Minimising Toxicity and Maximising Response: T-Cell Engagers for Elderly Patients with Multiple Myeloma

Abstract

The management of multiple myeloma (MM) in the elderly is challenging, exacerbated by age-related frailty and comorbidities. T-cell engagers (TCE) have been transformative to the treatment of relapsed MM, achieving deep and durable responses. This review evaluates the efficacy, toxicity, and other practical applications of approved and emerging TCEs in elderly MM patients. Broadly, approved monotherapy with TCEs produce overall response rates (ORR) of 60–70% in extensively treated populations. However, deeper and more durable responses have been observed with use in earlier lines of therapy or combined with conventional treatments. Cytokine release syndrome (CRS) and infection are the cardinal toxicities of TCEs. While CRS tends to be less severe than that observed with cellular immune therapies such as chimeric antigen receptor T-cell (CAR-T), the rate of severe infections appears to be higher, especially with BCMA-directed products, and strategies to mitigate this risk are being actively evaluated. TCEs offer logistical advantages over other cellular therapies, namely their off-the-shelf availability and simplified administration. TCEs are poised to redefine the care of elderly patients with MM and are being actively evaluated in this setting.

1. The Real and Growing Challenge of Elderly Patients with MM

MM is a hematologic malignancy characterised by the clonal proliferation of malignant plasma cells within bone marrow, resulting in a spectrum of clinical complications. This disease predominantly affects older adults, with a median age at diagnosis of 65 years [1]. For this review, we consider ‘elderly’ patients as individuals aged 75 and older, accounting for 1/3rd of patients at diagnosis and a higher percentage of the relapsed population. This demographic is growing rapidly as life expectancies increase globally with an expected 80% increase in the number of MM patients being >65 years at diagnosis by 2030 [2].

Advanced age and frailty each have an irrefutable impact on outcomes in MM, with population-based data showing significantly poorer survival in older patients. According to SEER data, the 5-year relative survival rate for patients aged ≥ 75 is just 31%, compared to 57% for those aged 65–74 and 76% for those under 65 [3]. These disparities persist even when accounting for disease stage and treatment access [4]. This impact is distinct from disease-specific factors, and holistic care is required to balance treatment tolerance with efficacy. Age-related physiological changes, along with a higher prevalence of comorbidities, frailty, and polypharmacy, underlie much of the differences observed in MM outcomes [5].

Recent clinical trials and real-world studies have demonstrated the transformative potential of TCEs, particularly in MM. Teclistamab and talquetamab have shown promising efficacy and manageable safety profiles in elderly and frail patients [6,7,8], underscoring the urgency of integrating these therapies into treatment algorithms tailored to vulnerable populations.

2. The Burden of Frailty and Treatment-Related Challenges

Frailty, which encompasses reduced physical, cognitive, and functional reserves, determines treatment possibilities for elderly MM patients. Assessing frailty is essential for optimising care; however, the uptake of validated geriatric assessment tools in routine clinical practice remains limited primarily due to time constraints. A summary of common validated frailty tools used in MM is provided (Table 1). These tools predict adverse events, treatment discontinuation, and survival in geriatric populations. The International Myeloma Working Group (IMWG) Frailty Score remains the most widely adopted and has shown predictive value for toxicity and survival even in patients aged over 80 [9]. The Revised Myeloma Comorbidity Index (R-MCI), which incorporates comorbidities, organ function, and performance status, supports personalised treatment algorithms, and correlates with both early mortality and treatment outcomes [10]. The Simplified Frailty Scale offers a more streamlined alternative for real-world use and has been shown to stratify outcomes in transplant-ineligible patients [11]. Tools like the Freiburg Index and Geriatric Assessment in Haematology (GAH) scale incorporate domains such as mobility, cognition, and nutrition, providing a more comprehensive geriatric lens to guide clinical decisions in older or vulnerable MM populations [12,13].

While historically clinical trials have relied upon the distinction between transplant eligible and ineligible, recently studies such as the phase 2 hovon 143 [14] demonstrates that trial design according to frailty assessment, in this case the IMWG frailty index, is feasible and informative. Here, the median age of patients was 81 years, and all patients were categorised as frail. Despite the use of a low-intensity regimen (ixazomib, low-dose dexamethasone, daratumumab), there was still a high early mortality signal 8% within 2 months, primarily secondary to treatment toxicity, highlighting the challenges of conventional therapy in this patient population.

Incorporating frailty scoring into routine practice allows for clinicians to tailor treatment intensity, reduce treatment-related morbidity, and avoid under- or overtreatment. For example, a patient classified as “fit” may be considered for a combination regimen including TCEs, while a “frail” patient might benefit more from TCE monotherapy with infection prophylaxis and reduced corticosteroid exposure. These considerations underscore the importance of aligning TCE use with geriatric assessments to minimise toxicity and optimise response in elderly MM patients.

Table 1. Comparison of commonly used frailty assessment tools in multiple myeloma.

Assessment Tool	Assessment Domains	Scoring Criteria	Risk Categories	Clinical Relevance in MM	Strengths/ Limitations
IMWG Frailty Score [9]	Age, CCI, ADL, IADL	0–5 points	Fit (0), Intermediate (1), Frail (≥2)	Predicts OS, PFS, and treatment toxicity	MM-specific, widely cited but time-consuming to calculate
Revised Myeloma Comorbidity Index [10]	Age, lung/kidney function, Karnofsky PS, frailty, cytogenetics	0–9 score	Low (0–3), Intermediate (4–6), High (7–9)	Associated with OS, early mortality, and guides treatment intensity	Incorporates organ function and disease biology, complex to apply routinely
Simplified Frailty Scale [11]	Age, ECOG performance status, CCI	0–3 score	Fit (0), Intermediate (1), Frail (≥2)	Correlates with outcomes, suitable for real-world use	Easier than IMWG, but may miss physical/cognitive nuance
Freiburg Frailty Score [12]	Timed Up and Go test, MMSE, nutrition (albumin)	0–3 score	Fit (0), Intermediate (1), Frail (≥2–3)	Identifies frailty-related toxicity risk	Good for cognitive/physical domains, less MM-specific
Geriatric Assessment in Haematology Tool [13]	Geriatric domains: ADL, IADL, cognition, nutrition, mood	Not always scored numerically	Risk-adapted	Broad geriatric tool used in haematology	Time-intensive, not MM-specific, may need trained staff
Mayo Frailty Risk Score [15]	Age, ECOG, ISS stage, LDH, cytogenetics	0–5 risk factors	Low (0–1), Intermediate (2–3), High (4–5)	Predicts early mortality and treatment intolerance	Easy to calculate, includes disease biology, not geriatric-specific

Summary of key frailty assessment tools applied in MM, including domains assessed, scoring systems, clinical relevance, and practical considerations. Tools vary in MM specificity, ease of use, and ability to capture cognitive or physical frailty. ADL: Activities of Daily Living, IADL: Instrumental Activities of Daily Living, ECOG: Eastern Cooperative Oncology Group, CCI: Charlson Comorbidity Index, MMSE: Mini Mental State Examination, ISS: International Staging System, LDH: Lactate Dehydrogenase, OS: Overall Survival, PFS: Progression-Free Survival.

