Bispecific Antibodies in Hematologic Malignancies: Attacking the Frontline

Abstract

Since blinatumomab’s approval as the first bispecific antibody (BsAb) in cancer therapy, these immunomodulatory agents have achieved substantial success in lymphoid malignancies. A decade after provisional approval in relapsed settings, blinatumomab became part of first-line induction therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL). Now, six additional BsAbs have FDA approvals for the treatment of B-cell non-Hodgkin’s lymphomas and multiple myeloma (MM), achieving high response rates in otherwise refractory scenarios. In lymphoma, epcoritamab, glofitamab, and mosunetuzumab show proof-of-principle for complete remission (CR) without chemotherapy or cell-based treatment. Single-agent remissions do not appear durable, but fortunately, these immunotherapies are readily combined with other treatment modalities. Therefore, their true potential to contribute to cures may be close on the horizon owing to ongoing and future trials. In MM, teclistamab, talquetamab, and elranatamab achieve impressive CR rates in the relapsed setting and similarly, are being investigated in earlier line combinations and in precursor entities such as smoldering myeloma and monoclonal gammopathy of undetermined significance (MGUS). With a unique mechanism of action and continued testing in earlier lines, BsAbs are poised to be among the winners in the race to the frontline treatment of hematologic malignancies.

Key Points

B-cell lymphomas and MM have seen regulatory approvals of multiple bispecific antibodies in recent years fueled by their clear ability to drive complete responses in many patients without chemotherapy

Single-agent responses generally are not permanent, but the ease of combining these therapies with other treatment modalities means bispecifics are increasingly moving into frontline treatment combinations aimed at curative outcomes through synergy with established treatments

Introduction

In 2014, blinatumomab became the first bispecific antibody (BsAb) to achieve regulatory approval. Initial accelerated approval for patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) went on to full approval in 2017 on the basis of the phase 3 TOWER study, which showed an improvement in median survival compared with standard chemotherapy [1, 2]. Blinatumomab is derived from an antitumor mouse monoclonal antibody targeting human CD19 and another engaging human CD3 eplison chain in the T-cell receptor (TCR) complex, fusing their single-chain variable fragments (scFvs) with a short peptide linker as a 55 kDA protein [3]. This design that excludes all other natural antibody components was given the tradename bispecific T-cell engager (BiTE) [4]. CD19 is a highly specific and yet ubiquitous marker of B-cell lineage cells, making it an ideal target for drugs against B-cell leukemia and lymphoma [4]. By forming a synapse between CD3⁺ T cells and CD19⁺ target cells, expression of cell adhesion molecules, cytolytic proteins, and inflammatory cytokines is enhanced, leading to the lysis of the CD19⁺ B cells by activated T cells [5].

Blinatumomab indications have expanded since approval in patients who are minimal residual disease (MRD)-positive after initial induction [6], and is currently under investigation as part of first-line induction in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) [7] and consolidation in MRD-negative disease [8]. Most recently, blinatumomab, added to induction chemotherapy, achieved significantly improved disease-free survival compared with chemotherapy alone in children with standard-risk ALL, prompting early termination of the study and marking a major breakthrough in the treatment of pediatric B-cell ALL as well as the first published use of BsAbs as part of frontline curative combination therapy [9].

While approval of this first-in-class BsAb drug was an exciting step forward for the treatment of R/R ALL, it also introduced the unique side effect profile associated with BsAbs. Specifically, clinically challenging cytokine-release syndrome (CRS) and what’s now called immune effector cell-associated neurotoxicity syndrome (ICANS) are frequent, complicated by the pharmacokinetics of blinatumomab’s BiTE design requiring long-term continuous infusion. This molecular format and functional characteristics of the binding arms (such as the binding affinity) are significant determinants of biodistribution, degree of T-cell activation or exhaustion, and toxicities [10, 11]. In the TOWER study, neutropenia (38% versus 58% of patients affected) and infections (34% versus 52%) were lower with blinatumomab, but all-grade CRS (5% versus 0%) was more frequent with blinatumomab. It was noted that CRS typically occurred in cycle 1 owing to early release from lymphocytes, but this could be mitigated by dexamethasone pretreatment [12]. Neurologic events occurred at similar rates in the TOWER study arms (9.4% versus 8.3% for blinatumomab and chemotherapy, respectively), but a unique set of potentially severe symptoms came to be associated with blinatumomab, ranging from mild confusion and somnolence to fatal seizures and cerebral edema. These side effects informed the development of subsequent BsAbs and novel anti-CD3 binding domains with more favorable properties [13].

While CD19 is expressed across B-cell malignancies, blinatumomab did not achieve similar success in B-cell lymphomas, showing a modest CR rate of 19% in R/R diffuse large B-cell lymphoma (DLBCL) [14]. Subsequent developments, including approval of CD19-directed chimeric antigen receptor (CAR) T cells, demonstrated that blinatumomab’s shortcomings for lymphoma were not due to the choice of target. The antibody-drug conjugate loncastuximab tesirine-lypyl (loncastuximab), for example, delivers its cytotoxic alkylating payload (SG3199) by way of a CD19 monoclonal antibody and is now approved for treatment of DLBCL [15] and a new option for R/R follicular lymphoma (FL) [16]. The clinical proof-of-principle that blinatumomab established, however, was instrumental in driving the development of the next-generation of bispefics now available for use. We will review the history of these developments (Fig. 1) in both the B-cell lymphomas and MM and look ahead at the potential for these therapies to join frontline combination regimens.

Fig. 1.

Historical timeline of bispecific antibody regulatory approvals

BsAb Antibody Formats and Implications

The BiTE formulation uses variable domains of two distinct monoclonal antibodies, one of which in nearly all BiTEs developed to date is a single-chain variable fragment (scFv) against CD3 to engage and activate T cells. The second, mediating tumor-cell engagement, is unique to each construct (e.g., CD19 recognition by blinatumomab). By excluding the invariant portions of heavy and light chain specificity arms, along with the entire Fc (fragment crystallizable) tail domain, the BiTE design creates a low molecular weight protein. In practice, however, this proved to be a major limitation owing to a requirement for continuous intravenous (IV) infusions to reach therapeutic dosing levels [17, 18]. Essentially, all the newer bispecifics instead are full length immunoglobulin G (IgG)-based monomers or multimers, some of which employ 2:1 tumor antigen:CD3 formats to enhance avidity and tumor cell binding (Fig. 2). Retention of Fc domains in particular provides improved pharmacologic properties, including sustained circulation half-life and additional effector functions such as antibody-dependent cellular cytotoxicity and completement mediated lysis [19, 20]. Another key difference is the high potency of BiTEs in redirecting T cells to kill tumor-associated antigen (TAA)-expressing cells. This higher CD3 affinity was aimed at promoting stronger efficacy of BiTEs, but contributed to T-cell activation-related toxicities such as CRS and ICANS [21].

Fig. 2.

