Next Article in Journal
Pseudohypoxia-Stabilized HIF2α Transcriptionally Inhibits MNRR1, a Druggable Target in MELAS
Previous Article in Journal
Design and Applications of Extracellular Matrix Scaffolds in Tissue Engineering and Regeneration
Previous Article in Special Issue
High-Risk Genetic Multiple Myeloma: From Molecular Classification to Innovative Treatment with Monoclonal Antibodies and T-Cell Redirecting Therapies
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 14
Issue 14
10.3390/cells14141077
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Resistance Mechanisms to BCMA Targeting Bispecific Antibodies and CAR T-Cell Therapies in Multiple Myeloma

by
Brandon Tedder
* and
Manisha Bhutani
*
Advocate Health Levine Cancer Institute, Charlotte, NC 28204, USA
*
Authors to whom correspondence should be addressed.
Cells 2025, 14(14), 1077; https://doi.org/10.3390/cells14141077
Submission received: 2 June 2025 / Revised: 29 June 2025 / Accepted: 2 July 2025 / Published: 15 July 2025
(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms and Therapy of Myeloma)
Browse Figures
Review Reports Versions Notes

Abstract

B-cell maturation antigen (BCMA)-targeted therapies including both chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs), have revolutionized the treatment landscape for relapsed/refractory multiple myeloma (MM), offering both deep and durable responses, even in heavily pretreated patients. Despite these advances, most patients ultimately experience relapse. This is likely related to the development of resistance mechanisms that limit the long-term efficacy and durability of BCMA-targeted approaches. In this review, we examine the current landscape of BCMA-directed therapies, including Idecabtagene Vileucel, Ciltacabtagene Autoleucel, Teclistamab, and Elranatamab and explore the multifactorial mechanisms driving resistance. These mechanisms include tumor-intrinsic factors, host-related and tumor-extrinsic factors, and factors related to the tumor-microenvironment itself. We outline emerging strategies to overcome resistance, such as dual-targeting therapies, γ-secretase inhibitors, immune-checkpoint blockade, armored CAR T constructs, and novel combination regimens. Additionally, we discuss the role of therapy sequencing, emphasizing how prior exposure to BsAbs or CAR T-cell therapies may influence the efficacy of subsequent treatments. A deeper understanding of resistance biology, supported by integrated immune and genomic profiling, is essential to optimizing therapeutic durability and ultimately improve patient outcomes for patients with MM.

1. Introduction

Despite recent advances, patients with multiple myeloma (MM) eventually relapse and develop resistance to standard-of-care therapies, including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies, resulting in limited treatment options in the relapsed/refractory setting. B-Cell maturation antigen (BCMA) has emerged as a pivotal therapeutic target in MM due to its selective expression on plasma cells, including malignant cells, and its absence on most normal tissues [1,2]. BCMA’s role in promoting plasma cell survival through interactions with its ligands, APRIL and BAFF, further underscores its relevance as a target [3]. BCMA-targeted therapies, including chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs), leverage T cell-mediated cytotoxicity to selectively eliminate myeloma cells and have become central to relapsed refractory MM (RRMM) treatment.
Clinically approved CAR T-cell therapies, such as Idecabtagene Vicleucel (Ide-cel) and Ciltacabtagene Autoleucel (Cilta-cel), as well as BsAbs like Teclistamab and Elranatamab, have significantly improved outcomes in heavily pretreated patients [4,5,6,7,8,9,10]. Ide-cel and Cilta-cel are approved for use after two and one prior lines of therapy, respectively, while BsAbs are indicated for patients with more advanced, refractory disease. These therapies are now being explored earlier in the treatment course and in combination regimens.
Despite these advances, long term durability remains a challenge, with relapses and resistance emerging over time. Resistance mechanisms fall into three broad categories: tumor-intrinsic, tumor microenvironment-mediated, and host-related/tumor-extrinsic factors. Furthermore, the distinct pharmacokinetic and immune-engagement properties of CAR T-cell therapies versus BsAbs may drive unique resistance patterns.
While alternative targets such as GPRC5D and FcRH5, and BCMA antibody drug conjugates are under active investigation, this review focuses on resistance mechanisms to BCMA-directed CAR T-cell and BsAb therapies, aiming to inform strategies that improve durability and extend therapeutic benefit.

2. BCMA as a Target for Immunotherapy in MM

BCMA, also known as TNFRSF17 or CD269, is a type III transmembrane glycoprotein and a member of the tumor necrosis factor receptor (TNFR) superfamily, encoded on chromosome 16p13.13 [1,11,12]. Expressed on mature B cells and plasma cells, but not other normal tissues, BCMA is essential for the survival of long-lived plasma cells through interactions with its ligands APRIL and BAFF, primarily secreted by bone marrow stromal cells, osteoclasts, and macrophages [13]. Upon ligand binding, BCMA activates multiple signaling pathways, including NF-κB, JNK, MAPK, and PI3K/AKT, leading to upregulation of genes involved in cell survival, proliferation, angiogenesis, drug resistance, and immunosuppression [14,15]. Elevated levels of APRIL and BAFF correlate with disease progression and poor prognosis in multiple myeloma [16,17]. APRIL and BAFF signal through multiple receptors, including BCMA, transmembrane activator and CAML interactor (TACI), and BAFF receptor (BAFF-R) [18,19,20]. While BAFF preferentially binds BAFF-R, APRIL has a higher affinity for BCMA. These interactions regulate B cell survival, maturation, and differentiation into plasma cells. Additionally, APRIL-TACI signaling can activate NF-κB, MAPK, and AKT pathways, promoting regulatory T-cell proliferation and the expression of immunosuppressive factors such as Foxp3, IL-10, TGF-β, and PD-L1 [21,22]. The high and relatively selective expression of BCMA on malignant plasma cells has made it the most clinically successful target to date for anti-myeloma immunotherapy.

3. Currently Approved BCMA Therapies in RRMM

Currently approved BCMA-targeted therapies for MM include CAR T-cell and BsAb therapies, all of which have shown promising efficacy, particularly in relapsed/refractory settings. Ide-cel demonstrated an overall response rate (ORR) of 73% and a median progression-free survival (PFS) of 8.6 months in the KarMMa trial, with improved outcomes in earlier lines of therapy as seen in the KarMMa-3 study (ORR 71%, median PFS 13.3 months) [4,5]. Cilta-cel achieved an ORR of 97.9% and median PFS of 34.9 months in CARTITUDE-1, with similarly robust results in the CARTITUDE-4 trial in earlier relapse settings (ORR 85.7%, median PFS not reached at data cutoff) [6,7]. BsAbs such as Teclistamab and Elranatamab have received approval, while Linvoseltamab, Etentamig, and HPN217 are still in clinical development. In the MajesTEC-1 trial, Teclistamab demonstrated an ORR of 63% and median PFS of 11.3 months, whereas Elranatamab showed an ORR of 61% and median PFS of 15 months in the MagnetisMM-3 study [8,10]. Unlike BsAbs, which are off-the-shelf agents requiring continuous dosing, CAR T-cell therapies involve a personalized manufacturing process and are administered as a one-time infusion, often resulting in deeper and more durable responses. Numerous other BCMA-directed therapies, including next-generation CAR T-cell products, allogeneic CAR T-cell products, bispecific, and trispecific antibodies, are currently in various stages of clinical development, aiming to further enhance efficacy, overcome resistance, and improve accessibility. Notably, many of these BCMA-targeted agents are being actively investigated in earlier lines of therapy, including in newly diagnosed MM, which may further shift treatment paradigms.

4. Key Mechanisms of Resistance to BCMA-Targeted Therapies

Resistance to BCMA-targeted therapies in MM can arise through various mechanisms, broadly classified into three categories: (i) tumor-intrinsic, (ii) tumor microenvironment-related, and (iii) host-related (Figure 1 and Figure 2) [23]. While these categories broadly apply to both CAR T-cell therapies and BsAbs, each modality may face distinct challenges in the context of these mechanisms. The specific nuances and differences between CAR T-cells and BsAbs will be described separately.

4.1. Tumor-Intrinsic Mechanisms of Resistance

Tumor-intrinsic mechanisms play an important role in limiting the efficacy of BCMA-targeted therapies by enabling malignant plasma cells to evade immune-mediated eradication. Resistance to both BCMA-targeted CAR T-cell therapy and BsAb primarily arises from alterations in antigen expression. Additionally, intrinsic resistance may result from changes in intracellular signaling pathways that affect apoptosis or antigen presentation, such as upregulation of anti-apoptotic proteins or defects in MHC class I expression, which impair immune recognition and promote tumor cell survival independent of antigen status.

