Ciara L. Freeman, MD, PhD

Ciara L. Freeman, MD, PhD, Assistant Member, Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, was impressed with the CARTITUDE-4 findings. She said “treaters and patients” will be “watching this space” to see how the results change the treatment landscape for relapsed or refractory multiple myeloma.

“These results are so exciting for patients because they show unprecedented durability of responses from a one-time therapy, which outperformed comparative standard regimens. When taken in context with the updated results from CARTITUDE-1, showing a median progression-free survival approaching 3 years in more heavily pretreated patients,¹ this lends support to the idea that in the future, patients may no longer be required to be on continuous therapy to experience deep and lasting responses,” she told The ASCO Post.

“A one-off treatment that could achieve the duration of responses reported in CARTITUDE-4, where ciltacabtagene autoleucel was employed in an earlier stage of the disease course without the need for maintenance, could be associated with significant improvements in quality of life, consistent with patients’ goals,” Dr. Freeman added.

The findings have implications for treatment sequencing, according to Dr. Freeman. Should ciltacabtagene autoleucel be approved for use after only one prior line of therapy in patients experiencing disease progression on lenalidomide, chimeric antigen receptor (CAR) T-cell therapy could become “a realistic option for many more patients, both those who underwent transplantation and those who did not but are still considered candidates for CAR-T,” she commented. “This could lead to a paradigm shift for how we treat myeloma in the second line.”

Timing of Cellular Therapy: Heading in the Right Direction

CARTITUDE-4’s invited discussant, Asher Chanan-Khan, MD, Professor of Medicine, Mayo Clinic Cancer Center, Jacksonville, Florida, suggested that the strong benefit observed with ciltacabtagene autoleucel in less refractory patients than in previous trials heralds a change in the treatment paradigm, with CAR T-cell therapy becoming preferred in early vs later lines. The results represent the “phenomenal success” that is being seen with CAR T-cell therapy, with the “timing” of this approach now “headed in the right direction,” he said.

Asher Chanan-Khan, MD

“What we have learned in myeloma and in lymphoma is that bringing CAR T-cell therapy earlier in the disease course is not only feasible and safe, but it also is associated with better patient outcomes,” Dr. Chanan-Khan continued. He noted the differences in progression-free survival according to the lines of therapy in the different -CARTITUDE trials. “Currently, availability is tightly regulated to specifically approved indications based on the right clinical and biological scenario for most optimal benefit,” he added.

What’s Next?

The next steps are to determine whether CAR T-cell therapy should replace autologous transplantation, as it is currently doing in lymphoma, and whether it should be incorporated as a “first line of attack,” akin to what happened with daratumumab, stated Dr. Chanan-Khan. Challenges also remain in identifying which patients may benefit most without undue toxicity and in improving geographic and financial access to a treatment that costs upward of $500,000 a year. “We must bring the cost to a community-affordable level, and we need to overcome issues of disparity,” he emphasized.

Dr. Chanan-Khan continued: “Although improved toxicity has opened doors to almost any age group for this cellular therapy, there are many areas still lagging behind, and they need to be addressed.” To this end, studies are underway to further examine CAR T-cell therapy as a front-line treatment, vs autologous transplantation, for a broader range of patients and for use in outpatient and community settings.

“CAR T-cell therapy today is complicated, cumbersome, costly, and yet potentially curable,” he said. Dr. Chanan-Khan predicts that future approaches, such as the following, may help to make the leap to cure:

• Duel-targeted CAR T-cell therapies (ie, B-cell maturation antigen [BCMA] and CD1)
• CAR T-cell therapies combined with checkpoint inhibition
• Allogeneic anti-BCMA CAR T-cell therapy, a simplified, scalable manufacturing process
• CAR T-cell therapy with natural killer cells, which uses cord blood natural killer shells; it is an off-the-shelf treatment and may be safer than current products
• CAR T-cell–ddBCMA (D-domain BCMA), an anti-BCMA CAR T-cell product that uses a novel, synthetic binding domain instead of a typical single-chain variable fragment binder
• CAR macrophages, which selectively recognize and phagocytose tumor-associated antigens
• Novel CAR T-cell targets, such as CD123 in myeloma. 

DISCLOSURE: Dr. Freeman reported financial relationships with Bristol Myers Squibb, Seattle Genetics, Celgene, AbbVie, Sanofi, Incyte, Amgen, ONK Therapeutics, and Janssen. Dr. Chanan-Khan reported financial relationships with Cellectar, Starton Therapeutics, Matthew & Asher, NanoDev Therapeutics, Scentage Pharma, BeiGene, and Ascentage Pharma Group.

REFERENCE

1. Berdeja JG, Madduri D, Usmani SZ, et al: Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy, in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet 398:314-324, 2021.