Targeting BCMA in multiple myeloma: A comprehensive review of immunotherapeutic strategies and clinical outcomes.

Introduction

Multiple myeloma (MM), a hematological malignancy driven by clonal proliferation of malignant plasma cells in the bone marrow, accounts for approximately 1% of all cancers and ranks as the second most prevalent hematologic malignancy globally. 1 With rising incidence rate, MM poses a significant clinical burden due to its incurable nature and inevitable relapse despite advances in targeted therapies in recent years. 2 Current therapies are limited by transient responses, toxicity, and intrinsic or acquired resistance, especially in high-risk patients, underscoring the urgent need for innovative strategies targeting novel molecular pathways. 3

B cell maturation antigen (BCMA), a transmembrane receptor selectively expressed on plasma cells and malignant MM cells, has emerged as a critical therapeutic target in the management of MM. 1 BCMA binds to B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL), activating nuclear factor κB (NF-κB) and JNK signaling pathways that drive tumor survival, proliferation, and immune evasion. 4 Critically, BCMA overexpression correlates with MM progression, drug resistance, and suppression of anti-tumor immunity by fostering an immunosuppressive tumor microenvironment. 5 These dual roles, as a driver of oncogenesis and a mediator of immune escape, position BCMA as both a predictive biomarker and a compelling therapeutic target.

Therapeutic strategies targeting BCMA have revolutionized MM treatment, with three main modalities leading clinical development: chimeric antigen receptor (CAR) T cell therapy, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). 6 , 7 While these approaches demonstrate unprecedented response rates in relapsed and refractory MM, several clinical challenges remain, including the development of drug resistance and adverse effects. 8 Furthermore, optimizing the durability of response and expanding the accessibility of these complex therapies remain critical unmet needs.

This review highlights the current landscape of BCMA-targeted immunotherapies, analyzing their mechanism of action, clinical efficacy, and limitation. We further explore emerging strategies to overcome resistance. By bridging preclinical insights with clinical trial data, this work aims to inform future research directions and therapeutic optimization for MM.

Structure and functions of BCMA

BCMA, also known as cluster of CD269 or tumor necrosis factor receptor superfamily 17, is a transmembrane glycoprotein predominantly expressed on late-stage or mature B lymphocytes and plasma cells. As a member of the tumor necrosis factor receptor superfamily, BCMA specifically recognizes and binds to two ligands: BAFF and APRIL, with APRIL exhibiting higher binding affinity due to structural specificity. 9

BCMA consists of 184 amino acids with an approximate molecular mass of 20 kDa. The structure of BCMA encompasses three domains ( Figure 1 ): the extracellular domain (amino acids 1–54) featuring a beta-hairpin motif followed by a helix-loop-helix structure. This domain is essential for ligand binding. 4 While both BAFF and APRIL can bind to the extracellular domain of BCMA, structural studies reveal that spatial orientation differences in the extracellular domain favor APRIL interaction. 14 Key residues, including Y13, D15, L17, and R27, mediate the binding of BCMA to APRIL. This ligand preference positions BCMA as a key mediator of APRIL-driven oncogenic signaling in MM. 14 , 15 The transmembrane domain (amino acids 55–77) anchors BCMA to the cell membrane. The intracellular domain (amino acids 78–184) includes a tumor necrosis factor receptor-associated factor (TRAF)-binding motif (amino acids 119–143) that recruits TRAF5 and TRAF, activating downstream NF-κB and JNK pathways critical for plasma cell survival and tumor progression. 16 , 17 In addition to its membrane-bound form and role in intracellular signaling, BCMA also exists as a soluble molecule with unique functions and clinical significance. Figure 1 Structure of BCMA (A) Schematic diagram of the primary structures of full-length BCMA. Amino acid (aa) 1–54 comprise the extracellular domain; aa 55–77 the transmembrane domain; and aa 78–184 the intracellular domain. (B) 3D structure of BCMA predicted by alphafold. 10 , 11 Yellow, extracellular domain; green, transmembrane domain; blue, intracellular domain. The predicted local distance difference test (pLDDT) from scale 0 to 100 indicates the confidence of the predictation. Confidence is very high (pLDDT > 90) or high (90 > pLDDT >70) for extracellular and transmembrane domain; low (70 > pLDDT > 50) or very low confident (pLDDT < 50) for intracellular domain. (C) 3D structure of the extracellular domain, featuring an N-terminal β-hairpin followed by a helix-loop-helix motif. Residues implicated in BCMA-APRIL binding (Y13, D15, L17, and R27) are labeled. Structures rendered from PDB entries 1OQD and 1XU2 . 12 , 13