4.1.1. Baseline BCMA Expression

Baseline BCMA expression varies considerably among patients and even within individual tumors. In heavily pretreated patients with MM, BCMA levels have not consistently correlated with response to BsAb or CAR T-cell therapies. Some studies suggest baseline BCMA expression on malignant plasma cells does not reliably predict response and survival, whereas others report that pretreatment BCMA levels may influence response depth and durability [4,8,24,25,26]. These conflicting findings likely reflect differences in assay sensitivity, such as the higher sensitivity of flow cytometry compared to immunohistochemistry used to quantify BCMA expression, as well as variations in baseline disease characteristics [27].
The γ-secretase complex cleaves BCMA from the cell surface, releasing soluble BCMA (sBCMA) into plasma and thereby reducing BCMA density on MM cells. Elevated sBCMA levels can act as a decoy or “sink”, potentially interfering with the binding of BCMA-targeted therapies to malignant cells. Using a TNFRSF17-transduced cell line model, Lee et al. demonstrated that sBCMA, surface BCMA density, tumor burden, and BsAb dose intensity collectively contribute to primary resistance [28]. Stepwise increases in sBCMA impaired BsAb bridging capacity, resulting in diminished activity, particularly with Teclistamab and Elranatamab. In contrast, Alnuctamab, a next-generation BsAb featuring a 2:1 BCMA binding configuration, appeared less affected by elevated sBCMA levels; however, its clinical development has been unfortunately discontinued. While preclinical data suggest that high sBCMA levels can reduce the cytolytic activity of BCMA-directed CAR T-cells [29], clinical studies have not observed a consistent association between baseline sBCMA levels and treatment response [25,30]. Nonetheless, sBCMA remains a promising biomarker for tumor burden and resistance monitoring.

4.1.2. Dynamic Changes in BCMA Expression with Treatment

Antigen escape through the selection of BCMA-negative or mutant clones is a relatively uncommon but clinically significant mechanism of secondary resistance to BCMA-targeted therapies [31]. This phenomenon is primarily driven by inherent genomic instability and alternative splicing in malignant plasma cells, resulting in mutations, downregulation, internalization, or complete loss of BCMA expression.
Loss of BCMA expression can occur via biallelic or monoallelic deletions of the TNFRSF17 gene, which encodes BCMA, as well as through mutations within the BCMA extracellular domain (ECD) [31]. Typically resistance by loss of target antigen requires the inactivation of the two copies of the of the TNFRSF17 gene. In a study, biallelic deletions or a combination of monoallelic deletions and mutations in TNFRSF17 were observed in 6 out of 14 patients (42.8%) at relapse following BsAb therapy [31]. Similarly, after initial BCMA CAR T-cell therapy, approximately 20% of cases demonstrated selection of clones with biallelic BCMA loss leading to a failure of CAR T-cell proliferation [31,32]. Moreover, preexisting deletions or mutations may favor the emergence of resistance. Monoallelic 16p deletion (encompassing TNFRSF17) has been identified in about 9% patients with newly diagnosed MM, particularly those harboring high-risk cytogenetic abnormalities, which may predispose them to biallelic TNFRSF17 loss upon relapse after BCMA-directed treatments [33].
Interestingly, patients refractory to BCMA CAR T-cell therapy often present with both BCMA-negative and -positive cells [34]. One explanation for this heterogeneity is antigenic drift, including non-truncating mutations, missense mutations, or in-frame deletions that alter the BCMA ECD. Such mutations selectively abrogate certain BCMA epitopes, thereby reducing the efficacy of BCMA-targeting therapies despite maintaining BCMA surface expression [31]. This variability underscores the importance of comprehensive molecular analysis of the TNFRSF17 gene locus and characterization of BCMA ECD mutations to better predict therapeutic outcomes, especially when considering sequential BCMA-targeted treatments.

4.1.3. Trogocytosis-Mediated Antigen Loss

Another resistance mechanism is trogocytosis, which is not purely a tumor-intrinsic. Emerging evidence shows it is a bidirectional process: malignant cells can transfer target antigens to CAR T-cells, reducing antigen expression on tumor cells and generating antigen-positive CAR T-cells, while tumor cells can also acquire CAR molecules, leading to antigen masking and reduced CAR expression on T cells. Although it remains unclear whether tumor-intrinsic factors regulate the extent of antigen trogocytosis by CAR T-cells, it has been shown that CARs can induce reversible BCMA loss through trogocytosis [35]. where CAR T-cells inadvertently strip BCMA molecules from tumor cell during immune synapse formation [36]. This process results in malignant plasma cells with reduced BCMA expression and CAR T-cells carrying BCMA on their own surfaces. The reduced target density impairs subsequent CAR T-cell engagement, while the presence of BCMA on CAR T cells may provoke unfavorable interactions with neighboring T cells, potentially promoting functional exhaustion and fratricide [37]. Understanding trogocytosis in the context of CAR T-cell therapy offers opportunities for improved CAR designs or combination therapies to overcome resistance.

4.1.4. Altered Intracellular Signaling Pathways and Antigen Presentation

Intrinsic resistance can also arise from alterations in intracellular signaling pathways that impair key cellular functions such as apoptosis and antigen presentation. For instance, upregulation of anti-apoptotic proteins like BCL-2, BCL-XL, MCL-1, and survivin in malignant plasma cells can confer resistance by preventing therapy-induced programmed cell death, thereby reducing the effectiveness of CAR T-cell or BsAb treatments [38]. Furthermore, defects in antigen presentation, including downregulation or loss of major histocompatibility complex (MHC) class I molecules, impair the ability of cytotoxic T lymphocytes to recognize and eliminate tumor cells, enabling immune evasion independent of BCMA expression. Notably, in some patients relapsing after BCMA-targeted BsAb, loss of MHC class I surface expression was observed, suggesting a mechanism of T cell evasion [39]. While BCMA directed therapies act independently of MHC class I, its downregulation often reflects a more immunosuppressive tumor microenvironment with increased T-regulatory cells, myeloid derived suppressor cells and decreased interferon signaling. These interconnected mechanisms underscore the complexity of tumor-intrinsic resistance and highlight the need for combination strategies that address both antigen-dependent and antigen-independent escape pathways to enhance therapeutic efficacy.

4.2. Host Related Mechanisms of Resistance

Host-related factors, including T-cell fitness, prior therapies, and immune senescence, impact the clinical efficacy of both BCMA CAR T-cell therapy and BsAbs. For CAR T cells, the quality of the autologous T-cell product is a key determinant of therapeutic efficacy. In contrast, BsAb therapy, which bridges CD3 on T-cell surfaces to BCMA on plasma cells by immune synapse formation, depends heavily on the endogenous T-cell repertoire. However, patients with heavily pretreated disease often exhibit T-cell exhaustion, senescence, or skewed T-cell subsets, which can impair the therapeutic response and negatively impact overall treatment outcomes.

4.2.1. T-Cell Fitness at Baseline

Primary resistance to BsAb, characterized by lack of response to the initial therapy, is seen in roughly one-third of patients [40]. Non-responders exhibit fewer CD8+ effector CX3CR1+ cells and a higher proportion of exhausted-like CD8+ T-cell clones in the bone marrow [39]. Lower baseline CD8+ T-cell counts in both peripheral blood and bone marrow, along with increased Tregs, and higher expression of exhaustion markers (PD-1, TIM-3), and reduced expression of activity markers (e.g., granzyme B) and lower proportion of naïve T cells, are associated with primary resistance to teclistamab [24,39,41].
T-cell fitness for CAR T-cell therapy remains to be comprehensively defined but is thought to involve multiple factors, including basic T-cell functions, metabolic fitness, and transcriptional or epigenetic programming. Patients with higher frequencies of early memory T cells in their leukapheresis product tend to experience better responses and enhanced CAR T-cell expansion [42]. Early memory T cells offer superior proliferative capacity, which is essential for effective CAR T-cell therapy. Additionally, a higher CD4/CD8 ratio in the leukapheresis product correlates with better CAR T-cell expansion and response [30,43]. T cells from CAR T-cell–resistant patients show high expression of exhaustion markers such as LAG-3, TIGIT, and PD-1, underscoring the importance of T-cell quality in CAR T-cell therapy outcomes [43]. Metabolic fitness further contributes to functional capacity, with effector CD4+ and CD8+ T cells engaging specific metabolic programs to meet high energetic and biosynthetic demands [44]. Aerobic glycolysis supports early IFN-γ production, while mitochondrial membrane potential correlates with cytokine output and survival [45,46]. These functional and metabolic features interact closely with transcriptional and epigenetic regulators, forming a broad landscape of potential markers for T-cell fitness and antitumor immunity. Given the complexity of these pathways, multi-parameter profiling techniques are increasingly used to capture dynamic changes in T-cell state pre- and post-infusion.

4.2.2. T-Cell Exhaustion During Treatment

There is increasing evidence that long-term exposure to BsAb and prolonged activation of CAR T-cells results in T-cell exhaustion. Triggered by prolonged antigen exposure, T-cell exhaustion is marked by high expression of checkpoint and activation markers, along with reduced effector function. It acts as a negative feedback mechanism to regulate T-cell activation. T-cell exhaustion, characterized by increased expression of inhibitory receptors such as PD-1, TIGIT, TIM-3, CTLA-4, and LAG-3 on both CD4+ and CD8+ T cells has been shown to be more pronounced in non-responders than responders [47,48,49]. While T cell exhaustion contributes to treatment resistance, these therapies also cause broader immunologic effects, including hypogammaglobulinemia, B cell apalsia, lymphopenia, and other immune deficiencies that increase susceptibility to infections. This toxicity concern is far from trivial and may limit these therapies for many patients.