Table 1. Comparison of commonly used frailty assessment tools in multiple myeloma.

Assessment Tool	Assessment Domains	Scoring Criteria	Risk Categories	Clinical Relevance in MM	Strengths/ Limitations
IMWG Frailty Score [9]	Age, CCI, ADL, IADL	0–5 points	Fit (0), Intermediate (1), Frail (≥2)	Predicts OS, PFS, and treatment toxicity	MM-specific, widely cited but time-consuming to calculate
Revised Myeloma Comorbidity Index [10]	Age, lung/kidney function, Karnofsky PS, frailty, cytogenetics	0–9 score	Low (0–3), Intermediate (4–6), High (7–9)	Associated with OS, early mortality, and guides treatment intensity	Incorporates organ function and disease biology, complex to apply routinely
Simplified Frailty Scale [11]	Age, ECOG performance status, CCI	0–3 score	Fit (0), Intermediate (1), Frail (≥2)	Correlates with outcomes, suitable for real-world use	Easier than IMWG, but may miss physical/cognitive nuance
Freiburg Frailty Score [12]	Timed Up and Go test, MMSE, nutrition (albumin)	0–3 score	Fit (0), Intermediate (1), Frail (≥2–3)	Identifies frailty-related toxicity risk	Good for cognitive/physical domains, less MM-specific
Geriatric Assessment in Haematology Tool [13]	Geriatric domains: ADL, IADL, cognition, nutrition, mood	Not always scored numerically	Risk-adapted	Broad geriatric tool used in haematology	Time-intensive, not MM-specific, may need trained staff
Mayo Frailty Risk Score [15]	Age, ECOG, ISS stage, LDH, cytogenetics	0–5 risk factors	Low (0–1), Intermediate (2–3), High (4–5)	Predicts early mortality and treatment intolerance	Easy to calculate, includes disease biology, not geriatric-specific

Summary of key frailty assessment tools applied in MM, including domains assessed, scoring systems, clinical relevance, and practical considerations. Tools vary in MM specificity, ease of use, and ability to capture cognitive or physical frailty. ADL: Activities of Daily Living, IADL: Instrumental Activities of Daily Living, ECOG: Eastern Cooperative Oncology Group, CCI: Charlson Comorbidity Index, MMSE: Mini Mental State Examination, ISS: International Staging System, LDH: Lactate Dehydrogenase, OS: Overall Survival, PFS: Progression-Free Survival.

Some standard MM treatments, such as autologous stem cell transplantation (ASCT) with high-dose chemotherapy, are not viable options for frail patients due to excessive toxicity and poor tolerance. Current guidelines support the use of ASCT in selected fit elderly patients up to 70–75 years of age, but there is limited evidence supporting its use in those ≥75 years, particularly in the absence of robust prospective data to guide patient selection beyond this age threshold [16]. As alternative therapeutics emerge, elderly MM patients stand to benefit from a personalised framework that integrates validated frailty assessments and incorporates adaptive treatment strategies [17]. This approach holds the promise of balancing efficacy and tolerability while addressing the unique challenges faced by this high-risk cohort.

While TCEs may address the therapeutic need outlined above, a key challenge in the utilisation of TCEs is the underrepresentation of frail patients in clinical trials. In the MajesTEC-1 trial, fewer than 15% of patients were aged ≥ 75 years [6]; in MagnetisMM-3, only 19% of participants were ≥75 years [17]; and in MonumenTAL-1, 23% of patients ≥ 75 years were enrolled [18]. Furthermore, as adequate organ function is mandated for participation in most pharmaceutical sponsored trials, the minority of elderly patients included in clinical trials is unlikely to be representative of real-world practice. As the impact of frailty on treatment outcomes is increasingly recognised, it is essential that new trials are designed to incorporate fitness levels and adjust therapies accordingly [5]. Such efforts will generate data that better reflect the real-world population of MM patients.

3. Mechanism of Action and Key Targets of T-Cell Engagers

TCEs have emerged as a transformative class of immunotherapies for MM, offering a unique approach to targeting malignant plasma cells. In this review, TCEs refers broadly to both bispecific (BsAbs) and trispecific antibody therapies. The term BsAbs is used only when discussing structural formats or specific trial data. These antibody constructs simultaneously bind two distinct antigens: one on the tumour cell, and the other on immune effector cells such as T-cells. By forming an immune synapse, BsAbs facilitate immune-mediated cytotoxicity, triggering a cascade of events that includes the activation and recruitment of additional immune cells to amplify the immune response [19]. This dual-targeting strategy enhances the precision and potency of therapy, making BsAbs particularly promising for patients with relapsed MM.

The structural diversity of BsAbs significantly influences their pharmacokinetics, efficacy, and tolerability and have evolved over time (Figure 1). Bispecific T-cell engagers (BiTEs) were the earliest clinically applied bispecific design. These are small, compact molecules optimised for rapid immune synapse formation. Their streamlined structure enables efficient tumour targeting, but results in a short half-life, necessitating frequent or continuous intravenous administration [20]. The most notable example, AMG-701, was a half-life extended BCMA-targeting BiTE that showed promising early activity, but was ultimately discontinued, partly due to logistical challenges and toxicity concerns in heavily pretreated patients. This prompted a shift toward alternative BsAb formats, particularly IgG-based designs, which offer extended half-lives and greater dosing flexibility.

IgG-based BsAbs, modelled on the structure of full-length antibodies, offer a longer half-life due to their Fc regions. Importantly, these Fc regions are typically engineered to be inactivated, preventing antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, while still engaging the neonatal Fc receptor (FcRn) to prolong serum half-life. This not only allows for extended dosing intervals, but also enhances stability and reduces off-target immune effects. This structural format has become the backbone of approved BsAbs, such as teclistamab, which targets B-cell maturation antigen (BCMA) and CD3. IgG-like BsAbs are particularly well-suited for outpatient administration, often delivered subcutaneously, offering significant advantages for elderly patients [21].

Next-generation TCEs incorporate innovative designs, including trispecific constructs that target multiple antigens simultaneously. For example, trispecific simultaneously engage BCMA, CD3, and CD38, broadening their therapeutic scope by enhancing immune activation and mitigating resistance mechanisms [22]. Advances in engineering technologies, such as knob-into-hole technology and CrossMab designs, have further improved the specificity, potency, and manufacturability of TCEs, ensuring their adaptability to various clinical needs [23]. By leveraging this structural diversity, TCEs are able to address a wide range of therapeutic challenges, offering potent and tolerable options for elderly and frail MM patients who may not tolerate intensive therapies like ASCT or CAR-T therapy.

The efficacy of TCEs relies on their ability to target specific antigens on myeloma cells, making antigen selection crucial. Understanding the biology of these antigens illustrates both their therapeutic potential and limitations. BCMA is the most extensively studied immunotherapeutic target in MM therapy [24]. BCMA is a trans-membrane receptor expressed on mature B cells and malignant plasma cells that supports plasma cell survival and proliferation via interactions with A Proliferation-Inducing Ligand (APRIL) and B-cell Activating Factor (BAFF) [25]. Soluble BCMA (sBCMA) levels, which is released from the cell surface by gamma-secretase-mediated shedding, correlates with disease burden and prognosis [26]. This shedding may compromise BCMA-targeted therapy efficacy by reducing antigen availability and acting as a therapeutic ‘sink’. BCMA’s restricted expression in normal tissues and essential role in plasma cell survival makes it a favourable target.