Membrane-bound BCMA undergoes γ-secretase-mediated ectodomain shedding, generating soluble BCMA (sBCMA) ( Figure 2 ). sBCMA acts as a decoy receptor, neutralizing APRIL and attenuating NF-κB activation. 18 γ-secretase activity reduces membrane BCMA density, potentially compromising anti-BCMA therapeutics. 19 Co-administration of γ-secretase inhibitors (GSIs) enhances transmembrane BCMA availability and therapeutic efficacy of anti-BCMA therapeutics in preclinical models. 20 On the other hand, elevated sBCMA levels correlate with tumor burden, disease progression, and poor survival in patients with MM. Specifically, patients ( n = 243) with sBCMA levels above the median demonstrated reduced progression-free survival (PFS; hazard ratio [HR] = 2.1) and overall survival (HR = 1.8). 21 sBCMA dynamics also reflect treatment response. CAR T cell therapy induces rapid declines in sBCMA within ten days after infusion, reaching minimal levels by day 30–60, followed by rebound upon relapse. 22 , 23 Figure 2 The APRIL/BCMA pathway APRIL binds to BCMA with significantly higher affinity than BAFF (∼about 1,000-fold). BCMA interacts with TRAF5 and TRAF6 to transmit signal to activate NF-κB. This leads to upregulation of anti-apoptotic proteins and downregulation of apoptosis regulators Bax and Bak. γ-secretase cleaves the extracellular domain of BCMA to release sBCMA as a decoy for APRIL and may also reduce the efficacy of BCMA-targeted therapy.

BCMA is essential for the survival of long-lived plasma cells, facilitating immunoglobulin class switching and antibody production. During malignant transformation, BCMA overexpression drives MM pathogenesis by constitutively activating NF-κB, promoting tumor cell proliferation, drug resistance, and immune evasion. 24 This dual role, including physiological regulator and oncogenic driver, underpins its therapeutic relevance in MM. Given the important role of BCMA in plasma cell biology and MM pathogenesis, studying its expression pattern in various cancers is critical for defining broader therapeutic applications.

Expression profile of BCMA

The expression profile of BCMA reveals both tissue specificity and oncogenic versatility, offering insights into therapeutic opportunities beyond MM.