4.2.3. CAR T-Cell Associated Resistance

Relapse after short-term remission in patients with RRMM receiving BCMA CAR-T therapy is often linked to CAR-T cell dysfunction, including limited persistence, exhaustion, and impaired proliferation. The quality of T cells used for manufacturing CAR-T cells is critical, yet in heavily pretreated patients, T cells are often senescent or functionally compromised due to prior therapies, genetic alterations, chronic infections, and age-related decline. Immunophenotypic features such as memory-like CD27+/CD45RO−/CD8+ T cells correlate with long-term remission, while exhausted subsets, including double-negative T cells expressing PD-1, TIGIT, 2B4, and KLRG1, are enriched in relapsed patients [50,51,52]. In relapsing patients, single-cell RNA sequencing of bone marrow plasma and immune cells reveals a shift in T cell populations. There is a marked enrichment of CD4+ and CD8+ TEMRA cells (a subset of terminally differentiated effector memory cells that re-express CD45RA and exhibit potent cytotoxicity with limited proliferative capacity) as well as memory T cells, suggesting a skewing toward more differentiated or terminally exhausted phenotypes [34]. Conversely, populations associated with immune regulation and early differentiation, such as Tc17 cells (a subset of CD8+ T cells that produce inflammatory cytokines IL-17 rather than exerting cytotoxic function), regulatory T cells, and naïve T cells are diminished, indicating a possible loss of immune plasticity and regulatory balance during relapse. Chronic antigen exposure, tumor microenvironment factors, and immune rejection of murine-derived CAR constructs also contribute to CAR-T cell loss [53].

5. Tumor Microenvironment Mediated Resistance

The tumor immune microenvironment plays an important role in resistance to BCMA-targeted therapies. It comprises various immunosuppressive cell types, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), regulatory B cells, tumor-associated macrophages, and dendritic cells. These cells promote immune evasion through direct interactions with MM cells and the release of suppressive cytokines and chemokines. Key resistance mechanisms include: (a) chronic antigenic stimulation and upregulation of immune checkpoints (e.g., PD-L1, LAG-3, TIM-3, CTLA-4, TIGIT); (b) secretion of inhibitory cytokines (e.g., IL-10, IL-4, TGF-β, VEGF) that blunt anti-tumor immunity; (c) stromal cell mediated activation of pro-survival pathways and upregulation of antiapoptotic proteins and (d) the presence of myeloma stem-like cells which contribute to therapy failure [54].
Elevated Tregs and granulocytic MDSCs suppress T-cell toxicity and proliferation, reducing the efficacy of BsAbs [48,55]. In teclistamab-treated patients, high baseline Treg counts and elevated CD38+ Tregs correlated with poorer responses and shorter PFS [24,47]. Similarly, increased myeloid cell populations in the bone marrow were linked to suboptimal response to elranatamab.
In BCMA CAR-T therapy, resistance is associated with limited T-cell receptor (TCR) diversity, exhausted hyper-expanded clones, and BAFF+/PD-L1+ myeloid cells [56]. Conversely, higher levels of CLEC9A+ dendritic cells, CD27+/TCF1+ T cells with diverse TCRs, and bone marrow-homing T cells (e.g., CXCR4+, CD69+) predict longer PFS [34]. Additionally, tumor-promoting monocytes and macrophages contribute to T-cell depletion and disease relapse, further highlighting the immunosuppressive nature of the TME [34]. The TME also impedes CAR T-cell infiltration by downregulating endothelial leukocyte adhesion molecules on endothelial cells, reducing vascular permeability, and promoting fibrotic extracellular matrix deposition, all of which create physical and molecular barriers in MM. Metabolic stress in the TME also contributes to CAR T-cell dysfunction and exhaustion through nutrient depletion, hypoxia, lactic acid accumulation, and immunosuppressive metabolites. See Table 1 for a summary of the key mechanisms of resistance to CAR T and BsAb therapies.

6. Key Strategies to Overcome Resistance to BCMA-Targeted Therapies

6.1. Preventing Antigen Escape

Antigen escape, primarily through loss or downregulation of BCMA, represents a key mechanism of acquired resistance to BCMA-targeted therapies. To address this challenge, several innovative strategies are under investigation.
One promising approach involves simultaneously targeting two distinct MM antigens to enhance efficacy and reduce the likelihood of resistance from loss of the original target antigen. For example, the phase 1b RedirecTT-1 study combined Teclistamab (targeting BCMA) and Talquetamab (targeting GPRC5D) in 94 heavily pretreated patients, achieving an ORR of 80%, including 61% in those with extramedullary disease [57]. While rates of cytokine release syndrome were similar to single agent therapies, the incidence of grade 3 or 4 infections was higher.
An alternative dual-targeting strategy is trispecific antibodies that simultaneously recognize two MM antigens alongside CD3 to enhance immune engagement and prevent antigen loss [58,59]. Several trispecific antibodies are currently in clinical development, including ISB 2001 (targeting BCMA, CD38, CD3), JNJ-79635322 (BCMA, GPRC5D, CD3), and SAR442257 (CD38, CD28, CD3).
In CAR T cell therapy, dual antigen targeting can be achieved through various designs, such as tandem CARs (a single receptor with two antigen-binding domains), bicistronic CARs (two CARs expressed from a single vector), and combinatorial strategies like ‘CAR-pools’ (co-expression or co-infusion of different CAR T cells). For instance, in a clinical trial (ChiCTR-OIC-17011272), combined infusion of anti-BCMA and anti-CD19 CAR T cells yielded an ORR of 92% and a CR rate of 60%, with a median PFS of 18.3 months [60]. Additional dual-target CAR T constructs targeting BCMA alongside CD19, GPRC5D, CD38, SLAMF7, TACI, FcRh5, or even intracellular antigens via T-cell receptor engineering are also under evaluation in ongoing clinical trials [61,62,63,64,65,66,67]. Dual-targeted CAR T cells may outperform pooled CAR T cell products, possibly because of enhanced bivalent immune synapse formation that improves activation and expansion. However, randomized trials are needed to determine the added efficacy of combinatorial approaches compared to single-agent BCMA-targeting. Given the infectious risks associated with simultaneous depletion of B cells and plasma cells, careful mitigation strategies to manage hypogammaglobulinemia and infection risk are essential when employing dual-targeting strategies.
Combination approaches that increase antigen density may also enhance the efficacy of BCMA-targeted therapies. γ-secretase inhibitors, which prevent BCMA cleavage and shedding, thereby increasing its surface expression, have shown potential to augment the activity of BCMA-targeted treatments [68]. Early clinical data from the MajesTEC-2 study, which combined the BsAb Teclistamab and γ-secretase inhibitor Nirogacestat, demonstrated a modest improvement in response rate, with ≥complete response (≥CR) observed in 52% of patient [69]. However, there was substantial increase in toxicity, notably diarrhea (any grade 64%; ≥grade 3 in 25%) compared with Teclistamab alone in the MajesTEC-1 study. In a single-center phase 1 study, Crenigacestat, another γ-secretase inhibitor, was administered prior to and following BCMA CAR T-cell therapy in relapsed/refractory MM [70]. The combination was well tolerated, with the most common non-hematological grade ≥ 3 adverse events including hypophosphatemia (78%), fatigue (61%), and hypocalcemia (50%). Importantly, Crenigacestat increased BCMA surface density on malignant plasma cells and decreased sBCMA levels, suggesting a favorable modulation of the BCMA expression.

6.2. Overcoming T-Cell Exhaustion

Beyond antigen escape, another critical barrier to durable responses in BCMA-targeted therapies is T-cell exhaustion, which limits the persistence and efficacy of CAR T and BsAb therapies. T-cell fitness could be improved or maintained by specific therapeutic interventions, such as combination therapy with immune checkpoint inhibitors, alternative bispecific antibody formats, optimizing CAR T-cell structure, and inhibiting intracellular exhaustion-related signals.
While combining BsAb with immune checkpoint inhibitors could enhance T-cell activation, this approach requires caution due to prior reports of severe toxicity with Pembrolizumab when combined with IMiDs in MM [71,72]. Currently, there are no available data on the combined activity of BsAbs with other checkpoint inhibitors, such as anti-TIGIT or anti-TIM3 antibodies. Combining BsAb with cereblon modulators like Iberdomide or Mezigdomide shows potential in restoring T-cell function and enhancing anti-myeloma activity in preclinical models [73]. To achieve T-cell redirection alongside a tumor-restricted immune checkpoint blockade, a trispecific antibody (CDR101) that simultaneously targets BCMA, CD3, and PD-L1 has shown promise in the xenograft model [74].
Additionally, combining CD3 BsAb with co-stimulatory BsAb, which deliver a second, tumor-specific co-stimulatory signal, further boosts T-cell activation, proliferation, and antitumor efficacy. Early clinical results using RO7227166 (targeting CD19 and 4-1BB) alongside Glofitamab (targeting CD20 and CD3) show enhanced antilymphoma activity and prevention of T-cell exhaustion, with manageable safety [75].
PD-1 checkpoint blockade with antibodies can improve CAR T-cell activity and promote tumor cell death. Preliminary results show that PD-1 inhibitor–based combination therapy may result in CAR T-cell expansion and anti-MM activity in a subset of patients progressing after BCMA CAR T-cell therapy [76]. Trials of PD-1 blockade after BCMA CAR-T therapy with pembrolizumab or nivolumab are ongoing (NCT04205409 and NCT05191472). Targeted modulation of PD-1 in CAR-T cell products through gene editing offers the advantage of protecting CAR-T cells from PD-1–mediated exhaustion, while sparing bystander T cells [77]. This selective approach may reduce the risk of autoimmune toxicities. Transduction and expansion of CAR T cells in the presence of PI3K inhibitors (e.g., Idelalisib or bb007) has been shown to enrich for less-differentiated CAR T cell phenotypes, reduce the expression of exhaustion markers such as PD-1 and TIM-3, enhance in vivo persistence, and improve antitumor efficacy in preclinical models of leukemia and multiple myeloma [78].
Since T cell fitness might be better early in the disease course, several studies of CART-cell therapy (CARTITUDE-5 and CARTITUDE-6) and BsAb (MajesTEC-3, MajesTEC-4, MajesTEC-7, MagnetisMM-5, MagnetisMM-6, MagnetisMM-7, CERVINO, LINKER-MM3) have been initiated in earlier lines of treatment.

