CAR T-Cell Therapy a Story of Opportunities and Challenges in MM

Chimeric antigen receptor (CAR) T-cell therapies have significant potential to change the treatment landscape for patients with multiple myeloma (MM), but a new review article notes that the therapeutic strategy is significantly limited by challenges—both logistical and clinical.

Writing in Blood and Lymphatic Cancer: Targets and Therapy, corresponding author Christin B. DeStefano, MD, of Walter Reed National Military Medical Center, and colleagues, said novel therapies have led to improvements in outcomes for people with MM, and CAR T-cell therapies may further improve survival rates, particularly for people with refractory disease.

“[Y]et their logistical and clinical limitations must be acknowledged to further improve patient outcomes,” DeStefano and colleagues cautioned.

The technology that developed into CAR T-cell therapies has been around for more than 3 decades, but the first CAR T-cell therapy for MM was not approved by the FDA until last year. The therapy involves taking a patient’s T cells and genetically modifying them before infusing them back into the patient.

“After infusion, CAR T-cells bind their target antigen(s), proliferate, release tumor antigens, induce epitope spreading, and recruit other immune cells, ultimately orchestrating a multi- faceted immune response resulting in robust cell kill,” DeStefano and colleagues said.

There are now 2 FDA approved CAR T-cell therapies for MM, idecaptagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti). Both are approved for relapsed or refractory MM following at least 4 lines of therapy.

The authors said it is difficult to compare the efficacy of the 2 approved therapies, due to a lack of direct-comparison clinical trials. However, the investigators said there is real-world evidence that suggests both therapies outperform conventional therapies.

Still, given the logistics and manufacturing of the treatments, their success will depend on more than just efficacy. It can take up to 4 weeks to manufacture the therapy given that each therapy is made to order for each individual patient.

“For timely treatment, one should consider availability of manufacturing slots, timing the salvage treatment, pre-CAR T-cell work-up and testing and apheresis at the treating facility,” DeStefano and colleagues said.

In addition, there is a significant risk of product failure, since myeloma is associated with changes in T cells that can make them ill-suited for the manufacturing process. Supply chain issues can also cause problems by limiting access to medications necessary for the treatment.

“When approaching CAR T-cell therapies under such limitations, physicians may defer utilization of CAR T-cell therapy until necessary conditioning and supportive medications are available,” they said.

Other logistical problems include a lack of available centers that can provide the therapy, and a price tag of more than $400,000 for either therapy, DeStefano and colleagues wrote.

Even if the therapy is successfully manufactured and infused, the authors noted that many patients will also face clinical challenges, including toxicities like cytokine release syndrome and infections.

Furthermore, some patients will develop resistance, and the mechanisms behind resistance are not yet clear. The investigators said other questions worthy of additional study include how best to treat patients who progress following CAR-T therapy, and how best to sequence therapies.

“Ongoing studies are assessing the efficacy of CAR T-cells in earlier lines of therapy, as well as novel targets and methods to decrease manufacturing time,” they concluded.

Reference

Rendo MJ, Joseph JJ, Phan LM, DeStefano CB. CAR T-Cell therapy for patients with multiple myeloma: current evidence and challenges. Blood Lymphat Cancer. 2022;12:119-136. doi:10.2147/BLCTT.S327016