In hematologic malignancies, BCMA is prominently expressed in non-Hodgkin lymphoma, particularly diffuse large B cell lymphoma (DLBCL). Analysis of primary DLBCL lymph node biopsies demonstrated consistent BCMA overexpression, corroborated by transcriptomic data from The Cancer Genome Atlas showing significantly elevated mRNA levels in DLBCL, as well as acute myeloid leukemia, compared to normal tissues ( Table 1 ; Figure 3 ). 24 Preclinical studies further validated the functional relevance of this expression. In BCMA-high DLBCL cells, the BCMA-targeted T cell engager CC-93269 induced potent cytotoxicity, suggesting that BCMA expression levels may predict therapeutic response. 24 These findings position DLBCL as a promising candidate for BCMA-directed immunotherapy. Table 1 Comparison of BCMA expression levels between tumor and normal samples in pan-cancers Abbreviation Name Normal sample Tumor sample p value BLCA bladder carcinoma 28 404 0.15 BRCA breast invasive carcinoma 291 1,085 0.21 CESC cervical squamous cell carcinoma and endocervical adenocarcinoma 13 306 0.13 CHOL cholangiocarcinoma 9 36 0.17 COAD colon adenocarcinoma 349 275 0.09 DLBC diffuse large B cell lymphoma 337 47 0.002 ESCA esophageal carcinoma 286 182 0.11 GBM glioblastoma 207 163 0.35 HNSC head-neck squamous cell carcinoma 44 519 0.17 KICH kidney chromophobe 53 66 0.28 KIRC kidney renal clear cell carcinoma 100 523 0.17 KIRP kidney renal papillary cell carcinoma 60 286 0.29 LAML acute myeloid leukemia 70 173 0.005 LGG low-grade glioma 207 518 0.57 LIHC liver hepatocellular carcinoma 160 369 0.36 LUAD lung adenocarcinoma 347 483 0.009 LUSC lung squamous cell carcinoma 338 486 0.008 OV ovarian cancer 88 426 0.23 PAAD pancreatic adenocarcinoma 171 179 0.06 PRAD prostate adenocarcinoma 152 492 0.37 READ rectum adenocarcinoma 318 92 0.07 SARC sarcoma 2 262 0.46 SKCM skin cutaneous melanoma 558 461 0.16 STAD stomach adenocarcinoma 211 408 0.17 TGCT testicular germ cell tumors 165 137 0.23 THCA thyroid carcinoma 337 512 0.31 THYM thymoma 339 118 0.14 UCEC uterine corpus endometrial carcinoma 91 174 0.26 Figure 3 Differential expression of BCMA in various disease states The horizontal bars from bottom to top within the box represent the 25th percentile, median, and 75th percentile of the normalized BCMA TPM mRNA levels. The upper and lower ends of the vertical lines correspond to the maximum and minimum values of the normalized BCMA TPM mRNA levels. ∗ indicates carcinomas with significantly higher BCMA expression level compared to normal tissue ( p < 0.05).

Notably, BCMA’s oncogenic role extends to solid tumors. In lung adenocarcinoma and lung squamous cell carcinoma, BCMA is aberrantly overexpressed alongside its ligands APRIL and transmembrane activator and CAML interactor (TACI). This triad forms an autocrine signaling axis that sustains constitutive activation of the mitogen-activated protein kinase pathway, a driver of tumor proliferation and survival in non-small cell lung cancer (NSCLC). 1 Such mechanistic synergy implies that disrupting BCMA signaling could attenuate oncogenic cascades in NSCLC, though clinical validation remains ongoing.

Beyond its direct pro-tumor effects, BCMA expression patterns carry critical clinical implications. For example, in plasma cell neoplasms like MM, BCMA surface density correlates with disease aggressiveness and resistance to conventional therapies. 25 Meanwhile, in DLBCL, quantitative BCMA assessment has emerged as a potential biomarker for patient stratification, with preclinical models indicating that tumors scoring >200 exhibit 3-fold higher response rates to anti-BCMA agents. 24 These observations underscore the importance of standardized BCMA detection methods in therapeutic decision-making. The prognostic and predictive value of BCMA expression in a variety of malignancies has been established. There are increasing efforts to investigate this target to develop innovative therapeutic approaches.

Targeting BCMA for cancer therapy

CAR T cell therapy

CAR T cell therapy employs genetically engineered T cells that express CARs to specifically recognize tumor-associated antigens, enabling precise tumor targeting. 26 BCMA-directed CAR T cells have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), demonstrating remarkable response rates in clinical trials.

