Chimeric antigen receptor T-cell (CAR T-cell) therapy, in which a patient's own T-cells are collected and then genetically modified to recognize specific antigens on cancer cells, is an approved treatment for relapsed and refractory multiple myeloma (MM). Idecabtagene vicleucel (ide-cel, Abecma) and ciltacabtagene autoleucel (cilta-cel, Carvykti) are B-cell maturation antigen (BCMA) targeting CAR T-cell therapy products that initially gained approval for MM in patients that had four or more lines of therapy. However, in early 2024, both products were approved for earlier lines (ide-cel: two prior lines, cilta-cel: one prior line) based on positive results from two phase III studies demonstrating improvement in outcomes of these CAR T-cell therapies compared to standard of care combination regimens (ref). This has led to a steady increase in use of CAR T-cell therapy as a treatment option for MM patients.
However, despite achieving high rates of minimal residual disease negativity and improvement in progression-free and overall survival, CAR T-cell therapy in multiple myeloma has not proven to be curative, highlighting the unmet need to further improve upon the benefit seen with these therapies. This is an area of active bench and clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. We are evaluating strategies to improve the CAR T-cell product to enhance efficacy and safety, study novel antigens, and use these therapies in earlier disease states, including newly-diagnosed MM and high-risk smoldering myeloma.
Cilta-cel is currently being studied in the Dana-Farber-led CAR-PRISM trial (NCT05767359), which is evaluating its efficacy in high-risk smoldering myeloma, a precursor state that carries a high risk of progression to symptomatic disease. This clinical trial will study two dose levels of cilta-cel in this patient population to determine safety and then will have an expansion cohort to study efficacy of this approach in this high-risk patient population. The preliminary results were presented at the 2024 ASH Annual Meeting in San Diego, CA.
As quadruplet-based combination therapies continue to show improvement in outcomes in newly-diagnosed multiple myeloma, the role of autologous stem cell transplantation (ASCT) continues to evolve. In the CARTITUDE-6 trial (NCT05257083) being conducted at Dana-Farber, CAR T-cell therapy with cilta-cel is being compared head-to-head to ASCT after induction therapy with daratumumab, lenalidomide, bortezomib, and dexamethasone in newly diagnosed MM. This trial will inform us regarding the comparative efficacy and safety of these approaches in the newly diagnosed setting.
GPRC5D is a novel target that is highly expressed on plasma cells and was discovered by Dana-Farber researcher, Eric Smith, MD, PhD. There is already an approved bispecific T-cell engager, talquetamab, that targets GPRC5D in relapsed and refractory MM. While talquetamab has demonstrated efficacy, there are on-target, off-tumor toxicities including dysgeusia, weight loss, and skin and nail bed changes that can impact quality of life. Our group is leading development of a CAR T-cell therapy targeting GPRC5D with Arlocabtagene autoleucel. A phase I study conducted at Dana-Farber demonstrated high response rates in heavily pre-treated patients, including those that have had prior BCMA-directed therapies, with lower rates of the on-target, off-tumor toxicities. This product is now being investigated in phase II and III trials and also in earlier disease states.
Our team is highly experienced in delivering CAR T-cell therapy for patients with multiple myeloma through a robust and growing outpatient program, allowing more and more patients to be treated with these exciting and effective therapies.