G-protein Coupled Receptor Family C Group 5 Member D (GPRC5D) is highly expressed on malignant plasma cells with limited expression in normal tissues, offering a promising target for BCMA-refractory cases. GPRC5D-targeting BsAbs, such as talquetamab, have demonstrated robust efficacy in these settings [27]. However, GPRC5D is also expressed in tissues like the skin and nails, which has been associated with unique toxicities, including dysgeusia and skin-related adverse events [28]. While these side effects require monitoring and often dose modification, the antigen’s non-overlapping expression with BCMA enables its use in combination with BCMA-directed therapies or in previously exposed patients [24].

Fc Receptor Homolog 5 (FcRH5) is uniformly expressed on myeloma cells and plays a role in plasma cell differentiation. Unlike BCMA, FcRH5 expression is present at lower levels on B cells, including naïve and memory B cells. Cevostamab, an FcRH5-directed BsAb, has shown efficacy in BCMA-exposed patients, similarly addressing this patient population like talquetamab [22]. In the updated Phase 1 GO39775, the ORR in patients with prior BCMA-targeted therapy was 44.3%, with a median duration of response of 10.4 months, rising to 21.2 months in patients achieving a very good partial response (VGPR) or better [29]. A high proportion of patients in this study were also TCE-exposed, including 44.4% who had received prior CAR T-cell therapy, which is important context for interpreting the ORR. These results highlight Cevostamab’s potential as a treatment option for patients previously exposed to BCMA-directed therapies.

CD38, widely expressed on plasma cells, is involved in adhesion, signalling, and calcium regulation. Its relevance in the therapeutic armenterium has been undeniably established by the monoclonal antibodies (mAbs) daratumumab and isatuximab [16]. CD38 expression extends to erythroid and myeloid cells and confounds serological transfusion practices; however, this can be overcome with simple modifications to conventional processes [17]. Emerging trispecific antibodies targeting CD38, BCMA, and CD3 enhance immune activation via the removal of CD38+ T-regulator cells and address resistance mechanisms through multi-antigen targeting [30]. Additionally, the combined use of CD38 and BCMA-directed BsAbs appears to enhance response rates and survival [31]. TRIMM-2’s preliminary results reported an ORR of 78% with ≥VGPR in 73% and complete response (CR) in 24%, with a median response time of 1 month. The upregulation of CD38+/CD8+ T-cells and proinflammatory cytokines were observed, supporting the scientific basis of this approach. Lastly, rates of CRS/Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were comparable to teclistamab monotherapy [32]. However, despite these encouraging results, the tolerability of such combinations in older populations remains unclear. In the TRIMM-2 trial, the median patient age was 63 years (range 37–81), but specific outcomes for patients ≥ 75 years were not reported, limiting our insight into safety and efficacy in this subgroup. Similarly, preliminary data from the ISB 2001 trispecific antibody study do not disclose participant age distribution. Together, these findings highlight the ongoing underrepresentation of elderly patients in TCE trials.

By targeting diverse antigens, TCEs provide a versatile therapeutic platform for MM. TCEs are capable of leveraging each antigens unique specificity and role in plasma cell biology, while addressing challenges like such as antigen shedding, T-cell exhaustion, and off-tumour effects, as well as antigen loss or modulation. This tailored approach has improved outcomes for younger patients and holds promise for elderly and frail patients. With their immunological mechanism of action in mind, it is crucial to consider where BsAbs will best fit within the broader therapeutic landscape, ideally utilising the preserved immune capacity of less extensively treated patients.

4. Immunotherapies Compared to the Current Landscape for Elderly MM Patients

Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 mAbs have long been standard components of MM therapy. However, elderly and transplant-ineligible patients are more susceptible to treatment-related toxicities, including peripheral neuropathy, myelosuppression, and infections. Several frontline trials (Table 2) in this population, including MAIA: daratumumab, lenalidomide, and dexamethasone (Dara-Rd vs. Rd), IMROZ: isatuximab, bortezomib-Rd (Isa-VRd vs. VRd), CEPHEUS: Dara-VRd vs. VRd, and BENEFIT: Isa-VRd vs. Isa-Rd-, have consistently reported increased infection rates, particularly in patients aged ≥ 75 years. The MAIA trial enrolled transplant-ineligible patients with a median age of 73 years (range 45–90), including 44% aged ≥ 75 and 18% ≥80, making it one of the only registrational studies to include a substantial number of patients > 80 years [33]. IMROZ included patients aged 18–80 with a median age of 72, and ~26% were aged 75–80 [34]. CEPHEUS had a median age of 70, with 55% aged ≥ 70, although specific data on those ≥75 were not reported [35]. The BENEFIT trial enrolled patients aged 65–79 (median 73), with ~31% ≥75, but limited enrolment to non-frail individuals, reflecting a fitter elderly cohort [36].

Grade ≥ 3 infections remain a major concern across frontline MM trials, although only MAIA provided age-stratified data. In MAIA, rates were 44% in patients aged ≥ 75 compared to 29% in those <75, highlighting increased vulnerability with age [33]. In IMROZ, the overall Grade ≥ 3 infection rate in the Isa-VRd arm was 45%, although age-specific data were not reported [34]. Similarly, the BENEFIT trial showed higher infection rates with Isa-Rd (53%) compared to Isa-VRd (47%) [36]. In CEPHEUS, Grade ≥ 3 infections occurred in 40% of patients receiving D-VRd versus 32% in the VRd arm [35].

Fatigue, diarrhoea, and constipation, secondary to lenalidomide and other agents, have major quality of life implications for patients receiving first-line therapy. In the MAIA trial (D-Rd), fatigue occurred in 36%, diarrhoea in 57%, and constipation in 41% of patients [33]. The IMROZ trial (Isa-VRd) reported fatigue in 35%, diarrhoea in 55%, and constipation in 36% [34]. In the BENEFIT trial, fatigue affected 30%, diarrhoea 49%, and constipation 39% of patients receiving Isa-VRd [36]. The CEPHEUS trial reported similar rates for these adverse events (Table 1). Peripheral neuropathy, a key toxicity concern-especially with bortezomib-containing regimens, was consistently observed. In MAIA, where bortezomib was not included, Grade ≥ 3 neuropathy occurred in 5% of patients [33]. In IMROZ, peripheral neuropathy of any grade was reported in 38% of patients receiving Isa-VRd, with Grade ≥ 3 in 6% [34]. The BENEFIT trial, directly comparing Isa-VRd to Isa-Rd, reported higher neuropathy with Isa-VRd (52% vs. 28%), reinforcing bortezomib’s known neurotoxicity [36].

Progression-free survival (PFS) and overall survival (OS) outcomes from the MAIA and IMROZ trials highlight the efficacy of daratumumab-based regimens in transplant-ineligible MM. In the MAIA trial, D-Rd significantly prolonged PFS, with a median of 61.9 months compared to 34.4 months for Rd alone. Median OS was not reached in the D-Rd arm versus 65.5 months in the Rd group, demonstrating a clear survival benefit [33]. In the IMROZ trial, which assessed Dara-VRd versus VRd, median PFS was not reached in the Dara-VRd group, while the VRd arm showed a median PFS of 54.3 months [34]. At the time of reporting, median follow-up was 5 years, and median OS had not been reached in either arm, reflecting the sustained efficacy of the regimen.