Idecabtagene vicleucel

Approved by the Food and Drug Administration (FDA) in March 2021, idecabtagene vicleucel (ide-cel) is a second-generation CAR T cell therapy incorporating an anti-BCMA single-chain variable fragment (scFv) with 4-1BB (CD137) and CD3ζ co-stimulatory domains. In the pivotal phase 2 KarMMa trial, ide-cel achieved an overall response rate (ORR) of 73% and a median PFS of 8.8 months in heavily pretreated patients with RRMM. However, significant challenges remain, including grade ≥3 cytopenias (91% neutropenia; 70% anemia) and limited CAR T cell persistence (59% detectable at 6 months). 20 Ongoing trials are investigating ide-cel in earlier-line settings and in combination regimens to enhance efficacy and overcome these limitations. 27 , 28 , 29

Ciltacabtagene autoleucel

Approved in February 2022, ciltacabtagene autoleucel (cilta-cel) utilizes two BCMA-targeting single-domain antibodies to enhance avidity. In the CARTITUDE-1 trial, cilta-cel achieved a 97.9% ORR and an 82.5% stringent complete response (sCR) rate, with a 27-month PFS of 54.9%. 30 Despite its remarkable efficacy, common adverse events such as neutropenia (95%), anemia (68%), and lymphopenia (50%) require rigorous monitoring. 30 , 31 , 32 The CARTITUDE-2 trial ( NCT04133636 ) further supports its utility in lenalidomide-refractory patients, with an 88.9% ORR, emphasizing its role in high-risk subgroups. 30 Long-term studies are ongoing to address durability and resistance mechanisms.

ALLO-715

ALLO-715 is an allogeneic anti-BCMA CAR T cell therapy designed to minimize graft-versus-host disease and CAR T cell rejection. In a phase 1 study, ALLO-715 administered after lymphodepletion with an anti-CD52 antibody achieved a 70.8% response rate, with 45.8% patients achieving a very good partial response (VGPR) or better, including 25% complete response. The median duration of response was 8.3 months. 33 While promising, this therapy required further optimization to mitigate immune rejection and enhance persistence.

BsAb and bispecific T cell engager

BsAbs represent a novel precision medicine designed to recognize two different epitopes or antigens. 34 , 35 This dual-targeting capability forces interactions between tumor and immune cells, thereby enhancing immune-mediated tumor destruction. 36 In cancer immunotherapy, BsAbs are engineered to target various biomarkers, with one arm typically engaging immune cells such as T cells or natural killer (NK) cells through CD3, or other specific antigens, and the other arm targeting specific tumor surface proteins, such as programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein (CTLA-4), and human epidermal growth receptor 2 (HER-2). 37 , 38 Various BsAbs are in clinical trials or under preclinical studies ( Table 2 ). Table 2 Information of BCMA-targeted therapies Drug class Drug name Efficacy Safety profile Clinical trial criteria CAR T cell therapy idecabtagene vicleucel (ide-cel) ORR: ∼73%; CR: ∼33%; median PFS: ∼11.8 months common AEs: cytokine release syndrome (CRS), B cell aplasia, infections; grade 3–4 AEs: neurological events, prolonged cytopenias inclusion: adult patients with relapsed/refractory multiple myeloma, previous therapies; exclusion: prior BCMA-targeted therapy, severe comorbidities ciltacabtagene autoleucel (cilta-cel) ORR: ∼97%; CR: ∼67%; median PFS: ∼20.6 months common AEs: CRS, neurotoxicity, infections; grade 3–4 AEs: B cell aplasia, prolonged cytopenia observed inclusion: relapsed/refractory multiple myeloma, sufficient organ function; exclusion: prior BCMA therapy, active infections. ALLO-715 early efficacy data demonstrate promise; ORR and CR rates under evaluation; median PFS is not yet available common AEs: CRS, cytopenias, infections; grade 3–4 AEs: immune-related adverse events requiring close monitoring inclusion: adults with relapsed/refractory multiple myeloma, good performance status; exclusion: severe active infections, history of severe allergic reactions Bispecific T cell engager (BiTE) AMG 420 (BI 836909) ORR: ∼25%–40% reported; CR: not specified; median PFS: not specified (data from ongoing trials) common AEs: CRS (up to grade 2), fatigue, infusion-related reactions; grade 3–4 AEs: cytopenias, neurological events noted inclusion: adults with relapsed/refractory multiple myeloma, at least two prior therapies; exclusion: active uncontrolled infections, other malignancies AMG 701 ongoing clinical evaluation; ORR: ∼30%–40%; CR: not specified; median PFS: not specified (ongoing evaluations) common AEs: CRS (varied grades), hypersensitivity, neurological events; grade 3–4 AEs: neutropenia, anemia observed inclusion: relapsed/refractory multiple myeloma, prior treatment history documented; exclusion: pre-existing neuropathy, significant cardiac comorbidities AFM26 early clinical trials indicate potential; ORR: ∼40%; CR: not specified; median PFS: data pending further studies. common AEs: CRS (up to grade 2), fatigue, infusion-related reactions; grade 3–4 AEs: cytopenias requiring potential transfusions inclusion: adults with multiple myeloma, previous lines of therapy; exclusion: CNS disease, severe pulmonary or cardiac disease Bispecific antibody (BsAb) EM901 (CC-93269, BCMA-TCB2) preliminary results indicate potential efficacy; ORR: ∼50% reported; CR: not specified; median PFS: not specified (early-phase trials ongoing) common AEs: CRS (grade 1–2), cytopenias, immune-related effects; grade 3–4 AEs: typically manageable with intervention inclusion: adults with relapsed/refractory myeloma, adequate organ function; exclusion: allergies to study drugs, significant autoimmune disorders MEDI2228 phase 1 trials show potential; ORR: not specified; CR: not specified; median PFS: not yet available common AEs: CRS (up to grade 2), headache, infusion-related adverse effects; grade 3–4 AEs: cytopenias reported with management plans in place inclusion: adults with relapsed/refractory myeloma, adequate organ function, previously treated; exclusion: significant pre-existing conditions affecting safety Antibody-drug conjugate (ADC) belantamab mafodotin (GSK2857916) ORR: ∼31%; CR: ∼10%; median PFS: ∼2.9 months common AEs: keratopathy (grade 1–2), fatigue, CRS, cytopenias; grade 3–4 AEs: severe corneal events, cytopenias requiring treatment adjustments inclusion: adults with relapsed/refractory myeloma, at least 4 prior therapies; exclusion: active keratopathy, other malignancies HDP-101 early-stage trials; ORR data emerging; CR: not specified; median PFS: not specified common AEs: CRS, occasionally requiring hospitalization; infusion-related events; grade 3–4 AEs generally manageable; specifics evolving inclusion: patients with multiple myeloma, prior treatments documented; exclusion: recent other malignancies, uncontrolled infections

