Ciltacabtagene Autoleucel (Cilta-cel), a BCMA-Directed CAR-T Cell Therapy, in Patients with Multiple Myeloma (MM) and Early Relapse after Initial Therapy: CARTITUDE-2 Cohort B 18-Month Follow-up

Introduction: In cohort B of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study, the efficacy and safety of cilta-cel are being evaluated in patients with multiple myeloma (MM) who had early relapse (≤12 months after autologous stem cell transplant [ASCT] or ≤12 months after start of initial treatment with anti-myeloma therapy). Because progression within 1 year of starting initial therapy is a poor prognostic factor, with overall survival <2 years in these patients, they have functionally high-risk disease and represent an unmet medical need. We present updated clinical results and cytokine analyses.

Methods: Eligible patients had MM, received 1 prior line of therapy (proteasome inhibitor and immunomodulatory drug required), had early disease progression (≤12 mo after ASCT or ≤12 mo after start of anti-myeloma therapy for patients who did not undergo ASCT), and were treatment-naive to CAR-T/anti-B-cell maturation antigen (BCMA) therapies. Bridging therapy was allowed between apheresis and CAR-T cell infusion. A single cilta-cel infusion (target dose 0.75×10⁶ CAR+ viable T cells/kg) was given post lymphodepletion. Safety and efficacy were assessed. The primary endpoint was minimal residual disease (MRD) negativity by next generation sequencing at 10^-5. Management strategies were implemented to minimize risk of movement/neurocognitive treatment-emergent adverse events (MNTs)/parkinsonism. Pharmacokinetics, CAR-T cell phenotype, and cytokine profiles are also being investigated.

Results: As of June 1, 2022, 19 patients (median age 58 years [range 44-67]; 74% male; 16% high-risk cytogenetics, 63.2% standard risk, 21.1% unknown) received cilta-cel and 16 remained on study. Median follow-up was 17.8 months (range 5.2-26.3). 79% of patients received prior ASCT. Overall response rate was 100%, with 100% achieving very good partial response or better, and 90% achieving complete response or better (Figure). Median time to first response and best response were 0.95 months (range 0.9 - 9.7) and 5.1 months (range 0.9 - 11.8), respectively. Of patients who were MRD-evaluable (n= 15), 14 (93 %) achieved MRD 10^-5 negativity during the study. Median DOR was not reached and 12-month event-free rate was 84%. The 12-month progression-free survival rate was 90%. Most common treatment-emergent AEs were hematologic (grade 3/4: neutropenia, 90%; lymphopenia, 42%; thrombocytopenia, 26%; leukopenia, 26%). Median time from cilta-cel infusion to onset of cytokine release syndrome (CRS) was 8 days (range 5-11) and occurred in 16 (84.2%) patients (grade 4, n=1). CRS resolved in all patients. Immune effector cell-associated neurotoxicity syndrome (grade 1) occurred in 1 patient and Movement and neurocognitive TEAEs/parkinsonism (grade 3) occurred in 1 patient (previously reported). Three patients died post cilta-cel at days 158, 417, and 451 due to progressive disease. Levels of interleukin (IL)-6, interferon gamma, IL-2Rα, and IL-10 increased post infusion, peaked at days 7-14, coincident with the timing of CRS, and returned to baseline levels within 2-3 months post infusion.

Conclusions: In this functionally high-risk patient population, all of whom relapsed within a year of treatment with standard of care upfront therapy (including 79% with ASCT), 90% remained progression-free at 1 year post cilta-cel infusion. Results at this longer (18 months) follow-up show durability and deepening of response to cilta-cel and maintenance of PFS rate. This represents a potentially significant advancement in a population with high unmet need.

Van De Donk:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Agha:GenCART Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Cohen:Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Ichnos, Janssen Oncology, Oncopeptides, Pfizer, Seattle Genetics, Genentech/Roche, AstraZeneca, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline and Novartis: Research Funding; Novartis: Patents & Royalties: CAR T-cells and biomarkers of cytokine-release syndrome. Cohen:Medison: Honoraria; GSK: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Neopharm: Honoraria. Roeloffzen:Amgen: Honoraria; Sanofi: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Honoraria. Schecter:Janssen: Current Employment, Current holder of stock options in a privately-held company. De Braganca:Janssen R&D: Current Employment. Jackson:Janssen R&D: Current Employment. Varsos:Janssen: Current Employment. Roccia:Janssen: Current Employment, Current equity holder in publicly-traded company. Li:Janssen R&D, a Johnson and Johnson company: Current Employment, Current equity holder in publicly-traded company. Zudaire:Janssen R&D, Johnson and Johnson: Current Employment. Corsale:Janssen R&D: Current Employment. Geng:Legend Biotech USA: Current Employment. Pacaud:Legend Biotech USA: Current Employment. Sonneveld:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Zweegman:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Cilta-cel is a CAR-T therapy approved for patients with relapsed/refractory multiple myeloma after 4 or more lines of therapy.