Прогресс и перспективы на будущее в химерикском антигенном рецепторе Т-клетке и биконкретной антителной терапии для множественных миелом.

INTRODUCTION

Multiple myeloma (MM) is a malignant neoplasm that originates in plasma cells. Although the introduction of highly effective agents—including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies—has considerably improved clinical outcomes, MM remains an incurable disease characterized by multiple relapses and therapeutic resistance.

Subsequent treatment outcomes are extremely poor once patients become triple-class exposed (TCE) or triple-class refractory (TCR) to PIs, IMiDs, and anti-CD38 antibodies. A retrospective multicenter study on patients who are TCR reported an overall response rate (ORR) and median overall survival (OS) of 29% and 9.2 months, respectively. 1 Similarly, a prospective real-world study of patients who are TCE demonstrated an ORR, a progression-free survival (PFS), and an OS of 29.8%, 4.6 months, and 12.4 months, respectively. This study also reported administering >90 different salvage regimens, highlighting the absence of an established standard of care (SOC). 2

Overall, these findings highlight the urgent need for developing novel therapies with mechanisms of action that are distinct from those of existing agents. Among these approaches, T-cell-redirecting therapies—including chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs)—have shown remarkable efficacy and have rapidly become key therapeutic options for relapsed/refractory MM (RRMM).

Numerous CAR T-cell therapies and BsAbs are currently undergoing clinical development for MM, making this a rapidly evolving and highly promising field. This review highlights representative CAR T-cell therapy and BsAbs currently in development, providing an up-to-date overview of their clinical profiles, including real-world data. By comparing these two modalities, this review clarifies their similarities and differences and provides perspectives on their respective roles and future potential in MM treatment.

CAR T-CELL THERAPY AND BSABS TARGETING B-CELL MATURATION ANTIGEN (BCMA)

T-cell-redirecting therapies for MM initially focused on targeting BCMA, a transmembrane protein belonging to the tumor necrosis factor (TNF) receptor superfamily. BCMA binds to ligands—including a proliferation-inducing ligand and B-cell activating factor—activating downstream signaling pathways, including nuclear factor-kappa B, which support plasma cells’ long-term survival. 3 – 5 It is expressed in mature B-cells and plasma cells, with particularly high expression in malignant plasma cells. 6 This restricted expression profile provides the biological rationale for developing BCMA-targeted therapies for MM. Table 1 presents the results of representative clinical trials investigating these BCMA-targeted therapies—including real-world data.

BCMA-targeted CAR T-cell therapy

Among the BCMA-targeted CAR T-cell therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have demonstrated high efficacy in pivotal single-arm trials for RRMM ( Table 1 ). 7 – 9 Both ide-cel and cilta-cel are autologous second-generation CARs, with anti-BCMA antibodies in the ectodomain and CD3ζ plus a costimulatory 4–1BB domain in the endodomain. However, their BCMA-binding ectodomains differ. Ide-cel uses a single-chain variable fragment (scFv) recognizing one BCMA epitope, whereas cilta-cel employs two single-domain antibodies that recognize two distinct epitopes, providing bivalent binding and higher avidity. 10 This unique biepitopic design is considered to contribute to the deeper and more durable responses observed with cilta-cel. 10 , 11

In the phase II KarMMa trial, patients with TCE disease who had received at least three prior regimens were treated with ide-cel. The ORR and rate of complete response (CR) were 73% and 33%, respectively. Minimal residual disease (MRD)–negative status, defined as <10 −5 nucleated cells, was achieved in 26% of patients. 7 In the phase II CARTITUDE-1 trial evaluating the efficacy of cilta-cel, participant eligibility required at least three prior regimens or double-refractory to a PI and an IMiD, and TCE disease, with documented disease progression within 12 months of the last regimen. Among the treated patients, the ORR and rate of CR were 97% and 67%, respectively. MRD-negative status, using the same threshold (<10 −5 nucleated cells), was achieved in 55% of patients. 8 Recently, long-term follow-up results from the CARTITUDE-1 trial have been reported, with a median follow-up of 61.3 months. The median OS was 60.7 months, and 33% of patients remained alive and progression-free for ≥5 years without receiving any additional antimyeloma therapy. 12 These findings suggest that a subset of patients may achieve prolonged disease control consistent with a potential functional cure. Subsequent randomized controlled trials comparing these therapies to the SOC confirmed the superiority of CAR T-cell therapies. 13 – 15

Real-world data further support the clinical utility of CAR T-cell therapies, demonstrating outcomes comparable to those observed in clinical trials. In a United States multicenter retrospective study, 159 of 196 patients who underwent leukapheresis ultimately received ide-cel, although 75% did not meet the KarMMa trial’s eligibility criteria. 7 , 16 Among the treated patients, the best ORR and complete response or better (≥CR) rate were 84% and 42%, respectively, with a median PFS of 8.5 months (95% confidence interval [CI] = 6.5–NR), similar to the trial results ( Table 1 ). 16 However, these findings should be interpreted cautiously considering the short median follow-up (6.1 months) and exclusion of non-infused patients, introducing a potential selection bias.

