Patients with relapsed or refractory multiple myeloma who achieve a long-lasting disease remission from chimeric antigen receptor (CAR) T-cell therapy may differ from patients who relapse sooner based upon their immune system and how it responds to the infused CAR T cells, as well as how it recovers from treatment, according to longitudinal, multi-omic findings from a small study published as a research letter in Blood Advances.
“CAR T-cell therapy has changed myeloma care, but not everyone maintains a long remission. We wanted to understand what’s happening in the immune system of patients who stay in remission for more than 5 years after a single infusion,” said senior study author Alessandro Lagana, PhD, Assistant Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. “This research shows that long remissions depend not only on the CAR T cells we give, but also on the patient’s own immune system."
Background and Study Design
The pivotal CARTITUDE-1 trial led to the approval for ciltacabtagene autoleucel for patients with relapsed/refractory multiple myeloma after at least four prior lines of therapy, as well as the second approval for ciltacabtagene autoleucel for patients with multiple myeloma after at least 1 lenalidomide-refractory line of therapy. The study demonstrated long-term remission in terms of 5-year progression-free survival in about one-third of patients after a single infusion. Since then, researchers have sought to understand what leads to prolonged remission in some patients and not in others.
Twenty-seven patients from the CARTITUDE-1 trial were treated at Mount Sinai, with 15 of these alive beyond 5 years and 12 with minimal residual disease–negative complete responses. Researchers from Mount Sinai explored multi-omic findings from 19 patients treated with ciltacabtagene autoleucel who achieved minimal residual disease negativity by flow cytometry. Ten patients with long-term remission of over 5 years were compared with nine patients who had a progression-free survival of less than 5 years.
The researchers looked at bone marrow aspirates and matched peripheral blood samples from baseline measurements as well as at month 1 and 2 post-infusion. They conducted single-cell sequencing, cytometry by time-of-flight, and serum proteomic testing for all patients, and generated adaptive immunosequencing libraries for patients in long-term remission.
Key Study Findings
The researchers found that patients who achieved durable disease control from a single infusion of ciltacabtagene autoleucel had preserved CD4-memory T-cell pools and a diverse presentation of endogenous and expanded T-cell clonotypes. Additionally, these patients lacked myeloid-derived suppressor cells in their immune system and showed low levels of sCD70 and sCD28 at baseline.
The study authors suggested that patients who achieve a long-term remission develop a significantly different immune state in early immune reconstitution than those with a shorter progression-free survival, including a naive–helper T-cell landscape that promotes CAR T-cell function and the maintenance of immune surveillance.
Going forward, the study authors suggested that strategies to preserve or enhance endogenous T-cell function could help to enhance the efficacy of CAR T-cell therapy and to allow patients to achieve long-term remissions.
"Understanding and leveraging the synergistic relationship between CAR-T and host immunity will be crucial for optimizing outcomes and moving closer to functional cures in multiple myeloma," the authors concluded in their letter. They hope to explore these findings further in larger studies to help clinicians identify the right patients for CAR T-cell therapy with a simple blood test or biomarker panel.
Disclosure: The study was funded in part by Mount Sinai's Center of Excellence for Multiple Myeloma and from collaborations with Johnson & Johnson. For full disclosures of the study authors, visit ashpublications.org.