Targets and bispecific antibody structures in B cell lymphomas and multiple myeloma

Bispecific Antibodies in R/R Lymphoma

Second-generation BsAbs continue to use CD3 to bind and activate T cells. For lymphoma, however, CD20 has become the antigen of choice to target the malignant cells. A variety of factors prompted this change, including concerns about CD19 antigen loss in patients exposed to CD19-directed CAR-T cells and loncastuximab. Three CD20 × CD3 full length IgG-based bispecifics—epcoritamab, glofitamab, and mosunetuzuamb—now have regulatory approvals in the USA and Europe, with more at various stages of development. Epcoritamab is a subcutaneous CD20 × CD3 BsAb with a 1:1 valency and heterodimeric IgG format (Table 1). It is approved to treat adult patients with R/R DLBCL, including cases transformed from indolent lymphomas, as well as high-grade B-cell lymphoma following two or more lines of systemic therapy (LOT) [22]. In addition, in June 2024, the FDA granted epcoritamab accelerated approval for use in R/R FL after two LOT. Approval for large B cell lymphoma (LBCL) was granted on the basis of the phase 1/2 EPCORE NHL-1 study achieving an objective response rate (ORR) of 49% including 41% CRs [22, 23], with a progression-free survival (PFS) of 27.8% at 24 months [24]. In a follow up report presented at the 2024 American Society of Hematology Annual Meeting (ASH 2024), median PFS was a modest 4.2 months (95 CI 2.8–5.5) [25]. These results, among others, suggest single agent BsAbs in large cell lymphoma will not be curative, in contrast to long-term data for chimeric antigen receptor (CAR)-T cells [26–28]. Epcoritamab is under investigation in combinations across multiple indications. When added to induction chemotherapy prior to autologous stem cell transplant (ASCT) in patients with R/R DLBCL, 55% proceeded to ASCT and 7% remained on the drug, with an ORR of 76% and CRs in 69%. Another subgroup of patients’ ineligible for or previously failed by ASCT received epcoritamab plus gemcitabine and oxaliplatin (GemOx) and experienced an ORR of 78% including 55% CRs. Within this subgroup, the median time to CR was 1.7 months and the median duration was 13.3 months [29, 30]. This suggested additive potential for incorporation of BsAbs in earlier LOT. R/R - relapsed or refractory; ALL - acute lymphoblastic leukemia; BiTE - bispecific T-cell engager; CRS - cytokine release syndrome; (D)LBCL - (diffuse) large B-cell lymphoma; LOT - lines of therapy; FL - follicular lymphoma; CR - complete response; MM - multiple myeloma; CAR - chimeric antigen receptor; ORR - overall response rate; BCMA - B-cell maturation antigen; ICANS - immune effector cell-associated neurotoxicity syndrome; REMS - Risk Evaluation and Mitigation Strategy; SCC - squamous cell carcinoma; CD - cluster of differentiation; GPRC5D - G protein-coupled receptor, class C, group 5, member D; DOR - duration of response; PFS - progression free survival; Q(2)W - every (two) week(s); C#D# - cycle# day#.

Table 1.

Properties and key clinical trials for lymphoma and multiple myeloma (MM)-targeting bispecific antibodies (BsAbs) discussed in the main body

BsAbs	Stage	Hematologic malignancy	Structure details	Valency	Target	Results of study leading to approval	Population	Schedule and logistics	Frequency of grade ≥ 3 AEs	Key limitations
Blinatumomab	Approved	R/R B-cell ALL	BiTE	1:1	CD19 (tumor antigen) × CD3 (T cell)	TOWER trial: Median survival improved from 4 to 7.7 months compared with standard chemotherapy. CR 34% blinatumomab, 16% SOC [2]	Adults and children	IV 9 µg/m2/day day 1–7. 28 µg/m2/day day 8–28. 6-week treatment cycles	Neutropenia 37.8%, infection 34.1%, elevated liver enzymes 12.7%, neurologic event 9.4%, CRS 4.9%, infusion reaction 3.4%, and lymphopenia 1.5%	Short half-life requiring continuous IV infusion, higher incidence of CRS
Epcoritamab	Approved	R/R DLBCL following 2+ LOT	IgG1	1:1	CD20 (tumor antigen) × CD3 (T cell)	EPCORE NHL-1 trial: 2.5-year extended follow-up w/ ORR 63%, CR 40% [29]	Adults	Cycle 1 day 1–8: 0.16, step-up dose 2 0.8 mg, cycle 1 day 15–22: 48 mg. cycle 2/3 day 1, 6, 15, 22: 48 mg. Cycles 4–9 day 1-15: 48 mg. cycle 10+ day 1: 48 mg. 28-day cycles.	CRS 49.7%, injection site reaction 19.7%, and neutropenia 17.8% with most AEs occurring in the first 12 weeks (cycle 1–3)	Indefinite dosing until disease progression or excessive toxicity
Glofitamab	Approved	R/R DLBCL or LBCL from FL after 2+ LOT	IgG1	2:1	CD20 (bivalent tumor antigen) × CD3 (T cell)	Median follow-up of 12.6 months, CR 39%, ORR 52% [31]	Adults	Pretreat: 1000 mg obinutuzumab IV 1-day prior. C1D1: obinutuzumab 1000 mg. C1D8: 2.5 mg. C1D15: step-up dose 2 of 10 mg. Cycle 2–12 day 1: 30 mg. 28-day cycles.	Neutropenia 27%, anemia 6%, thrombocytopenia 8%. CRS 63% associated with first three doses. High grade CRS 3%	Administered IV, higher risk of CRS during first cycle, requires obinutuzumab
Mosunetuzumab	Approved	R/R FL after 2+ LOT	IgG1	1:1	CD20 (monovalent tumor antigen) × CD3 (T-cell)	60% CR [37]	Adults	IV: C1D1: 1 mg, C1D8: 2 mg, C1D15: 60 mg, C2D1: 60 mg, Cycle 3+ day 1: 30 mg	CRS 44%, neutropenia 27%, hypophosphatemia 17%, hyperglycemia 8%, and anemia 8%	IV administration, may be less effective in patients with T-cell exhaustion or heavy prior therapies, high risk of CRS
Odronextamab	Not yet approved	N/A	IgG4	1:1	CD20 (tumor antigen) × CD3 (T-cell)	ELM-1 trial: ORR 91%, CR 72%. In DLBCL, 53% objective response in CAR T-naive, 33% in CAR T-treated patients. ELM-2 Trial: median follow-up of 26.2 months, ORR 52%, CR 31% [45]	Adults	C1: step-up doses of 0.7/4/20 mg. C2-4 day 1, 8, and 15: 160 mg. Maintenance treatment every 2 weeks: 320 mg every 2 weeks	Grade 3+ anemia 25%, lymphopenia 19%, and neutropenia 19%. Serious CRS 28%	Not fully approved in the US, lower response rates in CAR-T treated patients, indefinite dosing until disease progression or excessive toxicity
Teclistamab	Approved	R/R MM after 4+ prior LOT	IgG4	1:1	BCMA (B-cell maturation antigen, tumor antigen) × CD3 (T-cell)	MajesTEC-1 trial: Median follow-up 7.4 months, DOR 66.5% at 9 months [125]	Adults	C1: 0.06 mg/kg subq on day 1, 0.3 mg/kg on day 4, and 1.5 mg/kg on Day 7, followed by 1.5 mg/kg 1× weekly	CRS 72%, neurologic toxicity 57%, ICANS 6%, Grade 3 CRS 0.6%, Grade 3 or 4 neurologic toxicity 2.4%	Due to high risk of CRS and ICANS only available through REMS program, high risk of infections including opportunistic infections
Elranatamab	Approved	R/R MM after 4+ LOT	IgG2	1:1	BCMA (tumor antigen) × CD3 (T-cell)	MagnetisMM-3 trial: Median follow up 28.4 months, ORR 61%, CR 37.4%, and PFS 17.2 months [126]	Adults	C1D1: Step up dose 12 mg. C1D4: Step up dose 32 mg. C1D8: 1st txt dose 76 mg. Starting 1 week after 1st txt dose until week 25: 76 mg weekly	Grade 3/4 infections 42.3%, neutropenia grade 3/4 49.6%, anemia 37.4%, thrombocytopenia 23.6%, and lymphopenia 25.2%	Risk of secondary primary malignancies such as SCC, indefinite weekly or biweekly dosing until disease progression or excessive toxicity, only available through REMS
Talquetamab	Approved	R/R MM with 4+ LOT	IgG4	1:1	GPRC5D (tumor antigen) × CD3 (T-cell)	MonumenTAL-1 trial: Median follow-up 20-30 months, ORRs 67-74% across cohorts. DOR and PFS suggesting better durability in Q2W vs QW dosing [127]	Adults	C1D1: step-up dose 0.01 mg/kg. C1D4: Step-up dose 0.06 mg/kg. C1D7: First txt dose 0.4 mg/kg. Starting 1 week after 1st txt dose: 0.4 mg/kg once weekly	Most common grade 3/4 AE were hematologic. Infection rates grade 3/4 20.1%-25.5%. Any grade-taste-related AE 71.4%-75.6%, nail-related AE 53.2%-59%, and rash-related AE 29.9-39.9%.	Adverse effect to keratinized tissues such as skin and nails, indefinite dosing until disease progression or excessive toxicity, only available through REMS
Linvoseltamab	Not yet approved	N/A	IgG4	1:1	BCMA (tumor antigen) × CD3 (T-cell)	LINKER-MM1 trial: Median follow-up of 11.1 months, ORR 71%, CR 46%. 12-month response durability 78%, and for those achieving CR or better 92% [128]	Adults	Two Phase 2 full dose cohorts (50 mg and 200 mg) have been studied. A protocol amendment permitted pts progressing at 4–12 weeks on 50 mg to dose escalate to 200 mg	Grade 3/4 neutropenia 40%, grade 3/4 anemia 31%, grade 3/4 infection 34%	High risk of infection, limited clinical data and experience due to not being approved, indefinite dosing until disease progression or excessive toxicity