6.3. Targeting TME

Alternative CAR T cell constructs are currently being investigated that can enhance the CAR T cells efficacy in the tumor microenvironment by increasing the ability of CAR-T cells to infiltrate tumors, bind BCMA, and proliferate in response to antigen recognition. One such construct is the “Armored” CAR T Cell. Armored CARs are engineered with additional features to enhance their function and survival in the tumor microenvironment by secreting cytokines or express immune-modulating molecules to counteract the TME and boost T-cell activity [79,80]. Some have been modified to secrete IL-12, IL-15, IL-18, IL-7 and other cytokines upon activation which act locally to stimulate the CAR T-cells as well as the endogenous immune cells [81,82]. IL-15 can promote CAR T-cell persistence and proliferation, IL-7 can support T cell survival and recruitment, and IL-18 can lead to a more inflammatory tumor microenvironment converting suppressive myeloid cells into pro-inflammatory helpers [83,84]. Thus far, in preclinical studies, IL-18 secreting CARs have shown superior activity against relapsed MM models potentially indicating the ability to overcome these marrow suppressive signals by counteracting TGF-β [80]. A novel BCMA-targeted CAR-T cell therapy, CART-ddBCMA, utilizes a d-domain-based antigen-binding domain in place of traditional scFvs, effectively minimizing tonic signaling. This design has demonstrated promising clinical responses in a Phase I trial [85].
Members of the TNFR superfamily play a critical role in modulating CAR-T cell function through their co-stimulatory signals. Under conditions of persistent antigen exposure, BCMA-targeted CAR-T cells engineered with an OX40 co-stimulatory domain demonstrate superior proliferative capacity and more sustained anti-tumor activity compared to those incorporating a 4-1BB domain [86].
The efficacy of BsAb can be enhanced by combining them with immunomodulatory drugs (IMiDs; e.g., lenalidomide and pomalidomide) and Cereblon E3 ligase modulatory drugs (CELMoDs; e.g., Iberdomide and Mezigdomide). These agents enhance co-stimulatory signaling, suppress IL-2 promoter transcription, and strengthen immunological synapse formation to support effective T cell–mediated cytotoxicity.
CD38-targeting antibodies (e.g., Daratumumab and Isatuximab) deplete CD38+ immunosuppressive cells, including Tregs, MDSCs, and regulatory B cells, thereby enhancing T-cell numbers and activity. These mechanisms provide a rationale for combining CD38 monoclonal antibodies with BsAb. and several clinical trials evaluating these combinations are currently underway.

6.4. Sequencing BCMA-Targeted Therapies

A potentially effective strategy to address resistance is the sequential use of BsAb and CAR T-cell therapy. Emerging evidence suggests that sequencing these therapies can enhance disease control; however, the order of administration significantly influences overall efficacy.
While BsAbs and CAR T-cell therapies share some mechanisms of resistance, they also differ in important ways. Both approaches demonstrate limited efficacy in high-risk clinical scenarios, such as extramedullary disease, high-risk cytogenetics, plasma cell leukemia, and elevated sBCMA levels [8,9,87,88]. Moreover, both are susceptible to resistance mediated by TME, including the immunosuppressive influence of MDSC, increased T-regs, inhibitory cytokine profiles, and progressive T-cell exhaustion.
A major distinction lies in T-cell activation dynamics. BsAbs require repeated administration and continuous antigen engagement, whereas CAR T cells exert their effects during their expansion and persistence phases. As a result, antigen loss is rare with CAR T-cell therapy (2–4%) but significantly more common after BsAb therapy (up to 50%). In this regard, fixed duration schedule of BsAbs, with the intent of limiting immune system exploitation, are being studied [89].
In patients relapsing after CAR T-cell therapy, Teclistamab demonstrated promising results, with an ORR of 91.4%, a median PFS of 9.1 months, and an OS not reached at a median follow-up of 21 months [90]. Conversely, prior exposure to BsAb may reduce the efficacy of later BCMA-directed CAR T-cell therapy, driven by BCMA downregulation, T-cell exhaustion, or the selection of clones resistant to T-cell–mediated killing. This was evident in Cohort C of the CARTITUDE-2 trial, where patients previously treated with BsAbs had reduced ORR (57.1%) and median PFS (5.3 months) to cilta-cel [91]. Similarly, a retrospective study by the US Myeloma CAR T Consortium evaluating ide-cel after BsAb exposure reported an ORR of 74% and median PFS of 2.8 months [92]. Interestingly, both studies indicated improved outcomes when CAR T-cell therapy was administered after a longer interval from prior BsAb exposure, suggesting that timing may play a critical role in optimizing sequencing strategies. Alternatively, in the setting of relapse post-CAR T-cell therapy, switching to a BsAb targeting a different antigen, such as GPRC5D or FcRH5, may offer an effective approach. There is also growing interest in combining or sequencing BsAb after CAR T-cell therapy as maintenance therapy. The rationale is that BsAbs may serve as a “patrolling” therapy to eliminate residual antigen-positive cells. However, concurrent use raises concerns due to the potential for overlapping toxicities and presents logistical challenges in administering two potent immunotherapies. Importantly, BsAbs and CAR T-cell therapies share similar toxicity profiles, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, prolonged immune suppression, and increased infection risk. These adverse effects may be intensified when therapies are sequenced, underscoring the need to carefully evaluate safety and patient tolerability when designing sequencing strategies.

7. Conclusions

BCMA targeted therapies have transformed the treatment paradigm for MM, offering meaningful clinical benefit to patients with relapsed or refractory disease. However, the durability of these responses remains a challenge, as treatment resistance emerges. Key contributors to resistance include intrinsic T-cell dysfunction, a tolerogenic bone marrow microenvironment, and antigen escape through BCMA loss. As these therapies move earlier in the disease course and are integrated into sequential or combination strategies, a deeper understanding of resistance mechanisms becomes imperative. Comprehensive genomic and transcriptomic profiling of both the tumor cells and immune components will be vital to unravel resistance pathways, identify patients at highest risk of relapse, and guide the development of dynamic, predictive biomarkers. Advancing the field will require tightly integrated translational research embedded within clinical trials, including high-resolution immune profiling and correlative studies. These efforts are key to distinguishing primary from acquired resistance and guiding the design of rational, personalized interventions. Looking ahead, the future of BCMA-targeted immunotherapy lies in the strategic combinations and sequencing of therapies, including dual-target or multi-specific antibodies, next-generation CAR T cells, and immune-enhancing agents that preserve T-cell fitness and prevent exhaustion. Such integrative strategies hold the promise not only of overcoming resistance but of achieving more sustained responses, and ultimately long-term disease control or cure for patients with MM. As these approaches are explored, careful consideration of their unique toxicity profiles will be essential in designing safe and effective clinical trials.

Author Contributions

Conceptualization, M.B. and B.T.; Investigation M.B. and B.T.; Resources, M.B. and B.T.; Data Curation, M.B. and B.T.; Writing—Original Draft Preparation, M.B. and B.T.; Writing—Review & Editing, M.B. and B.T.; Visualization/Figures, B.T. and M.B.; Supervision, M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

This manuscript did not include any original data.

Acknowledgments

During the preparation of this manuscript, the author(s) used AI software “ChatGPT for MS Word” for the purposes of spell-check as well as grammar checking. The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Conflicts of Interest

B.T. declares no conflict of interests. M.B. serves on the advisory board for Caribou Biosciences, and has received research funding (to institution) for clinical trials from Janssen, Amgen, Bristol Myers Squibb/Celgene, Takeda, Abbvie, Caribou Biosciences and The Binding Site.

