Early Safety and Efficacy of CAR-T Cell Therapy in Precursor Myeloma: Results of the CAR-PRISM Study Using Ciltacabtagene Autoleucel in High-Risk Smoldering Myeloma

Introduction: CAR-T cell therapy has been used in relapsed multiple myeloma (MM) with deep and durable responses but some patients still eventually relapse. We hypothesized that the use of Ciltacabtagene Autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, can be safe and highly effective in patients with high-risk smoldering myeloma (HR-SMM), where the tumor burden is lower with less genomic complexity and the immune system is more fit, potentially leading to less toxicity and improved durable remissions in this high risk precursor condition. To our knowledge, this is the first study to examine the use of CAR T-cell therapy without any induction therapy in a precursor malignant condition.

Methods: This is a phase II, single arm study of cilta-cel in HR-SMM, defined per the Mayo/IMWG 20-2-20 model, IMWG risk score of 9 or greater, high-risk FISH, evolving pattern or the PETHEMA criteria. Patients with >40% bone marrow plasmacytosis were excluded. Patients receive lymphodepletion (LD) with fludarabine and cyclophosphamide followed by cilta-cel infusion. The first 6 patients comprise a safety run-in cohort, with the first 3 patients dosed at a lower target dose of 0.5 x 10⁶ CAR-positive T-cells/kg. If there are no dose limiting toxicities (DLTs), the next 3 patients will be dosed at the standard target dose of 0.75 x 10⁶ CAR-positive T-cells/kg. The primary objective of this study is to determine the safety of cilta-cel in HR-SMM. Secondary objectives will assess efficacy, MRD negativity rates and progression-free survival. Correlative studies will assess in vivo proliferation, persistence, and activation of CAR T-cells after infusion as well as characteristics of malignant cells and the tumor microenvironment.

Results: Six patients have been treated in the safety run-in with a median follow up of 6 months (60 days to 1 year). The median age is 55 (range 53-66) with 3 females and 3 males. The isotypes were IgG (4), light chain only (1) and IgD (1). No DLTs were observed in the safety run-in for both 0.5 and 0.75 x 10⁶ CAR-positive T-cells/kg doses. Accrual of additional patients at the dose of 0.75 x 10⁶ CAR-positive T-cells/kg is ongoing.

Grade 3 or greater hematologic toxicities were expected, transient and attributed to LD (neutropenia 100%, anemia 33%, thrombocytopenia 17%). Grade 3 or greater non-hematologic toxicities included AST and ALT increased (17%, during CRS and expected), hypertriglyceridemia (17%), and lymphocytosis (17%). No grade 3 or greater infections have been observed to date.

All patients experienced low grade cytokine release syndrome (CRS) (Grade 1 in 67% and grade 2 in 33%) and no high grade CRS events were observed. Tocilizumab was administered to 4 patients and 2 patients received dexamethasone. There have been no instances of ICANS, Parkinsonism or secondary malignancies to date. One patient experienced grade 1 Bell’s palsy that was self-limiting and resolved within 2 weeks. One patient experienced grade 4 immune related thrombocytopenia secondary to fludarabine, which resolved within 2 weeks after treatment with dexamethasone, IVIG and romiplostim.

CAR T-cells expanded in all patients with peak expansion on days 12-14 after infusion. By flow cytometry, median absolute CAR+T cell count at peak expansion was 3.8 K/uL (range 0.7 – 30 K/ul). CAR T cells were predominately CD4+ with an effector memory phenotype and remained detectable at 3 months in 2 patients. CAR T cell expansion and persistence were similar at both dose levels.

All patients achieved MRD negativity at 10^-6 by day 28 and MRD negativity is sustained in all patients to date without any evidence of progression. The overall response rate is 100%, with complete response rate of 50% and responses deepening over time, consistent with delayed paraprotein clearance in the setting of MRD negativity.

Conclusions: This is the first study of CAR T-cell therapy in a precursor cancer setting, where cilta-cel was used as a primary therapy with no induction therapy for patients with HR-SMM. There have been no DLTs in the safety run-in cohort. CRS was minimal and no ICANS were observed and there were no grade 3 or greater infections. All patients achieved MRD negative (10^-6 ) disease and long-term follow up is required to determine whether these responses will be sustained. The benefit of no induction therapy and potential long-term remissions may be disruptive for future therapeutic algorithms in MM.