R/R relapsed or refractory; ALL acute lymphoblastic leukemia; BiTE bispecific T-cell engager; CRS cytokine release syndrome; (D)LBCL (diffuse) large B-cell lymphoma; LOT lines of therapy; FL follicular lymphoma; CR complete response; MM multiple myeloma; CAR chimeric antigen receptor; ORR overall response rate; BCMA B-cell maturation antigen; ICANS - immune effector cell-associated neurotoxicity syndrome; REMS Risk Evaluation and Mitigation Strategy; SCC squamous cell carcinoma; CD cluster of differentiation; GPRC5D G protein-coupled receptor, class C, group 5, member D; DOR duration of response; PFS progression free survival; Q(2)W every (two) week(s); C#D# cycle# day

Development of glofitamab occurred in parallel with epcoritamab. It received accelerated approval from the FDA in June 2023 for adults with R/R DLBCL or transformed follicular lymphoma (tFL) after two or more LOT. Approval was granted on the basis of a phase 2/3 trial with 155 patients, 33% of whom had received prior CD19 CAR-T cells. During this trial, patients received obinutuzumab pretreatment followed by glofitamab for 12 cycles as a predefined fixed-duration schedule. The primary end point, CR, was achieved by 39%, while the ORR was 52% at a median follow-up of 12.6 months, and PFS was 46% at 6 months. The most common adverse event was CRS (63%), but grade 3+ occurred in only 4% [31]. A 3-year extended follow up found the median duration of CR to be 29.8 months and PFS was 57% at 2 years for patients in CR at the end of treatment, showing encouraging durability in patients achieving CR but with ongoing relapses not yet supportive of curative outcomes [32]. More recently, the STARGLO study led to the National Comprehensive Cancer Network (NCCN) incorporating the combination of glofitamab with GemOx as a category 1 for relapsed patients with no intention to proceed to transplant [33]. Intriguingly, the ODAC committee in May of 2025 voted against approval of this regimen, citing concerns on applicability in the USA population, with demonstrated benefits restricted to southeast Asian cohorts [34].

While glofitamab and epcoritamab are both full-length CD20 × CD3 BsAbs, some distinct differences exist. Glofitamab is administered IV while epcoritamab is given subcutaneously. Both glofitamab and epcoritamab undergo step-up dosing to mitigate CRS risk. Glofitamab is administered at 2.5 mg IV on cycle 1 day 8, 10 mg IV on cycle 1 day 15, and 30 mg IV on cycle 2 day 1 and onward with fixed 12 cycles in total despite response (8–9 months) [31]. Epcoritamab is administered at 0.16 mg subcutaneously on cycle 1 day 1, 0.8 mg on cycle 1 day 8, 48 mg on cycle 1 day 15, and 48 mg onwards from cycle 2. It is administered weekly for cycles 1–3, biweekly in cycles 4–9, and then monthly indefinitely until disease progression or excessive toxicity [22]. Therefore, epcoritamab permits subcutaneous administration but with no predefined treatment end point, while glofitamab’s IV dosing is on a fixed-duration schedule of 12 cycles.

Both treatments require similar premedications, but a key difference is the administration of obinutuzumab, a CD20 monoclonal antibody prior to the first cycle of glofitamab to reduce the risk of CRS. In addition, 24-hour hospitalization is mandatory after the first step-up dose of glofitamab given on day 8 of the first cycle, and this is recommended for subsequent doses if CRS has occurred. This is based on the high incidence of CRS occurring during cycle 1 in the early-phase studies of glofitamab, a problem that was less severe for epcoritamab [31]. An ASH 2024 presentation of retrospective data across multiple LBCL trials suggested longer duration of CR associated with potential overall survival (OS) benefit for epcoritamab compared with glofitamab [35]. For now, though, clinical decision-making to choose between these molecules remains uninformed by peer-reviewed data or any direct comparison in a trial designed to answer this question.

Mosunetuzumab is approved for R/R FL after two or more prior therapies but not for LBCL [36]. FL is an indolent, incurable lymphoma characterized by multiple relapses with shorter duration of response with subsequent treatments. Thus, mosunetuzumab brings T cell-engaging therapy into the challenging landscape of R/R FL. In a phase 2 multicenter single-arm trial with a median follow-up of 37.4 months, fixed-duration mosunetuzumab showed a 60% CR rate, which the investigators compared favorably to a historical CR rate of 14% for copanlisib, a PI3K inhibitor that was subsequently withdrawn from the market (p < 0.0001) [37]. Notably, 21% of patients had prior ASCT and about half had progression of disease within 24 months (POD24), a known high-risk group in FL. CRS was the most common adverse event with mosunetuzumab, affecting 44% of patients and mostly during cycle 1. Only 2% of patients experienced grade 3+ CRS [38].

Owing to the fixed duration dosing of 21-day cycles, favorable safety profile, and potential administration as an outpatient regimen, mosunetuzumab was FDA approved in December 2022. The compound is administered for a total of 8 cycles if patients achieve CR and a maximum of 17 cycles if response is deemed to be partial or stable after the first 8 cycles [39]. Unlike glofitamab, mosunetuzumab does not require obinutuzumab or other CD20 antibody premedication and undergoes slow IV titration to full dose during cycle 1 (similar to epcoritamab). However, it is approved for IV administration, similar to glofitamab, though fixed-duration subcutaneous administration has been studied, leading to promising rates of deep and durable responses [36]. Mosunetuzumab was also tested in a phase 1/2 study for patients with R/R mantle cell lymphoma (MCL), with the first reported efficacy and safety data revealing a best ORR of 44% and CR rate of 24% [40].

While studies related to predictive biomarkers are still ongoing in relation to BsAbs, the utilization of a virtual population of digital twins with a mechanistic quantitative systems pharmacology model has been used to determine features that may differentiate clinical responders from nonresponders receiving mosunetuzumab. In a population of non-Hodgkin’s lymphoma patients receiving mosuntuzumab, responder patients within the medium and high dose mosuntuzumab simulations were found to have a greater expansion of T cells, likely owing to T-cell activation and proliferation in the presence of target B cells. In addition, the estimated maximum effect of B-cell killing rate and T-cell activation rate were higher in responders, proposing a skew of the B:T-cell ratio to lower values in responders owing to a greater T-cell infiltration at baseline [41].

While epcoritamab, glofitamab, and mosunetuzumab are approved in both the USA and Europe, odronextamab is currently approved only in Europe. Another CD20 × CD3 BsAb is in the later stages of development, and is under investigation in the ongoing Olympia trials. The FDA recently announced the review of the Biologics License Application (BLA) resubmission of odronextamab after the drug achieved an FDA-mandated enrollment target plus positive results from the ELM-1 and ELM-2 trials [42, 43]. In Europe, odronextamab was approved in August 2024 for adults with R/R FL and DLBCL owing to the ELM trials showing strong response rates [44, 45]. ELM-1 was a single-arm, phase 1 trial in adults with CD20-positive R/R B-cell malignancies previously treated with CD20-directed antibodies, revealing a manageable safety profile and promising activity, including durable responses in heavily pretreated patients. Adverse events seen with odronextamab usage include grade 3 anemia (25%), lymphopenia (19%), and neutropenia (19%), while 28% of patients experienced low grade CRS and 61% experienced serious events. In FL, the drug’s ORR was 91%, with a 72% CR. However, odronextamab in DLBCL was found to have varying response rates on the basis of prior CAR T-cell therapy exposure, with 53% ORR in CAR T-naive and 33% in CAR T-treated patients [45]. ELM-2 demonstrated long-term efficacy and safety of odronextamab in R/R DLBCL. After a median follow-up of 26.2 months, ORR was 52%, CR rate 31%, consistent across high-risk groups, median duration of response of 10.2 months, and a probability of maintaining CR for 24 months of 48%. Overall, this study showed encouraging clinical activity of odronextamab with continued treatment. Therefore, odronextamab is an important potential option for future management of R/R DLBCL and will continue to be investigated in phase 3 trials [46].