Since conducting a prospective head-to-head randomized trial comparing ide-cel and cilta-cel is impractical, real-world comparative analyses may provide insights into their appropriate clinical use and selection. Hansen et al. conducted a multicenter retrospective comparison of ide-cel and cilta-cel using data from 641 patients in the United States who underwent leukapheresis in routine clinical practice. 11 They evaluated the efficacy and safety outcomes for each product using inverse probability of treatment weighting to adjust for baseline characteristics. Cilta-cel showed increased rates of grade ≥3 cytokine release syndrome (CRS), infections, second primary malignancies (SPMs), and delayed neurotoxicity but superior CR rates, PFS, and OS. Subgroup analyses based on clinical factors—including the presence of extramedullary disease or high-risk cytogenetics—generally favored cilta-cel. PFS did not differ in patients with Eastern Cooperative Oncology Group performance status ≥2 at the time of lymphodepleting (LD) chemotherapy, 11 suggesting that the relatively greater toxicity of cilta-cel counteracted its efficacy in this subgroup. Despite limitations—particularly residual confounding after propensity score matching—these findings may inform personalized treatment decisions based on a patient’s risk tolerance and therapeutic goals.

BCMA-targeted BsAbs

Among BCMA-targeted BsAbs under development, elranatamab and teclistamab are the most advanced, 17 , 18 both demonstrating promising efficacy in pivotal single-arm trials for TCE RRMM ( Table 1 ). A long duration of response (DOR) is expected, particularly in deep responders; the median DOR was not reached, with a 66.9% probability of maintaining response at 24 months for elranatamab. 19 In teclistamab, the median DOR was 24 months; however, it was not reached for patients with ≥CR, and the 30-month DOR was 60.8%. 20

Real-world data on BsAbs are emerging, although clinical outcomes appear slightly inferior to those reported in trials ( Table 1 ). 21 , 22 BsAbs, unlike CAR T-cell therapies, are off-the-shelf agents, enabling immediate treatment without manufacturing delays. This is particularly advantageous for patients with rapidly progressing diseases who cannot afford to wait. BsAbs have more manageable safety profiles, making them a viable option for frail patients who may not tolerate CAR T-cell-related toxicities. BsAb therapy does not require center certification, facilitating broader institutional access. Consequently, real-world cohorts typically include heterogeneous and clinically complex populations, including a small proportion of patients with previous exposure to BCMA-targeted therapies. These differences likely contribute to the modestly reduced efficacy observed in retrospective studies. However, as adoption expands, future real-world cohorts are expected to include patients who are TCE treated with earlier lines of therapy, supported by greater clinical experience and improved supportive care, potentially improving outcomes.

Clinical significance of soluble BCMA (sBCMA) in BCMA-directed therapies

sBCMA, generated by γ-secretase–mediated cleavage of membrane BCMA, has emerged as both a dynamic disease marker and a clinically relevant modifier of treatment response in MM. Elevated serum sBCMA levels correlate with tumor burden and poor clinical outcomes, 23 and importantly, can attenuate the activity of BCMA-targeting BsAbs by acting as a decoy receptor. Clinical studies have shown that high baseline sBCMA levels, particularly ≥400 ng/mL, are independently associated with refractoriness to BsAb therapy and shorter PFS. 24 Strategies to overcome this barrier include the use of γ-secretase inhibitors to reduce sBCMA shedding and increase membrane BCMA density, 25 or switching to non-BCMA-directed targets such as G protein-coupled receptor class C group 5 member D (GPRC5D). In contrast, CAR T-cell therapies appear relatively less affected than BsAbs by circulating sBCMA, possibly because of their high avidity and sustained effector function; 24 however, both CAR T and BsAbs remain influenced by overall disease burden and effector-to-target ratios. Collectively, sBCMA functions both as a dynamic prognostic biomarker and as a modifier of treatment efficacy, informing patient stratification for T-cell-redirecting therapies.

