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T-cell engaging immunotherapies are emerging as highly targeted therapies for patients with hematological malignancies, including multiple myeloma. To date, three T-cell engagers (TCEs) have been approved in relapsed/refractory (R/R) multiple myeloma, all of which target the B cell maturation antigen (BCMA); the chimeric antigen receptor (CAR)-T therapies ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), and the bispecific antibody (BsAb) teclistamab.
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.”
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).
Dr Trudel notes that many BCMA-targeted BsAbs evaluated in clinic have a similar ORR of roughly 65%, “suggesting that the mechanisms of resistance may be similar to all of this class of drugs.” Some of the proposed mechanisms she discusses include tumor-related factors such as antigen loss, as well as T-cell characteristics and immune microenviroment, which investigators are attempting to overcome by combining agents. Combinations undertaken with teclistamab so far include the addition of daratumumab, and combination of teclistamab, lenalidomide and dexamethasone.
Though Dr Trudel explains that cytokine release syndrome (CRS) and neurotoxicity rates are lower with BCMA-targeted BsAbs than with BCMA-targeted CAR-Ts, neutropenia and anemia are commonly reported at both grades 1-2 and 3-4, and “infections remain the Achilles heel of BCMA-targeted bispecifics.”
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%.”
He notes that elranatamab is a “very effective therapy in heavily pretreated population,” but that concerns about infection remain, as they were reported in 66.7% of patients in MagnetisMM-3.
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.
Prof. Lin highlights how the results of ide-cel in the real-world are comparing to those from KarMMa (NCT03361748). For instance, in a large US consortium of 150 patients where 75% had organ dysfunctions or disease characteristics that would have excluded them from KarMMa, the manufacturing failure rate was quite low. Additionally, says Prof. Lin, the ORR and rates of adverse events such as CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) are fairly comparable to KarMMa, though response rate is decreased in those who had been previously exposed to BCMA-targeted therapy or had high-risk disease features.
Prof. Lin also explores the prognostic role of measurable residual disease negativity (MRD-) and free light chain (FLC) in patients treated with CAR-T, and how these may help inform risk-adapted intervention to extend and deepen response. Prof. Lin also highlights trials such as KarMMa-2 (NCT03601078) and KarMMa-3 (NCT03651128) being undertaken to bring ide-cel into earlier lines of therapy, and efforts to overcome challenges associated with the limited manufacturing slots available for CAR-T.
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.
Dr Cohen also highlights ongoing studies that aim to answer some of the pressing questions surrounding the use of BCMA-targeting CAR-T, including CARTITUDE-2 (NCT04133636), exploring the use of cilta-cel in patients with different degrees of pre-treatment; CARTITUDE-4 (NCT04181827) comparing cilta-cel to physician’s choice of triplet therapy; CARTITUDE-5 (NCT04923893) assessing cilta-cel as a frontline treatment in those ineligible for transplant; and CARTITUDE-6 (NCT05257083) comparing cilta–cel to transplant.
In order to overcome BCMA-targeted therapy resistance and relapse, GPRC5D has been identified as a promising target for therapy, as Eric Smith, MD, PhD, Dana-Farber Cancer Institute, Boston, MA, explains in this video.
Dr Smith explores the development of GPRC5D-targeted CAR-T therapy, presenting results from the first-in-human trial of one such construct, and a multi-center study that was conducted in a population with a large percentage of patients with high-risk cytogenetics and with extramedullary plasmacytoma. In the later trial, he reports: “there was a 89.5% ORR across all of the dose levels, including approximately half of the patients that achieved a CR.” Dr Smith adds that though “GPRC5D is an attractive target for immunotherapy of myeloma,” questions around treatment sequencing and the potential for combining GPRC5D and BCMA-targeting agents remain.
Dr Smith also discusses the safety of the product, with CRS being common but typically low grade, on-target off-tumor toxicities to the nail and skin being mild, and infections occurring at a lower rate than with some BCMA-targeted therapies.
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.”
Overall, the development of both bispecific and CAR-T TCEs is helping overcome the unmet needs of patients with triple–class exposed and refractory multiple myeloma. However, questions remain about the optimal positioning of these TCEs within the treatment paradigm, whether their safety profile supports their shift into earlier treatment lines, and how they can complement one another in providing a potential cure for patients with multiple myeloma.
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