Future Directions of BsAbs in Lymphoma

In the rapidly advancing field of cancer immunotherapy, the ability of BsAbs to engage multiple targets provides a powerful weapon against treatment resistance in hematologic malignancies. Combining these therapies with other targeted and chemotherapeutic agents aims to exploit synergistic effects, enhancing both immune activation and tumor eradication, while reducing the likelihood of treatment failure. Blinatumomab is under assessment as part of a chemotherapy-free regimen as first-line therapy combined with the tyrosine kinase inhibitors (TKI) ponatinib in patients with Ph-positive acute lymphoblastic leukemia (ALL). Early results showed the combination achieved a CR/CRi in 98% of patients with complete molecular remission (CMR) of 84%, with 91% negative for MRD [47]. Similarly, CD20 × CD3 BsAbs are increasingly being studied for inclusion in first-line combinations for lymphoma (Table 2). In DLBCL, at least a third of patients do not adequately respond to first-line treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [48, 49]. The phase 3 EPCORE DLBCL-2 study (NCT05578976) is assessing the addition of epcoritamab to R-CHOP in adults with newly diagnosed CD20⁺ DLBCL, either de novo or tFL, and high-risk international prognostic index (IPI) score. The primary end point is PFS [50]. Initial peer-reviewed data from the trial revealed ORR of 100% and complete metabolic response (CMR) of 77% among efficacy-evaluable patients [51]. EPCORE DLBCL-3 is also evaluating fixed-duration epcoritamab monotherapy or epcoritamab and lenalidomide in anthracycline-ineligible patients with large B cell lymphoma as first line therapy, with early results showing an ORR of 78% and CR of 70% in the epcoritamab monotherapy arm [52]. Epcoritamab was also combined with bendamustine and rituximab as first-line treatment for FL showing an ORR of 96% at a median follow-up of 30.4 months [53]. In addition, one study found debulking with rituximab before initiation of full dose epcoritamab in patients with bulky FL showed a best ORR of 100% and CMRs by positron emission tomography (PET) in 92%, along with a potential lowering of grade 2+ CRS [54].

Table 2.

Ongoing clinical trials evaluating the respective BsAbs as first-line treatment

BsAbs	Ongoing clinical trials evaluating the drug as first-line treatment	Hematologic malignancy drug under first-line evaluation	Phase of study and study plan	Available results
Blinatumomab	NCT05557110	ALL	Completed, phase 2 study; Reduced-intensity chemotherapy followed by blinatumomab
	NCT03480438	ALL	Completed, phase 2 study; 3 additional blinatumomab cycles alternating with age adapted consolidation cycles	OS 80% 1 year. 67% 3 years [129]
	NCT02003222	ALL	Active, phase 3 study; 4 cycles of blinatumomab + four cycles of consolidation chemotherapy versus four cycles of consolidation chemotherapy alone	OS 85% 3 years. Relapse-free survival at 3 years 80% with blinatumomab. 64% with chemotherapy alone [8]
	NCT03914625	ALL	Active, phase 3 studycomparing across risk groups and based on responses including MRD status.
	NCT04554485	ALL	Completed, phase 2 study; two cycles induction therapy with single cycle of blinatumomab followed by chemotherapy
Epcoritamab	NCT04663347	DLBCL	Active, phase 1/2 study; SC epco + R-CHOP for six cycles followed by single-agent epco every 4 weeks up to 1 year
	NCT05783609	Follicular lymphoma	Active, phase 2 study
	NCT05783609	Follicular lymphoma	Active, phase 2 study. Epcoritamab + Rituximab as first line treatment
	NCT06045247	DLBCL	Active, phase 2 study; Epcoritamab + R-miniCVP
	NCT06112847	Follicular lymphoma	Active, phase 2 study; Lenalidomide and epcoritamab as first line treatment
	NCT06796998	MZL	Not yet recruiting patients; Epcoritamab monotherapy
Glofitamab	NCT05783596	FL and MZL	Active, phase 2 trial; glofitamab + obinutuzumab as first line therapy for FL and MZL
	NCT06047080	LBCL	Active, phase 3 trial. glofitamab + Pola-R-CHP vs Pola-R-CHP in participants with CD20-positive LBCL
	NCT04980222	DLBCL	Active, phase 2; Glofitamab + R-CHOP in individuals with ctDNA high-risk DLBCL
	NCT05861050	Mantle Cell Lymphoma	Active, phase 1/2 trial; glofitamab (with obinutuzumab pretreatment), venetoclax, and lenalidomide
Mosunetuzumab	NCT06569680	Extranodal MZL	Active, phase 2 trial
	NCT05389293	FL	Active, phase 2 trial
	NCT05410418	FL	Phase 2 trial; mosunetuzumab and polatuzumab vedotin
	NCT04792502	FL and MZL	Phase 2 trial; mosunetuzumab with lenalidomide augmentation
	NCT03677141	DLBCL	Phase 2 trial; mosunetuzumab with CHOP	2-year PFS 65.4%, event-free survival 60.4% [130]
Odronextamab	NCT06091865	DLBCL	Active, phase 3 trial; odronextamab + CHOP (part 1), Odro-CHOP to R-CHOP (part 2)
	NCT06091254	FL	Phase 3 trial; odronextamab versus investigator’s choice (R-CHOP, R-CVP, or R-bendamustine)
Teclistamab	NCT06758375	MM	Phase 2 study; three cycles of VRd followed by consolidation with four doses of teclistamab
	NCT06100237	High risk SMM	Phase 2 study; teclistamab + Daratumumab or combination talquetamab + daratumumab for delaying onset of MM
	NCT05849610	MM	Active, phase 2 study; teclistamab + Daratumumab and talquetamab + daratumumab
	NCT05552222	Multiple myeloma	Active, phase 2 study; teclistamab, daratumumab, lenalidomide, talquetamab in combination with daratumumab + lenalidomide versus daratumumab, lenalidomide, dexamethasone
Elranatamab	NCT06183489	High risk SMM	Active, phase 2 trial
	NCT05317416	MM s/p ASCT	Phase 3 study currently recruiting. Elranatamab monotherapy versus lenalidomide monotherapy in newly diagnosed multiple myeloma after undergoing ASCT
Talquetamab	NCT06100237	High risk SMM	Active, phase 2 study; teclistamab + Daratumumab or combination talquetamab + daratumumab for delaying onset of MM
	NCT05552222	MM	Active, phase 2 study; teclistamab + daratumumab, lenalidomide and talquetamab + daratumumab, lenalidomide vs daratumumab, lenalidomide, dexamethasone
	NCT05849610	MM	Active, phase 2 study; teclistamab + Daratumumab and talquetamab + Daratumumab
	NCT05695508	MM	Active, phase 2 study; teclistamab- and talquetamab-based combination therapies
Linvoseltamab	NCT05828511	MM	Active, phase 1/2 study
	NCT05955508	High risk SMM	Active, phase 2; linvoseltamab in SMM with high risk of progression to MM

ALL acute lymphoblastic leukemia; OS overall survival; PFS progression-free survival; MRD minimal residual disease; SC subcutaneous; R  rituximab; CHOP ritixumab, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP cyclophosphamide, vincristine, prednisone; (D)LBCL (diffuse) large B-cell lymphoma; MZL marginal zone lymphoma; (S)MM (smouldering) multiple myeloma; ASCT autologous stem cell transplantation; Pola polatuzumab

Glofitamab underwent frontline DLBCL evaluation in a single-arm phase 1b study combined with R-CHOP. Participating patients received R-CHOP for 6–8 cycles with IV glofitamab step-up dosing starting in cycle 2. After 17.1 months of median follow-up, the best ORR was 92.9% and the CMR rate was 83.9%. The median time to CMR was 1.8 months. Unfortunately, 75% of patients experienced grade 3 and greater AEs and 10.7% of patients experienced CRS (all occurring during C2–3) [55]. Glofitamab has also been studied with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in treatment naive DLBCL or high grade B cell lymphoma, with an international prognostic index (IPI) > 2 showing an ORR of 95% and CR rate of 80% [56]. Results of these studies are early and largely not peer reviewed, and randomized studies will be necessary to potentially alter well-established frontline standards of care.