GPRC5D-TARGETED CAR T-CELLS AND BSABS

GPRC5D is an orphan G protein-coupled receptor with an incompletely understood physiological function. 26 , 27 It is primarily expressed in plasma cells, with minimal to no expression in normal B cells, T cells, natural killer cells, monocytes, or granulocytes. 27 Although GPRC5D is detectable at low levels in normal plasma cells, it is consistently and markedly upregulated in malignant plasma cells, 28 supporting selective tumor targeting. Outside the immune system, GPRC5D is found in epithelial tissues, including hair follicles, eccrine glands, and the base of filiform papillae on the tongue. 27 It is highly expressed in MM independent of BCMA levels, 29 making it a promising target in BCMA-low tumors or patients relapsing post-BCMA-targeted therapy.

Although no GPRC5D-targeted CAR T-cell therapy has been approved to date, its clinical development is progressing. Current evidence remains limited to early-phase trials with relatively small cohorts ( Table 2 ). 30 , 31 Among investigational agents, arlocabtagene autoleucel (arlo-cel; BMS-986393) is the most advanced candidate. In the updated results from a phase I trial, patients had received a median of five earlier lines of therapy (range, 3–15), with 49% previously treated with BCMA-targeted therapies. Among the 79 efficacy-evaluable patients, the ORR was 87%, with a median PFS of 14.5 months after 14.6 months of follow-up. CRS occurred in 82% of the patients, primarily grade 1-2, with a single grade V event at the highest dose. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 10% of patients (grade 3 in 2%). On-target/off-tumor toxicities involving the skin, nails, and oral mucosa were observed in 19–31% of patients, predominantly grade 1-2. 31 Arlo-cel is being investigated in a phase II trial for TCE RRMM after >3 prior regimens ( NCT06297226 ) and in a randomized phase III trial comparing it with the SOC in patients with 1–3 prior regimens ( NCT06615479 ).

Talquetamab is the most advanced GPRC5D-targeted BsAb, with clinical trials demonstrating promising efficacy ( Table 2 ). It has also shown activity as salvage therapy in patients previously treated with T-cell-redirecting therapy. In the MonumenTAL-1 study, talquetamab demonstrated clinical activity in patients with TCE MM and ≥3 prior lines of treatment, including those previously exposed to T-cell redirecting therapies; 32 , 33 ORR in the previous T-cell redirecting therapy cohort was 67% (95% CI = 55–77), comparable to that observed in T-cell-redirecting therapy–naïve patients ( Table 2 ). 33

Similar results were observed in a real-world multicenter study involving 139 patients with RRMM post-BCMA-targeted CAR T-cell therapy, including 28 who received talquetamab. The ORR and CR rates were 79% and 39%, respectively. With a median follow-up of 8.6 months (95% CI = 7.6–9.6), median OS was not reached in the talquetamab group, compared with 5.4 months (95% CI = 3.7–7.0) in patients treated with IMiD-, PI-, or anti-CD38–based regimens. 34

In addition to BsAb-associated immunologic toxicities—including CRS and neurotoxicity—on-target/off-tumor adverse events (AEs) attributable to GPRC5D targeting have been reported for talquetamab. Skin-, nail-, and oral-related toxicities frequently occurred ( Table 2 ). The most commonly observed skin toxicities include skin exfoliation, pruritus, and dry skin. Oral toxicities—including dysgeusia, dry mouth, and dysphagia—were frequent but generally limited to grade 1-2. 32 Although these events are generally mild in severity, symptoms—including dysgeusia—can significantly impair patients’ quality of life. Dose reduction or schedule modification may improve tolerability and compliance without compromising efficacy. 35 Further investigations are warranted to determine whether GPRC5D-associated toxicities can be managed effectively through such adjustments.

SAFETY PROFILES OF CAR T-CELL AND BSAB THERAPIES

While CAR T-cell therapies and BsAbs are effective in RRMM treatment, their clinical use is accompanied by distinct AEs, which differ from those observed with conventional MM therapies. Effectively managing these AEs is essential for optimizing T-cell-redirecting therapy outcomes. The following discussion is primarily based on the evidence from BCMA-targeted therapies.

