T-клеток, перенаправляющих терапию на рецидив миеломы.

Introduction

The armamentarium for the treatment of multiple myeloma (MM) has exponentially expanded with corresponding improvements in overall clinical outcomes in patients. Despite advances in conventional therapies, MM remains incurable, and patients almost always relapse. Historically, patients with triple-class refractory disease and penta-class refractory diseases had very poor outcomes, with overall response rates (ORR) of 29% and 30% and median overall survival (mOS) of 9.2 months and 5.6 months, respectively [ 1 ].

Immunotherapy has emerged as a novel therapeutic option in the MM treatment paradigm, with CAR T-cell therapy and T cell engagers (TCE) being at the forefront. These strategies harness the immune system’s ability to eradicate malignant plasma cells by leveraging key tumor antigens as targets.

This current review explores the efficacy and safety profiles of CAR T-cell therapy and TCE in the treatment of MM, highlighting some of the potential strategies to manage or attenuate toxicities, as well as the other novel therapies that could shape the future of MM treatment.

Methods

A comprehensive literature review was conducted to identify relevant studies evaluating CAR T-cell therapies and TCE in patients with MM. The search included publications up to April 30, 2025, using the following electronic databases: PubMed, Embase, and Web of Science. Search terms included combinations of:

“multiple myeloma , ” “relapsed , ” “refractory , ” “CAR-T , ” “chimeric antigen receptor , ” “bispecific antibody , ” “BiTE , ” “BCMA , ” “GPRC5D , ” “FcRH5 , ” “immunotherapy , ” and “T-cell redirecting therapies.” Both Medical Subject Headings (MeSH) and free-text terms were used to maximize coverage.

We included original clinical trials (phase I–III), meta-analyses, systematic reviews, and relevant preclinical studies published in English. Conference abstracts from major hematology and oncology meetings (e.g., ASH, EHA, ASCO, and IMS) were also screened for emerging data. Articles were selected based on relevance to the clinical development, efficacy, toxicity, and mechanisms of action in MM.

TCEs and their clinical outcomes (Table 1 )

TCEs are antibodies designed with a F ab domain that binds CD3 on T-cells, and coupled with one or more F ab domains that simultaneously bind tumor-associated antigen (TAA) on tumor cells. TCE binding redirects T-cells into the tumor microenvironment and initiates T-cell activation and downstream T-cell mediated tumor cell killing by the release of granzymes, perforins and pro-inflammatory cytokines [ 2 ].

B-cell maturation antigen (BCMA) targeting TCE

B-cell maturation antigen (BCMA) is a transmembrane protein predominantly expressed on mature B lymphocytes and plasma cells. It serves as an optimal target for TCEs in MM due to its high expression on malignant plasma cells and minimal presence in non-hematopoietic tissues.

Teclistamab was the first BCMA × CD3 TCE to receive FDA approval, based on the MajesTEC-1 trial. Other agents including Elranatamab, Linvoseltamab, and ABBV-383 have emerged as promising therapeutic options.

Across studies, these agents have consistently produced high ORRs, often exceeding 60%, with many patients achieving deep responses, including complete remission (CR) and minimal residual disease (MRD) negativity in a high proportion of patients (Table 1 ). For example, with teclistamab, 85.7% of evaluable patients achieved MRD negativity at the 10⁻⁵ threshold. Durability of response also appears promising, with median durations of response (mDOR) and progression-free survival (PFS) ranging from 8 to over 17 months. Importantly, many of these therapies maintain activity in patients with penta-refractory disease and those previously exposed to CAR T-cell therapy.

ABBV-383, for example, utilizes a bivalent BCMA-binding domain and a low-affinity CD3 component designed to reduce inflammatory cytokine production, potentially translating to a more favorable safety profile with less frequent dosing. Linvoseltamab, a fully human BCMA TCE, and elranatamab have both shown encouraging response durability, while teclistamab remains the most mature in terms of long-term data. Updated results from MajesTEC-1 showed that with a median follow-up of 30.4 months, the mDOR, mPFS, and mOS with Teclistamab were not reached. The estimated 30-month DOR, PFS, and OS rates were 60.8%, 61.0%, and 74.2%, respectively [ 3 ].

These trial results are increasingly being complemented by real-world evidence, which supports the efficacy and tolerability of BCMA TCEs in more diverse and frail populations. In a large retrospective German study of teclistamab [ 4 ]conducted across 18 centers and including patients who were predominantly triple-class (93%) or penta-drug (60%) refractory, apart from patients with high risk disease such as (extramedullary disease, ISS stage III) and ide-cel pretreated patients, the overall safety and efficacy profile remained comparable to that reported in clinical trials. The observed ORR and mPFS were comparable to MajesTEC-1 and 59.3% and 8.7 months respectively. Similarly, real-world use of elranatamab through a French compassionate access program demonstrated meaningful responses and survival outcomes [ 5 ]. In this heavily pretreated relapsed/refractory MM (RRMM) population, a majority of whom would have been ineligible for the pivotal trial, the ORR was 51.5% with a ≥ VGPR rate of 42%. With a median follow-up of 15.5 months, the 1-year PFS and OS were 34% and 42%, respectively. Notably, ECOG performance status ≥ 2—unlike prior BCMA-directed therapy or extramedullary disease—was significantly associated with inferior response and survival.

Moving to earlier lines, in newly diagnosed multiple myeloma (NDMM), teclistamab in combination with daratumumab-based regimens (DRd or DVRd) demonstrated remarkable efficacy in the MajesTEC-5 study. All evaluable patients ( n = 46) achieved MRD negativity after just three induction cycles and maintained negativity through cycle six, highlighting teclistamab’s potential as a frontline treatment option [ 6 ].