The incorporation of CD38-based regimens has set a high benchmark, yielding substantial PFS and OS benefits for many patients. However, these regimens necessitate frequent oncology visits and involve continuous therapy, contributing to a cumulative treatment burden. Moreover, the limited inclusion of patients over 80 years and those who are frail restricts the generalisability of these results to the broader elderly MM population. Steroid use, particularly dexamethasone, remains a cornerstone in MM treatment, but poses significant challenges in elderly patients, including mood disturbances, delirium, and unstable blood glucose levels. Recent findings have underscored the potential of steroid-sparing approaches. Notably, the IFM2017-03 phase 3 trial demonstrated that frail patients with newly diagnosed MM benefited from a dexamethasone-sparing regimen [37]. The study reported improved PFS and OS when using Dara plus R with only two cycles of dexamethasone, compared to continued dexamethasone treatment. This suggests that reducing steroid exposure can mitigate associated toxicities while maintaining therapeutic efficacy.

Table 2. Comparison of frontline clinical trial outcomes in elderly and transplant-ineligible patients with MM, focusing on infection risk, adverse events, and steroid burden. The table summarises key trials including MAIA, IMROZ, CEPHEUS, and BENEFIT, with emphasis on patients aged ≥ 75 years and adverse event profiles, particularly infections, fatigue, gastrointestinal symptoms, and peripheral neuropathy. PFS and OS outcomes are reported where available, alongside steroid use considerations.

Trial/Regimen	Population Details	Arm	Grade ≥ 3 Infections	Other AEs (Fatigue/Diarrhoea/ Constipation)	Peripheral Neuropathy	PFS (Months)	OS Outcome	Steroid Use
MAIA [33]	Median age 73 (44% ≥75)	D-Rd	41%	36% (9%)/57% (9%)/41% (1%)	28% (2% Grade 3)	~62	66% 5-yr	Dexamethasone included
		Rd	29%	27% (5%)/45% (6%)/37% (1%)	18% (<1% Grade 3)	34	53% 5-yr
IMROZ [34]	Median age 72 (26% ≥75)	Isa-VRd	45%	35% (8%)/55% (8%)/36% (2%)	54% (7% grade 3)	Not reached	72% 5-yr	Dexamethasone included
		VRd	38%	26.5% (7%)/49% (8%)/41% (2%)	61% (6% Grade 3)	54	66% 5-yr
CEPHEUS [35]	Median age 70 (55% ≥70)	D-VRd	40%	32% (9%)/57% (12%)/38% (2%)	56% (8%)	Not reached	OS Immature	Dexamethasone included
		VRd	32%	31% (8%)/59% (9%)/42% (3%)	61% (8%)	53	OS Immature
BENEFIT [36]	Median age 73 (~31% ≥75)	Isa-Rd	53%	36% (14%)/48% (22%)/30% (14%)	28% (10%)	Not reached	91.5% 24 months	Dexamethasone included
		Isa-VRd	47%	30% (18%)/49% (29%)/39% (22%)	52% (27%)	Not reached	91.1% 24 months

ORR: Overall Response Rate, OS: Overall Survival, PFS: Progression-Free Survival, AE: Adverse Events (>grade 3/>grade 2 in BENEFIT). Daratumumab, lenalidomide, and dexamethasone: Dara-Rd. Isatuximab, bortezomib, lenalidomide, and dexamethasone: Isa-VRd. Daratumumab, bortezomib, lenalidomide, and dexamethasone: Dara-VRd. NR: not reported.

Table 2. Comparison of frontline clinical trial outcomes in elderly and transplant-ineligible patients with MM, focusing on infection risk, adverse events, and steroid burden. The table summarises key trials including MAIA, IMROZ, CEPHEUS, and BENEFIT, with emphasis on patients aged ≥ 75 years and adverse event profiles, particularly infections, fatigue, gastrointestinal symptoms, and peripheral neuropathy. PFS and OS outcomes are reported where available, alongside steroid use considerations.

Trial/Regimen	Population Details	Arm	Grade ≥ 3 Infections	Other AEs (Fatigue/Diarrhoea/ Constipation)	Peripheral Neuropathy	PFS (Months)	OS Outcome	Steroid Use
MAIA [33]	Median age 73 (44% ≥75)	D-Rd	41%	36% (9%)/57% (9%)/41% (1%)	28% (2% Grade 3)	~62	66% 5-yr	Dexamethasone included
		Rd	29%	27% (5%)/45% (6%)/37% (1%)	18% (<1% Grade 3)	34	53% 5-yr
IMROZ [34]	Median age 72 (26% ≥75)	Isa-VRd	45%	35% (8%)/55% (8%)/36% (2%)	54% (7% grade 3)	Not reached	72% 5-yr	Dexamethasone included
		VRd	38%	26.5% (7%)/49% (8%)/41% (2%)	61% (6% Grade 3)	54	66% 5-yr
CEPHEUS [35]	Median age 70 (55% ≥70)	D-VRd	40%	32% (9%)/57% (12%)/38% (2%)	56% (8%)	Not reached	OS Immature	Dexamethasone included
		VRd	32%	31% (8%)/59% (9%)/42% (3%)	61% (8%)	53	OS Immature
BENEFIT [36]	Median age 73 (~31% ≥75)	Isa-Rd	53%	36% (14%)/48% (22%)/30% (14%)	28% (10%)	Not reached	91.5% 24 months	Dexamethasone included
		Isa-VRd	47%	30% (18%)/49% (29%)/39% (22%)	52% (27%)	Not reached	91.1% 24 months

ORR: Overall Response Rate, OS: Overall Survival, PFS: Progression-Free Survival, AE: Adverse Events (>grade 3/>grade 2 in BENEFIT). Daratumumab, lenalidomide, and dexamethasone: Dara-Rd. Isatuximab, bortezomib, lenalidomide, and dexamethasone: Isa-VRd. Daratumumab, bortezomib, lenalidomide, and dexamethasone: Dara-VRd. NR: not reported.

4.1. BsAbs: A Logistically Feasible and Effective Approach

The toxicity profiles of BsAbs (Table 3), vary significantly, reflective of differences in construct design and antigen targets. First-in-class agents like teclistamab and talquetamab demonstrated relatively high CRS rates in their registrational trials (72%; Grade ≥ 3: <1%) [38] and (47–62%; mostly Grade 1–2, Grade ≥ 3: <1%), respectively [39] compared to subsequent TCEs such as linvoseltamab (37%; all Grade 1–2, Grade ≥ 3: 1%) [40]. Undoubtedly, the latter agents have benefited from optimised step-up dosing and increased familiarity with TCE associated CRS in myeloma. However, both linvoseltamab and etentamig have additionally engineered CD3 regions with reduced T-cell binding affinity, providing a mechanistic basis for reduced CRS.