AMG 420 (BI 836909)

AMG 420 is a bispecific scFv that targets CD3 and BCMA. It induces T cell activation and cytokine release, leading to apoptosis for MM cells and T cell proliferation. In mouse xenograft studies, AMG420 reduces the tumor size and prolonged host survival. 39 AMG420 demonstrated picomolar binding affinity and efficacy in cytotoxicity assays, and its half-life in non-human primates was 112 h following a single 15 μg/kg dose. 40 In a phase 1 clinical trial ( NCT02514239 ), AMG420 demonstrated a 70% ORR, including 5 minimal residual disease-negative complete responses. However, continuous intravenous dosing and significant adverse events (AEs) pose challenges, leading to its discontinuation in favor of developing AMG701, a half-life-extended BCMA bispecific T cell engager (BiTE). 41

AMG 701

AMG 701 is a half-life-extended BiTE for once-weekly dosing, showing potent T cell-mediated lysis of MM cell, including those resistant to immunomodulatory imide drugs (IMiDs). In the preclinical NCI-H929 xenograft model, AMG 701 blocked tumor growth 5 days after the first injection and completely eradicated tumor growth after 3 injections at all dose levels (0.02, 0.2, and 2 mg/kg), supporting further investigation as monotherapy or in combination with IMiDs. A phase 1 clinical trial was proposed for evaluating the safety and tolerability of AMG 701 monotherapy ( NCT03287908 ). 38 , 42 Although promising, AMG701 development was discontinued in 2022 due to the strategic decision.