G-protein-coupled receptor class C group 5 member D (GPRC5D) targeting TCEs

GPRC5D is an orphan receptor whose gene is located on chromosome 12p13. It is a 7-pass transmembrane protein with a short extracellular N-terminal domain. Its unique structure makes it less likely to shed into the serum, maintaining its effectiveness as a target for therapy [ 7 – 9 ]. GPRC5D is predominantly expressed on plasma cells, with minimal to no expression on other immune cells, such as B-cells, T-cells, and natural killer cells, reducing the risk of cytopenias and infections compared to BCMA-targeted therapies [ 10 , 11 ]. However, GPRC5D is also expressed on epithelial cells of hard keratinized tissues, including the hair shaft, eccrine sweat glands, nails, and tongue papillae, leading to potential side effects such as rash, dry skin and desquamation.

Currently, there are two TCEs that target GPRC5D: Talquetamab and Forimtamig.

Talquetamab is a first-in-class IgG4 TCE that targets GPRC5D positive MM cells by recruiting CD3 + T-cells. It received accelerated approval from the FDA in August 2023 for RRMM patients with at least four prior lines of therapy (LOT), including those with triple-class refractory disease, based on results from the MonumenTAL-1 trial [ 12 ]. The Phase 1 study established two recommended phase 2 doses (RP2D): 0.4 mg/kg subcutaneously (SC) weekly and 0.8 mg/kg SC biweekly. At a median follow-up of 23.4 months in the biweekly cohort, the mDOR was 17.5 months, and for those achieving ≥ CR, it was not reached (95% CI, 21.2–NE). Median PFS was 11.2 months, and the 24-month OS rate was 67.1%. DOR and PFS were superior in the biweekly cohort, with fewer side effects, making it the preferred dosing regimen [ 13 ] (Table 1 ).

The clinical promise of talquetamab has also been supported by real-world data. In a multicenter analysis of 118 heavily pretreated patients, most of whom were triple-class (72%) or penta-drug refractory (44%) disease and a majority with prior BCMA therapy (71%), response rates and depth of response mirrored those observed in the pivotal trial, underscoring the drug’s effectiveness in broader clinical practice [ 14 ].

Forimtamig (RG6234), another GPRC5D × CD3 TCE, is currently in early-phase development. Its bivalent GPRC5D-binding and monovalent CD3-binding configuration is designed to enhance potency while maintaining tolerability. Preliminary data from both intravenous and subcutaneous cohorts have shown encouraging antitumor activity with a manageable safety profile, suggesting it may serve as a future therapeutic option, particularly for patients with limited alternatives [ 15 ].

Together, GPRC5D-targeted TCEs represent a critical expansion of the immunotherapeutic landscape in multiple myeloma, particularly for patients with prior BCMA exposure or those intolerant to BCMA-based approaches.

FcRH5 targeting TCEs

FcRH5 is a cell surface marker expressed on B-cells and plays a role in B-cell proliferation. It is encoded on chromosome 1q21, a region frequently amplified in MM [ 16 , 17 ]. FcRH5 expression is elevated on malignant plasma cells, particularly in cases with the 1q21 chromosomal abnormality (a common abnormality), and is sustained in RRMM. This makes it a compelling therapeutic target, particularly for patients who are refractory to immunomodulatory drugs (IMiDs), proteosome inhibitors (PI), and CD38 monoclonal antibodies [ 18 , 19 ].

While the FcRH5 antibody-drug conjugate DFRF4539A demonstrated limited efficacy in early trials, FcRH5-targeting TCEs have shown more promise [ 19 , 20 ].

Cevostamab, an IgG1-based TCE targeting FcRH5 and CD3, facilitates T-cell-mediated cytotoxicity against myeloma cells. In a Phase 1 clinical trial involving 160 heavily pretreated MM patients, Cevostamab demonstrated encouraging results, supporting its potential role in treating RRMM [ 21 ] (Table 1 ).

CAR T-cell therapy and their clinical outcomes (Table 2 )

The concept behind CAR T-cell therapy is the recognition of a tumor specific antigen by T-cells in the absence of major histocompatibility complex protein copresentation. For autologous CAR T-cell therapy, T-cells are first collected via leukapheresis and genetically modified to express a chimeric antigen receptor that targets TAA expressed on MM cells. This is typically achieved using viral vectors to introduce the CAR gene into the T-cells. The CAR construct includes an extracellular antigen recognition domain that is usually a single-chain variable fragment (scFv), a hinge region, a transmembrane domain, and intracellular signaling domains [ 22 ]. The intracellular domains often include CD3ζ for T-cell activation and co-stimulatory domains such as 4-1BB to enhance T-cell proliferation and persistence by maintaining T-cell memory and preventing exhaustion [ 23 ]. Patients receive lymphodepleting chemotherapy prior to CAR T-cell infusion to reduce the number of endogenous lymphocytes, creating a more favorable environment for the infused CAR T-cells to expand and function. Once the engineered CAR T-cells are infused back into the patient and encounter TAA, the CAR T-cells bind to the antigen, leading to T-cell activation, proliferation, and the release of cytotoxic molecules resulting in tumor cell killing. Activated CAR T-cells also secrete cytokines such as IFN-γ and TNF-α, which enhance the antitumor immune response. This process leads to the direct killing of myeloma cells and the recruitment of other immune cells to the tumor site [ 24 ].

BCMA-targeting CAR T-cell therapy

The approval of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) by the FDA in 2021 marked a major milestone in the treatment of RRMM after four or more prior lines of therapy. Both agents target BCMA.

Ide-cel, the first FDA-approved BCMA CAR T-cell therapy, employs a single murine-derived scFv targeting one BCMA epitope, along with a 4-1BB co-stimulatory domain and CD3ζ signaling domain. In the pivotal KarMMa trial, ide-cel demonstrated high ORR and meaningful clinical benefit in a heavily pretreated population (mPFS 8.8 and mOS of 19.4 months in patients with a median of six prior LOT) [ 25 ] (Table 2 ).

