Bispecific antibodies have transformed the treatment of relapsed or refractory B-cell lymphomas and multiple myeloma. By redirecting a patient’s own T cells toward malignant cells, these agents have produced deep responses even after several previous therapies. The field is now testing whether the same approach can improve outcomes earlier in the disease course, and in combination with established therapies, while trispecific antibodies are being developed to engage more than one tumor target or add a second immune signal.
The central question has therefore shifted. Bispecific antibodies have already demonstrated activity in the relapsed/refractory setting. The next challenge is to determine where they add the greatest value, how their toxicities should be managed over time, and whether more complex multispecific designs can improve on established treatments.
Transforming Relapsed and Refractory Disease
When I began practising as a hematologist in 2017, patients with lymphoma or myeloma who had relapsed multiple times often had few effective therapeutic options. Bispecific antibodies have changed that clinical conversation by creating the possibility of deep responses even after exposure to several previous lines of treatment.
Most bispecific antibodies used in blood cancers bind CD3 on T cells and a tumor-associated antigen on malignant cells. This brings the two cells together, creates an immune synapse and triggers T-cell-mediated killing.
The target varies by disease. CD19 is used in B-cell acute lymphoblastic leukemia, CD20 in B-cell non-Hodgkin lymphomas, and B-cell maturation antigen, or BCMA, and GPRC5D in multiple myeloma. Blinatumomab, a CD19×CD3 bispecific antibody, provided early clinical validation of this approach in acute lymphoblastic leukemia and showed that redirected T-cell activity could produce meaningful benefit beyond chemotherapy. This proof of concept supported the development of newer bispecific platforms with different targets, antibody structures, routes of administration and dosing schedules.
In multiple myeloma, BCMA-directed bispecific antibodies such as teclistamab and elranatamab have shown substantial activity in heavily pretreated populations. In the phase 1/2 MajesTEC-1 study, teclistamab produced an overall response rate of 63%, with complete responses or better in approximately 39% of patients. GPRC5D-directed talquetamab provides an alternative target in relapsed myeloma.
In B-cell lymphomas, CD20×CD3 antibodies including mosunetuzumab, epcoritamab and glofitamab have also produced meaningful responses in relapsed disease. In the pivotal glofitamab study in relapsed or refractory diffuse large B-cell lymphoma, 39% of patients achieved a complete response.
Bispecific antibodies also offer a practical advantage over autologous CAR-T therapy: they are available without leukapheresis or individual manufacturing. This can shorten the time from treatment decision to administration. That being said, the two approaches are not interchangeable. CAR-T therapy is a finite intervention, whereas many bispecific regimens require repeated dosing. The choice of therapy depends on various factors including disease biology, previous target exposure, clinical urgency, patient fitness and access to specialist care.
Expanding the Treatment Strategy
One approach to broader target coverage is combining two bispecific antibodies. In the phase 1b/2 RedirecTT-1 study, talquetamab and teclistamab were administered together to target GPRC5D and BCMA, respectively, while both engaged CD3. At the recommended phase 2 regimen, the overall response rate was 80% among patients with heavily pretreated relapsed or refractory multiple myeloma.
This combination is relevant for two reasons. First, it shows that simultaneous targeting of two myeloma antigens is clinically feasible. Second, it provides a conceptual bridge to trispecific antibodies.
Trispecific antibodies add a third binding function to the T-cell redirection model. Some bind CD3 and two tumor antigens, with the aim of recognizing heterogeneous malignant populations and reducing escape through loss of a single antigen. Others combine tumor targeting and CD3 engagement with a co-stimulatory signal such as CD28 or 4-1BB to strengthen T-cell activation.
Multiple myeloma is the most advanced area of development, with early studies evaluating BCMA×CD38×CD3 and BCMA×GPRC5D×CD3 constructs. Early phase 1 studies have reported activity in heavily pretreated patients, but the cohorts are small and follow-up remains limited. The available evidence does not yet support reliable comparisons with approved bispecific antibodies.
B-cell trispecific constructs targeting CD19×CD3×CD2, CD20×CD3×CD8, and CD38×CD3×CD28 are in active clinical trials.
The real test for trispecific antibodies will not be whether they can produce responses. They must show that the third specificity improves response durability, reduces antigen escape, preserves tolerability or extends survival. Greater molecular complexity will only be justified if it produces a clear clinical advantage.
Moving into Earlier Treatment Lines
One rationale for earlier use is the possibility that immune function may be better preserved earlier in the disease course. Whether this translates into greater efficacy or better long-term outcomes remains under investigation.
