-715 at varying dose levels (40, 160, 320, and 480 × 10⁶ CAR+ T cells) without bridging therapy and various conditioning regimens with ALLO-647 (61). The ORR was 60% at the 320 × 10⁶ dose level. The most common grade ≥3 AEs were anemia (42%), neutropenia (42%), lymphopenia (29%). No neurotoxicity or GVHD has been reported. CRS was observed in 45% of patients, all grade ≤2. Thirteen (42%) patients had infection. There was a single death related to PD and the conditioning regimen (cyclophosphamide and ALLO-647). Improved cell expansion was noted in patients who received higher cell doses and persistence was observed up to month 4 in some patients treated at dose level 3. Enrollment is ongoing at the higher cell doses (ALLO-715) and lymphodepletion (ALLO-647), and the combination of ALLO-715 and nirogacestat is being investigated.

Mechanisms of relapse or resistance

For anti-BCMA CAR T cell therapy in MM, 3–40% of these patients will become refractory and 15–50% of patients who achieve a CR will relapse during the first year of follow-up (48, 50, 52, 54, 56, 62, 63). Although the data is still preliminary, there is evidence that a proportion of patients will relapse with longer follow-up. Although the mechanisms of resistance are not fully elucidated, observations and hypotheses regarding potential limitations of BCMA-directed therapies have been reported and may be affected by antigen escape mechanisms.

Anti-CAR antibodies

For BCMA-directed CAR T cells, the use of non-human-derived scFv may contribute to CAR T cell inactivation due to HLA-restricted T-cell mediated immune response and the presence of anti-CAR T cell antibodies (47, 64, 65). Xu and colleagues found anti-CAR T cell antibodies in 6 patients before or after relapse from cilta-cel that has a llama variable heavy chain scFv (64). The presence of these antibodies was associated with a reduction in the number of residual CAR T cells (64). Multiple CAR T products have used fully human scFv (e.g., orva-cel) to reduce antigenicity and thus increase persistence and improve efficacy. This strategy may allow for re-challenge with the same or different CAR.

T cell fitness and subset composition

T cell fitness and subset composition have been found to affect expansion and response. CAR T cells manufactured from older donor T cells had worse transduction efficiency and impaired effector functions when compared to younger donor T cells (66). Multiple studies are ongoing to evaluate the use of CAR T cell therapy in earlier lines of treatment (KarMMa-4, KarMMa-2, CARTITUDE-2, CARTITUDE-4). There is evidence that tailored composition of T cell subsets could increase efficiency and persistence. A higher CD4⁺/CD8⁺ T cell ratio in the product has been associated with better expansion and response. More naïve T_SCM and central memory T cells have also been associated with better expansion and clinical response (63). Therefore, various products (e.g., orva-cel) are manufactured using a 1:1 ratio before and after gene transfer to homogenize the amount of T cells infused and enhance crosstalk between CD4+ and CD8+ T cells. To enrich for memory-like T cells, bb21217 uses bb007, a PI3K inhibitor during ex vivo culture to block T cell differentiation signaling with the expectation that it will enhance persistence and potency. P-BCMA-101 using the non-viral piggyBac^® (PB) DNA Modification System favors enrichment of T_SCM phenotype.

Tumor and soluble BCMA

sBCMA can bind to and interfere with anti-BCMA therapies thereby potentially affecting efficacy and durability (67). The presence of sBCMA could also be an obstacle to CAR T cell therapy. A minimum threshold of antigen expression may be needed for CAR T cell activation (68, 69). A reduction in the density of BCMA on the tumor cell surface may not allow it to reach the threshold that triggers the effector functions of CAR T cells and would hamper the scFv domain of the CAR. Preclinical data suggest that high concentrations of sBCMA may interfere with cytokine production and cytolytic capacity of anti-BCMA CAR T cells (70). Increased levels of sBCMA have been correlated with disease progression and shorter OS in MM (62). Drugs that inhibit γ-secretase may enhance the efficacy of BCMA-targeted therapy by reducing BCMA shedding from the cell surface and subsequent interference by sBCMA. Preclinical models have demonstrated that GSI increase BCMA surface density, decrease sBCMA levels, and augment anti-tumor efficacy of anti-BCMA CAR T cells. A proof-of-concept study using crenigacestat, a GSI, in combination with an anti-BCMA CAR T therapy preliminarily showed that the combination resulted in rapid response in participants who had failed prior BCMA-directed therapy (71). Among the 6 evaluable patients, ORR was 100% (5 VGPR, 1 PR). Multiple clinical trials are now evaluating the combination of BCMA-directed therapy with a GSI.

Loss or downregulation of BCMA may confer resistance to anti-BCMA therapies (62, 63). BCMA antigen loss after CAR T therapy, including a case of biallelic deletion of chromosome 16p encompassing the BCMA locus, have been reported (62, 72). Mechanisms of relapse may include: (1) immune selection pressure – pre-existing BCMA negative or low BCMA expressing subclones may become dominant clones after selective stress generated by anti-BCMA therapies; (2) gene mutations – mutations have been described with the subsequent loss of expression of BCMA. To overcome this form of resistance, other target antigens are being explored in MM, including GPRC5D, CD19, FcRH5. The discussion of these targets is beyond the scope of this manuscript, but comprehensive reviews that address these topics are available (73). Targeting multiple antigens may also counteract antigen escape. Different approaches are being explored, including sequential treatment or co-administration of different single-target CAR T cell products, co-expression of two different CAR molecules on the T cell surface (dual CARs), expression of two scFvs in extracellular domains in “single-stalk” intracellular module (tandem CARs) (47, 73). In the preclinical setting, combinations including BCMA/CD19, BCMA/SLAMF7, BCMA/GPRC5D have shown promising results. In the clinical setting, preliminary results with BCMA/CD38, BCMA/CD19, and BCMA/TACI are encouraging (74–77).

Summary and future perspectives

BCMA is a promising novel target for the treatment of MM. Different classes of anti-BCMA therapies, including ADCs, bispecific constructs, and CAR T cell therapies have shown robust antimyeloma activity in RRMM patients and will play an important role in addressing a critical unmet need in the treatment of MM (5). Trials are currently underway investigating the efficacy of various anti-BCMA modalities for patients with NDMM or early relapse since these therapies have high MRD negativity rates, high ORR, and durable responses in RRMM. Since MRD negativity is associated with prolonged survival, further study is warranted to investigate whether BCMA-targeted therapies could provide durable responses or even a cure when used in earlier lines of therapy.

In most of the earlier clinical trials on BCMA-directed treatments patients previously treated with anti-BCMA therapy are excluded. This exclusion criteria limits sequential anti-BCMA treatment, and trials assessing anti-BCMA therapies should carefully consider patient selection until we have a better biological and clinical understanding of which population derives the most benefit. With the FDA approval of belantamab mafodotin and idecabtagene vicleucel, there will be a growing population of RRMM patients who have been exposed to anti-BCMA therapy. An anti-BCMA CAR T trial observed that although the majority of patients showed a decline in BCMA intensity post infusion, the membrane BCMA expression increased back toward baseline in the majority of patients (63). Moreover, since a majority of relapses after BCMA-directed therapy involves BCMA-positive disease, retreatment with different BCMA-targeting modalities may be feasible (78). Sequencing of these therapies will need to be investigated in future clinical trials. Ultimately, clinical data from large, randomized trials are needed to further understand the role of BCMA-directed therapies in the treatment of MM, including potential differences among anti-BCMA ADCs, bispecific constructs, and CAR T cell therapies.