Cilta-cel, approved shortly after, incorporates a dual epitope-binding construct using camelid heavy-chain-only domains, resulting in enhanced binding avidity and improved potency. In the CARTITUDE-1 study, this unique design translated into deep and durable responses, with a significant proportion (62.9%) of patients remaining progression-free beyond 36 months [ 26 ] (Table 2 ).

While scFv-based CAR constructs offer specificity, they may be prone to oligomerization and tonic signaling, potentially compromising CAR T-cell persistence and efficacy. To overcome these limitations, next-generation CARs utilizing synthetic D-domain binding scaffolds have been developed. These domains promote proper folding, minimize self-aggregation, and enhance surface expression, potentially improving persistence within the tumor microenvironment [ 27 ].

Anito-cel represents a first-in-class CAR T-cell therapy employing a fully synthetic D-domain for BCMA recognition. In early-phase studies, it has shown a favorable safety profile, with a notable absence of delayed neurotoxic events such as cranial nerve palsy or Parkinsonism-like syndromes, which have been observed with other BCMA-targeted agents [ 28 ].

Despite encouraging outcomes in registrational trials, long-term follow-up reveals that most patients eventually relapse. mPFS across pivotal trials ranges from 13 to 35 months, although a small subset of patients experience prolonged remissions exceeding five years. The longest follow-up for LCAR-B38M demonstrate a 5-year PFS of 21% and OS of 49%, with survival curves flattening over time, indicating a plateau in long-term survivors [ 29 ]. Durable responses have been most consistently observed in patients achieving MRD negativity, in whom CAR T-cell persistence is maintained, and who lack high-risk features such as extramedullary disease or adverse cytogenetics.

Real-world data have provided critical insights into the broader applicability of these therapies outside of clinical trial settings. The U.S. Myeloma CAR T Consortium reported outcomes from 196 patients undergoing ide-cel leukapheresis across 11 centers, with 75% of patients failing to meet KarMMa eligibility criteria—primarily due to comorbidities or disease burden [ 30 ]. The ORR in the real-world setting was 84%, with a CR rate of 42%. Median PFS was 8.8 months, and OS was 19.4 months. The incidence of CRS was 84% (grade ≥ 3 in 5%) and ICANS occurred in 18% (grade ≥ 3 in 3%), closely mirroring the KarMMa trial results. Similarly, real-world experience with cilta-cel confirms its efficacy in a broader patient population. In an analysis of 153 patients undergoing apheresis, 57% would have been ineligible for CARTITUDE-1 31 . Nonetheless, response rates and toxicity profiles aligned closely with trial data, ORR was 89% with a CR rate of 56%. CRS occurred in 80% (grade 3: 5%) and ICANS in 18% (grade 3: 6%). Delayed neurotoxicity was observed in 12%, most commonly presenting as 7th cranial nerve palsy (6%); Parkinsonism-like movement and neurocognitive toxicity (MNT) was seen in 1%. At a median follow-up of 6 months, median PFS had not yet been reached, with an estimated 6-month PFS of 79%. These studies support the translatability of BCMA CAR T-cell therapies into routine practice, even among patients with greater frailty and clinical heterogeneity.

BCMA CAR T-cell therapy in earlier lines of treatment

Emerging evidence supports the use of BCMA-targeted CAR T-cell therapy in earlier lines of treatment, particularly for patients with high-risk features or early relapse. The KarMMa-2 trial evaluated ide-cel in patients with suboptimal outcomes following frontline therapy, across three distinct cohorts. Ide-cel demonstrated deep and durable responses in patients who relapsed early after autologous stem cell transplant (ASCT) [ 32 ] with mPFS of 11.4 months, and mOS was not reached; early progression without prior ASCT [ 33 ] with 12- and 24-month PFS 70% and 63%, respectively; or achieved only a suboptimal response post-ASCT [ 34 ] with 24-month PFS rate of 83.1%, and OS rate of 100%, highlighting its potential in settings of early treatment failure (Table 2 ).

Similarly, the CARTITUDE-2 cohort B explored cilta-cel in high-risk patients experiencing early relapse [ 35 ]. In this cohort, high response rates (ORR 88.9%, 27.8% CR) and achievement of MRD negativity among all evaluable patients underscored the efficacy of cilta-cel, even in patients with aggressive disease biology.

The efficacy of CAR T-cell therapy in earlier treatment settings was further confirmed in two randomized phase 3 trials. KarMMa-3 compared ide-cel to standard of care (SOC) regimens in patients with 2–4 prior lines of therapy who were refractory to their most recent treatment. Ide-cel significantly improved PFS (mPFS 13.8 vs. 4.4 months; HR, 0.49), with the most pronounced benefit observed in those with only two prior lines. The interim OS analysis did not demonstrate a statistically significant difference, and the crossover design likely influenced this outcome [ 36 , 37 ].

CARTITUDE-4 assessed cilta-cel vs. SOC in lenalidomide-refractory patients with 1–3 prior therapies, demonstrating superior PFS (NR vs. 11.8 months; HR, 0.26), response depth, and MRD negativity rates compared to standard of care [ 38 ] (Table 2 ). These results contributed to the expanded FDA approvals of ide-cel and cilta-cel for use after two prior lines of therapy and in early relapse settings, respectively.

Ongoing trials, including KarMMa-4, CARTITUDE-5, and CARTITUDE-6, are now investigating the integration of CAR T-cell therapy into frontline treatment strategies. These studies aim to refine patient selection and define the optimal timing of CAR T-cell therapy in NDMM, particularly for those with high-risk features or inadequate early responses.

GPRC5D-targeting CAR T-cell therapy

GPRC5D has also emerged as a promising target for CAR T-cell therapy in RRMM, particularly for patients who have progressed following BCMA-targeted treatments. Several GPRC5D-directed constructs are under clinical evaluation, showing encouraging activity in heavily pretreated populations.