BCMA-targeting BsAbs are more frequently associated with infections due to plasma cell and terminal B-cell depletion, as well as severe hypogammaglobulinemia. In the MajesTEC-1 study, Grade 3 or 4 infections occurred in 45% of patients, with pneumonia (18.1%) and COVID-19 (12.5%) among the most common serious infections. Importantly, infectious rates have diminished with the prophylactic use of intravenous immunoglobulin (IVIG) [38]. This is important for elderly patients where infections are more morbid and frequently fatal. Conversely, GPRC5D-directed BsAbs typically cause mucosal, skin, and nail toxicities related to off-tumour antigen expression. In the MonumenTAL-1 registrational trial, dysgeusia occurred in 47–50% of patients, and weight loss was reported in 33–35%, depending on the dosing schedule [41]. These adverse events, while generally low grade, can significantly impact nutritional status. This is particularly challenging for elderly patients, for whom the effects of malnutrition are amplified-leading to sarcopenia, reduced treatment tolerance, and increased morbidity. These trade-offs make patient-specific factors such as comorbidities and tolerability increasingly central to treatment selection, as efficacy remains broadly consistent across agents.

Table 3. Summary table of registrational or primary phase I/II trials for bispecific antibodies.

Agent (Antigen Targeted)	Trial Name/ NCT/Phase	Population (n)/Age (Range/Median)	ORR		PFS (months)	Infection (Grade ≥ 3)	CRS	ICANS
Teclistamab (BCMA) [38]	MAJESTEC-1 (NCT04557098) Phase II	n = 165 33–84 years (med: 64) ≥75 years: 14.5%	63%		11.3	76% (45%)	72% (Grade ≥ 3: <1%)	~3% (Grade ≥ 3: 0)
Elranatamab (BCMA) [42]	MagnetisMM-3 (NCT04649359) Phase II	n = 123 36–89 (med: 68) ≥75 years: 21%	61%		Not Reached 15-month PFS rate: 51%	70% (40%)	58% (Grade ≥ 3: 0)	3% (Grade ≥ 3: 0)
Linvoseltamab (BCMA) [40]	LINKER-MM1 (NCT03761108) Phase II	n = 179 37–90 (med: 66) ≥70 years: NR	64%		NR	200 mg cohort: 43% (26%)	200 mg cohort: 37% (Grade ≥ 3: 1%)	200 mg cohort: (Grade ≥ 3: 2%)
ABBV-383/ Etentamig (BCMA) [43]	- (NCT03933735) Phase I/II	n = 124 35–92 (med: 68) ≥70 years: NR	57%		Not Reached 12-month PFS: 58%	≥40 mg cohort 44% (~25%)	≥40 mg cohort 73% (Grade ≥ 3: 4%)	≥40 mg cohort ~2% (Grade ≥ 3: 2%)
Talquetamab (GPRC5D) [39]	MonumenTAL-1 (NCT03399799/NCT04634552) Phase 1/II	n = 375 NR (med: 68) ≥75: NR	QW	74%	7.5	54% (20%)	62% (Grade ≥ 3: 2%)	1% (Grade ≥ 3: 0%)
			Q 2W	69%	11.9	58% (23%)	47% (Grade ≥ 3: 1%)	1% (Grade ≥ 3: 0%)
Cevostamab (FcRH5) [44]	- (NCT03275103) CAMMA-2 (NCT05535244) Phase 1/11	n = 160 33–82 (med: 64) ≥75 years: NR	160 mg cohort: 54%		NR	42% (19%)	80% (Grade ≥ 3: 1%)	13% (Grade ≥3: 1%)

ORR: Overall Response Rate; PFS: Progression-Free Survival; CRS: Cytokine Release Syndrome; ICANS: Immune Effector Cell-Associated Neurotoxicity Syndrome. NR: not reported. Trial names are listed where available; “-” indicates no assigned name.

Table 3. Summary table of registrational or primary phase I/II trials for bispecific antibodies.

Agent (Antigen Targeted)	Trial Name/ NCT/Phase	Population (n)/Age (Range/Median)	ORR		PFS (months)	Infection (Grade ≥ 3)	CRS	ICANS
Teclistamab (BCMA) [38]	MAJESTEC-1 (NCT04557098) Phase II	n = 165 33–84 years (med: 64) ≥75 years: 14.5%	63%		11.3	76% (45%)	72% (Grade ≥ 3: <1%)	~3% (Grade ≥ 3: 0)
Elranatamab (BCMA) [42]	MagnetisMM-3 (NCT04649359) Phase II	n = 123 36–89 (med: 68) ≥75 years: 21%	61%		Not Reached 15-month PFS rate: 51%	70% (40%)	58% (Grade ≥ 3: 0)	3% (Grade ≥ 3: 0)
Linvoseltamab (BCMA) [40]	LINKER-MM1 (NCT03761108) Phase II	n = 179 37–90 (med: 66) ≥70 years: NR	64%		NR	200 mg cohort: 43% (26%)	200 mg cohort: 37% (Grade ≥ 3: 1%)	200 mg cohort: (Grade ≥ 3: 2%)
ABBV-383/ Etentamig (BCMA) [43]	- (NCT03933735) Phase I/II	n = 124 35–92 (med: 68) ≥70 years: NR	57%		Not Reached 12-month PFS: 58%	≥40 mg cohort 44% (~25%)	≥40 mg cohort 73% (Grade ≥ 3: 4%)	≥40 mg cohort ~2% (Grade ≥ 3: 2%)
Talquetamab (GPRC5D) [39]	MonumenTAL-1 (NCT03399799/NCT04634552) Phase 1/II	n = 375 NR (med: 68) ≥75: NR	QW	74%	7.5	54% (20%)	62% (Grade ≥ 3: 2%)	1% (Grade ≥ 3: 0%)
			Q 2W	69%	11.9	58% (23%)	47% (Grade ≥ 3: 1%)	1% (Grade ≥ 3: 0%)
Cevostamab (FcRH5) [44]	- (NCT03275103) CAMMA-2 (NCT05535244) Phase 1/11	n = 160 33–82 (med: 64) ≥75 years: NR	160 mg cohort: 54%		NR	42% (19%)	80% (Grade ≥ 3: 1%)	13% (Grade ≥3: 1%)

ORR: Overall Response Rate; PFS: Progression-Free Survival; CRS: Cytokine Release Syndrome; ICANS: Immune Effector Cell-Associated Neurotoxicity Syndrome. NR: not reported. Trial names are listed where available; “-” indicates no assigned name.

4.2. CAR-T Therapy: Durable Responses with Logistical Barriers in the Elderly

CAR-T therapy, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), has revolutionised MM treatment by providing deep and durable responses in heavily pretreated patients. Their respective registrational trials demonstrating ORR exceeding 80% and PFS of 9–36 months. However, the applicability of CAR-T in frail and elderly patients remains limited. In the KarMMa (ide-cel) and CARTITUDE-1 trial (cilta-cel), the median age was 61 years, and patients aged ≥ 75 were underrepresented, accounting for only 16% of the KarMMa cohort [45]. Real-world data confirm limited uptake in elderly patients ≥ 75, comprising only 10% of CAR-T recipients in a recent population-based analysis, despite similar safety profiles across age groups [46]. Importantly, these real-world cohorts have highlighted additional concerns relevant to older patients, including delayed-onset neurotoxicity, which may occur several weeks after CAR-T infusion and can present as atypical parkinsonism, facial nerve palsies, or aphasia—the former being a particularly worrying complication in the elderly, where baseline neurologic reserve and mobility are limited [47]. Additionally, frailty appears to significantly impact outcomes: 61% of patients in a multicentre cohort were classified as frail at the time of CAR-T infusion and experienced higher ICANS rates (39% vs. 17%) and shorter PFS (6.9 vs. 11.1 months) and OS (14 months vs. not reached) compared to non-frail patients [47]. The need for lymphodepleting chemotherapy, prolonged hospitalisation, and high rates of CRS (80–90%) and neurotoxicity (10–15%) further constrain the use of CAR-T in patients ≥ 75 years.