References

  1. Laabi, Y.; Gras, M.P.; Brouet, J.C.; Berger, R.; Larsen, C.J.; Tsapis, A. The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed. Nucleic Acids Res. 1994, 22, 1147–1154. [Google Scholar] [CrossRef] [PubMed]
  2. Carpenter, R.O.; Evbuomwan, M.O.; Pittaluga, S.; Rose, J.J.; Raffeld, M.; Yang, S.; Gress, R.E.; Hakim, F.T.; Kochenderfer, J.N. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 2013, 19, 2048–2060. [Google Scholar] [CrossRef]
  3. Xu, S.; Lam, K.P. B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. Mol. Cell Biol. 2001, 21, 4067–4074. [Google Scholar] [CrossRef] [PubMed]
  4. Munshi, N.C.; Anderson, L.D., Jr.; Shah, N.; Madduri, D.; Berdeja, J.; Lonial, S.; Raje, N.; Lin, Y.; Siegel, D.; Oriol, A.; et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N. Engl. J. Med. 2021, 384, 705–716. [Google Scholar] [CrossRef] [PubMed]
  5. Rodriguez-Otero, P.; Ailawadhi, S.; Arnulf, B.; Patel, K.; Cavo, M.; Nooka, A.K.; Manier, S.; Callander, N.; Costa, L.J.; Vij, R.; et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N. Engl. J. Med. 2023, 388, 1002–1014. [Google Scholar] [CrossRef]
  6. Berdeja, J.G.; Madduri, D.; Usmani, S.Z.; Jakubowiak, A.; Agha, M.; Cohen, A.D.; Stewart, A.K.; Hari, P.; Htut, M.; Lesokhin, A.; et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet 2021, 398, 314–324. [Google Scholar] [CrossRef]
  7. San-Miguel, J.; Dhakal, B.; Yong, K.; Spencer, A.; Anguille, S.; Mateos, M.V.; Fernandez de Larrea, C.; Martinez-Lopez, J.; Moreau, P.; Touzeau, C.; et al. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N. Engl. J. Med. 2023, 389, 335–347. [Google Scholar] [CrossRef]
  8. Moreau, P.; Garfall, A.L.; van de Donk, N.; Nahi, H.; San-Miguel, J.F.; Oriol, A.; Nooka, A.K.; Martin, T.; Rosinol, L.; Chari, A.; et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2022, 387, 495–505. [Google Scholar] [CrossRef]
  9. Bahlis, N.J.; Costello, C.L.; Raje, N.S.; Levy, M.Y.; Dholaria, B.; Solh, M.; Tomasson, M.H.; Damore, M.A.; Jiang, S.; Basu, C.; et al. Elranatamab in relapsed or refractory multiple myeloma: The MagnetisMM-1 phase 1 trial. Nat. Med. 2023, 29, 2570–2576. [Google Scholar] [CrossRef]
  10. Lesokhin, A.M.; Tomasson, M.H.; Arnulf, B.; Bahlis, N.J.; Miles Prince, H.; Niesvizky, R.; Rodriotaguez-Otero, P.; Martinez-Lopez, J.; Koehne, G.; Touzeau, C.; et al. Elranatamab in relapsed or refractory multiple myeloma: Phase 2 MagnetisMM-3 trial results. Nat. Med. 2023, 29, 2259–2267. [Google Scholar] [CrossRef]
  11. Laabi, Y.; Gras, M.P.; Carbonnel, F.; Brouet, J.C.; Berger, R.; Larsen, C.J.; Tsapis, A. A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma. EMBO J. 1992, 11, 3897–3904. [Google Scholar] [CrossRef]
  12. Kozlow, E.J.; Wilson, G.L.; Fox, C.H.; Kehrl, J.H. Subtractive cDNA cloning of a novel member of the Ig gene superfamily expressed at high levels in activated B lymphocytes. Blood 1993, 81, 454–461. [Google Scholar] [CrossRef] [PubMed]
  13. Day, E.S.; Cachero, T.G.; Qian, F.; Sun, Y.; Wen, D.; Pelletier, M.; Hsu, Y.M.; Whitty, A. Selectivity of BAFF/BLyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA. Biochemistry 2005, 44, 1919–1931. [Google Scholar] [CrossRef] [PubMed]
  14. Hatzoglou, A.; Roussel, J.; Bourgeade, M.F.; Rogier, E.; Madry, C.; Inoue, J.; Devergne, O.; Tsapis, A. TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. J. Immunol. 2000, 165, 1322–1330. [Google Scholar] [CrossRef] [PubMed]
  15. Shen, X.; Guo, Y.; Qi, J.; Shi, W.; Wu, X.; Ju, S. Binding of B-cell maturation antigen to B-cell activating factor induces survival of multiple myeloma cells by activating Akt and JNK signaling pathways. Cell Biochem. Funct. 2016, 34, 104–110. [Google Scholar] [CrossRef]
  16. Moreaux, J.; Legouffe, E.; Jourdan, E.; Quittet, P.; Reme, T.; Lugagne, C.; Moine, P.; Rossi, J.F.; Klein, B.; Tarte, K. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004, 103, 3148–3157. [Google Scholar] [CrossRef]
  17. Pan, J.; Sun, Y.; Zhang, N.; Li, J.; Ta, F.; Wei, W.; Yu, S.; Ai, L. Characteristics of BAFF and APRIL factor expression in multiple myeloma and clinical significance. Oncol. Lett. 2017, 14, 2657–2662. [Google Scholar] [CrossRef]
  18. Moreaux, J.; Sprynski, A.C.; Dillon, S.R.; Mahtouk, K.; Jourdan, M.; Ythier, A.; Moine, P.; Robert, N.; Jourdan, E.; Rossi, J.F.; et al. APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop. Eur. J. Haematol. 2009, 83, 119–129. [Google Scholar] [CrossRef]
  19. Bolkun, L.; Lemancewicz, D.; Jablonska, E.; Kulczynska, A.; Bolkun-Skornicka, U.; Kloczko, J.; Dzieciol, J. BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma. Ann. Hematol. 2014, 93, 635–644. [Google Scholar] [CrossRef]
  20. Marsters, S.A.; Yan, M.; Pitti, R.M.; Haas, P.E.; Dixit, V.M.; Ashkenazi, A. Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI. Curr. Biol. 2000, 10, 785–788. [Google Scholar] [CrossRef]
  21. Moreaux, J.; Cremer, F.W.; Reme, T.; Raab, M.; Mahtouk, K.; Kaukel, P.; Pantesco, V.; De Vos, J.; Jourdan, E.; Jauch, A.; et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 2005, 106, 1021–1030. [Google Scholar] [CrossRef] [PubMed]
  22. Tai, Y.T.; Lin, L.; Xing, L.; Cho, S.F.; Yu, T.; Acharya, C.; Wen, K.; Hsieh, P.A.; Dulos, J.; van Elsas, A.; et al. APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: Therapeutic implications. Leukemia 2019, 33, 426–438. [Google Scholar] [CrossRef]
  23. Tedder, B. 2025. Available online: https://BioRender.com/a2ezh17 (accessed on 29 June 2025).
  24. Cortes-Selva, D.; Casneuf, T.; Vishwamitra, D.; Stein, S.; Perova, T.; Skerget, S.; Ramos, E.; van Steenbergen, L.; De Maeyer, D.; Boominathan, R.; et al. Teclistamab, a B-Cell Maturation Antigen (BCMA) x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Correlative Analyses from MajesTEC-1. Blood 2022, 140, 241–243. [Google Scholar] [CrossRef]
  25. Raje, N.; Berdeja, J.; Lin, Y.; Siegel, D.; Jagannath, S.; Madduri, D.; Liedtke, M.; Rosenblatt, J.; Maus, M.V.; Turka, A.; et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2019, 380, 1726–1737. [Google Scholar] [CrossRef] [PubMed]
  26. Brudno, J.N.; Maric, I.; Hartman, S.D.; Rose, J.J.; Wang, M.; Lam, N.; Stetler-Stevenson, M.; Salem, D.; Yuan, C.; Pavletic, S.; et al. T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. J. Clin. Oncol. 2018, 36, 2267–2280. [Google Scholar] [CrossRef]
  27. Salem, D.A.; Maric, I.; Yuan, C.M.; Liewehr, D.J.; Venzon, D.J.; Kochenderfer, J.; Stetler-Stevenson, M. Quantification of B-cell maturation antigen, a target for novel chimeric antigen receptor T-cell therapy in Myeloma. Leuk. Res. 2018, 71, 106–111. [Google Scholar] [CrossRef]
  28. Lee, H.; Durante, M.; Skerget, S.; Vishwamitra, D.; Benaoudia, S.; Ahn, S.; Poorebrahim, M.; Barakat, E.; Jung, D.; Leblay, N.; et al. Impact of soluble BCMA and non-T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma. Blood 2024, 144, 2637–2651. [Google Scholar] [CrossRef]
  29. Pont, M.J.; Hill, T.; Cole, G.O.; Abbott, J.J.; Kelliher, J.; Salter, A.I.; Hudecek, M.; Comstock, M.L.; Rajan, A.; Patel, B.K.R.; et al. gamma-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood 2019, 134, 1585–1597. [Google Scholar] [CrossRef]
  30. Cohen, A.D.; Garfall, A.L.; Stadtmauer, E.A.; Melenhorst, J.J.; Lacey, S.F.; Lancaster, E.; Vogl, D.T.; Weiss, B.M.; Dengel, K.; Nelson, A.; et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J. Clin. Investig. 2019, 129, 2210–2221. [Google Scholar] [CrossRef]