MCARH109 is an autologous, second-generation CAR T-cell therapy utilizing a GPRC5D-targeted single-chain variable fragment with 4-1BB and CD3ζ signaling domains. In a phase 1 dose-escalation study, 17 heavily pretreated RRMM patients (median of 3 prior therapies) received MCARH109, with a maximum tolerated dose identified at 150 × 10⁶ CAR T-cells. At this dose, no grade ≥ 3 CRS, ICANS or cerebellar toxicity was observed. The ORR was 71%, with a mDOR of 8.6 months. Notably, 70% of patients with prior BCMA-targeted therapy responded and the 3-year OS estimate was 59% [ 39 , 40 ]. BMS-986,393, a CAR structurally identical to MCARH109 demonstrated high ORR (75%) and CR rates (46%), with MRD negativity in 100% of evaluable patients in CR at ≥ 10⁻⁵ sensitivity [ 41 ]. Patients with prior BCMA-targeted therapy achieved an ORR of 75%.

Similarly, OriCAR-017, a GPRC5D-targeting CAR T-cell therapy with a proprietary signal activation domain, showed favorable responses in a heavily pre-treated population, with mPFS 11 months, and mOS not reached [ 41 ]. YK-CAR-042, another GPRC5D-targeting CAR T-cell, showed responses in all 9 patients with prior BCMA CAR T-cell therapy, including those who had previously failed repeated BCMA CAR T infusions [ 42 ]. Details of responses are included in Table 2 .

Taken together, these studies support the feasibility and efficacy of GPRC5D-targeted CAR T-cell therapy in RRMM. In particular, the ability of these therapies to induce responses in patients previously exposed or refractory to BCMA-directed treatments highlights the potential role of GPRC5D as a sequential or complementary target in evolving treatment paradigms. Ongoing clinical trials will help clarify optimal integration and sequencing of GPRC5D-directed therapies within the broader CAR T-cell landscape.

Sequencing therapy

The optimal sequencing of CAR T-cell therapy and TCEs RRMM remains an area of ongoing investigation. CAR T-cell therapy offers the advantage of a one-time infusion; however, it requires a vein-to-vein manufacturing time of approximately 3–8 weeks, necessitating bridging strategies for patients with rapidly progressing disease. In contrast, TCEs are readily available off-the-shelf agents that allow for rapid treatment initiation and may be preferable for patients’ ineligible for lymphodepleting chemotherapy or those unable to tolerate the potential toxicities associated with CAR T-cell therapy.

Despite their accessibility, TCEs require continuous administration, which can contribute to T-cell exhaustion and antigen escape. T-cell exhaustion is characterized by diminished proliferative capacity, impaired antitumor activity, and reduced persistence due to chronic antigen stimulation and exposure to an immunosuppressive tumor microenvironment (TME) [ 43 ].

A distinguishing advantage of CAR T-cell therapy is its potential to provide a treatment-free interval, which has been associated with improved quality of life, reduced psychological distress, and alleviation of physical symptoms at three- and six-months post-infusion [ 44 ]. Differences in toxicity profiles between CAR T-cell therapy and TCEs further influence their clinical application.

The sequential use of CAR T-cell therapy and TCEs targeting BCMA has demonstrated efficacy in heavily pretreated RRMM populations. Studies evaluating CAR T-cell therapy following TCE exposure have shown responses, albeit with shorter PFS [ 45 ]. For example, the CARTITUDE-2 Cohort C study reported an ORR of 57% and a median PFS of 5.3 months in patients receiving cilta-cel after prior BCMA TCE exposure [ 46 ]. Similarly, real-world data on ide-cel after BCMA TCE therapy reported an ORR of 86% and a median PFS of 2.8 months [ 47 ].

Conversely, TCEs administered after BCMA CAR T-cell therapy have demonstrated more promising outcomes. In the MagnetisMM studies, elranatamab achieved an ORR of 52.8%, with median PFS not reached in patients previously treated with BCMA CAR T-cell therapy [ 48 ]. Similarly, teclistamab achieved an ORR of 45% with median PFS not reached in the MajesTEC-1 cohort [ 49 ]. Real-world data have reported ORRs ranging from 33 to 60%, with median PFS between 1.8 months and not reached [ 4 , 50 , 51 ].

Recent guidelines from the International Myeloma Working Group (IMWG) provide recommendations on the sequencing of immunotherapies. When both BCMA CAR T-cell therapy and BCMA TCEs are viable options, CAR T-cell therapy is preferred, given the established efficacy of TCEs following CAR T-cell therapy failure and the potential for a prolonged treatment-free interval post-infusion. However, in cases of rapidly progressing disease where the CAR T-cell manufacturing process is not feasible, TCEs are recommended due to their immediate availability. If CAR T-cell collection is required after TCE exposure, a minimum four-weeks washout period is advised following the last TCE dose. Alternatively, T-cell collection prior to TCE initiation should be considered to mitigate potential interference [ 52 ].

To optimize response rates, it may be prudent to minimize prior BCMA-directed therapies in patients planning to receive BCMA CAR T-cell therapy. Additionally, BCMA TCEs should be avoided as bridging therapy during CAR T-cell manufacturing. While the optimal interval between BCMA CAR T-cell therapy and subsequent BCMA TCE therapy remains uncertain, a minimum six-month gap is recommended to enhance response likelihood. In the future, biomarkers such as tumor BCMA expression or soluble BCMA levels may serve as useful tools to guide treatment decisions.

Non-BCMA-directed TCEs, such as talquetamab, have demonstrated efficacy following BCMA CAR T-cell therapy. The MonumenTAL-1 trial reported an ORR of 73.5% and a 12-month PFS rate of 50% in patients receiving the GPRC5D-targeted TCE talquetamab after BCMA CAR T-cell therapy. Similarly, sequential CAR T-cell therapies targeting different antigens have shown promise. GPRC5D-directed CAR T-cell therapy administered after BCMA-directed CAR T-cell therapy has demonstrated high efficacy, with reported ORRs ranging from 70 to 100% and median PFS not reached in prospective trials [ 39 , 53 ]. These findings underscore the potential benefit of antigen-switching strategies to optimize treatment outcomes.