EM901

EM901 ( CC-93269 , BCMA-TCB2 ) is a BiTE that binds bivalently to BCMA and monovalently to CD3. 4 In preclinical studies, EM901 showed promising single-agent activity, induced T cell activation and MM cell death, and promoted tumor regression in mice and cynomolgus monkey models. In a phase 1 clinical trial ( NCT03486067 ) involving patients with RRMM, EM901 achieved an 83.3% ORR, with 58.3% of patients attaining a VGPR or better, and a 33.3% sCR rate. EM901 demonstrated a manageable safety profile and promising efficacy, particularly in patients receiving doses of at least 6 mg. 43

AFM26

AFM26 is a first-in-class tetravalent BsAb targeting BCMA on MM cells and CD16A on NK cells. It induced NK cell-mediated cytotoxicity with reduced cytokine release compared to T cell-based approaches, even in cells with low BCMA expression. AFM26 exhibited prolonged cell retention and was less susceptible to competition from high levels of circulating IgG, due to its high-affinity bivalent binding to CD16A. In vitro studies showed that AFM26 produced lower levels of pro-inflammatory cytokines in the presence of target cells than BCMA-directed T cell-activating approaches. Its ability to target cells with nearly undetectable surface levels of BCMA highlighted its potential for enhanced anti-MM activity. AFM26 offers a unique mechanism of action compared to other monoclonal antibodies and BsAbs and is currently in preclinical development. 44 , 45 , 46

ADCs

ADC combines monoclonal antibodies with cytotoxic chemical agents (payload) for targeted drug delivery, reducing off-target effects and providing options for patients ineligible for CAR T cell therapy. 47 , 48

Belantamab mafodotin

Belantamab mafodotin (GSK2857916) is an anti-BCMA humanized IgG1 monoclonal antibody conjugated with a cytotoxic agent maleimidocaproyl monomethyl auristatin F. It has been approved by the US FDA as a monotherapy for patients with RRMM. 49 , 50 Belantamab mafodotin demonstrated a 60% ORR in a phase 1 study of heavily pretreated patients with MM, with a median PFS of 7.9 months. 50 , 51 , 52

Subsequently, an open-label phase 2 study ( NCT03525678 ) investigated the safety and efficacy of two different doses of belantamab mafodotin administered every 3 weeks (2.5 or 3.4 mg/kg). Over 30% of patients in both dosing groups responded to treatment. Reported adverse events included keratopathy, cornea damage, low platelet counts, anemia, and low white blood cell counts. 53 , 54

Another ongoing phase 1/2 clinical trial ( NCT03848845 ) is exploring the combination of belantamab mafodotin with PD-1 antibody pembrolizumab in RRMM. This combination has shown promising clinical activity, with an ORR of 67% in the 2.5 mg/kg arm. 55 Multiple phase 1 and 2 clinical trials are currently recruiting or underway to investigate the use of belantamab mafodotin in various states of MM and in combination with other therapies. 55 , 56 , 57 , 58 , 59 , 60 , 61

HDP-101

HDP-101 is an anti-BCMA antibody conjugated to amanitin via a non-cleavable linker. At low concentration, amanitin effectively binds to RNA polymerase II in eukaryotic cells, inhibiting RNA transcription regardless of the proliferation state of the target cells. HDP-101 shows promising preclinical results with specific targeting and internalization in BCMA-positive MM cells. 62 , 63 A phase 1/2 clinical trial ( NCT04879043 ) is underway to evaluate its safety, tolerability, pharmacokinetics, and the therapeutic potential in MM. 64

MEDI2228

MEDI2228 is an ADC that consists of a fully human antibody conjugated site-specifically to a pyrrolobenzodiazepine (PBD) dimer through a protease-cleavable linker. The PBD dimer binds to the minor groove of DNA, causing crosslinking and subsequent DNA damage, leading to apoptotic cell death. MEDI2228 demonstrated its anti-tumor activity in vitro in 8 out of 10 MM cell lines, including those with low BCMA expression. 65 , 66 In a phase 1 trial ( NCT03489525 ), MEDI2228 demonstrated a 65.9% ORR. 66 , 67 , 68 However, MEDI2228 was discontinued due to safety concerns. It offered insights into the challenges of ADC development, particularly regarding ocular toxicity and the impact of sBCMA.