  31. Lee, H.; Ahn, S.; Maity, R.; Leblay, N.; Ziccheddu, B.; Truger, M.; Chojnacka, M.; Cirrincione, A.; Durante, M.; Tilmont, R.; et al. Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma. Nat. Med. 2023, 29, 2295–2306. [Google Scholar] [CrossRef]
  32. Samur, M.K.; Fulciniti, M.; Aktas Samur, A.; Bazarbachi, A.H.; Tai, Y.T.; Prabhala, R.; Alonso, A.; Sperling, A.S.; Campbell, T.; Petrocca, F.; et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat. Commun. 2021, 12, 868. [Google Scholar] [CrossRef]
  33. Samur, M.K.; Aktas Samur, A.; Corre, J.; Lannes, R.; Shah, P.; Anderson, K.; Avet-Loiseau, H.; Munshi, N. Monoallelic deletion of BCMA is a frequent feature in multiple myeloma. Blood Adv. 2023, 7, 6599–6603. [Google Scholar] [CrossRef]
  34. Li, W.; Zhang, B.; Cao, W.; Zhang, W.; Li, T.; Liu, L.; Xu, L.; Gao, F.; Wang, Y.; Wang, F.; et al. Identification of potential resistance mechanisms and therapeutic targets for the relapse of BCMA CAR-T therapy in relapsed/refractory multiple myeloma through single-cell sequencing. Exp. Hematol. Oncol. 2023, 12, 44. [Google Scholar] [CrossRef]
  35. Chen, Y.; Xin, Q.; Zhu, M.; Qiu, J.; Qiu, J.; Li, R.; Tu, J. Trogocytosis in CAR immune cell therapy: A key mechanism of tumor immune escape. Cell Commun. Signal 2024, 22, 521. [Google Scholar] [CrossRef]
  36. Hamieh, M.; Dobrin, A.; Cabriolu, A.; van der Stegen, S.J.C.; Giavridis, T.; Mansilla-Soto, J.; Eyquem, J.; Zhao, Z.; Whitlock, B.M.; Miele, M.M.; et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature 2019, 568, 112–116. [Google Scholar] [CrossRef]
  37. Zhai, Y.; Du, Y.; Li, G.; Yu, M.; Hu, H.; Pan, C.; Wang, D.; Shi, Z.; Yan, X.; Li, X.; et al. Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape. Signal Transduct. Target. Ther. 2023, 8, 457. [Google Scholar] [CrossRef]
  38. Zhang, Z.; Su, M.; Jiang, P.; Wang, X.; Tong, X.; Wu, G. Unlocking Apoptotic Pathways: Overcoming Tumor Resistance in CAR-T-Cell Therapy. Cancer Med. 2024, 13, e70283. [Google Scholar] [CrossRef]
  39. Friedrich, M.J.; Neri, P.; Kehl, N.; Michel, J.; Steiger, S.; Kilian, M.; Leblay, N.; Maity, R.; Sankowski, R.; Lee, H.; et al. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients. Cancer Cell 2023, 41, 711–725.e716. [Google Scholar] [CrossRef]
  40. Letouze, E.; Moreau, P.; Munshi, N.; Samur, M.; Minvielle, S.; Touzeau, C. Mechanisms of resistance to bispecific T-cell engagers in multiple myeloma and their clinical implications. Blood Adv. 2024, 8, 2952–2959. [Google Scholar] [CrossRef] [PubMed]
  41. Philipp, N.; Kazerani, M.; Nicholls, A.; Vick, B.; Wulf, J.; Straub, T.; Scheurer, M.; Muth, A.; Hanel, G.; Nixdorf, D.; et al. T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals. Blood 2022, 140, 1104–1118. [Google Scholar] [CrossRef] [PubMed]
  42. Finney, O.C.; Yeri, A.; Mao, P.; Pandya, C.; Alonzo, E.; Hopkins, G.; Hymson, S.; Hu, T.; Foos, M.; Bhadoriya, S.; et al. Molecular and Phenotypic Profiling of Drug Product and Post-Infusion Samples from CRB-402, an Ongoing: Phase I Clinical Study of bb21217 a BCMA-Directed CAR T Cell Therapy. Blood 2020, 136, 3–4. [Google Scholar] [CrossRef]
  43. Leblay, N.; Maity, R.; Barakat, E.; McCulloch, S.; Duggan, P.; Jimenez-Zepeda, V.; Bahlis, N.J.; Neri, P. Cite-Seq Profiling of T Cells in Multiple Myeloma Patients Undergoing BCMA Targeting CAR-T or Bites Immunotherapy. Blood 2020, 136, 11–12. [Google Scholar] [CrossRef]
  44. Mehta, P.H.; Fiorenza, S.; Koldej, R.M.; Jaworowski, A.; Ritchie, D.S.; Quinn, K.M. T Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy. Front. Immunol. 2021, 12, 780442. [Google Scholar] [CrossRef]
  45. Chang, C.H.; Curtis, J.D.; Maggi, L.B., Jr.; Faubert, B.; Villarino, A.V.; O’Sullivan, D.; Huang, S.C.; van der Windt, G.J.; Blagih, J.; Qiu, J.; et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013, 153, 1239–1251. [Google Scholar] [CrossRef]
  46. Sukumar, M.; Liu, J.; Mehta, G.U.; Patel, S.J.; Roychoudhuri, R.; Crompton, J.G.; Klebanoff, C.A.; Ji, Y.; Li, P.; Yu, Z.; et al. Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. Cell Metab. 2016, 23, 63–76. [Google Scholar] [CrossRef]
  47. Vishwamitra, D.; Skerget, S.; Cortes, D.; Perova, T.; Lau, O.; Davis, C.; Guo, Y.; Miao, X.; Stephenson, T.; Hodin, C.; et al. Longitudinal Correlative Profiles of Responders, Nonresponders, and Those with Relapse on Treatment with Teclistamab in the Phase 1/2 MajesTEC-1 Study of Patients with Relapsed/Refractory Multiple Myeloma. Blood 2023, 142, 455. [Google Scholar] [CrossRef]
  48. Verkleij, C.P.M.; O’Neill, C.A.; Broekmans, M.E.C.; Frerichs, K.A.; Bruins, W.S.C.; Duetz, C.; Kruyswijk, S.; Baglio, S.R.; Skerget, S.; Montes de Oca, R.; et al. T-Cell Characteristics Impact Response and Resistance to T-Cell-Redirecting Bispecific Antibodies in Multiple Myeloma. Clin. Cancer Res. 2024, 30, 3006–3022. [Google Scholar] [CrossRef]
  49. Neri, P.; Ahn, S.; Lee, H.; Leblay, N.; Friedrich, M.; Maity, R.; Tilmont, R.; Barakat, E.; Raab, M.S.; Bahlis, N.J. Dysfunctional Hyper-Expanded Clonotypes and Lack of TCR Clonal Replacement Predict Resistance to T Cell Engagers in Multiple Myeloma. Blood 2022, 140, 2093–2094. [Google Scholar] [CrossRef]
  50. Klebanoff, C.A.; Gattinoni, L.; Torabi-Parizi, P.; Kerstann, K.; Cardones, A.R.; Finkelstein, S.E.; Palmer, D.C.; Antony, P.A.; Hwang, S.T.; Rosenberg, S.A.; et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl. Acad. Sci. USA 2005, 102, 9571–9576. [Google Scholar] [CrossRef]
  51. Klebanoff, C.A.; Scott, C.D.; Leonardi, A.J.; Yamamoto, T.N.; Cruz, A.C.; Ouyang, C.; Ramaswamy, M.; Roychoudhuri, R.; Ji, Y.; Eil, R.L.; et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Investig. 2016, 126, 318–334. [Google Scholar] [CrossRef]
  52. Berger, C.; Jensen, M.C.; Lansdorp, P.M.; Gough, M.; Elliott, C.; Riddell, S.R. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J. Clin. Investig. 2008, 118, 294–305. [Google Scholar] [CrossRef] [PubMed]
  53. Xu, X.; Sun, Q.; Liang, X.; Chen, Z.; Zhang, X.; Zhou, X.; Li, M.; Tu, H.; Liu, Y.; Tu, S.; et al. Mechanisms of Relapse After CD19 CAR T-Cell Therapy for Acute Lymphoblastic Leukemia and Its Prevention and Treatment Strategies. Front. Immunol. 2019, 10, 2664. [Google Scholar] [CrossRef]
  54. Yue, T.; Sun, Y.; Dai, Y.; Jin, F. Mechanisms for resistance to BCMA-targeted immunotherapies in multiple myeloma. Blood Rev. 2025, 70, 101256. [Google Scholar] [CrossRef] [PubMed]
  55. Perez, C.; Botta, C.; Zabaleta, A.; Puig, N.; Cedena, M.T.; Goicoechea, I.; Alameda, D.; San Jose-Eneriz, E.; Merino, J.; Rodriguez-Otero, P.; et al. Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma. Blood 2020, 136, 199–209. [Google Scholar] [CrossRef]
  56. Dhodapkar, K.M.; Cohen, A.D.; Kaushal, A.; Garfall, A.L.; Manalo, R.J.; Carr, A.R.; McCachren, S.S.; Stadtmauer, E.A.; Lacey, S.F.; Melenhorst, J.J.; et al. Changes in Bone Marrow Tumor and Immune Cells Correlate with Durability of Remissions Following BCMA CAR T Therapy in Myeloma. Blood Cancer Discov. 2022, 3, 490–501. [Google Scholar] [CrossRef] [PubMed]
  57. Cohen, Y.C.; Magen, H.; Gatt, M.; Sebag, M.; Kim, K.; Min, C.K.; Ocio, E.M.; Yoon, S.S.; Chu, M.P.; Rodriguez-Otero, P.; et al. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2025, 392, 138–149. [Google Scholar] [CrossRef]