Incorporating CAR T-cell therapy earlier in the treatment course may further improve patient outcomes. Early referral to specialized centers for CAR T-cell evaluation ensures timely access to this therapy, potentially reducing patient attrition due to disease progression during manufacturing and preserving optimal physical condition at the time of infusion. Moreover, earlier administration may enhance CAR T-cell product characteristics, lower tumor burden, and reduce toxicity rates. Given the logistical complexity and individualized nature of treatment sequencing, further research is needed to refine patient selection criteria and optimize the timing of CAR T-cell and TCE therapies in MM.

In practice, the choice and sequencing of TCEs and CAR T-cell therapies should be individualized based on disease characteristics, patient fitness, logistical feasibility, and access. For patients with rapidly progressing disease or poor performance status, TCEs offer the advantage of immediate initiation. In contrast, eligible patients with access to specialized centers may derive longer-term benefit from CAR T-cell therapy. Non-BCMA-directed therapies represent important salvage options post-BCMA failure. As the landscape evolves, institutional algorithms incorporating clinical, logistical, and biological parameters will be essential to guide optimal sequencing strategies.

Challenges and limitations

Relapse and resistance

Relapse and resistance in MM represent significant clinical challenges due to the disease’s substantial clonal heterogeneity, dynamic genomic alterations, and a complex bone marrow microenvironment, all of which facilitate tumor cell evasion of therapeutic interventions.

In the context of BCMA-directed therapies, several mechanisms of antigen escape have been elucidated. One of the most recognized is the loss or downregulation of surface BCMA expression on malignant plasma cells. The TNFRSF17 gene encodes BCMA, and while monoallelic copy number loss is identified in approximately 4–6% of MM patients prior to exposure to T-cell–based therapies [ 54 ]the incidence of BCMA loss increases significantly following treatment. Recent studies have demonstrated that up to 40% of patients who relapse after anti-BCMA CAR T-cell or TCE develop BCMA-negative clones, primarily due to biallelic deletions or extracellular domain mutations in TNFRSF17 . Notably, these BCMA-null clones may be present as rare subpopulations (< 1%) at baseline and can undergo clonal expansion under the selective pressure of BCMA-directed therapy, ultimately contributing to relapse [ 55 ].

This dynamic clonal evolution underscores the need for sensitive baseline assessments and ongoing disease monitoring during treatment. Moreover, reversible BCMA downregulation may occur via γ-secretase–mediated shedding of BCMA from the cell surface, leading to the accumulation of soluble BCMA (sBCMA) in circulation. sBCMA can function as a decoy, sequestering anti-BCMA agents and thereby diminishing their tumor-binding capacity. Chen et al. demonstrated that elevated sBCMA levels in RRMM patients correlate with impaired anti-BCMA antibody binding to myeloma cells, further supporting this resistance mechanism [ 56 ].

These findings have several therapeutic implications. First, they highlight the importance of strategic sequencing of T-cell engagers and the potential limitations of reusing BCMA-directed therapies after antigen escape. Second, they justify the development and early incorporation of dual-targeting strategies (e.g., BCMA + GPRC5D) to mitigate selective antigen loss. Finally, they point to a need for novel approaches to restore antigen expression or bypass dependence on single-antigen recognition.

Access and logistical considerations for T-cell redirecting therapies

TCEs are “off-the-shelf” agents that that allow for rapid treatment initiation without the need for patient-specific manufacturing. This immediacy is particularly valuable in patients with aggressive disease. However, their use is associated with specific logistical and clinical challenges. Due to the risk of CRS, initial dosing typically requires inpatient monitoring or closely supervised outpatient care. Many centers, particularly when treating frail or high-risk patients, mandate hospitalization during the step-up dosing phase, which may limit feasibility in community settings or in resource-constrained healthcare systems. Outpatient administration however, has been increasingly adopted and has demonstrated safety in selected populations when supported by adequate infrastructure [ 57 ].

Despite these advances, TCEs require continuous dosing, frequent clinic visits, and close infection surveillance, placing a substantial burden on both patients and healthcare systems. These demands may restrict widespread implementation outside of tertiary care centers and underscore the need for modified care pathways to enable broader access. Nonetheless, their immediate availability and the development of subcutaneous formulations support expanded use across diverse clinical settings.

In contrast, CAR T-cell therapy involves a highly individualized and complex process, including leukapheresis, ex vivo cellular engineering, and a manufacturing period of several weeks. During this interval, patients often require bridging therapy to maintain disease control, and 10–15% may not proceed to infusion due to disease progression or clinical deterioration [ 38 ]. Access to CAR T-cell therapy is confined to specialized centers with the necessary infrastructure for cell collection, product coordination, and post-infusion monitoring. These limitations create significant barriers in low- and middle-income countries and among underserved populations within high-income nations.

Despite these logistical hurdles, CAR T-cell therapy offers the potential for a one-time treatment capable of inducing deep and durable remissions. Cost-effectiveness analyses indicate that CAR T-cell therapy, particularly with ciltacabtagene autoleucel, can approach or fall within commonly accepted willingness-to-pay thresholds in the United States (e.g., $100,000–$150,000 per QALY), provided that long-term progression-free survival is achieved. For example, one analysis estimated an incremental cost-effectiveness ratio (ICER) of $112,191 per QALY for ciltacabtagene autoleucel versus standard therapy [ 58 , 59 ]. TCE therapies, such as teclistamab, are less expensive per patient than CAR T-cell therapies but direct comparative cost-effectiveness data are limited.

As both TCEs and CAR T-cell therapies are evaluated in earlier lines of therapy and in combination strategies, questions regarding optimal sequencing, resistance mechanisms (e.g., antigen escape, T-cell exhaustion), and long-term value remain areas of active investigation. Treatment selection should be individualized based on disease characteristics, patient comorbidities, urgency of intervention, and available healthcare infrastructure.

