Developments in the TCE field were a highlight of discussion at the iwMyeloma meeting 2023, and in this video, María-Victoria Mateos, MD, PhD, University Hospital of Salamanca, Salamanca, Spain, examines the current TCEs approved and under development for triple-class exposed and refractory patients – a population which continues to have high unmet need. 

In addition to discussing the available targets for TCEs, including BCMA, GPRC5D and FCRH5, Dr Mateos also explains the key considerations when selecting between CAR-T or BsAbs, with the main considerations being efficacy, safety, and patient characteristics. 

She also highlights key themes in TCE research: “What is the future? The TCEs will definitely move to the earlier lines of therapy, and we have some Phase III clinical trials ongoing in patients after one to three prior lines of therapy.” 

Teclistamab

In her presentation, Suzanne Trudel, MD, FRCPC, Princess Margaret Hospital, Toronto, Canada, discusses BCMA-targeting BsAbs focusing on teclistamab, “a BsAb that targets BCMA on myeloma cells and CD3 allowing for T-cell redirected cytotoxicity.” Teclistamab was approved based on the MajesTEC-1 study (NCT04557098), where in a heavily pre-treated patient population objective response rate (ORR) was 63%, median progression-free survival (PFS) 11.3 months and many achieved a very good partial response (VGPR). 

Elranatamab 

The BCMA-targeting bispecific TCE elranatamab is discussed by Nizar Bahlis, MD, University of Calgary, Calgary, Canada, in this video as having a “very promising” ORR of 64% in the MagnetisMM-1 Phase I trial (NCT03269136) in which over half of the patients were previously exposed to BCMA-targeted therapy: “the median PFS on this trial was 11.9 months, and among responders the median duration of response (mDOR) was 17.1 months.” 

In the MagnetisMM-3 follow up study (NCT04649359), where over half of the patients were non-BCMA-targeted therapy exposed, Dr Bahlis states the ORR was 61%, including 27% complete remission (CR). Dr Bahlis also emphasized that responses were seen irrespective of line of therapy, age, or Eastern Cooperative Oncology Group (ECOG) status, and that the responses were durable and deepening over time: “overall was 84.4% at nine months, and at nine months PFS was 63%.” 

Ide-cel

In this presentation from iwMyeloma, Yi Lin, MD, PhD, Mayo Clinic, Rochester, MN, discusses the application of ide-cel, one of the two approved BCMA-targeting CAR-T therapies, in patients with R/R myeloma. 

Cilta-cel

In this video, Adam Cohen, MD, University of Pennsylvania, Philadelphia, PA, presents on cilta-cel, exploring the long-term follow up data from the LEGEND-2 Phase I/II trial (NCT03090659), which enrolled patients with less heavily pre-treated disease, but higher rates of extramedullary and high-risk disease: “What we saw in this long term follow up experience was that the mDOR was now reached at a little under two years and median PFS was 18 months, though it was significantly better in those three-quarters of patients who achieved a CR.” Dr Cohen adds that “there are a number of patients that are now getting out three and close to four years who have not yet relapsed,” even though there is no real plateau in the survival curve. 

Dr Cohen also discusses the two-year follow-up from CARTITUDE-1 (NCT03548207), “Median six prior lines of therapy, 98% response rate, 82% CR or better.… The median PFS had not been reached at the time of this follow up, with about 55% of patients still alive and progression free at 27 months, and OS looking around 75%.” 

Dr Cohen goes onto discuss the importance of sustained MRD- in CAR-T treated patients, and comments on neurotoxicity with cilta-cel in CARTITUDE-1: “about 21% of patients had any neurotoxicity in this study; 16 had the classic ICANS which occurred around the time of CRS or shortly thereafter. But 12 patients developed delayed or late neurotoxicity.” Of those patients, seven developed conditions that were largely reversible and mild, but five developed a movement to neurocognitive disorder, called Parkinsonism: “one of the key features that stood out from these five patients was a very high CAR-T cell expansion, far beyond what was seen with the other groups, and that seemed to be more persistent as well.” As a result, mitigation strategies are being implemented in future studies, but the optimal time to implement these, as well as how to treat Parkinsonism, are under debate. 

Talquetamab

Another therapeutic in the GPRC5D-targeting space is the BsAb talquetamab, which Paula Rodriguez-Otero, MD, PhD, University Clinic of Navarra, Pamplona, Spain, discusses in her presentation. In the heavily pretreated population of the Phase I/II MonumenTAL-1 trial (NCT03399799/NCT04634552), all of which were triple-class exposed and the majority were triple-class refractory, the “ORR is quite encouraging; 74.1% for the patients that were treated with the 400 µg weekly and 73.1% for patients treated in the 800 µg every other week, with close to 60% of the patients achieving at least VGPR and close to 35% of the patients achieving CR or stringent CR.” 

Additionally, comments Dr Rodriguez-Otero, “patients that were treated with the 400 µg weekly had a median PFS of 7.5 months and patients that were treated with the 800 µg every other week had a median PFS of 12 months.”