In indolent lymphoma, efforts to incorporate BsAbs in earlier lines are also ongoing. At the Dana Farber Cancer Institute, a study (NCT05783596) is ongoing, which is studying the efficacy and safety of glofitamab and obinutuzumab in treating patients with FL and marginal zone lymphoma as first line therapy [57]. Similarly, Lynch et al. reported on the use of mosunetuzumab monotherapy in FL and marginal zone lymphoma in first line, showing an ORR of 100% and CR of 83% in the patients completing mosunetuzumab therapy and no grade 2+ CRS or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) [58]. Finally, a phase 2 trial (NCT04792502) is studying a novel therapeutic approach as a first line treatment of FL and marginal zone lymphoma by combining mosunetuzumab with low dose lenalidomide. This study is particularly of interest owing to the current first-line treatment for high burden FL and marginal zone lymphoma (bendamustine with rituximab), leading to prolonged T-cell depletion presenting challenges for later use of T-cell engaging BsAbs [59]. SWOG S2308 is an ongoing phase 3 trial comparing mosunetuzumab versus rituximab in low-burden FL. The study is based on the hypothesis that BsAbs will be more effective in earlier lines and even possibly offer a curative option in low tumor burden indolent lymphomas, which is yet to be achieved. Overall, these studies highlight the potential for BsAbs to become incorporated in the first-line treatment regimens in lymphoma, leading to meaningful improvement in OS, which has been elusive for decades in large-cell lymphomas.

Expanding Lymphoma Targets

CD30 is a tumor-associated antigen (TAA) highly expressed in certain hematologic malignancies, including Hodgkin’s lymphoma and anaplastic large-cell lymphomas. It is normally expressed on subsets of activated B and T cells. Existing treatments such as brentuximab vedotin, an antibody-drug conjugate, specifically target CD30. However, some patients are unable to tolerate these treatments, do not respond well, or develop progressive disease. To improve therapeutic options for CD30-positive lymphomas, CD30 targeting treatments, such as GEN3017 (a BsAb), acimtamig (a tetravalent, bispecific NK-cell engager), and AFM13 (a CD30/CD16A BsAb) are currently under investigation [60–62].

Another emerging target in the field of BsAbs is CD79b; its high expression on B-cell leukemia and lymphoma cells makes it an attractive target. CD79b is a component of the B-cell receptor complex. It is essential in the development and maintenance of mature B cells and plays a key role in signaling for B cell survival. Polatuzumab vedotin, a CD79b-directed antibody–drug conjugate, utilizes this antigen owing to its expression in most non-Hodgkin’s lymphoma subtypes [63]. Owing to the promising results of existing anti-CD79b treatments, anti-CD79b × CD3 BsAbs are currently being evaluated in vitro for their activity against lymphoma cell lines. Preclinical studies indicate that these antibodies exhibit potent cytotoxicity against B cells, suggesting they may hold promise as a therapeutic agent for clinical development in B cell malignancies [64].

BsAbs in R/R MM

Akin to lymphoma, the landscape of MM treatment has shifted in the last five years with the introduction of BsAbs. Patients progressing after immunomodulatory agents (lenalidomide and pomalidomde), proteasome inhibitors (bortezomib and carfilzomib), and anti-CD38 antibodies (daratumumab) tend to have a poor prognosis. Prior to the BsAb teclistamab, three B-cell maturation antigen (BCMA)-targeted therapies were approved; the antibody–drug conjugate, belantamab mafodotin, and two CAR-T agents, idecabtagene cicleucel and ciltacabtagene autoleucel. Belantamab mafodotin showed response rates around 31% in heavily pretreated patients with MM [65].

Teclistamab, the first bispecific BCMA-directed CD3 T-cell engager, was granted accelerated approval on 25 October 2022 by the FDA for usage in adults with R/R MM who had received at least four prior therapies [66]. Patients with prior exposure to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody, for teclistamab treatment, were found to have an ORR of 63% with the use of teclistamab in the MajesTEC-1 study [67]. With extended follow-up of 30.4 months, the ORR remained at 63%, and 46.1% of patients achieved CR. In addition, 85.7% of MRD-evaluable patients were found to be MRD-negative and the median DOR increased to 24 months, while median PFS and OS improved to 11.4 and 22.1 months, respectively [68]. Adverse events included infections (76.4%; grade 3 or 4, 44.8%), and ICANS was seen in 14.5% of patients, with no grade 3+ reported [67]. It should be noted that 18 of 22 grade 5 infections were linked to coronavirus disease 19 (COVID-19) owing to the timing of the study. The onset of new severe infections decreased throughout the study, coinciding with the switch to biweekly dosing and increased intravenous immunoglobulin (IVIG) use. Adverse events leading to dose reduction (one case) or discontinuation (eight cases, five owing to infection) were rare [68]. Given crucial findings, such as the risk of fatal reactions specifically related to CRS and ICANS, teclistamab is only available through a restricted FDA program called the teclistamab Risk Evaluation and Mitigation Strategy (REMS) [69].

The BCMA × CD3 BsAb elranatamab was granted accelerated approval by the FDA in August 2023 for patients with R/R MM after at least four prior LOT [70]. Approval followed MagnetisMM-3, an open-label, single-arm, multi-center study [71] that demonstrated early and sustained responses with manageable safety. In these heavily pretreated high-risk patients, at a median follow up of 28.4 months, ORR was 61%, with 37.4% of patients achieving CR or better and 4.9% achieving partial response (PR). The study also found that maintaining a response at 24 months was observed in 66.9% and 84% of patients who switched from Q2W dosing to Q4W dosing and maintained CR at 6 months after the switch. Importantly, benefit was consistent across multiple subgroups, including patients who had high-risk features such as elevated bone marrow plasma cells, poor performance status, and adverse cytogenetics [72]. Unfortunately, treatment-emergent adverse events (TEAEs) were common with elranatamab use, including grade 3 or 4 events. Grade 1 or 2 TEAEs included CRS and ICANs. Grade 3 or 4 TEAs included anemia, neutropenia, and diarrhea [71]. With elranatamab usage, patients also developed the unique adverse event of secondary primary malignancies, including three cases of squamous cell carcinoma of the skin and one malignant neoplasm of the external ear [73]. Multiple factors contribute to these malignancies in elranatamab-treated patients, but research has shown that keratinocytes express tumor necrosis factor (TNF) superfamily members and their receptors, including BCMA. Therefore, use of elranatamab may alter the immune environment within the skin, contributing to emergence of malignancies in these tissues [74].

Similar to teclistamab, elranatamab is available through REMS owing to the risk of CRS and ICANS and requires step-up dosing. Both teclistamab and elranatamab are administered subcutaneously and have an indefinite duration of therapy. Key differences include weight-based dosing for teclistamab compared with fixed dosing for elranatamab. While teclistamab has to be administered on a weekly basis, patients on elranatamab can progress to biweekly dosing if their disease remains stable for 6 months or longer [70].

The last approved BsAbs for R/R MM is talquetamab, which received FDA accelerated approval for adults with R/R MM who had received at least four prior LOT [75]. Unlike elranatamab, talquetamab targets the G protein-coupled receptor, family C, group 5, member D (GPRC5D) on MM cells. GPRC5D is an attractive therapeutic target owing to it being an orphan receptor with no known ligand, expression on malignant plasma cells, and minimal detection on normal tissues [76].