Toxicities related to T-cell redirecting therapies and supportive management (Tables 3 and 4 )

Cytokine release syndrome (CRS)

CRS is a well-characterized toxicity associated with T-cell redirecting therapies. The American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system is the standard framework for assessing CRS severity. Among patients with multiple myeloma treated with TCEs, CRS has been reported in 45–78% of cases, predominantly as low-grade events, with grade 3 or higher CRS occurring in 0–2%. CRS typically manifests early in the TCE treatment course, particularly during step-up dosing and the administration of the first full dose [ 15 , 21 , 60 – 66 ]. In the context of CAR T-cell therapy, the incidence of CRS is higher, ranging from 58 to 100%, with grade 3 or higher events observed in 0–6% of cases [ 25 , 26 , 36 , 38 ].

CRS cytokine release syndrome, ICANS Immune effector cell-associated neurotoxicity syndrome, G grade, IV intravenous, SC subcutaneous.

The management of CRS should be individualized based on the therapeutic agent and guided by available clinical evidence. The primary objective is to prevent or mitigate symptoms. Recent guidelines from the IMWG recommend strategies such as effective tumor debulking prior to CAR T-cell infusion, vigilant monitoring, and the use of pre-medications during TCE administration [ 2 , 67 ]. Early intervention with supportive therapies, including tocilizumab and corticosteroids, is advised for CRS management. Importantly, the administration of these agents has not been shown to negatively impact overall treatment efficacy [ 68 , 69 ].

Immune effector cell-associated neurotoxicity syndrome (ICANS) and delayed neurotoxicity

ICANS is a common adverse effect associated with T-cell redirecting therapies, particularly CAR T-cell treatment. ICANS typically occurs concurrently with CRS and can range from mild alterations in consciousness to severe complications such as cerebral edema and coma, which may lead to death. The ASTCT consensus grading guidelines are the current standard for assessing the severity of ICANS.

The incidence of ICANS is lower in patients treated with TCEs compared to those receiving CAR T-cell therapy. In pivotal trials of TCEs, the overall incidence of ICANS was less than 15%, with very few cases reaching grade 3 or higher. Management of ICANS should follow the Risk Evaluation and Mitigation Strategy and Risk Management Plan for product-specific protocols. The primary treatment for ICANS involves corticosteroids, with the addition of tocilizumab if CRS is present concurrently [ 15 , 21 , 60 – 66 ].

Increasingly, there have been reports of rare, subacute to late neurological toxicities following BCMA-targeted CAR T-cell therapy. These adverse events include parkinsonism (PD), cranial nerve (CN) palsies, and peripheral neuropathies, including Guillain-Barré syndrome (GBS). Data from a global IMWG registry indicated that 52 patients developed these toxicities, with a median of four prior lines of treatment. The majority of patients (92%) received cilta-cel, while a smaller number had received ide-cel or investigational CAR T-cell therapies. Among the reported cases, 16 patients had PD, 37 developed CN palsies, and four patients with CN palsies also developed peripheral neuropathy or GBS. The median time to onset for PD and CN palsies was 26 days (range: 15–87 days) and 37.5 days (range: 7–482 days), respectively [ 70 ].

Risk factors for delayed neurotoxicity include high-grade CRS, prior ICANS, high tumor burden, and rapid expansion of CAR T-cells. In the CARTITUDE-4 trial, where cilta-cel was administered in earlier lines of therapy with enhanced cytoreduction and early aggressive treatment of CRS, the incidence of parkinsonism was reduced to 1% compared to 6% in CARTITUDE-1. However, facial nerve palsy was still observed in 9.1% of patients in CARTITUDE-4. Currently, there are no established standard strategies for managing these delayed neurotoxicities, although treatments such as corticosteroids, intravenous immunoglobulin (IVIg), intravenous cyclophosphamide, and intrathecal methotrexate have been explored [ 70 ].

In patients receiving GPRC5D-targeted CAR T-cell therapies, cerebellar toxicity has been reported. Two patients treated with MCARH109 developed grade 3 cerebellar disorders at the highest dose level [ 39 ]. However, no such cases have been reported with GPRC5D TCEs, and further studies are needed to better understand the pathophysiology, risk factors, and potential mitigation strategies for these neurotoxicities [ 39 ].

Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS)

In the ASTCT expert consensus paper, IEC-HS is defined as the development of a pathological and biochemical hyperinflammatory response, with features resembling macrophage activation syndrome or hemophagocytic lymphohistiocytosis (HLH), attributable to IEC therapy [ 71 ]. IEC-HS is typically associated with the progression or new onset of cytopenias, hyperferritinemia, coagulopathy with hypofibrinogenemia, and/or transaminitis. Although there is no consensus on the optimal management strategies for IEC-HS, expert opinion recommends the use of interleukin-6 (IL-6) blockade and corticosteroids as initial therapies. This may be followed by additional cytokine blockade, such as anakinra, and targeted therapies, such as ruxolitinib. If evidence of CAR T-cell expansion or persistence is present, lymphotoxic drugs, including cyclophosphamide or antithymocyte globulin, may also be considered as part of the treatment regimen [ 67 ].

Cytopenias

Hematological toxicities represent some of the most frequently observed high-grade adverse effects in clinical trials of T-cell redirecting therapies. The underlying mechanisms contributing to these toxicities are multifactorial, including poor marrow reserve due to prior MM therapies, the use of lymphodepletion chemotherapy, CRS, concomitant medications, and, in some patients, pre-existing clonal hematopoiesis.

Recent studies have elucidated the role of immune cell subset dynamics in the development of hematological toxicities, including cytopenias. Fischer et al. demonstrated that an increased frequency of CD8 + T-cells at the time of leukapheresis and lymphodepletion was associated with improved therapeutic outcomes; however, this increase also correlated with a higher incidence of severe CRS and subsequent cytopenias [ 72 ]. Similarly, Zhou et al. identified that changes in CAR-negative T-cell subsets significantly influenced the persistence of cytopenias. Specifically, elevated frequencies of CD4 + naïve T-cells (CD4Tn) were found to correlate with anemia, while increased CD8 + effector T-cells (CD8Teff) were associated with lymphocytopenia. Furthermore, a higher proportion of CD4 central memory T-cells (CD4Tcm) was linked to the development of leukocytopenia [ 73 ]. These findings suggest that alterations in immune cell composition at baseline may influence hematological outcomes following T-cell redirecting therapies.