Conclusions and future perspectives

BCMA-targeted therapies, including CAR T cells, BsAbs, and ADC, have redefined therapeutic paradigms for patients at the third relapse or beyond, achieving unprecedented response rates in late-line settings. 5 , 69 CAR T cell therapies provide the potential for durable, long-lasting remissions following a single infusion, as the engineered T cells can proliferate and persist in vivo . These cells may also acquire memory-like properties, enabling ongoing immune surveillance and reducing the risk of disease recurrence. BsAbs, as off-the-shelf dual-targeting immunotherapies, enable rapid initiation of treatment and provide a valuable option for patients who are ineligible for individualized cellular therapies or require urgent intervention. ADCs are designed to selectively bind BCMA expressed on malignant plasma cells, facilitating the targeted delivery of cytotoxic agents directly into tumor cells upon internalization, thereby minimizing off-target effects compared to conventional chemotherapy ( Table 3 ). Table 3 Comparisons of the BCMA-targeted therapies Aspect CAR T cell therapies Bispecific antibodies (BsAbs) Antibody-drug conjugates (ADCs) Feasibility complex manufacturing; specialized centers required off-the-shelf; ready-to-use; easy administration off-the-shelf; similar to mAb infusion Cost-effectiveness high upfront costs; possible long-term savings via durable response lower costs; can be repeated dosing moderate costs; less complex than cell therapy Scalability limited due to individualized process high; mass production feasible high; established mAb manufacturing platforms Patient eligibility restricted by age, fitness, and manufacturing time broad; suitable for frail or acutely ill patients broad; suitable for wide patient population Advantages potential for long-term remission and immune memory immediate treatment; engages endogenous T cells; flexible use targeted cytotoxicity; minimized off-target effects Limitations manufacturing delays; CRS/ICANS risk; limited access risk of CRS; requires repeated dosing resistance development; off-target toxicity risk

Despite the remarkable efficacy of these novel therapies, several challenges and limitations persist that impede their widespread adoption and long-term success. The management of RRMM remains a significant challenge due to clonal evolution, immune evasion, and cumulative treatment resistance.

CAR T cell therapies leverage the immune system’s cytotoxic potential, often including durable remissions with a single infusion. GC012F, a dual-targeting anti-BCMA and anti-CD19 CAR T, demonstrated durable responses with a median PFS of 38 months. 70 , 71 However, their widespread application is constrained by several factors, including manufacturing delays (typically 3–4 weeks for autologous products), high rates of cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). In a phase 3 clinical trial of autologous anti-CD19 CAR T therapy in large B cell lymphoma, CRS was observed in 58%–93% of patients. 72 Furthermore, antigen loss or downregulation contributes to relapse in 30%–40% of cases, prompting the development of dual-targeted CAR T cells and the use of GSIs to enhance BCMA expression. CAR T cell therapies are also associated with substantial financial costs, and most clinical trials evaluating their safety and efficacy are conducted in high-income countries. Consequently, access to gene therapies such as CAR T remains severely restricted in low- and middle-income countries, due to insufficient healthcare infrastructure, regulatory hurdles, and a shortage of trained professionals. 73

BsAbs and BiTEs provide immediate, off-the-shelf access to T cell-redirected cytotoxicity. However, they have high risk, with CRS (grade ≥3 in 4%–5% of patients) and hypogammaglobulinemia from BCMA + plasma cell depletion remaining significant concerns. Moreover, the efficacy of BsAbs was limited by T cell exhaustion and the short half-life of the drug. Continuous exposure to BsAbs can induce progressive T cell dysfunction, which is only partially reversed by treatment-free intervals. For example, sustained exposure to a CD19/CD3 BsAb induced in a marked decline in T cell cytotoxicity over time, with mean specific lysis decreasing from 88.4% on day 7 to 8.6% on day 28. 74 Ongoing trials are evaluating their use in earlier lines of therapy, such as post-autologous stem cell transplant consolidation, and in combination with IMiDs to amplify T cell activation.