  58. Pillarisetti, R.; Yang, D.; Yao, J.; Smith, M.; Luistro, L.; Vulfson, P.; Testa, J., Jr.; Packman, K.; Brodeur, S.; Attar, R.M.; et al. Characterization of JNJ-79635322, a Novel BCMAxGPRC5DxCD3 T-Cell Redirecting Trispecific Antibody, for the Treatment of Multiple Myeloma. Blood 2023, 142, 456. [Google Scholar] [CrossRef]
  59. Pihlgren, M.; Hall, O.; Carretero, L.; Estoppey, C.; Drake, A.; Pais, D.; Loyau, J.; Berret, J.; Gruber, I.; Suere, P.; et al. ISB 2001, a First-in-Class Trispecific BCMA and CD38 T Cell Engager Designed to Overcome Mechanisms of Escape from Treatments for Multiple Myeloma By Targeting Two Antigens. Blood 2022, 140, 858–859. [Google Scholar] [CrossRef]
  60. Yan, Z.; Cao, J.; Cheng, H.; Qiao, J.; Zhang, H.; Wang, Y.; Shi, M.; Lan, J.; Fei, X.; Jin, L.; et al. A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: A single-arm, phase 2 trial. Lancet Haematol. 2019, 6, e521–e529. [Google Scholar] [CrossRef]
  61. Garfall, A.L.; Cohen, A.D.; Susanibar-Adaniya, S.P.; Hwang, W.T.; Vogl, D.T.; Waxman, A.J.; Lacey, S.F.; Gonzalez, V.E.; Fraietta, J.A.; Gupta, M.; et al. Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy. Blood Cancer Discov. 2023, 4, 118–133. [Google Scholar] [CrossRef]
  62. Shi, M.; Wang, J.; Huang, H.; Liu, D.; Cheng, H.; Wang, X.; Chen, W.; Yan, Z.; Sang, W.; Qi, K.; et al. Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: A phase I/II trial. Nat. Commun. 2024, 15, 3371. [Google Scholar] [CrossRef] [PubMed]
  63. Tang, Y.; Yin, H.; Zhao, X.; Jin, D.; Liang, Y.; Xiong, T.; Li, L.; Tang, W.; Zhang, J.; Liu, M.; et al. High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma. J. Exp. Clin. Cancer Res. 2022, 41, 2. [Google Scholar] [CrossRef] [PubMed]
  64. Jiang, D.; Huang, H.; Qin, H.; Tang, K.; Shi, X.; Zhu, T.; Gao, Y.; Zhang, Y.; Tian, X.; Fu, J.; et al. Chimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma. Nat. Commun. 2023, 14, 3642. [Google Scholar] [CrossRef] [PubMed]
  65. Zah, E.; Nam, E.; Bhuvan, V.; Tran, U.; Ji, B.Y.; Gosliner, S.B.; Wang, X.; Brown, C.E.; Chen, Y.Y. Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma. Nat. Commun. 2020, 11, 2283. [Google Scholar] [CrossRef]
  66. Lee, L.; Draper, B.; Chaplin, N.; Philip, B.; Chin, M.; Galas-Filipowicz, D.; Onuoha, S.; Thomas, S.; Baldan, V.; Bughda, R.; et al. An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma. Blood 2018, 131, 746–758. [Google Scholar] [CrossRef]
  67. Yang, Y.; McCloskey, J.E.; Yang, H.; Puc, J.; Alcaina, Y.; Vedvyas, Y.; Gomez Gallegos, A.A.; Ortiz-Sanchez, E.; de Stanchina, E.; Min, I.M.; et al. Bispecific CAR T Cells against EpCAM and Inducible ICAM-1 Overcome Antigen Heterogeneity and Generate Superior Antitumor Responses. Cancer Immunol. Res. 2021, 9, 1158–1174. [Google Scholar] [CrossRef]
  68. Chen, H.; Yu, T.; Lin, L.; Xing, L.; Cho, S.F.; Wen, K.; Aardalen, K.; Oka, A.; Lam, J.; Daley, M.; et al. gamma-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation. Blood Cancer J. 2022, 12, 118. [Google Scholar] [CrossRef]
  69. Offner, F.; Decaux, O.; Hulin, C.; Anguille, S.; Sophie Michallet, A.; Costa, L.; Touzeau, C.; Boyd, K.; Vishwamitra, D.; Guo, Y.; et al. S194: Teclistamab (Tec) + Nirogacestat (Niro) in Relapsed/Refractory Multiple Myeloma (Rrmm): The Phase 1b Majestec-2 Study. HemaSphere 2023, 7 (Suppl. S3). [Google Scholar] [CrossRef]
  70. Cowan, A.J.; Pont, M.J.; Sather, B.D.; Turtle, C.J.; Till, B.G.; Libby, E.N., 3rd; Coffey, D.G.; Tuazon, S.A.; Wood, B.; Gooley, T.; et al. gamma-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: A phase 1, first-in-human trial. Lancet Oncol. 2023, 24, 811–822. [Google Scholar] [CrossRef]
  71. Usmani, S.Z.; Schjesvold, F.; Oriol, A.; Karlin, L.; Cavo, M.; Rifkin, R.M.; Yimer, H.A.; LeBlanc, R.; Takezako, N.; McCroskey, R.D.; et al. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): A randomised, open-label, phase 3 trial. Lancet Haematol. 2019, 6, e448–e458. [Google Scholar] [CrossRef]
  72. Mateos, M.V.; Blacklock, H.; Schjesvold, F.; Oriol, A.; Simpson, D.; George, A.; Goldschmidt, H.; Larocca, A.; Chanan-Khan, A.; Sherbenou, D.; et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): A randomised, open-label, phase 3 trial. Lancet Haematol. 2019, 6, e459–e469. [Google Scholar] [CrossRef] [PubMed]
  73. Paiva, B.; Gaffney, B.; Burnett, K.; Castiglioni, P.; Angelo, M.; Pierce, D.W.; Boss, I.W. Synergistic Antitumor Activity of Alnuctamab (ALNUC.; BMS-986349; CC-93269), a BCMA 2+1 T Cell Engager (TCE), and Celmod Agents in Multiple Myeloma (MM) Preclinical Models. Blood 2022, 140, 7054–7055. [Google Scholar] [CrossRef]
  74. Vrohlings, M.; Müller, J.; Jungmichel, S.; Senn, D.; Howald, A.B.; Schleier, T.; Scheifele, F.; Wendelspiess, S.; Richle, P.; Merten, H.; et al. Preclinical Assessment of CDR101—A BCMAxCD3xPD-L1 Trispecific Antibody with Superior Anti-Tumor Efficacy. Blood 2021, 138, 1583. [Google Scholar] [CrossRef]
  75. Hutchings, M.; Carlo-Stella, C.; Gritti, G.; Bosch, F.; Morschhauser, F.; Townsend, W.; Offner, F.; Walter, H.S.; Ghesquieres, H.; Houot, R.; et al. CD19 4-1BBL (RO7227166) a Novel Costimulatory Bispecific Antibody Can be Safely Combined with the T-Cell-Engaging Bispecific Antibody Glofitamab in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma. Blood 2022, 140, 9461–9463. [Google Scholar] [CrossRef]
  76. Waldschmidt, J.M.; Sotudeh, N.; Arora, S.; Vijaykumar, T.; Anand, P.; Stuart, H.; Frede, J.; Campbell, T.; Kaiser, S.M.; Zheng, X.; et al. Nivolumab to restore T-cell fitness in CAR-T refractory multiple myeloma. Blood Adv. 2025, 9, 1132–1136. [Google Scholar] [CrossRef] [PubMed]
  77. Rupp, L.J.; Schumann, K.; Roybal, K.T.; Gate, R.E.; Ye, C.J.; Lim, W.A.; Marson, A. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 2017, 7, 737. [Google Scholar] [CrossRef] [PubMed]
  78. Alsina, M.; Shah, N.; Raje, N.S.; Jagannath, S.; Madduri, D.; Kaufman, J.L.; Siegel, D.S.; Munshi, N.C.; Rosenblatt, J.; Lin, Y.; et al. Updated Results from the Phase I CRB-402 Study of Anti-Bcma CAR-T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma: Correlation of Expansion and Duration of Response with T Cell Phenotypes. Blood 2020, 136, 25–26. [Google Scholar] [CrossRef]
  79. Yeku, O.O.; Brentjens, R.J. Armored CAR T-cells: Utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem. Soc. Trans. 2016, 44, 412–418. [Google Scholar] [CrossRef]
  80. Alabanza, L.M.; Xiong, Y.; Vu, B.; Webster, B.; Wu, D.; Hu, P.; Zhu, Z.; Dropulic, B.; Dash, P.; Schneider, D. Armored BCMA CAR T Cells Eliminate Multiple Myeloma and Are Resistant to the Suppressive Effects of TGF-beta. Front. Immunol. 2022, 13, 832645. [Google Scholar] [CrossRef]
  81. Shum, T.; Omer, B.; Tashiro, H.; Kruse, R.L.; Wagner, D.L.; Parikh, K.; Yi, Z.; Sauer, T.; Liu, D.; Parihar, R.; et al. Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells. Cancer Discov. 2017, 7, 1238–1247. [Google Scholar] [CrossRef]
  82. Kuhn, N.F.; Purdon, T.J.; van Leeuwen, D.G.; Lopez, A.V.; Curran, K.J.; Daniyan, A.F.; Brentjens, R.J. CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response. Cancer Cell 2019, 35, 473–488.e476. [Google Scholar] [CrossRef] [PubMed]
  83. Battram, A.M.; Bachiller, M.; Lopez, V.; Fernandez de Larrea, C.; Urbano-Ispizua, A.; Martin-Antonio, B. IL-15 Enhances the Persistence and Function of BCMA-Targeting CAR-T Cells Compared to IL-2 or IL-15/IL-7 by Limiting CAR-T Cell Dysfunction and Differentiation. Cancers 2021, 13, 3534. [Google Scholar] [CrossRef]