The management of cytopenias in patients receiving T-cell engagers typically involves dose modifications and supportive care strategies. The administration of growth factors can facilitate hematopoietic recovery; however, their use must be carefully timed to avoid exacerbating CRS [ 2 ].

In patients undergoing CAR T-cell therapy, hematologic toxicity is nearly universal, necessitating proactive identification of risk factors prior to lymphodepleting chemotherapy. The CAR-HEMATOTOX score has been established as a predictive tool for identifying patients at increased risk of severe hematotoxicity [ 74 ]. Aggressive supportive care measures, including the use of hematopoietic growth factors following the resolution of CRS, are essential to mitigate prolonged cytopenias [ 67 ]. Erythropoietic and thrombopoiesis-stimulating agents may provide additional benefit in select cases. In instances of persistent or severe cytopenias, an autologous stem-cell boost, when available, has demonstrated significant efficacy in promoting engraftment and restoring hematopoietic function [ 75 , 76 ].

Infections

Infections are a common side effect of T-cell redirecting therapies, with contributing factors including T-cell immune dysfunction, hypogammaglobulinemia and neutropenia [ 77 ]. In pivotal TCE trials, 40–80% of patients experienced infections of all grades, with 25–68% classified as grade 3 or higher. Upper and lower respiratory tract infections were most common, along with opportunistic infections such as Pneumocystis jirovecii (PCP), cytomegalovirus (CMV) [ 15 , 21 , 60 – 66 ].

To mitigate infection risks, expert recommendations include up-to-date vaccinations (e.g., respiratory syncytial virus, influenza, COVID-19, varicella zoster, pneumococcal) and prophylaxis with acyclovir for herpes simplex and varicella zoster, and trimethoprim-sulfamethoxazole for PCP, with bacterial prophylaxis advised for patients with prolonged neutropenia or recurrent bacterial infections. Immunoglobulin replacement is recommended for patients with IgG levels < 400 mg/dL or those with severe recurrent infections and G-CSF use is recommended to maintain an ANC > 1000/µL 78 .

In CAR T-cell therapy, infections are common, especially in patients with prolonged neutropenia, high-dose steroid use, multiple doses of tocilizumab, severe CRS, or second-line agents for CRS/HLH or neurotoxicity management. Prophylaxis strategies for CAR T-cell therapy include antiviral treatment (valacyclovir or acyclovir) for 1 year and trimethoprim-sulfamethoxazole or similar therapy for PCP. PCP prophylaxis is continued typically for 6 months and until CD4 counts is > 200cells/uL for longer than 3 months. Antibacterial and antifungal prophylaxis are also recommended. The use of immunoglobulin replacement remains controversial due to limited clinical trial data but may be considered for patients with IgG levels < 400 mg/dL or recurrent infections [ 67 ]. Vaccination strategies remain unclear, though some centers recommend influenza, COVID-19, and RSV vaccines per institutional guidelines [ 67 ].

In GPRC5D-targeting T-cell redirecting therapies, infections are reported less frequently compared to BCMA-targeted therapies, likely due to the more limited expression of GPRC5D in the immune system and on normal plasma cells, which may help preserve normal plasma cell function during treatment [ 79 ]. However, prophylaxis as for BCMA targeted therapies is also recommended.

Other toxicities

On-target off-tumor side-effects

The co-expression of the GPRC5D antigen on keratinized tissues, such as the hair shaft, eccrine sweat gland epithelial cells, nails, and filiform papillae of the tongue, has led to common adverse events (AEs) in patients receiving anti-GPRC5D T-cell redirecting therapies [ 80 ].

These AEs include rash, dry skin, pruritus, nail loss, dysgeusia (taste changes), dry mouth, and desquamation of the skin albeit less commonly. Most of these toxicities are low-grade and manageable, rarely requiring dose modifications with talquetamab [ 79 ] or GPRC5D CAR T-cell therapy [ 39 ]. Rashes typically respond well to emollients, and both topical and oral corticosteroids are effective treatments.

Dysgeusia, a commonly reported AE, occurs more frequently with TCEs than with CAR T-cell therapies, likely due to the continuous administration of TCEs. This side effect can lead to anorexia and significant weight loss requiring proactive management. Supportive measures such as artificial saliva, regular dental visits, and careful attention to medications for glycemic control and weight management are recommended. In some cases, dose adjustments may be necessary to improve patients’ quality of life. Additionally, nail hardeners can be used to protect nails if needed [ 2 ].

GI toxicities (IEC-Colitis)

IEC-associated enterocolitis has been reported as a toxicity following CAR T-cell therapy. Patients typically present with non-bloody diarrhea, with a negative infectious workup, beginning 1–3 months after CAR T-cell infusion. The exact etiology remains unclear, but it is considered a rare yet distinct entity, occurring in 1.2% of patients out of over 1,200 BCMA-directed CAR T-cell infusions across multiple study centers. Steroids are commonly used as first-line treatment; however, in steroid-refractory cases, the addition of biologic immunosuppressive agents, such as infliximab or vedolizumab, may provide clinical benefit [ 81 ].

Secondary primary malignancies (SPM)

In a systemic review, the incidence of SPMs in patients with MM post CAR T-cell therapy was 0-20.6%, with hematologic malignancies accounting for 33% of all SPMs in MM, with the time from CAR T-cell infusion to diagnosis of SPM being 8–32 months [ 82 ]. The etiology is likely multifactorial and includes the cumulative effects of prior chemotherapy, underlying pre-disposition such as clonal hematopoiesis of indeterminate potential, loss of immune surveillance, and lifestyle associated risk factors amongst others.