CRS and other inflammatory syndromes

CRS is caused by strong T-cell activation post-CAR T-cell or BsAb therapy, resulting in the release of pro-inflammatory cytokines—including interleukin-6, TNF-α, and interferon-gamma. 36 These cytokines further stimulate immune and non-immune cells, amplifying the inflammatory response and shaping CRS clinical presentation. 36 Typically, fever is the initial symptom, followed by chills, rigors, headaches, arthralgia, and anorexia. Severe cases may progress to hypotension, hypoxia, or multiorgan dysfunction. 37 Specifically, severe CRS is more frequent with CAR T-cell therapies than with BsAbs ( Table 1 ). 38 , 39 A key difference may lie in the effector cells’ biology; CAR T-cells become activated and undergo substantial in vivo expansion, intensifying cytokine release. BsAbs activate endogenous T-cells with limited expansion, resulting in a more tempered inflammatory profile. 40 Additionally, BsAb regimens incorporate CRS mitigation strategies, including step-up dosing and premedication, to reduce CRS severity.

Standardized CRS grading algorithms apply to CAR T-cell therapies and BsAbs and should be followed according to established clinical management guidelines. 39 , 41 Infection must be carefully ruled out and treated, as it remains a key differential diagnosis in febrile patients receiving these therapies. 36

Macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH)

MAS/HLH is a rare but potentially fatal CAR T-cell therapy complication driven by excessive immune activation and cytokine release. This hyperinflammatory state triggers macrophages’ and other immune effector cells’ infiltration into various organs, resulting in multiorgan failure. 42 Clinically, patients present with high-grade fever, pancytopenia, coagulopathy, and markedly elevated levels of inflammatory markers—including ferritin. MAS/HLH occurs several days post-CRS onset but can develop weeks after the CRS resolves in rare cases. 43 It appears to be exceedingly rare post-BsAb therapy. A literature search did not identify any definitive reports of BsAb-associated MAS/HLH to date.

Neurologic toxicity

ICANS

Neurologic toxicity is a common AE of T-cell-redirecting therapies, with most cases being ICANS. 37 ICANS typically follows CRS and results from increased blood–brain barrier permeability and neuroinflammation. 44 Its symptoms range from early word-finding difficulties, aphasia, and confusion to somnolence, seizures, impaired consciousness, and cerebral edema in severe cases. 39 , 45 Accurate diagnosis of ICANS requires careful distinction from other conditions—including infections, stroke, and drug-induced toxicity (fludarabine-associated neurotoxicity and antiepileptic drug-induced encephalopathy). 46 Brain magnetic resonance imaging, cerebrospinal fluid analysis, and electroencephalography (EEG) are the three commonly recommended diagnostic modalities for ICANS evaluation. 47 Among them, a single-center retrospective study found EEG to have the greatest therapeutic impact. EEG can identify seizures or status epilepticus in patients without overt clinical seizures, leading to treatment escalation and aiding in distinguishing ICANS from antiepileptic drug-induced encephalopathy. 46

ICANS is generally more frequent and severe with CAR T-cell therapies than with BsAbs ( Table 1 ). CRS severity is strongly correlated with ICANS risk, highlighting the importance of early CRS management. 39 ICANS severity was evaluated using the Immune Effector Cell-associated Encephalopathy score, which assesses orientation, attention, language, command-following, and writing. 39 Its management, guided by toxicity grade, commonly encompasses corticosteroids, anti-cytokine therapies, and antiepileptic agents—including levetiracetam; intensive care support may be required in severe cases. 37 , 39

Non-ICANS neurotoxicity

Delayed-onset neurotoxicity is more commonly associated with CAR T-cell therapy, particularly cilta-cel, and may emerge post-CRS and ICANS recovery. 48 These events are typically persistent and irreversible. Clinical presentations vary and comprise Parkinsonian motor symptoms—including tremors, bradykinesia, shuffling gait, apraxia, rigidity, and micrographia—and cognitive and behavioral changes—including memory impairment and affective flattening. 37 Peripheral motor and/or sensory neuropathies—including Guillain–Barré syndrome, cranial nerve palsy, and diplopia—have been reported as non-ICANS neurotoxicities. 10 , 45 , 49

Other neurotoxic manifestations—including dizziness, ataxia, dysarthria, and/or nystagmus—have been observed in patients treated with arlo-cel 31 and the pathophysiology underlying these events is poorly understood.

Delayed neurotoxicity with BsAb therapy is rare and possibly reflects opportunistic infections—including viral encephalitis. A phase I/II teclistamab study reported one fatal case of progressive multifocal leukoencephalopathy (PML). 18 We also encountered a PML case during elranatamab treatment at our institution (unpublished data).