5. Key Trial and Real-World Data in Elderly (≥75 Years) MM Patients

Despite the rapid adoption of TCEs in MM treatment, their performance in elderly patients aged ≥ 75 years and those classified as frail remains underexplored. In Table 2 above, none of these BsAb trials provide detailed age-stratified analyses for ORR, PFS, or toxicity. While some mention consistency across age groups or provide age distributions, they lack specific efficacy or safety data for elderly cohorts. Recent real-world studies provide crucial insights into how BsAbs, particularly teclistamab, perform in these populations. In a multicentre U.S. cohort of 83 patients aged ≥ 75 years treated with teclistamab across 13 academic centres, outcomes were comparable to those observed in the pivotal MajesTEC-1 trial, with an ORR of 62% and a median PFS of 10.7 months [6]. Notably, the incidence of CRS and ICANS was lower in this older cohort, with only one case of Grade ≥ 3 CRS reported, possibly secondary to immunosenescence. These findings support the tolerability and preserve efficacy of teclistamab in appropriately selected elderly patients.

A retrospective review of teclistamab use across U.S. community oncology practices evaluated outcomes in a real-world population with broader eligibility than the MajesTEC-1 trial. The study included 101 patients with a median age of 65 years (range 51–92), many of whom had comorbidities such as renal impairment (24%) and anaemia (33%). Despite these risk factors, the ORR was 76%, and 6-month PFS was estimated at 83%. Importantly, CRS occurred in only 34% of patients, with all CRS events being grade 1–2. Grade ≥ 3 infections occurred in approximately 2% of patients, leading to treatment discontinuation in only two cases [7]. These findings underscore the tolerability and efficacy of teclistamab in elderly and frail patients often excluded from clinical trials, reinforcing the generalisability of MajesTEC-1 outcomes to real-world settings.

Data from the International Myeloma Foundation (IMF) immunotherapy database further support the feasibility of TCE use in frail patients aged ≥ 70 years treated with teclistamab (Figure 2). In this multicentre real-world analysis of 81 patients (median age 76, range 70–91), 73% were classified as frail using the simplified/IFM frailty index. The ORR was 66% in frail patients and 50% in fit patients, suggesting that frailty did not preclude clinical benefit. However, toxicity patterns differed between groups. Grade ≥ 2 CRS occurred in 29% of frail patients versus 8% of fit patients, and ICANS (any grade) occurred in 14% of frail patients, including two grade 4 cases. Grade ≥ 3 infections were also more frequent in the frail group (23% vs. 9%). Interestingly, 12-month PFS and OS were similar between frail and fit groups (PFS: 42.4% vs. 47.6%; OS: 61.5% vs. 64.9%). This may reflect a higher disease burden in the fit group, who had received more prior lines of therapy (median: 6 vs. 5) and had a greater proportion of high-risk cytogenetics and refractory disease, potentially offsetting the advantages of physiological fitness [8]. These findings reinforce that teclistamab remains effective in frail older adults, but highlight the need for proactive supportive care to mitigate increased toxicity risks.

Recent data from the safety run-in cohort of the Tec-DR arm (teclistamab + daratumumab + lenalidomide) in the phase 3 MajesTEC-7 trial support the adoption of TCEs as first-line treatment for elderly patients with MM. Among 26 patients (median follow-up 13.8 months), the ORR was 92.3%, with 73.1% achieving a CR or better. CRS occurred in 61.5% (mostly Grade 1), and, notably, 100% experienced infections, with Grade ≥ 3 infections in ~30%. One death from influenza-associated pneumonia occurred in cycle 3 [48]. While its efficacy appears to be highly promising, the infectious risk in this transplant-ineligible population is concerning and emphasises the need for preventive strategies in future frontline use. These real-world outcomes reaffirm both the efficacy and safety profile observed in registrational trials for their respective TCEs and are summarised in Table 4.

Table 4. Summary of real-world outcomes of teclistamab in elderly (≥75 years) and frail MM patients.

Study/Source	Population	ORR		PFS	OS	CRS	ICANS	Grade ≥ 3 Infections
US Academic Centres (≥75 y) [6]	83 patients, all ≥75 years	62%		10.7 months	Not Reached	52%, 1 case Grade ≥ 3	19%, 3 cases Grade 3	Not specified
US Community Oncology Practices [7]	101 patients, median age 66 (range 56–84)	74%		79% at 6 months	Not specified	37% (all Grade 1–2)	11% (majority grade 1–2)	26% (none discontinued)
IMF Real-World Frailty Dataset [8]	81 patients, median age 76 (range 70–91), 73% frail, 27% fit	Frail	66%	42% 12 months	61% 12-mo OS	47% (29% Grade 2)	14% (3 cases ≥ grade 3)	59% (23% ≥ grade 3)
		Fit	50%	48% 12 months	65% 12-mo OS	55% (8% Grade 2)	9% (mostly grade 1)	45% (9% ≥ grade 3)
MajesTEC-7 (Tec-DR Arm) Phase 3 Safety Run-In [48]	26 patients, transplant-ineligible	92%		NR	NR	61.5% (mostly Grade 1)	Not specified	~30% One treatment-related death

ORR: Overall Response Rate, PFS: Progression-Free Survival, OS: Overall Survival, CRS: Cytokine Release Syndrome, ICANS: Immune Effector Cell-Associated Neurotoxicity Syndrome. NR: not reported. Data drawn from multicentre real-world studies across academic and community settings, including frailty-focused analyses. Outcomes reflect varying degrees of patient comorbidity, age distribution, and prior lines of therapy.

Table 4. Summary of real-world outcomes of teclistamab in elderly (≥75 years) and frail MM patients.

Study/Source	Population	ORR		PFS	OS	CRS	ICANS	Grade ≥ 3 Infections
US Academic Centres (≥75 y) [6]	83 patients, all ≥75 years	62%		10.7 months	Not Reached	52%, 1 case Grade ≥ 3	19%, 3 cases Grade 3	Not specified
US Community Oncology Practices [7]	101 patients, median age 66 (range 56–84)	74%		79% at 6 months	Not specified	37% (all Grade 1–2)	11% (majority grade 1–2)	26% (none discontinued)
IMF Real-World Frailty Dataset [8]	81 patients, median age 76 (range 70–91), 73% frail, 27% fit	Frail	66%	42% 12 months	61% 12-mo OS	47% (29% Grade 2)	14% (3 cases ≥ grade 3)	59% (23% ≥ grade 3)
		Fit	50%	48% 12 months	65% 12-mo OS	55% (8% Grade 2)	9% (mostly grade 1)	45% (9% ≥ grade 3)
MajesTEC-7 (Tec-DR Arm) Phase 3 Safety Run-In [48]	26 patients, transplant-ineligible	92%		NR	NR	61.5% (mostly Grade 1)	Not specified	~30% One treatment-related death

ORR: Overall Response Rate, PFS: Progression-Free Survival, OS: Overall Survival, CRS: Cytokine Release Syndrome, ICANS: Immune Effector Cell-Associated Neurotoxicity Syndrome. NR: not reported. Data drawn from multicentre real-world studies across academic and community settings, including frailty-focused analyses. Outcomes reflect varying degrees of patient comorbidity, age distribution, and prior lines of therapy.