Future directions

The landscape of immunotherapy in MM continues to evolve rapidly, with the development of next-generation T-cell redirecting therapies aimed at improving efficacy, minimizing toxicity, and overcoming mechanisms of resistance.

One notable area of potential is the use of platforms that have resulted in significant reduction in the time required for CAR T-cell manufacturing. For example, PHE885, a CAR T-cell product targeting BCMA and manufactured using the T-Charge system reduces manufacturing time to < 2 days and can preserve T-cell stemness is currently in phase 1 clinical trials ( NCT04318327 ). This innovation has allowed patients to proceed from apheresis to lymphodepletion in a median of 16 days, and only 28% of patients in the study required bridging therapy. Preliminary results show an ORR of 98% (42 of 43 patients) across all dose levels, with a CR rate of 42% (18 of 43 patients) at the 10 × 10 6 CAR T-cell dose [ 83 ].

Efforts to further reduce manufacturing time are underway, with point-of-care CAR T-cell production being explored as a promising approach. This method has demonstrated vein-to-vein times of 7–14 days for non-cryopreserved products, potentially accelerating the delivery of CAR T-cell therapy to patients. Additionally, in vivo CAR T-cell manufacturing is being investigated as another strategy to shorten production timelines [ 84 ].

Given the heterogeneity of MM, strategies to overcome tumor antigen escape are essential. One such approach involves the use of two single-targeted CAR T-cells or bispecific CAR T-cells that incorporate two distinct single-chain variable fragments within a single CAR structure. A recent study investigating the combined infusion of humanized anti-CD19 and anti-BCMA CAR T-cells achieved a 92% ORR in 62 RR MM patients, with 60% of patients achieving a CR or better. Importantly, the mPFS was 18.3 months and there were no excessive infective complications observed. Nevertheless, longer follow-up and larger cohort studies are needed to draw definitive conclusions [ 85 ].

Next-generation CAR T-cell therapies are being actively developed to address key limitations of earlier constructs, including suboptimal durability and resistance driven by the immunosuppressive tumor microenvironment. One promising strategy involves the creation of armored CAR T-cells—engineered to co-express additional molecules that enhance their function, persistence, or resistance to inhibitory signals. These modifications may include the secretion of pro-inflammatory cytokines, expression of co-stimulatory ligands, or incorporation of dominant-negative receptors. For instance, BCMA-targeted CAR T-cells armored with a dominant-negative TGF-β receptor have demonstrated enhanced resistance to TGF-β–mediated immunosuppression, a major hurdle in the myeloma bone marrow niche. Preclinical studies show that these modified CAR T-cells exhibit superior cytotoxicity, persistence, and polyfunctionality compared to conventional CAR T-cells, particularly under immunosuppressive conditions [ 86 ].

Another promising therapeutic strategy includes trispecific antibodies. One such compound is ISB 2001 that targets both BCMA and CD38 on MM cells (and CD3) within a single TCE. While patients with MM are often treated with monotargeted TCEs, an increasing number of patients may develop irreversible antigen loss. Dual-antigen-targeting therapies, such as ISB 2001, could help prevent this escape by targeting cells expressing either BCMA or CD38, even if at a lower potency. In vitro studies have shown that ISB 2001 exhibits 10–100 times greater cytotoxic potency than teclistamab, without inducing a proportional increase in cytokine release. These findings suggest that trispecific TCEs can achieve high cytotoxic potency without significantly increasing the risk of CRS [ 87 ].

Combination strategies are gaining traction to enhance the efficacy of immunotherapy. Notably, γ-secretase inhibitors (GSIs) have shown promise in increasing surface BCMA expression and reducing sBCMA, which otherwise acts as a decoy receptor and hampers TCE efficacy. Preclinical models and early-phase trials (e.g., MajesTEC-2, MagnetisMM-4, NCT05137054 , NCT05259839 ) support the combination of GSIs with anti-BCMA TCEs or CAR T-cells to enhance cytotoxicity [ 88 , 89 ].

Immune checkpoint inhibitors, such as PD-1/PD-L1 blockade, are also being investigated alongside CAR T-cell therapies to combat T-cell exhaustion and improve durability, though this remains investigational in MM [ 23 ].

As the immunotherapy armamentarium expands, biomarker-driven approaches are critical to optimizing therapy selection. Antigen profiling (e.g., BCMA, GPRC5D, CD38, CD138) and resistance mechanism characterization may inform the selection and sequencing of CAR T or TCEs. Despite this potential, such precision-guided approaches are not yet standard of care.

Despite scientific advances, challenges persist in ensuring equitable access to these therapies. CAR T-cell products remain limited to specialized centers with the infrastructure for apheresis, cell engineering, and post-treatment monitoring. Logistical and financial barriers are especially pronounced in low- and middle-income countries. Strategies to improve access include point-of-care manufacturing, expansion of generic and biosimilar options, and collaborative initiatives to improve infrastructure and workforce training.

The continued refinement of immunotherapies for MM hinges on optimizing manufacturing, improving antigen targeting, and integrating novel agents into rational combination strategies. The development of durable and accessible treatments must be matched by improvements in supportive care, toxicity mitigation, and patient selection. Ongoing research into T-cell biology, the tumor microenvironment, and resistance mechanisms will be instrumental in achieving long-term disease control and functional cures for patients with MM.

Author contributions

MSYT and TH wrote the main manuscript under the supervision of DD. DD developed the concept, supervised the work and participated in writing of the manuscript . All authors reviewed and approved the submitted version of the manuscript.

Funding

No external funding sources were used to prepare this work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

DD declares consulting with personal payment from: Alexion, Apellis, Argenyx, BMS, Janssen, Regeneron, Roche-Genentech, Sanofi, Sorrento and Takeda. Clinical trial support to institution: K36 Therapeutics.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Melinda S. Y. Tan and Tamer Hellou contributed equally to the work.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.