MonumenTAL-1 was a phase 1/2 evaluation of talquetamab's safety and efficacy in patients with R/R MM, including those previously treated with BCMA-targeted therapies. Treated patients achieved an ORR of 70% in the weekly 405 µg/kg group (30 patients total) and 71% for the biweekly 800 µg/kg group (23 patients total) [77]. For patients both naive and previously exposed to T-cell redirecting therapies such as CAR-T or other BsAb treatments, a high ORR was seen, ranging from 67–74% [78]. Talquetamab therefore is a consideration for patients who may have already received BCMA-targeted immunotherapies.

Both BCMA- and GPRC5D-targeted BsAbs have manageable safety profiles, though they exhibit side effects related to their targets. Talquetamab's adverse effects include skin and nail disorders, owing to GPRC5D expression in keratinized tissues [79]. The most frequent grade 3 or 4 adverse events seen with talquetamab usage were hematologic, such as anemia (31.5%, 25.3%, 26.9%) and neutropenia (30.8%, 21.4%, 47.4%). Infection rates were consistent with previous studies, with any grade infections at 60.8%, 70.1%, and 76.9%, and grade 3 or 4 infections at 22.4%, 20.1%, and 25.6% [78]. Similar to elranatamab and teclistamab, talquetamab is only available through REMS.

Linvoseltamab is another BCMA × CD3 BsAb, but does not currently have regulatory approval. In August 2024, the U.S. FDA issued a Complete Response Letter for BLA use in R/R MM after at least three prior therapies. The issue was linked to a preapproval inspection at a third-party manufacturing site, not concerns about the drug’s efficacy or safety [80].

Overall, when comparing the different BsAb classes (CD20 × CD3, BCMA × CD3, and GPRC5D × CD3), unique side effect profiles owing to their distinct targets are observed. All BsAbs have a risk of CRS, ICANS, cytopenias, and infections. CRS is mitigated by step-up dosing, utilized by all BsAbs. However, GPRC5D and BCMA-targeting BsAbs have a higher risk of CRS and ICANS, which is why all MM FDA approved antibodies are only available through the REMS program. In addition, owing to the potential presence of GPRC5D and BCMA on keratinized tissues, skin and nail disorders are unique side effects seen with this class of BsAbs. Lastly, BCMA-targeting antibodies have an increased risk of infection when compared with GPRC5D and CD20-targeting BsAbs.

Future Directions of BsAbs in MM

Currently, BsAb monotherapies for R/R MM are reserved for patients who have undergone at least four prior LOT. Despite the amount of newly diagnosed cases for MM remaining consistent over the last 10 years, the prognosis of MM has improved owing to treatment advances [81]. A study utilizing a global health research platform including patients from Europe and the USA reported an improvement in median survival from 35.6 months in 1999–2009 to 68.7 months in 2015–2020. The 5-year survival is now 48%, up from 28% [82]. Yet, MM remains an incurable disease, highlighting the need for combination strategies to further enhance treatment effectiveness [83]. In addition, patients tend to be of advanced age at diagnosis and experience associated comorbidities. The initial promise of single-agent elranatamab, talquetamab, and teclistamab described above [71, 77, 84] has prompted testing of combination therapies for earlier LOT in MM, at which point, the theoretical advantage of more fit T-cells might leverage improved outcomes compared with heavily pretreated patients [84–86].

Examples include the MajesTEC-2 trial for patients after at least two prior LOT, which is assessing teclistamab with lenalidomide [84]. At a median follow-up of 10.1 months, the combination promoted an ORR of 74.2%, including CRs of 35.5% with a median time to first response of 1.2 months [84]. MajesTEC-7 meanwhile is investigating teclistamab, daratumumab, and lenalidomide as an initial treatment for patients with newly diagnosed MM who are ineligible for ASCT, comparing it to standard therapy options [85]. Similarly, results presented at ASH 2024 included MonumenTAL-2, a phase 1b evaluation of talquetamab, daratumumab, and lenalidomide in newly diagnosed patients with MM who are transplant ineligible. After median follow up of 10.5 months, ORR was 100% (88% PR, 12% CR) [86]. Talquetamab is also under assessment in combination with daratumumab and pomalidomide as second-line therapy [87]. Finally, another approach taken by Cohen et al. was to combine both teclistamab and talquetamab by considering their different targets. Yet, perhaps unsurprisingly, the grade 3 and 4 infections with talquetamab plus teclistamab were higher than has been observed with either therapy alone, and clinical feasibility of combining bispecifics remains to be established [88]. The studies referenced above, along with additional ongoing research, will play a crucial role in evaluating the feasibility, safety, and effectiveness of incorporating BsAbs into combination therapies for the treatment of multiple myeloma at earlier stages.

Elranatamab is also being studied in combination therapy and showing favorable results. In the MagnetisMM-5 phase 3 study, elranatamab was administered alone versus in combination with daratumumab in patients with R/R MM who have had at least three prior LOT. The results showed the elranatamab-daratumumab combination having favorable responses with manageable side effects, and no instances of ICANS or grade 3 + CRS [89]. However, MagnetisMM-6 (NCT05623020) is testing elranatamab, daratumumab, and lenalidomide against daratumumab, lenalidomide, and dexamethasone in newly diagnosed patients with transplant-ineligible MM [90]. This study is currently ongoing.

Expanding MM Targets

As previously mentioned, BCMA and GPRC5D are key targets in MM treatment. BCMA, a type III transmembrane glycoprotein in the tumor necrosis factor receptor family, is highly expressed in malignant plasma cells and certain mature B cells. Although teclistamab and elranatamab are approved BCMA-targeting antibodies for R/R MM, other IgG-like BsAbs targeting BCMA, are actively being developed in clinical trials. For example, alnuctamab (CC-93269) [91], HPN217 [92], WVT078 [93], ABBV-383 [94], and REGN5458 [95] are current BsAbs in the pipeline that are in clinical development. These antibodies differ in their administration route (IV versus subcutaneous), dosing frequency (weekly or Q3W after initial treatment), and the requirement for step-up dosing [91–95].

Conversely, GPRC5D is primarily expressed on malignant plasma cells, with lower levels found on normal plasma cells, hard keratin-producing cells, and within the inferior olivary nucleus [96]. Currently, talquetamab is the only approved BsAb that targets GPRC5D [75, 76]. However, forimtamig is another GPRC5D-targeting BsAb under investigation for use in MM. Similar to talquetamab, forimtamig has shown rapid responses in the heavily pretreated patients with MM but also has a similar toxicity profile to talquetamab. Notably, forimtamig has shown higher efficacy and better results when administered IV compared with subcutaneous [97].

Another therapeutic opportunity is Fc receptor-homolog 5 (FcRH5), a membrane surface protein uniquely expressed in the B cell lineage. FcRH5 appears first in pre-B cells and increases in expression as B cells mature into plasma cells. This restricted expression in B cells, combined with its elevated presence in MM cells, makes FcRH5 an appealing target for MM treatment and the focus of ongoing trials. For instance, cevostamab, a FcRH5xCD3 BsAb is under evaluation in patients with extensive prior treatment. It has demonstrated a manageable toxicity profile, with adverse effects seen with other BsAb treatments, such as CRS, cytopenias, and infections [98].

CD38, a receptor for CD31, is also highly expressed on malignant plasma cells and is a well-established target in MM therapies, as evidenced by its use in monoclonal antibodies such as daratumumab and isatuximab. CD38 is now being explored as a target for BsAbs. For example, ISB 1342, a CD38xCD3 BsAb, is under investigation in a phase 1 dose-escalation trial for patients with R/R MM. ISB 1342 is designed to overcome resistance to daratumumab by effectively targeting MM cells and MM cell lines with low daratumumab sensitivity [99]. Another new BsAb is ISB 1442, an antibody targeting CD38 and CD47 to induce tumor cell death through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. ISB 1442 is currently in a phase 1 trial for R/R MM and continues to actively recruit patients [100].