6. Comparative Effectiveness of Different Immunotherapies in the Elderly (≥75 Years) MM Population

Real-world data suggest that teclistamab offers a favourable balance between efficacy and tolerability in elderly MM patients, particularly when compared to CAR-T therapy. While CAR-T therapies such as ide-cel and cilta-cel provide the deepest responses (ORR 80–95%), their use in frail and elderly patients is constrained by logistical and clinical challenges, including the need for lymphodepleting chemotherapy, prolonged hospitalisation, and high rates of toxicity. CRS occurs in 80–90% of CAR-T recipients, often with greater severity, and ICANS in 10–15% [49]. In contrast, TCEs such as teclistamab demonstrate comparable efficacy to ide-cel in elderly patients (ORR 60–76%), with milder CRS (30–50%, predominantly grade 1–2) and ICANS in fewer than 5% of cases [6,7,8]. TCEs offer a more manageable safety and logistical profile for patients aged ≥ 75 years.

One of the major challenges in TCE therapy for elderly patients is infection prevention. While any-grade infections are common-reported in up to 60–80% of teclistamab-treated patients, the incidence of clinically significant (Grade ≥ 3) infections varies. In the IMF frailty dataset, 23% of frail patients experienced Grade ≥ 3 infections, compared to 9% in fit patients [8]. These findings underscore the importance of IVIG support, antimicrobial prophylaxis, and proactive infection surveillance in older patients receiving TCEs. As further real-world data emerge, personalised treatment strategies will be critical for improving both survival outcomes and quality of life in the oldest and most vulnerable MM populations.

7. Optimising Treatment Outcomes: Managing Safety and Toxicity in Elderly MM Patients

While standard regimens, such as those studied in MAIA, IMROZ, CEPHEUS, and BENEFIT, have demonstrated efficacy in elderly transplant-ineligible patients, they are associated with significant neuropathy, fatigue, myelosuppression, and gastrointestinal symptoms, particularly in patients ≥ 75 years [35,36,50,51]. TCEs offer an alternative immune-modulatory approach; nonetheless, infectious risk remains a major challenge particularly in older adults. This risk is especially prominent with BCMA-targeting agents, which deplete plasma cells and significantly impair humoral immunity.

Recent expert consensus guidelines recommend a multifaceted prophylactic approach to reduce infection-related morbidity [52,53]. Vaccination against pneumococcus, influenza, and SARS-CoV-2 are endorsed, ideally prior to starting therapy, where feasible. Antiviral prophylaxis—typically with acyclovir or valacyclovir—is advised for all patients to prevent herpesvirus reactivation. Antifungal prophylaxis may be appropriate for select high-risk patients based on treatment history and institutional protocols. For patients with documented hypogammaglobulinemia and recurrent infections, IVIG replacement is advised to restore humoral immunity. Routine monitoring of immunoglobulin levels, particularly IgG, should be implemented during treatment. Granulocyte colony-stimulating factor (G-CSF) may be considered in patients with prolonged neutropenia to reduce infectious complications. Prompt recognition and empiric antimicrobial treatment at the first signs of infection are also emphasised as critical components of care. In the IMF frailty dataset, Grade ≥ 3 infections occurred in 23% of frail patients compared to 9% in fit patients [8], reinforcing the importance of proactive infection prevention measures tailored to vulnerable subgroups. These strategies are particularly crucial in the elderly population, where infection-related morbidity may compromise both quality of life and treatment continuity.

Given the high attrition rates seen in elderly patients across treatment lines, it is essential to prioritise effective yet tolerable therapies earlier in the disease course. While mature data are awaited, several clinical trials evaluating TCEs in the newly diagnosed setting for transplant ineligible patients are underway [48,54]. These trials aim to evaluate the safety and preliminary efficacy of BCMA-directed TCEs in combination with lenalidomide and/or daratumumab. Early response data are promising [55,56]; however, infectious complications are prevalent, and further follow-up is required. For patients who relapse or progress despite upfront BCMA-directed TCE’s, the ideal next line of therapy may only be speculated. One consideration is that patients previously exposed to BCMA-directed therapy response sub optimally to BCMA-directed CAR-T [57], possibly compromising this approach. There is no precedence to predict their likely response to PI’s or IMID’s, but, given their distinct mechanisms of action, cross-therapy resistance seems unlikely.

Dose optimisation is a critical advancement in the treatment of relapsed/refractory MM, particularly for elderly patients. Adjusting dosing schedules for TCEs has shown the potential to maintain efficacy while reducing toxicity and logistical challenges. Levoseltamab patients who achieve a VGPR or better have been able to switch from weekly to monthly dosing after 24 weeks, without compromising PFS. Moreover, dose reduction reduced infection rates [40]. Taelquetamab has been evaluated at both weekly and biweekly doses (0.4 mg/kg and 0.8 mg/kg SC, respectively), with ORRs of 74.1% and 71.7%, indicating that reduced-frequency dosing preserved efficacy while easing the treatment burden [36]. However, off-target side effects of dysgeusia and weight loss were significant at both dose schedules, and the ways in which dose reduction can mitigate these side effects is being investigated. In MajesTEC-1 trial, patients who achieved a CR or better for ≥6 months were permitted to reduce teclistameb frequency from weekly to biweekly. At a median follow-up of 11.1 months post-switch, median duration of response among biweekly patients was 20.5 months, with two-thirds of patients remaining in response [58]. These real-world and trial-based strategies have improved adherence, minimised toxicity, and supported continued treatment in older and frail patients. Response-adapted dosing regimens represent a promising direction for improving the safety and tolerability of TCEs in elderly patients.

Response-adapted dosing regimens represent a promising direction for improving the safety and tolerability of TCEs in elderly patients. Equally important is the proactive management of side effects such as dysgeusia and weight loss, which are particularly prominent with GPRC5D-targeting agents. While supportive care guidelines specific to TCE-induced side effects are currently lacking, borrowing from other therapies, practical measures—including flavour enhancement, oral hygiene, and zinc supplementation—have shown benefit in cancer-related taste alterations [59,60]. Similarly, early dietetic intervention and nutritional supplementation are supported across oncology populations as strategies to preserve function and treatment adherence [61].