ADCs offer a distinct approach by delivering cytotoxic payloads directly to tumor cells. However, ADCs face unique hurdles, such as interference from sBCMA, which reduced MEDI2228’s efficacy by 70% in high-sBCMA cohorts, ultimately leading to its discontinuation. Next-generation ADCs with non-cleavable linkers and RNA polymerase inhibitors aim to mitigate these issues while broadening therapeutic indices.

Looking forward, the integration of BCMA-targeted therapies into earlier treatment lines, guided by biomarkers such as sBCMA dynamics and baseline T cell profiles, holds great promise for enhancing patient outcomes in high-risk RRMM. Combination strategies, such as pairing CAR T cell with BsAbs to eliminate antigen-low subclones or combining ADCs with GSIs to enhance target density, may deepen responses and delay resistance. In relapsed or refractory B cell lymphomas, the efficacy of CD20/CD3 BsAbs in patients previously treated with CD19 CAR T cell therapy has been investigated. Patients with prior CD19 CAR T cell therapy demonstrated increased lymphocyte counts, including both CD4 and CD8 T cells. These findings suggest a potential interaction between the two treatment modalities and support the feasibility of combination strategies involving CAR T cells and BsAbs. 75

Further, improving biomarker-based patient selection is essential. Addressing potential tumor heterogeneity, such as by evaluating multiple tumor samples or employing imaging techniques to assess BCMA expression throughout the tumor mass, may optimize patient selection. 76 Additionally, sBCMA may serve as a valuable biomarker during therapy, as elevated sBCMA levels have been associated with poorer outcomes in some studies. 77

Another limitation of BCMA-targeted immunotherapies is the development of drug resistance. Mechanisms of resistance include cellular immune responses, antigen loss or downregulation, impaired CAR T expansion, and the immunosuppressive effects of the bone marrow microenvironment. Ongoing clinical trials addressing these resistance mechanisms have shown encouraging results. For example, initial phase 1 data from ALLO-715, a CAR T cell therapy with a human scFV and a 4-1BB co-stimulatory domain, showed a promising ORR of 60%, a VGFR of 40% or higher, and no observed graft-versus-host disease. 78 Bispecific CAR T cell therapy targeting both BCMA and GPRC5D, a novel antigen selectively expressed on plasma cells, has shown promise in preclinical models. In vivo studies demonstrated that patients with BCMA escape or dual-antigen positivity experienced significantly improved survival compared to those with a single antigen target. 79 Additionally, the combination of GSIs with BCMA CAR T cell immunotherapy for RRMM is currently being evaluated in phase 1 clinical trials. Early results indicate that this combination was well tolerated and increased target antigen density, potentially enhancing therapeutic efficacy. 80

In conclusion, while BCMA-targeted immunotherapies have transformed the management of RRMM, their full potential remains unrealized. Addressing biological resistance, refining toxicity management, and expanding accessibility through technological and logistical innovations will be critical to achieving durable remissions. As these therapies evolve, a paradigm shift toward personalized, biomarker-driven treatment sequences, supported by robust clinical trial data, will be essential to extending survival and improving quality of life for patients worldwide.

Acknowledgments

This study was supported by the Hong Kong General Research Fund from the Research Grants Council of the Hong Kong Special Administrative Region , China (project nos. 12102120 and 12102322 ), and Theme-based Research Scheme from the Research Grants Council of the Hong Kong SAR, China (project no. T12-201/20-R ).

Author contributions

C.H.C.: writing – original draft, writing – review and editing, visualization, and conceptualization; X.Y., M.L., Z.C., and Y.L.: investigation and visualization; G.Z.: writing – review and editing; Y.Y.: writing – review and editing, supervision, project administration, funding acquisition, and conceptualization.

Declaration of interests

The authors declare no competing interests.

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