Management of Adverse Events

BsAbs targeting CD3 × CD20 can lead to severe toxicity owing to T-cell activation, necessitating clear guidance on managing adverse events. To assist with providing guidance on managing adverse events, an international panel of providers with experience using CD3 × CD20 BsAbs developed consensus-based recommendations. These guidelines also address the management of BsAb toxicities and how it differs from CAR T-cell therapies [101].

Toxicities and risk profiles associated BsAb therapy and CAR-T therapy are typically related to patient-specific factors, including baseline immune function, underlying malignancy characteristics, and therapeutic approach. When comparing BsAb therapy adverse events to CAR-T adverse events, CRS and ICANS are typically milder with the use of BsAb therapy compared with CAR-T therapy. CRS typically emerges within the first 1–3 days of treatment, managed by step-up dosing regimens. C-reactive protein, ferritin, and interleukin (IL)-6 levels are typically monitored as they are commonly observed as surrogate markers for cytokine-mediated inflammation [102]. ICANS in BsAb therapy typically emerges later and coincides with CRS resolution. Overall, complications in BsAb therapies mirror those seen with CAR-T therapy and require similar diagnostic vigilance and therapeutic strategies. Long-term monitoring is also required with both CAR-T and BsAb therapy, as late complications such as prolonged cytopenia and infection are associated with both and require ongoing surveillance [101].

Before treatment, in addition to standard laboratories and physical exam, baseline cardiac assessment, though optional, may help gauge cardiac reserve for managing CRS-related hemodynamic changes. To prevent CD20 × CD3 BsAb-related toxicities, specifically CRS, step-up dosing and premedications are recommended for each treatment. For mosunetuzumab, patients should receive acetaminophen (500–1000 mg), diphenhydramine (50–100 mg), and dexamethasone (20 mg) or methylprednisolone (80 mg) prior to cycle 1 and cycle 2 doses, with continuation if CRS occurs with previous doses. With epcoritamab usage, premedication includes acetaminophen (650–1000 mg), diphenhydramine (50 mg), and dexamethasone (15 mg) prior to cycle 1 dose and for 3 days postadministration. Dexamethasone should be continued if grade 2 or 3 CRS is observed. For glofitamab, premedications include acetaminophen (500–1000 mg), diphenhydramine (50 mg), and dexamethasone (20 mg) before treatments on cycle 1 day 8, cycle 1 day 15, cycle 2 day 1, and cycle 3 day 1, with continuation if CRS is present after prior doses. Lastly, for odronetamab, acetaminophen (650 mg), diphenhydramine (25 mg), and dexamethasone (10 mg) are administered during step-up dosing, with additional dexamethasone (20 mg IV) on the dosing day and 10 mg orally the following day if CRS or infusion-related reactions occur with previous doses [101]. CRS risk varies by disease, bispecific antibody type, administration route (IV or subcutaneous), and schedule. In addition to close monitoring, patients should have access to a nearby intensive care unit (ICU) in case a higher level of care is needed and at least two doses of tocilizumab available. Hospitalization during specific doses is advised, especially for epcoritamab (cycle 1 day 15) and glofitamab (cycle 1 day 8). Patients should also be educated to monitor vital signs (e.g., fever above 100.4c °F) and symptoms such as hypoxia or hypotension [101]. Signs that may indicate severe CRS include fever during IV BsAb infusion, prompting infusion suspension. Grade 1 CRS can be managed at home, but grade 2+ requires urgent care. Patients with persistent symptoms should take acetaminophen and dexamethasone (10 mg every 12 h). In severe CRS cases, early anticytokine therapy (e.g., tocilizumab) is advised to prevent progression to more severe outcomes. European Medicines Agency guidelines for glofitamab and mosunetuzumab recommend no more than two tocilizumab doses per CRS event (8 h apart) or three doses within 6 weeks; if additional doses are needed, consider alternative therapies such as anakinra [101].

For grade 3 CRS, tocilizumab or alternative agents, such as anakinra or siltuximab, are recommended. In addition, sepsis evaluation, empiric antibiotics, and dexamethasone should be utilized until CRS reduces to grade 1 or lower. For additional supportive care, acetaminophen 1000 mg IV may be administered 3–4 times daily as needed. Grade 4 CRS, though rare, can be life-threatening and warrants all grade 3 supportive measures, with corticosteroids potentially increased to dexamethasone 20 mg every 6 h [101].

Patients also require close surveillance for ICANS. Although ICANS events were rare in studies, guidance for management was provided by the panel for guidance if they do occur. The panel recommended an ICE score for all patients with neurologic symptoms. For grade 1 ICANS (ICE 7–9), observation is recommended on the basis of the clinical scenario and a single 10 mg dose of dexamethasone can be used. For grade 2 ICANS (ICE 3–6), patients should be admitted and treated with dexamethasone 10 mg IV every 12 h, followed by a taper. For grade 3 ICANS (ICE 0–2), intensive care unit (ICU) monitoring is advised, with dexamethasone 10 mg IV every 6 h, followed by a taper. Antiepileptic medications should be used for seizure management as needed, and anakinra 100 mg every 12 h may be added if symptoms persist beyond 24 hours. Lastly, grade 4 ICANS (ICE 0) can be managed similar to grade 3 ICANS [101].

Additional adverse events include cytopenias and infections. Cytopenias are common with BsAb antibody treatment, which may have multiple causes including involvement of disease, prior therapies, or direct effects from BsAb treatment. It is recommended to provide growth factor support if the patient is neutropenic, and BsAb therapy may continue if the cytopenias are linked to lymphoma-related marrow infiltration or organomegaly [61]. However, if a patient develops an active infection, BsAb treatment should be paused. If this occurs, then immunoglobulin levels should be monitored owing to treatment-related hypogammaglobulinemia. IV immunoglobulin replacement therapy can be utilized for recurrent infections. Lastly, patients should also receive prophylaxis against Pneumocystis jirovecii pneumonia and varicella zoster virus for up to 6 months post-treatment [101].

Unfortunately, there are no consensus guidelines for the management of BsAbs used for R/R MM, and approaches vary across institutions and products. For example, it is known that there are infectious complications with the use of BCMA targeting BsAbs. To mitigate this risk, it is best to closely monitor patients receiving BCMA-targeting BsAbs, as well as institution of antimicrobial prophylaxis and immunoglobulin preplacement therapy [94]. One study called “Tocilizumab Prophylaxis for Patients with Relapsed and Refractory Multiple Myeloma Treated with Teclistamab, Elranatamab or Talquetamab” presented at ASH 2024 found that tocilizumab may also be an effective preventative measure for patients treated with BsAbs for R/R MM. This recommendation was made on the basis of a single center study, which studied patients with R/R MM receiving prophylactic tocilizumb prior to BsAb treatment with teclistamab, elranatamab, or talquetamab. Low rates of CRS and ICANS was noted within the study population [103]. GPRC5D-targeting BsAbs, such as talquetamab, face unique complications not identified with BCMA-targeting agents such as skin and nail changes [79]. Current strategies for managing toxicities related to GPRC5D include topical corticosteroids, oral antihistamines, mouthwash, and the incorporation of liquid diets and nutrition supplementation [79]. The lack of specific guidelines related to the use of BsAb treatments for R/R MM should prompt their development as clinical utilization of these products is likely to continue growing in both clinical trials and routine practice in the years ahead.

Future Directions for T-Cell Engaging Immunotherapies

The BsAb clinical breakthrough is fueling a flurry of further developments, the full extent of which exceeds the scope of this or any one review article. Here, we will cover selected novel clinical approaches built on the bispecific proof-of-principle and which are perhaps closer to significant clinical deployment. Though specific resistance mechanisms remain under evaluation, it is assumed on the basis of CAR-T experiences, in B-ALL especially, that antigen escape is prominent among them. Therefore, multispecific products are already under clinical evaluation to exploit simultaneous targeting of two tumor-specific antigens. For example, the CD19 × CD20 × CD3 trispecific antibody, PIT565, is under clinical evaluation in refractory B-cell malignancies (NCT05397496), leveraging preclinical results that demonstrated superior T-cell activation by trispecific compared to bispecific reagents [104].