8. New Horizons: Novel Constructs and Combination Strategies

TCEs are rapidly advancing, with novel constructs and combination therapies transforming the therapeutic landscape for MM. Despite their promise, resistance mechanisms, as illustrated in Figure 3, can impede their efficacy. Tumour-intrinsic factors such as antigen loss via downregulation or increased shedding (e.g., sBMCA release) reduce target antigen density for BsAb engagement, often driven by genetic or epigenetic changes. Tumour-extrinsic factors, including T-cell exhaustion mediated by PD-1/PD-L1 interactions and immunosuppressive cytokines (e.g., IL-10, TGF-β) secreted by regulatory T-cells (Tregs), further diminish BsAb effectiveness. Additionally, interactions between myeloma cells and the bone marrow microenvironment—supported by adhesion molecules and stromal cells—promote tumour resistance and survival [62].

To address these challenges, several strategies are under investigation. Dual-targeting TCEs, which bind multiple antigens (e.g., GPRC5D and FcRH5), can reduce antigen escape and improve treatment durability. Sequential antigen targeting, where TCEs directed at different targets are used in sequence, addresses tumour heterogeneity and prevents resistance due to single-antigen loss. Administering TCEs earlier in the disease course when immune systems are more robust could enhance responses. Incorporating γ-secretase inhibitors to prevent sBCMA shedding to increase antigen density on myeloma cells and augment BsAb efficacy, especially in patients with high disease burden [62].

Research into antigens beyond BCMA, including GPRC5D and FcRH5, is important for the growing population of BCMA-exposed individuals who respond sub-optimally to subsequent BCMA-directed agents [57,63]. Talquetamab, a GPRC5D-targeting BsAb, has shown an ORR of 73% in patients with relapsed/refractory MM previously treated with anti-BCMA therapies [28]. Cevostamab, which targets FcRH5, had a 44% ORR at the 160 mg dose level in a dose-expansion cohort of heavily pretreated patients, including 58% with prior BCMA-targeted therapy and 24% with prior TCE exposure [44]. Trispecific antibodies that simultaneously target BCMA, CD3, and another antigen (e.g., GPRC5D or CD38) are an innovative solution to enhance T-cell activation and tumour recognition while mitigating antigen escape.

Combination therapies are a promising strategy to overcome resistance. TCEs used alongside immune checkpoint inhibitors (e.g., PD-1/PD-L1 blockers) can reverse T-cell exhaustion and restore function. Agents like IMiDs and cereblon E3 ligase modulator (CELMoDs) augment T-cell activity, enhancing BsAb-mediated cytotoxicity. Additionally, therapies targeting the bone marrow microenvironment, such as anti-CD38 antibodies like daratumumab, disrupt protective interactions between myeloma cells and stromal support, providing a multifaceted approach to sustaining anti-tumour activity [62].

The true potential for TCEs lies in their readiness to pair with existing MM therapies to augment responses. Trials such as TRIMM-2 [32] have demonstrated robust responses from dual-antigen-targeting combinations, like teclistamab with daratumumab (Tec/Dara), even in heavily pretreated populations. This combination demonstrated promising efficacy, with ORRs ranging from 70% to 100% across different dose cohorts. Notably, responses were rapid, with a median time to first confirmed response of approximately 1 month [64]. Similarly, the MajesTEC-7 trial evaluated teclistamab combined with daratumumab and lenalidomide (Tec-DR) in newly diagnosed transplant-ineligible MM patients. This regimen improves PFS and achieves high rates of minimal residual disease (MRD) negative complete responses, with an ORR of 92.3% and 80.8% of patients achieving a CR or better especially in patients unable to tolerate stem cell transplantation [49]. The MonumenTAL-2 trial, combining talquetamab with pomalidomide in 35 heavily pretreated MM patients, demonstrated ORRs exceeding 80% [65], underscoring the synergy between BsAbs and immunomodulatory drugs.

These combination approaches are particularly promising for elderly patients, offering enhanced efficacy with manageable toxicity. They represent a new frontier in MM treatment, leveraging dual antigen targeting, immune modulation, and bone marrow microenvironment disruption to sustain anti-tumour activity and improve outcomes.

9. Overcoming Ageism and Expanding Access to TCE Therapies

Ageism is pervasive in MM treatment; elderly patients are often excluded from clinical trials, confounding the adoption of these therapies in real-world practice. The emerging evidence shown above supports for the efficacy and tolerability of TCEs in patients aged 75 years and older, challenging the notion that age should limit access drug access.

There is growing recognition of the need to design clinical trials tailored to elderly fit and elderly frail populations [66]. Past trials categorised all patients > 70 years into a single transplant-ineligible category, obscuring the significant heterogeneity which exists among older individuals. Trials tailored to patients’ frailty would provide clinicians with greater certainty on the optimal way to manage this vulnerable patient group, rather than having to extrapolate on a best-guess basis, enabling more personalised and effective care.

Democratising patient care requires fostering a healthcare environment where advanced treatments are accessible to all patients, regardless of age. Expanding trial eligibility criteria to include older and frail patients ensures equitable access to cutting-edge therapies. In clinical practice, integrating comprehensive geriatric assessments facilitates treatment strategies tailored to older patients’ physiological and functional needs, moving away from reliance on chronological age alone [2]. Educating healthcare providers on the unique needs of older adults is vital to dismantling misconceptions about the tolerability and efficacy of advanced therapies in this population.

Inclusive policies reflecting evidence of TCEs safety and efficacy in older patients are critical to overcoming age-related disparities. Such changes address inequities, empower older patients in treatment decisions, and create equitable patient-cantered care frameworks that optimise outcomes for elderly patients [67]. These efforts highlight the transformative potential of TCEs in addressing historically unmet needs in this vulnerable population while reinforcing the ethical imperative of delivering high-quality care to all patients.

10. Conclusions

TCEs have been transformative in the treatment of MM, offering high response rates and manageable toxicity profiles. For elderly and frail patients, TCEs provide an attractive alternative to conventional therapies and cellular immunotherapies, addressing the unique challenges of this population. Real-world data confirm that TCEs are as effective in frail elderly patients, with manageable toxicity when appropriate supportive care measures are implemented. While CAR-T therapy remains an option for select fit elderly patients, its logistical barriers and toxicity profile often make TCEs the preferred next-line therapy, especially for patients aged 75 and older. Looking ahead, future research should prioritise optimising treatment schedules to reduce infectious risk while maintaining efficacy and further individualising TCE therapy based on frailty assessments rather than chronological age alone.

Additional areas of investigation include the use of time-limited or response-adapted approaches, such as discontinuing therapy upon achieving MRD negativity, to reduce cumulative toxicity and enhance patient quality of life. Identifying optimal partner agents-including IMiDs, PIs, and next-generation CELMoDs to further enhance response depth and durability. There is also growing interest in novel dosing strategies, such as alternating CELMoDs with TCEs, which could help preserve T-cell fitness and mitigate immune exhaustion associated with continuous TCE exposure.

In parallel, defining optimal sequencing strategies following frontline TCE use will be critical, particularly as these agents move earlier in the treatment paradigm. Finally, developing tailored strategies for the management of ultra-high-risk patients or those refractory to TCEs remains an urgent unmet need and may require combination approaches or integration of emerging modalities such as antibody–drug conjugates or allogeneic cellular therapies. This personalised and adaptive approach will allow for TCEs to be utilised more effectively, ensuring better patient outcomes and improved quality of life for elderly patients with MM worldwide.