Hematologic toxicity

Hematologic toxicity, particularly cytopenia, is a frequently observed AE post-T-cell-redirecting therapy. The concept of immune effector cell-associated hematotoxicity (ICAHT) has been proposed to characterize these events in CAR T-cell therapy. 50 Besides early onset cytopenia occurring within 30 days—typically post-LD chemotherapy and CRS—some patients experience prolonged cytopenia even post-CRS resolution or a biphasic course characterized by initial recovery followed by delayed relapse (late ICAHT, beyond day +30). 50 In severe cases, this can progress to profound bone marrow aplasia that is unresponsive to supportive care. Similarly, cytopenia is commonly observed as an AE in patients receiving BsAb therapy. 17 , 18 One common mechanism of hematologic toxicity is cytokine production by the bone marrow microenvironment, which impairs hematopoiesis. 51 , 52 Established risk factors for severe cytopenia include advanced age, high-intensity LD chemotherapy, high tumor burden, extensive prior therapy, compromised baseline hematopoiesis, and high-grade CRS-associated systemic inflammation. 39

Management strategies include supportive care—such as granulocyte colony-stimulating factor (G-CSF) administration for neutropenia and blood transfusions. Early G-CSF use post-CAR T-cell infusion is controversial because of its unclear impact on CRS. While some studies report no significant effect, 53 , 54 others suggest that it exacerbates CRS. 55 , 56 Thrombopoietin receptor agonists may be considered for refractory thrombocytopenia; however, robust clinical evidence is limited. 57 In patients with prolonged cytopenia post-CAR T-cell therapy, autologous stem cell rescue may be a therapeutic option if previously collected cells are available. 58

Temporary treatment interruption, according to product labeling, accompanied by adequate supportive care—including G-CSF use—is essential for mitigating severe hematologic complications in BsAb-related cytopenia. However, the safety of G-CSF administration during BsAb-induced CRS remains unclear.

Infectious complications

Infections are a clinically significant AE and a major cause of non-relapse mortality (NRM) in patients receiving T-cell-redirecting therapies. 51 , 59 , 60 Target antigens—including BCMA and GPRC5D—are expressed on normal plasma cells and their depletion results in hypogammaglobulinemia. Prolonged hypogammaglobulinemia, T-cell dysfunction, and compromised hematopoiesis together increase infection risk. 37 A recent systematic review and meta-analysis of 7,604 patients—including those with lymphoma—from 46 studies examined the causes of NRM post-CAR T-cell therapy. Over half of the NRMs were because of infections, followed by secondary malignancies (7.8%), highlighting infection as the leading cause of NRM in this setting. 59

Regarding BsAbs, severe infections (grades 3–4 and V) were frequently reported in pivotal trials, occurring in 55.2% and approximately 11% of patients treated with teclistamab and 39.8% and 6.5% of those treated with elranatamab, respectively. 17 , 18 , 61 These findings highlight the importance of infection prevention and management as critical components for optimizing BsAb treatment outcomes. However, these trials were conducted before the widespread implementation of effective coronavirus disease 2019 (COVID-19) mitigation strategies, and many infection-related deaths were attributed to COVID-19. 17 , 18 More recently, Hammons et al. reported in a multicenter real-world analysis that patients treated with GPRC5D-targeting BsAbs had a significantly lower incidence of severe infections (grade ≥3) than those receiving BCMA-targeting BsAbs (36% vs. 58%, P = 0.04), with infection-related mortality observed only in the BCMA group. 62 These findings suggest that GPRC5D-directed therapies may confer a relatively lower risk of severe infections than BCMA-directed therapies. A possible biological explanation is that BCMA is essential for the survival of long-lived plasma cells, 63 a key component of humoral immunity, whereas GPRC5D expression on normal plasma cells is minimal. 28 Consequently, GPRC5D-targeted therapies may be less likely to cause severe hypogammaglobulinemia and its associated infectious complications. 62

The timing and pattern of infection risk differ between CAR T-cell therapy and BsAbs. A retrospective comparison of BCMA-targeted therapies demonstrated that CAR T-cell therapy carries a high early infection risk, largely attributable to acute and profound bone marrow suppression and lymphoid dysfunction resulting from LD chemotherapy and CRS. However, this risk markedly decreased after 6 months. 64 BsAbs carry a higher overall incidence of severe infections (40% vs. 26%) and a greater proportion of fatal infections (7% vs. 0%) than CAR T-cell therapy. 64 Notably, BsAbs have been linked to a more sustained infection risk, 64 likely reflecting the cumulative immunosuppressive effects of continuous treatment.

