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ASH2025 BsAb MM
Key Updates on Bispecific Antibody Therapy in Relapsed/Refractory Multiple Myeloma From ASH 2025

Released: December 31, 2025

Caitlin Costello
Caitlin Costello, MD
Jens Hillengass
Jens Hillengass, MD, PhD
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Key Takeaways
  • In the phase III MajesTEC-3 trial, the combination of daratumumab plus teclistamab significantly improved PFS and OS vs standard daratumumab-based regimens in patients with 1-3 prior lines of MM therapy, most of whom were anti-CD38 antibody naive.
  • Dual targeting with talquetamab plus teclistamab produced deep, durable responses across EMD sites in patients with triple class–exposed R/R MM and true EMD in the phase II RedirecTT-1 trial.

Although there are now 4 bispecific antibody (BsAb) agents approved for use in relapsed/refractory (R/R) multiple myeloma (MM) after at least 4 prior lines of therapy, important questions remain regarding their optimal integration into care, including the role of combination strategies, treatment sequencing, and identification of patient subgroups most likely to benefit. In addition, there remains a critical need for randomized data evaluating earlier use of BsAbs and their incorporation into combination regimens for patients with MM.

MajesTEC-3: Teclistamab Plus Daratumumab vs Daratumumab-Based Regimens in Patients With R/R MM

Caitlin Costello, MD:
MajesTEC-3 is a randomized phase III trial investigating the efficacy of daratumumab plus teclistamab vs investigator’s choice of daratumumab and dexamethasone with either pomalidomide or bortezomib in patients with MM who have received 1-3 prior lines of therapy. Although there are multiple treatment options for these patients, the experimental regimen combines 2 drugs that are very effective as monotherapies and have a reasonable safety profile. Furthermore, these 2 drugs are expected to be synergistic in their mechanism of action. 

One challenge when interpreting the outcomes of MajesTEC-3 is that in the United States, most patients will have been exposed to one of the 2 available CD38 antibodies (daratumumab or isatuximab) after frontline treatment, and a significant number will be refractory to at least 1. In MajesTEC-3, only approximately 5% of patients on either arm had prior therapy with an anti-CD38 antibody, and for obvious reasons, these patients could not be refractory to anti-CD38 antibody therapy.

When looking at the primary endpoint, progression-free survival (PFS), the combination of daratumumab and teclistamab was significantly more effective, with a 36-month PFS rate of 83.4% vs only 29.7% in the standard-of-care arm. Overall survival (OS), a secondary endpoint, was also significantly better with the combination, with 36-month OS rates of 83.3% in the experimental arm and 65.0% in the standard-of-care arm. This superiority of teclistamab with daratumumab was seen across all prespecified subgroups. The combination treatment was slightly more toxic, with more cytopenias and infections, but these seemed to be manageable. After amending the protocol to more strongly recommend intravenous immunoglobulin replacement, there was only 1 additional death due to infection.

MajesTEC-3: Clinical Implications 

Jens Hillengass, MD, PhD:
The combination of daratumumab and teclistamab is an excellent treatment option for patients with R/R MM, with the major limitation being that most patients at present will have been pretreated with daratumumab, so data for this group of patients will be important. Furthermore, with the availability of ciltacabtagene autoleucel as a BCMA-directed CAR-T cell therapy, it is unclear which of these 2 options would be preferred. There are concerns that long-term therapy with BsAbs like teclistamab might cause T-cell exhaustion, which would make CAR T-cell therapy afterwards potentially less effective. However, these data still underline the excellent efficacy and manageable toxicity of these agents, especially in combination, and will certainly lead to further improvements in patient outcomes and, hopefully, ultimately to a cure.

RedirecTT-1 Update: Talquetamab Plus Teclistamab in R/R MM With Extramedullary Disease

Caitlin Costello, MD:
Extramedullary disease (EMD), defined by soft tissue or organ-associated plasmacytomas that are not contiguous with bone, is associated with poor outcomes in patients with R/R MM. Prior data suggest that dual BsAb targeting may be beneficial in this setting, as GPRC5D and BCMA are heterogeneously expressed across EMD lesions. This provides a strong biologic rationale for combining agents with complementary targets. The phase II RedirecTT-1 trial is evaluating the combination of the anti-GPRC5D BsAb talquetamab and the anti-BCMA BsAb teclistamab in patients with R/R MM.

At the 2025 American Society of Hematology annual meeting, updated analyses from this trial reported outcomes in the EMD cohort after a median follow-up of 16.8 months. An important aspect of the study design is the emphasis on imaging, which is particularly critical for assessing response in patients with soft tissue and extramedullary lesions. To ensure consistency and accuracy, the RedirecTT-1 trial incorporated centralized radiologic image review and used standardized IMPETUS and Deauville criteria for response assessment.

With an overall response rate of 79% and 62.1% of patients remaining in remission at 12 months, this trial demonstrates highly encouraging activity in a population with otherwise limited treatment options and historically poor outcomes. Of note, baseline tumor burden correlated with response, with overall response rates of 93%, 67%, and 65% among patients with tumor volumes of <25 cm², 25-50 cm², and >50 cm², respectively. The safety profile was consistent with that of the individual agents, with infections representing a key toxicity that required appropriate prophylaxis and management.

RedirecTT-1: Clinical Implications and Real-world Considerations 

Jens Hillengass, MD, PhD:
Although this dual-BsAb combination was generally well tolerated, its use raises important considerations related to logistics and potential treatment burden, as both agents are administered over extended periods (until treatment progression in this trial). Future studies will determine whether limited-duration therapy, treatment de-escalation, or discontinuation after sustained remission can preserve these favorable outcomes while reducing treatment burden.

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