Trispecifics have also gained momentum in MM research. In a phase 1, open-label, multicohort study (NCT06375044), an IgG4-based trispecific CD3/BCMA/GPRC5D T-cell engager called SIM0500 is being studied for use in patients who have received at least three prior lines of anti-MM therapy (including a proteasome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulatory drug). This therapy operates by binding to human T-cells through CD3 and to MM cells expressing BCMA and/or GPRC5D, which allows recruitment of activated T-cells to kill MM cells [105]. In addition, another humanized trispecific antibody against CD3/BCMA/GPRC5D for R/R MM is being studied, called MBS314, which has already shown remarkable antitumor activity in preliminary data, even at low doses [106]. JNJ-5322 is also a BCMA- and GPRC5D-targeting trispecific antibody comprising novel binding domains and low affinity CD3 binding. In the ongoing phase 1 study, ORR was found to be 100% among patients naive to anti-BCMA and anti-GPRC5D therapies with Q4 week dosing, suggesting the potential of the approach [107]. A trispecific antibody targeting CD3/BCMA/CD38 called ISB 2001 has also gained momentum owing to its ability to target two TAAs and having an ORR of 75% and median time to response of 36 days, with a median follow-up of 6 months [108].

Another strategy involves coadministering an antibody-like fusion protein that delivers a costimulatory signal to T cells, such as the CD28 and 4-1BB costimulatory domains used in CAR-T therapies. For instance, englumafusp Alfa is a fusion protein that functions similarly to a co-stimulatory antibody, targeting CD19 on B cells and 4-1BB on immune cells. Preclinical in vivo models have demonstrated that combining Englumafusp Alfa with glofitamab enhances, prolongs, and deepens antitumor activity. This was confirmed in the final dose escalation of BP41072 (NCT04077723), a phase 1b study evaluating the combination of englumafusp Alfa and glofitamab in patients with R/R B-NHL [109]. Similarly, CD28 × CD19 (RG6333) is currently in preclinical development to further enhance efficacy of CD20-targeting BsAbs in lymphoma [110].

Natural killer (NK) cells play a crucial role as the immune system's defenses against tumor cells, demonstrating robust antitumor activity. These cells express a range of inhibitory and activating receptors; for example, inhibitory receptors bind major histocompatibility complex class I (MHC Class I) molecules to limit autoimmune responses, while the loss of MHC expression on tumor cells can trigger NK cell-mediated killing. BiKEs (bispecific killer-cell engager) have been designed to leverage NK cells for cancer treatment by connecting NK cells directly to tumor cells to facilitate killing. The substitution of the anti-CD3 domain by an anti-CD16 domain allows the recruitment of NK cells. By utilizing Fc-mediated engagement, or the interaction of the Fc region of an antibody with the Fc receptors expressed on NK cells, NK cells are recruited. However, recruiting NK cells through Fc-mediated engagement poses challenges, as the chosen format must ensure that the Fc domain binds effectively to CD16 [111, 112]. Most constructs targeting CD16 on NK cells use a CD16-specific scFv moiety (an engineered antibody fragment) rather than the natural IgG Fc domain, which typically binds to CD16. This design reduces side effects associated with the Fc domain, enhances potency, and offers a better safety profile compared with Fc domain-mediated CD16 engagement [113]. A promising example is AFM13, a tetravalent bispecific tandem diabody (TandAb) targeting CD30 and CD16A, showing efficacy and cytotoxicity in early trials for CD30⁺ malignancies, such as Hodgkin’s lymphoma (NCT01221571) [114]. In addition to CD16A, emerging studies are exploring the activation of NK cell receptors such as NKG2D for enhanced antitumor effects [115]. Dual TAA binding has also been pursued in NK cell engagers to expand the range of effective treatment options [116].

BsAbs also face the challenge of developing antibodies that are effective and safe, especially when targeting two antigens simultaneously. Artificial intelligence (AI) is being utilized in the development of bispecifics with the use of machine learning models by analyzing hundreds of membrane proteins as targets to predict the likelihood of successful drug development for various target combinations [117]. Lastly, studies have found the benefit of the neutrophil/lymphocyte ratio (NLR) as a widely available biomarker correlating with immune suppression of myeloid cells. A high NLR at diagnosis and/or increasing NLR during frontline treatment has been associated with a poor prognosis in large B-cell lymphoma. This has been expanded to the use of BsAbs, showing that a high baseline NLR can be associated with inferior PFS in BsAb therapy [118].

Challenges Related to BsAb Response Durability

A significant challenge with BsAbs is the potential for resistance, driven by mechanisms such as T-cell exhaustion and antigen escape. T-cell exhaustion can result from potent T-cell activation in the setting of chronic antigen exposure, leading to the upregulation of immune checkpoints such as programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1). This ultimately leads to a spectrum of highly proliferative T cells with stem-like properties (known as precursor-exhausted T cells) to T cells with lack of effector function and replicative capacity (known as terminally exhausted T cells), leading to poorer patient survival [119]. To counteract the possibility of T-cell exhaustion, several studies are underway to investigate the promising strategy of combining BsAbs with PD-1 inhibitors, a class of drugs designed to block a key immune check point. For instance, the TRIMM3 trial (NCT05338775) is evaluating the combination of talquetamab or teclistamab with a PD-1 inhibitor for R/R MM. Furthermore, BsAbs targeting dual immune check points are being developed to overcome resistance driven by T-cell anergy. Treatment regimens are exploring combinations of BsAbs with immune check point inhibitors targeting PD-1-PD-L1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin mucin receptor 3 (TIM3), and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT) pathways to overcome the upregulation of immune check points. Overall, these regimens aim to restore the function of tumor-infiltrating cells by integrating dual immune check point inhibitors.

The possibility of success with this strategy has made the development of BsAbs with dual inhibitory check points an area of intense research interest. However, this also comes with challenges owing to the concern for systemic unspecific T-cell activation due to a lack of an anti-TAA moiety for redirection with the use of a single molecule. Trispecific antibodies with a PD-1 and CTLA-4 antagonist plus a CD137 agonist have been studied in the past due to this [120]. Currently, there are very few studies related to cost effectiveness of BsAbs owing to the lack of long-term clinical data. However, improved efficacy in clinical trials may translate to cost-effectiveness, but should be weighed carefully against the high costs of the drug alone, along with costs related to adverse events management. Typically, treatments for hematologic malignancies include the summed cost of hospital visits, labs, drug costs, physician visits, imaging, and other supportive care. While BsAb drug costs are high, BsAbs are known to be less toxic compared with CAR-T therapy owing to the lower risk of CRS and ICANs events. However, BsAb therapy typically involves multiple sessions while CAR-T therapy is a one-time session, creating higher associated costs related to BsAb therapy. With the expansion of BsAb options and possible decreases in the duration of therapy when used in earlier lines, drug costs may decrease in the future [121].

Concluding Remarks

BsAbs have revolutionized the treatment of B-lymphomas and MM. Numerous strategies to enhance T cell-directing therapies are ongoing. These include trispecific antibodies (targeting three instead of two antigens) [104, 122], coadministration of an antibody-like fusion protein that delivers a costimulatory signal to BsAbs, such as the CD28 and 4-1BB costimulatory domains used in CAR-T therapies [109, 110, 123], and utilization of novel effector cells, such as NK cells, CD8⁺ T-cells, and macrophages [114, 124]. With an ever expanding repertoire of immune cell-based therapies, the success of BsAbs in lymphoma and MM in the relapsed setting has ignited the race again to reshape therapy in earlier lines and sprint to be part of standard therapy in the frontline.

Declarations

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

A.T. and T.S. disclose no conflict of interest. A.A. is an employee at Qiming Venture Partners USA. J.H.S. declares consultancy/advisory roles for Affimed, Acrotech, and WCG Clinical.

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Authors' contributions

T.S. and A.T. are the primary authors of the paper who drafted and edited the paper. A.A. and J.H.S. provided revisions to the content of the manuscript and conceived ideas for the design of the paper.

Availability of Data and Materials

No datasets were generated or analyzed during the current study.