Infection prevention strategies

Standard infectious prophylaxis for T-cell-redirecting therapies includes antiviral agents against herpes simplex and varicella-zoster viruses, hepatitis B virus (HBV) screening, and HBV prophylaxis for at-risk patients. Prophylaxis for Pneumocystis jirovecii pneumonia is generally recommended, while antifungal agents should be reserved for patients with defined risk factors—including prolonged neutropenia or prior colonization. 39 Antibacterial prophylaxis is not routinely indicated but may be considered in prolonged neutropenia or recurrent infection cases, with levofloxacin being commonly used. 39 G-CSF may promote neutrophil recovery, although its timing requires caution because of its potential effects on CRS. 53 – 56

While immunoglobulin replacement for hypogammaglobulinemia may reduce severe infection risk, evidence remains largely retrospective. 51 , 65 – 67 In a multicenter study of 225 patients receiving BCMA-targeted BsAb, primary intravenous immunoglobulin (IVIG) prophylaxis was associated with longer infection-free survival than no prophylaxis (all-grade: 7.7 vs. 3.0 months; grade ≥3: 14.0 vs. 7.5 months). 66 Furthermore, in the MajesTEC-1 trial, prophylactic IVIG therapy was associated with a lower severe infection risk in 52 patients treated with teclistamab at the Amsterdam University Medical Center. The cumulative incidence of infections at 6 months was 5.3% and 54.8% in the IVIG and observation-only groups, respectively. 68

Although COVID-19-related mortality has declined owing to improved vaccination, treatment, and the emergence of less virulent variants, 69 , 70 patients receiving T-cell-redirecting therapies may exhibit impaired vaccine responses 71 , 72 and prolonged viral shedding. 67 , 73 Based on local epidemiology, the continued use of protective measures—including wearing masks and prompt testing in symptomatic patients—is recommended throughout treatment.

SPMs

To date, limited evidence suggests that an increased SPM incidence is directly attributable to T-cell-redirecting therapies. The well-established risk factors for SPM development include prior exposure to alkylating agents, high-dose melphalan with autologous stem cell transplantation, multiple transplants, and prolonged lenalidomide maintenance therapy. 37 Extended follow-up increases the opportunities for SPM detection as survival improves with these therapies, underscoring the need for sustained surveillance.

Specifically, randomized phase III trials have not demonstrated a significant difference in SPM incidence between the CART-cell and SOC arms. In the KarMMa-3 trial, SPMs were reported in 6% and 4% of patients in the ide-cel and control groups, respectively. 13 Similarly, in the CARTITUDE-4 trial, SPMs occurred in 4.3% of patients treated with cilta-cel compared with 6.7% in the control arm. 14 Among SPMs, myeloid malignancies—including myelodysplastic syndrome and acute myeloid leukemia—were observed in 1.3% and 0% of patients in the KarMMa-3 trial and 1.4% and 0% in the CARTITUDE-4 trial (CAR T vs. SOC group, respectively), 13 , 14 indicating that such events remain relatively uncommon, although further follow-up is needed. Clinicians should consider secondary myeloid malignancies in the differential diagnosis of persistent cytopenia post-CAR T-cell therapy.

Pivotal clinical trials of BsAbs—including elranatamab and teclistamab, have not reported any clear increase in SPM risk to date. 17 , 18 Consequently, long-term monitoring is required.

CAR-positive T-cell lymphoma is a rare but increasingly recognized CAR T-cell therapy-associated AE. In the CARTITUDE-4 trial, two cases of malignant monoclonal T-cell proliferation were reported post-cilta-cel therapy, with clonal T-cells showing CAR transgene expression and integration. These events likely reflect multifactorial pathogenesis involving intrinsic and extrinsic factors. Although insertional mutagenesis is a theoretical concern, its direct role in lymphomagenesis remains unproven. 74

CLINICAL CONSIDERATIONS FOR TREATMENT SELECTION

Both CAR T-cell and BsAb therapies are highly effective immune therapy options with overlapping approval indications in RRMM. Given the incurable nature of the disease, most patients will eventually be treated with both modalities during their disease course. However, the optimal selection is influenced by logistics, disease characteristics, patient-related factors, and physician preference. Table 3 summarizes the key clinical considerations for CAR T-cell therapies and BsAbs in managing RRMM.

