Bispecific T-cell engagers are transforming multiple myeloma treatment, but their effectiveness varies significantly based on treatment setting and patient selection, according to insights shared at the 2025 Immune Cell Effector Therapy (ICE-T) Conference.
Dr. Shebli Atrash, medical oncologist at Levine Cancer Institute and clinical associate professor of Medicine at Wake Forest University, emphasized that strategic positioning of these agents is crucial for optimizing patient outcomes. His analysis reveals that using talquetamab-tgvs (Talvey), a GPRC5D bispecific antibody, as a pre-CAR T therapy can help control myeloma while reducing the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
Treatment Setting Impacts Efficacy
The timing and clinical context of bispecific T-cell engager administration significantly influence treatment outcomes. Atrash noted that using bispecifics in patients with rapidly progressing disease and high disease burden may not provide the same level of efficacy or clinical benefit compared to other patient populations.
"Using those bispecific [T-cell] engagers in the right setting is important," Atrash explained. "For example, utilizing talquetamab, a GPRC5D bispecific antibody, as a pre-CAR T drug to control myeloma prior to administering CAR T has helped us with decreasing CRS and ICANS."
His experience with teclistamab further illustrates this variability, as the agent demonstrated reduced efficacy when used in patients with rapidly progressing disease and large disease burden.
Advantages and Challenges
T-cell engagers have produced deep responses not previously seen with other agents in multiple myeloma treatment. The advantages include fewer overall adverse effects, more convenient administration involving a single drug with fewer steroids, and more durable responses compared to standard therapies.
However, infections represent the primary disadvantage of bispecific T-cell engagers. BCMA-targeting bispecifics commonly cause infections, while GPRC5D-targeting agents are associated with skin rash, dysgeusia, weight loss, and nail changes.
Understanding Treatment Resistance
A significant challenge in the field involves the approximately 30% of patients who do not respond to bispecific T-cell engager treatment. Atrash observed that survival curves show a drop of about 30% in the first month or two of treatment, indicating early treatment failure in this subset of patients.
"Predicting who [make up that] 30% is important, and this has to do with the host immune system, fitness, as well as the cancer cell soluble BCMA levels," he stated.
Future Treatment Strategies
To address prolonged adverse effects, particularly infections, researchers are exploring fixed-duration treatment approaches. These strategies involve treating patients with bispecific antibodies for a defined period, such as one to two years, followed by observation periods.
While these fixed-duration concepts remain in early development, multiple trials are investigating this approach as a potential solution to mitigate infection-related complications while maintaining therapeutic benefit.
The evolving understanding of bispecific T-cell engagers in multiple myeloma underscores the importance of patient selection, treatment timing, and the need for predictive biomarkers to identify optimal candidates for these transformative therapies.