In newly diagnosed multiple myeloma, the phase 2 MajesTEC-5 study evaluated teclistamab with daratumumab and lenalidomide, with or without bortezomib, in 49 transplant-eligible patients. All patients responded, and 91.8% achieved an MRD-negative complete response by the premaintenance assessment. These results demonstrate substantial depth of response, but the study was small, nonrandomized and had limited follow-up to evaluate progression-free and overall survival.
Other studies are testing elranatamab in transplant-ineligible or transplant-deferred newly diagnosed myeloma and in high-risk smoldering myeloma.[7,8] In the latter study, time to active myeloma is a secondary endpoint, reflecting the aim of determining whether earlier intervention can delay progression. Current follow-up is too short to establish that outcome. Treating patients before symptomatic disease develops demands a more favorable benefit-risk balance than treatment in patients with relapsed disease.
The first-line B-cell NHL strategy differs by subtype. In a phase 2 study of previously untreated, high-tumor-burden follicular lymphoma, subcutaneous mosunetuzumab produced a 95% overall response rate and an 80% complete response rate, with an estimated 12-month progression-free survival rate of 88%. A randomized phase 3 study is now comparing mosunetuzumab with rituximab in low-tumor-burden follicular lymphoma.
The distinction between low- and high-tumor-burden follicular lymphoma is important. Patients with low-burden disease may not need immediate treatment, and when treatment is chosen, rituximab monotherapy is one established option. In higher-burden disease, combination chemo-immunotherapy is more common. Bispecific studies are therefore asking different questions in these groups: whether treatment can control disease without chemotherapy in patients who need therapy, and whether a short, fixed-duration course can limit treatment exposure while leaving future options available. Mosunetuzumab is also being studied with lenalidomide induction followed by mosunetuzumab maintenance. This reflects a broader effort to identify combinations that deepen response without returning to conventional chemotherapy.
Diffuse large B-cell lymphoma presents a higher threshold because first-line chemoimmunotherapy already cures many patients. Epcoritamab is being studied as an alternative for older patients who cannot receive anthracyclines. In patients eligible for standard treatment, results from bispecific combinations have been mixed. Mosunetuzumab plus Pola-CHP did not demonstrate an advantage over Pola-R-CHP and produced more serious adverse events, whereas the single-arm COALITION study reported encouraging activity with glofitamab combined with R-CHOP or Pola-R-CHP. Randomized evidence will be needed to determine which combinations and patient groups derive meaningful benefit.
Together, these studies show that moving bispecific antibodies earlier cannot follow a single formula. The disease subtype, existing standard, selected combination and duration of treatment all influence whether a regimen adds meaningful benefit.
Safety, Treatment Burden and Quality of Life
Cytokine release syndrome is the most common acute immune-mediated toxicity, while ICANS is less frequent but can be serious. Step-up dosing, premedication and established management pathways have made these events more predictable. With wider use, however, longer-term immune suppression has become at least as important as acute toxicity.
Infections, hypogammaglobulinemia and cytopenias are major concerns, particularly with BCMA-directed treatment, with trial findings supporting proactive antimicrobial prophylaxis, immunoglobulin replacement where appropriate and close monitoring.
A subcutaneous route of administration can reduce treatment burden significantly, though repeated visits, monitoring and infection management still create a treatment burden. Patient-reported outcomes from MajesTEC-1 showed that the proportion of patients reporting clinically meaningful improvement increased over time; improvements in pain were reported by at least 40% of patients at most assessment points. These data suggest that clinical response can translate into symptom benefit.
The Next Phase of Development
Bispecific antibodies have established a role in relapsed and refractory B-cell NHL and multiple myeloma. The next phase will be more demanding. Earlier-line studies must show that deeper responses translate into durable benefit, while controlling infection risk and treatment burden. Trial design must also account for major biological differences between indolent lymphoma, aggressive lymphoma and myeloma.
Three questions now matter most: Can earlier use improve progression-free or overall survival? Can treatment duration and immune suppression be reduced without losing efficacy? And can trispecific antibodies demonstrate a measurable advantage over established bispecific approaches?
As we get additional clinical evidence, multispecific therapies are likely to become more personalized, matched more precisely to disease biology, prior target exposure and patient fitness. This evolution is shifting the field from proving that T-cell redirection works to designing treatments that deliver deeper and more durable responses for patients across blood cancers.
References
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