CAR T-cell therapy requires a manufacturing period of several weeks, during which bridging therapy is often needed to maintain disease control—a challenge in heavily pretreated patients with limited options. In contrast, BsAbs are readily available, off-the-shelf therapies that can be initiated promptly, which is particularly valuable for patients with aggressive disease. BsAbs generally require continuous dosing but can often be administered in community settings after step-up dosing, improving accessibility.

Patient-related factors are central to treatment selection. CAR T-cell therapy requires adequate cardiopulmonary reserve and overall fitness and is typically offered to patients with good performance status. 75 Chronological age is sometimes considered; however, its predictive value is limited. Real-world data suggest that even patients classified as frail, defined by the simplified frailty scale, 76 can achieve survival outcomes comparable to those achieved by non-frail patients; however, toxicity rates, especially ICANS, are higher. 77 These findings are derived from cohorts in which frail patients had already been deemed eligible for CAR T-cell therapy by treating physicians, indicating an inherent selection bias. Therefore, these results should not be generalized to all frail patients, and careful clinical judgment is essential when considering CAR T-cell therapy in truly frail populations. Conversely, BsAbs are often preferred in older or frail patients because of their lower rates of CRS and ICANS. In a single-center study of 102 patients receiving BCMA-directed BsAbs, 39% were frail, defined by the simplified frailty scale. The ORR was similar between frail (80%) and non-frail (73%) patients, and the median PFS (not reached vs. 11 months) and OS (37 vs. 25 months) were not significantly different. 78

Treatment sequencing has become a major clinical consideration. A recent International Myeloma Working Group consensus recommends prioritizing CAR T-cell therapy when both options are feasible. 79 This recommendation is supported by evidence that BsAbs generally retain efficacy following CAR T-cell therapy, whereas the reverse sequence—administering CAR T-cell therapy after prior BsAb exposure—has been associated with higher rates of manufacturing failure and shorter PFS. 79 , 80 Although BsAb efficacy may decline after CAR T-cell therapy, particularly when targeting the same antigen such as BCMA, outcomes appear more favorable than those observed with the reverse sequence. 81

Finally, antigen target also influences treatment choice. BCMA-directed BsAbs are associated with higher risks of infectious complications, including severe and opportunistic infections, and infection-related mortality, warranting caution in patients with recurrent severe infections or profound immunosuppression. In contrast, GPRC5D-directed BsAbs appear to carry a lower risk of severe infections than BCMA-targeted agents 62 but are linked to unique on-target/off-tumor toxicities such as dysgeusia, skin and nail disorders, and weight loss, the latter being particularly challenging in patients with preexisting cachexia. These differences highlight that the choice between BCMA- and GPRC5D-targeted therapies is determined not only by prior exposure and sequencing considerations but also by patient-specific vulnerabilities and comorbidities.

FUTURE PERSPECTIVES OF T-CELL-REDIRECTING THERAPIES IN MM

T-cell-redirecting therapies have rapidly evolved as effective options for RRMM. Their applications are expected to expand across diverse clinical settings, along with the development of novel agents.

Expansion to newly diagnosed MM

The use of CAR T-cell and BsAb therapies is being actively investigated in the frontline setting, with several phase III randomized trials currently underway. The rationale for introducing T-cell-redirecting therapies earlier in the treatment course is to enhance efficacy by engaging the immune system before it becomes compromised by extensive prior therapies. Early administration may also mitigate the risk of developing high-risk disease features—including del(17p), 1q gain, and extramedullary plasmacytomas—which are associated with poor prognosis and suboptimal response to conventional therapies.

However, the early use of these immunotherapies can increase the risk of immune-mediated toxicities, necessitating careful safety assessments. The substantial economic burden associated with these therapies should be considered. Nevertheless, achieving a deep response early in the disease course may delay the need for subsequent treatments and improve long-term cost-effectiveness.

For CAR T therapy, cilta-cel is being investigated in two key studies. The CARTITUDE-5 trial ( NCT04923893 ) is evaluating cilta-cel versus bortezomib, lenalidomide, and dexamethasone, followed by lenalidomide and dexamethasone (Ld) in transplant-ineligible patients with newly diagnosed MM, while the CARTITUDE-6 trial ( NCT05257083 ) is assessing cilta-cel versus autologous stem cell transplantation as consolidation therapy in transplant-eligible patients.

BsAbs are being evaluated as maintenance strategies post-autologous stem cell transplantation to establish a novel immunologic maintenance paradigm distinct from traditional IMiDs. The MajesTEC-4 trial ( NCT05243797 ) compares the effects of teclistamab monotherapy, teclistamab + lenalidomide, and lenalidomide monotherapy. Similarly, the MagnetisMM-7 trial ( NCT05317416 ) evaluates elranatamab versus lenalidomide as maintenance therapy.

