The treatment landscape for relapsed/refractory multiple myeloma (RRMM) has evolved significantly with the emergence of T-cell engaging therapies, prompting experts to establish guidelines for optimal sequencing and bridging strategies to maximize patient outcomes.
CAR T vs Bispecific Antibodies: Sequencing Considerations
Recent guidelines from the International Myeloma Working Group (IMWG) and American Society of Clinical Oncology (ASCO) recommend using chimeric antigen receptor (CAR) T-cell therapy before bispecific antibodies when feasible. This recommendation is based on CAR T's potential to deliver deeper and more durable responses in eligible patients.
"CAR T therapy offers the possibility of long-term disease control in a single treatment session, which makes it an attractive first option for eligible patients who can wait for the manufacturing process," explains clinical experts in the field.
In practice, the decision between these therapies depends on several factors. CAR T is preferred when patients have stable disease and can manage the waiting period for cell manufacturing. Conversely, bispecific antibodies become the treatment of choice when rapid disease control is necessary or when patients are not candidates for CAR T therapy.
Bridging and Holding Strategies
For patients awaiting CAR T therapy, clinicians must decide between bridging and holding strategies based on disease characteristics:
- Bridging therapy actively controls aggressive disease during the CAR T manufacturing period
- Holding therapy aims to stabilize less aggressive disease while minimizing immune suppression
The distinction is crucial, as the choice of interim therapy can impact the success of subsequent CAR T treatment.
Optimal Bridging Therapy Options
Several options exist for bridging therapy, each with distinct considerations:
Bispecific Antibodies
B-cell maturation antigen (BCMA)-targeted bispecifics like teclistamab and elranatamab have demonstrated efficacy in controlling disease. However, using these agents before BCMA-directed CAR T therapy raises concerns about potential antigen competition.
GPRC5D-targeted bispecifics such as talquetamab offer an alternative approach. "When bridging to BCMA-directed CAR T therapy, targeting a different antigen like GPRC5D with talquetamab may preserve the efficacy of the subsequent CAR T treatment," note myeloma specialists.
Selinexor-Based Regimens
Selinexor combinations have shown activity in refractory disease and may synergize with proteasome inhibitors. Data from the BOSTON, STOMP, and COSTA analyses suggest these regimens may support favorable outcomes with subsequent CAR T therapy.
Conventional Approaches
More traditional options include:
- Cytotoxic chemotherapy regimens (VD-PACE, DCEP + IMiD) for aggressive disease, though these may impair bone marrow and T-cell function
- Radiation therapy for localized disease or symptom management
Disease Progression Rate: A Key Decision Factor
The rate of disease progression has emerged as a critical factor in treatment selection for RRMM patients:
- Patients with rapidly progressing disease benefit from the immediate availability of bispecific antibodies, which can be administered without manufacturing delays
- Those with slower progression may be better candidates for CAR T therapy, allowing time for the manufacturing process while offering potential for durable responses
"Understanding the kinetics of disease progression helps us match the right therapy to the right patient at the right time," explains myeloma experts. "This personalized approach optimizes outcomes while managing the practical constraints of novel immunotherapies."
Comprehensive Treatment Landscape
Beyond T-cell engaging therapies, the RRMM treatment arsenal includes:
- Second autologous stem cell transplantation for select patients with favorable performance status and durable initial response
- Specific CAR T products including idecabtagene vicleucel (ide-cel), supported by KarMMa-3 trial data, and ciltacabtagene autoleucel (cilta-cel) from the CARTITUDE-4 study
Future Directions
As experience with these therapies grows, the focus is shifting toward optimizing sequencing strategies and developing predictive models to guide treatment selection. Ongoing research aims to identify biomarkers that can predict response to specific therapies and inform personalized treatment approaches.
The evolving treatment paradigm emphasizes tailoring therapy based on disease characteristics, prior treatments, and patient-specific factors, with growing emphasis on strategic sequencing to maximize the benefit of novel immunotherapies in RRMM.