  84. Joedicke, J.J.; Grosskinsky, U.; Gerlach, K.; Kunkele, A.; Hopken, U.E.; Rehm, A. Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages. Mol. Ther. Methods Clin. Dev. 2022, 24, 181–198. [Google Scholar] [CrossRef]
  85. Frigault, M.J.; Bishop, M.R.; Rosenblatt, J.; O’Donnell, E.K.; Raje, N.; Cook, D.; Yee, A.J.; Logan, E.; Avigan, D.E.; Jakubowiak, A.; et al. Phase 1 study of CART-ddBCMA for the treatment of subjects with relapsed and refractory multiple myeloma. Blood Adv. 2023, 7, 768–777. [Google Scholar] [CrossRef]
  86. Tan, J.; Jia, Y.; Zhou, M.; Fu, C.; Tuhin, I.J.; Ye, J.; Monty, M.A.; Xu, N.; Kang, L.; Li, M.; et al. Chimeric antigen receptors containing the OX40 signalling domain enhance the persistence of T cells even under repeated stimulation with multiple myeloma target cells. J. Hematol. Oncol. 2022, 15, 39. [Google Scholar] [CrossRef] [PubMed]
  87. Martin, T.; Usmani, S.Z.; Berdeja, J.G.; Agha, M.; Cohen, A.D.; Hari, P.; Avigan, D.; Deol, A.; Htut, M.; Lesokhin, A.; et al. Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up. J. Clin. Oncol. 2023, 41, 1265–1274. [Google Scholar] [CrossRef] [PubMed]
  88. Hashmi, H.; Hansen, D.K.; Peres, L.C.; Puglianini, O.C.; Freeman, C.; De Avila, G.; Sidana, S.; Shune, L.; Sborov, D.W.; Davis, J.; et al. Factors associated with refractoriness or early progression after idecabtagene vicleucel in patients with relapsed/refractory multiple myeloma: US Myeloma Immunotherapy Consortium real world experience. Haematologica 2024, 109, 1514–1524. [Google Scholar] [CrossRef]
  89. Chakraborty, R.; Cheruvalath, H.; Patwari, A.; Szabo, A.; Schinke, C.; Dhakal, B.; Lentzsch, S.; D’Souza, A.; Mohyuddin, G.R.; Julian, K.; et al. Sustained remission following finite duration bispecific antibody therapy in patients with relapsed/refractory myeloma. Blood Cancer J. 2024, 14, 137. [Google Scholar] [CrossRef]
  90. Van Oekelen, O.; Nath, K.; Mouhieddine, T.H.; Farzana, T.; Aleman, A.; Melnekoff, D.T.; Ghodke-Puranik, Y.; Shah, G.L.; Lesokhin, A.; Giralt, S.; et al. Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy. Blood 2023, 141, 756–765. [Google Scholar] [CrossRef]
  91. Cohen, A.D.; Mateos, M.V.; Cohen, Y.C.; Rodriguez-Otero, P.; Paiva, B.; van de Donk, N.; Martin, T.; Suvannasankha, A.; De Braganca, K.C.; Corsale, C.; et al. Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents. Blood 2023, 141, 219–230. [Google Scholar] [CrossRef]
  92. Ferreri, C.J.; Hildebrandt, M.A.T.; Hashmi, H.; Shune, L.O.; McGuirk, J.P.; Sborov, D.W.; Wagner, C.B.; Kocoglu, M.H.; Rapoport, A.; Atrash, S.; et al. Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy. Blood Cancer J. 2023, 13, 117. [Google Scholar] [CrossRef] [PubMed]
Cells 14 01077 g001
Figure 1. BCMA Targeting Therapy Mechanisms of Resistance with expected, normal response depicted in the upper left quadrant. Tumor Microenvironment Related Resistance Mechanisms depicted elsewhere with mechanisms including: Dense Tumor Microenvironment, Inhibitory Cytokine Release by Regulatory T cells, as well as Exhausted T cells increasing Inhibitory Receptors therefore decreasing cytokine release. Created in BioRender. Tedder, B. (2025) https://BioRender.com/a2ezh17 (accessed on 29 June 2025).
Figure 1. BCMA Targeting Therapy Mechanisms of Resistance with expected, normal response depicted in the upper left quadrant. Tumor Microenvironment Related Resistance Mechanisms depicted elsewhere with mechanisms including: Dense Tumor Microenvironment, Inhibitory Cytokine Release by Regulatory T cells, as well as Exhausted T cells increasing Inhibitory Receptors therefore decreasing cytokine release. Created in BioRender. Tedder, B. (2025) https://BioRender.com/a2ezh17 (accessed on 29 June 2025).
Cells 14 01077 g001
Cells 14 01077 g002
Figure 2. BCMA Targeting Therapy Mechanisms of Resistance related to Tumor Intrinsic Mechanism on the Left of the figure as well as Tumor Extrinsic Mechanisms on the Right of the figure. Tumor Intrinsic mechanisms depicted include: γ-secretase cleaving BCMA from the myeloma cell, loss of expression of BCMA on myeloma cell through downregulation of gene expression, and increased expression of inhibitory ligand, PDL1 on the surface of myeloma cells. Tumor Extrinsic Mechanisms include soluble BCMA (from released BCMA during cleavage by γ-secretase) leading to off-target binding. In addition, CAR T cell exhaustion can occur as well as the phenomenon of trogocytosis where the CAR T inadvertently removes BCMA during binding and expresses it on its cell surface. Created in BioRender. Tedder, B. (2025) http://BioRender.com/a2ezh17 (accessed on 29 June 2025).
Figure 2. BCMA Targeting Therapy Mechanisms of Resistance related to Tumor Intrinsic Mechanism on the Left of the figure as well as Tumor Extrinsic Mechanisms on the Right of the figure. Tumor Intrinsic mechanisms depicted include: γ-secretase cleaving BCMA from the myeloma cell, loss of expression of BCMA on myeloma cell through downregulation of gene expression, and increased expression of inhibitory ligand, PDL1 on the surface of myeloma cells. Tumor Extrinsic Mechanisms include soluble BCMA (from released BCMA during cleavage by γ-secretase) leading to off-target binding. In addition, CAR T cell exhaustion can occur as well as the phenomenon of trogocytosis where the CAR T inadvertently removes BCMA during binding and expresses it on its cell surface. Created in BioRender. Tedder, B. (2025) http://BioRender.com/a2ezh17 (accessed on 29 June 2025).
Cells 14 01077 g002
Table 1. Summary of BCMA Targeting Therapy Mechanisms of Resistance.
Table 1. Summary of BCMA Targeting Therapy Mechanisms of Resistance.
BCMA Targeting Mechanisms of Resistance Table Summary
Tumor IntrinsicTumor Extrinsic/Host-RelatedTumor Microenvironment
Loss of BCMA expression through mutations in TNFRSF17 GeneT Cell Fitness (CAR-T Therapy)Presence of MDSCs
Downregulation of BCMAT Cell Exhaustion (BsAb and CAR-T Therapy)Activation of T-regulator cells
BCMA shedding through Secretase via Secretase EnzymeAgeIncreased Inhibitory Cytokine release such as IL-10, TGF-B
TrogocytosisGenetic Factors that compromise immune fitnessPhysical barriers causing poor therapeutic infiltration
Upregulation of Anti-Apoptotic Proteins and MHC Class I Loss
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Tedder, B.; Bhutani, M. Resistance Mechanisms to BCMA Targeting Bispecific Antibodies and CAR T-Cell Therapies in Multiple Myeloma. Cells 2025, 14, 1077. https://doi.org/10.3390/cells14141077

AMA Style

Tedder B, Bhutani M. Resistance Mechanisms to BCMA Targeting Bispecific Antibodies and CAR T-Cell Therapies in Multiple Myeloma. Cells. 2025; 14(14):1077. https://doi.org/10.3390/cells14141077

Chicago/Turabian Style

Tedder, Brandon, and Manisha Bhutani. 2025. "Resistance Mechanisms to BCMA Targeting Bispecific Antibodies and CAR T-Cell Therapies in Multiple Myeloma" Cells 14, no. 14: 1077. https://doi.org/10.3390/cells14141077

APA Style

Tedder, B., & Bhutani, M. (2025). Resistance Mechanisms to BCMA Targeting Bispecific Antibodies and CAR T-Cell Therapies in Multiple Myeloma. Cells, 14(14), 1077. https://doi.org/10.3390/cells14141077

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop