Dr Cirstea on Sequencing Considerations in R/R Multiple Myeloma

[Sequencing] no longer means simply CAR T vs bispecific. What it means is that you have to be able to choose the right immune therapy at the right time, based on the disease tempo, the target exposure, patient fitness, logistics, and future options.

Diana Cirstea, MD, an attending physician in the Center for Multiple Myeloma at Massachusetts General Hospital, as well as an assistant professor of medicine at Harvard Medical School, discussed sequencing considerations in relapsed or refractory multiple myeloma in the era of T-cell–redirecting therapies.

Cirstea outlined how sequencing considerations in multiple myeloma have evolved significantly, emphasizing that treatment decisions are no longer centered simply on choosing between CAR T-cell therapy and bispecific antibodies. Rather, she explained that clinicians needed to select the right immune-based therapy at the appropriate time based on several patient and disease factors, including disease tempo, prior target exposure, patient fitness, logistical considerations, and the availability of future treatment options.

She noted that for fit patients with controlled disease who could tolerate the manufacturing wait time, CAR T-cell therapy could potentially offer the best opportunity for achieving deep, treatment-free, and durable responses. In contrast, for patients with rapidly progressive disease who could not wait for cell manufacturing associated with CAR T-cell therapy, an off-the-shelf bispecific antibody–based approach may represent a more practical and clinically appropriate option.

Cirstea further emphasized that sequencing questions had become increasingly complex as bispecific combinations moved into earlier lines of therapy. She referenced emerging data from studies such as the phase 3 MajesTEC-3 (NCT05083169), which supported the March 2026 FDA approval of teclistamab-cqyv (Tecvayli) in combination with daratumumab and hyaluronidase-fihj (Darzalex Faspro) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy. In this context, she highlighted the importance of preserving both antigen target expression and T-cell fitness when patients were exposed to multiple BCMA-directed therapies over time.

To address these challenges, Cirstea described several evolving strategies, including approaches involving therapies directed against alternative targets such as GPRC5D and FcRH5, as well as dual-targeted strategies to overcome resistance associated with prior exposure to BCMA-directed therapy. She also discussed the concept of finite-duration bispecific therapy rather than indefinite continuous treatment, allowing treatment-free intervals during which standard therapies could be used to facilitate T-cell recovery before subsequent immune-based interventions.

Finally, Cirstea observed that logistical considerations would likely become increasingly important as bispecific antibodies moved into earlier disease settings, including smoldering myeloma and frontline treatment, largely because the off-the-shelf availability of bispecific therapies may simplify treatment delivery compared with CAR T-cell approaches.