The use of BsAbs is further being explored in newly diagnosed, transplant-ineligible patients. The MajesTEC-7 trial ( NCT05552222 ) is a phase III study evaluating the efficacy and safety of two bispecific antibody-based triplet regimens—teclistamab + daratumumab + lenalidomide / talquetamab + daratumumab + lenalidomide—with the standard regimen of daratumumab + Ld (D-Ld) in transplant-ineligible patients with newly diagnosed MM. A similar investigation is ongoing in the MagnetisMM-6 trial ( NCT05623020 ), which is comparing the efficacy of elranatamab, daratumumab and lenalidomide with D-Ld.

Expansion to novel targets

FcRH5 is a promising target beyond BCMA for RRMM. Cevostamab, a CD3 x FcRH5 BsAb, demonstrated an ORR of 54.5% and a median DOR of 16 months within a heavily pretreated RRMM population in a phase I trial ( NCT03275103 ). 82 CRS did not increase in a dose-dependent manner. An ongoing phase II study, CAMMA-2 ( NCT05535244 ), is evaluating its efficacy in patients previously treated with BCMA-targeted therapies. These data could support FcRH5’s potential as a novel therapeutic target in RRMM, particularly in this patient cohort.

Multi-antigen targeting strategies

Multi-antigen targeting strategies are being developed to counteract resistance mechanisms, including antigen escape. 83 A notable example is the combination of BsAbs targeting BCMA (teclistamab) and GPRC5D (talquetamab), which was evaluated in the phase Ib RedirecTT-1 trial. At the recommended phase II dose, the combination achieved an ORR and CR rate of 80% and 52%, respectively. Among patients with extramedullary disease—a population known for poor prognosis—a response was observed in 61% of patients, with an 18-month response durability of 82%, comparable to that observed in the overall cohort. 84 These results support the feasibility and potential of dual-target T-cell-redirecting therapy, even in high-risk populations.

Further innovation includes trispecific antibodies simultaneously targeting two tumor-associated antigens and CD3. ISB 2001 engages CD38, BCMA, and CD3 ( NCT05862012 ), while JNJ-79635322 targets GPRC5D, BCMA, and CD3 ( NCT05652335 ). These agents aim to broaden antigen coverage, mitigate immune escape, and achieve deeper and more durable clinical responses.

CONCLUDING REMARKS

T-cell-redirecting therapies have markedly transformed the treatment landscape for RRMM, particularly in patients who are TCE. They introduce novel mechanisms of action but also present unique challenges—including immune-mediated toxicities—uncommon in conventional therapies. Effectively managing these toxicities is essential for maximizing therapeutic benefits. Currently, no standardized algorithm exists to guide the choice between CAR T-cell therapy and BsAbs. Treatment decisions should be individualized, considering drug-specific characteristics, patient eligibility, logistical constraints, and institutional infrastructure. Patient-related factors—including age, frailty, comorbidities, and disease burden—are critical for optimizing outcomes. Given the challenges of prospective head-to-head comparisons, real-world data will increasingly inform clinical decision-making. Integrating T-cell-redirecting therapies into earlier lines of treatment—including ongoing trials in newly diagnosed MM—and advances in molecular engineering and cell manufacturing technologies reflect the field’s rapid evolution. Ultimately, these advances are expected to further enhance survival and quality of life for patients with MM.

ACKNOWLEDGMENTS

None.

Footnotes

CONFLICT OF INTEREST

Dr. Suzuki had honoraria from Sanofi, Chugai Pharmaceutical, Genmab, Astellas Pharma, Janssen Pharmaceutical, Nippon Shinyaku and Pfizer. Dr. Iida received grants from Sanofi, Takeda Pharmaceutical, Janssen Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Pfizer Japan, Daiichi Sankyo, Amgen, AbbVie, Caelum, Shionogi, GlaxoSmithKline, Celgene, Chugai Pharmaceutical, and Novartis; consulting fees from Novartis, AbbVie, Bristol Myers Squibb, Pfizer, GlaxoSmithKline, Sanofi, Regeneron, Janssen Pharmaceutical; and honoraria from Sanofi, Takeda Pharmaceutical, Janssen Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Pfizer Japan, and AstraZeneca.

FUNDING

None.

ETHICAL APPROVAL

Not applicable.

AVAILABILITY OF DATA AND MATERIALS

Not applicable.

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