Integrating CAR T and Bispecific Antibodies in MM Treatment

Medscape

4 hours ago

MILAN — The treatment landscape for relapsed and refractory multiple myeloma (RRMM) has shifted dramatically with the emergence of immunotherapies such as chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (bsAbs). These novel approaches have delivered unprecedented outcomes in heavily pretreated patients. Yet determining the optimal treatment strategy remains a clinical challenge.
Here at the 2025 European Hematology Association (EHA) Annual Meeting in Milan, Italy, leading experts weighed the strengths and limitations of both approaches, emphasizing that it is not a contest of superiority but a question of sequence and patient selection.
Bispecific Antibodies: Off-the-Shelf Convenience With Strong Responses
BsAbs work by redirecting T cells toward myeloma cells, binding simultaneously to a tumor antigen and CD3. In his presentation, Philippe Moreau, MD, head of the hematology department at the University Hospital of Nantes, France, reviewed the four agents approved in Europe: teclistamab, elranatamab, and linvoseltamab, which target beta cell maturation antigen (BCMA); and talquetamab, which targets G protein-coupled receptor class C group 5 member D (GPRC5D).
These agents deliver overall response rates (ORRs) of 60%-70% in heavily pretreated patients, with median progression-free survival (PFS) of 12-18 months and overall survival (OS) of 24-30 months. Talquetamab in particular induces rapid responses within 1 month but is associated with unique toxicities — such as skin reactions, dysgeusia, and mucosal effects — related to GPRC5D expression in nonhematopoietic tissues like skin.
BsAbs offer immediate treatment without the delays associated with CAR T manufacturing. They are also viable for frail patients and more broadly accessible outside of specialized centers. Toxicities, including cytokine release syndrome and infections, are generally manageable with step-up dosing and prophylactic tocilizumab.
However, resistance remains a main concern. Roughly one third of patients — particularly those with high-risk cytogenetics, International Staging System stage III disease, or extramedullary disease — exhibit primary resistance.
CAR T-Cell Therapy: Durable Outcomes With Earlier Use
CAR T-cell therapies have redefined expectations in RRMM, particularly with ciltacabtagene autoleucel, which has achieved a median PFS of 35 months and a median OS approaching 61 months in heavily pretreated populations. Notably, recent data show that one third of patients remain progression-free at 5 years: an unprecedented milestone.
'Phase 3 trials now show improved PFS, OS, and quality of life compared to standard-of-care regimens,' said Paula Rodriguez-Otero, MD, medical coordinator of the Central Unit for Clinical Trials at the University of Navarra, Pamplona, Spain.
However, CAR T therapy faces logistical hurdles, including manufacturing delays and the need for specialized infrastructure. High-risk patients with rapid progression or poor bridging therapy responses may still experience suboptimal results, but these challenges are mitigated when CAR T therapy is used earlier in the disease course, before T-cell exhaustion occurs.
It's Not One or the Other
Both speakers agreed that the future of MM treatment is not about choosing between CAR T and bsAbs but about defining the optimal sequence and integrating both modalities based on patient needs and disease features.
BsAbs offer fast, outpatient-ready options for frail or rapidly progressing patients. CAR T therapies, though more complex, offer long remissions and potential treatment-free intervals, especially when used early.
Still, Moreau cautioned, many questions remain. What is the best treatment sequence? Should clinicians switch targets — for example from BCMA to GPRC5D — or stick with the same? How should resistance mechanisms, such as antigen loss, be tackled? Can we move toward fixed-duration therapy to reduce costs?
Scientific progress must also account for patient priorities. As Solène Clavreul, PhD, noted in an interview with Medscape Medical News , longer survival for myeloma patients means that quality of life is increasingly central. Clavreul is patient advocate and head of medical education and scientific engagement at Myeloma Patients Europe. 'The treatment choices should always be based on research data, but understanding patients' preferences is critical for shared decision-making,' she said.
What's Next: BsAb Combinations and Trispecifics
'With 19 new drugs or combinations approved in the past two decades, we've made incredible progress,' said Jesús San Miguel Izquierdo, MD, PhD, director of clinical and translational medicine at the University of Navarra, Pamplona, Spain, in his EHA 2025 Lifetime Achievement Award lecture.
Two industry-sponsored studies presented at EHA 2025 point to the next wave of innovation.
RedirecTT-1: Dual-Antigen BsAb Combination
The phase 2 RedirecTT-1 trial evaluated the combination of talquetamab and teclistamab in patients with extramedullary disease.
'Patients with true extramedullary disease are up to 87% less likely to respond to conventional therapy,' said Shaji Kumar, MD, consultant, professor, and researcher at the Mayo Clinic, Rochester, USA.
The combination treatment in the trial yielded an ORR of 78.9% and a complete response rate of 54.4%, with a 12-month PFS rate of 61% and OS rate of 74.5%. Adverse events were not significantly higher than in monotherapy trials, and less frequent dosing (biweekly or monthly) improved tolerability.
'These results showed deep and durable responses in a population with a significant unmet need,' Kumar said.
Moreau, who was not involved in the study, added, 'This could be the pivotal trial that leads to approval of the first bsAb combination.'
JNJ-5322: First-in-Human Trispecific Antibody
JNJ-5322, a trispecific antibody targeting both BCMA and GPRC5D, showed remarkable efficacy in BCMA/GPRC5D-naive patients in a phase 1 trial.
'Despite recent progress, we still need to reduce treatment burden and improve outcomes,' said Rakesh Popat, MD, hematologist at University College Hospital, London, UK.
Among patients with triple-class exposed RRMM, the ORR was 100%, with a 70.4% complete response rate and 12-month PFS of 95%. Grade 3/4 infections occurred in 28.6% of patients, but the safety profile — including mild cytokine release syndrome — was manageable.
'JNJ-5322 demonstrated manageable safety and an ORR comparable to CAR T, with convenient, off-the-shelf, weekly dosing, with one step-up dosing to facilitate outpatient dosing,' Popat concluded.
Popat, Clavreul, and Kumar reported no relevant financial relationships. Moreaureported honoraria from and advisory board memberships with Janssen, Celgene, Takeda, Amgen, AbbVie, Sanofi, Pfizer, and GSK. Rodriguez Otero reported honoraria from lectures from BMS-Celgene, J&J Innovative Medicines, Sanofi, GSK, Regeneron, and Pfizer; participation in Ad Board meetings for BMS, Janssen, Sanofi, Oncopeptides, Pfizer, Roche, Regeneron, AbbVie, AstraZeneca, H3 Biomedicine, and GSK; consultancy work for BMS-Celgene, AbbVie, Roche, J&J Innovative Medicines, and Pfizer; and research funding and travel support from Pfizer. San Miguel Izquierdo reported participation on advisory boards and consulting services, on behalf of his institution, for AbbVie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Pfizer, Takeda, Regeneron, Roche, Sanofi, Secura Bio, and Gilead-Kite.
The two industry-sponsored studies mentioned were funded by Johnson & Johnson.