Ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed/refractory multiple myeloma (R/R MM): Updated results from CARTITUDE-1.
Authors: Usmani Saad Zafar , Berdeja Jesus G. , Madduri Deepu , Jakubowiak Andrzej J. , Agha Mounzer E. , Cohen Adam D. , Hari Parameswaran , Yeh Tzu-Min , Olyslager Yunsi , Banerjee Arnob , Jackson Carolyn Chang , Allred Alicia Jones , Zudaire Enrique , Deraedt William , Wu Xiaoling , Carrasco-Alfonso Marlene , Akram Muhammad , Lin Yi , Martin Thomas G. , Jagannath Sundar 
Published: June 2021

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Background: CARTITUDE-1 (NCT03548207) is a phase 1b/2 study evaluating ciltacabtagene autoleucel (cilta-cel; JNJ-68284528), a CAR T-cell therapy with two BCMA–targeting single-domain antibodies, in patients (pts) with R/R MM. Here, we report updated results in pts with a longer duration (median 12.4 months) of follow-up. Methods: Eligible pts had MM and received ≥3 prior regimens or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody. After apheresis, bridging therapy was permitted. Pts received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg; range 0.5-1.0×106) 5–7 days (d) after lymphodepletion (300 mg/m2 cyclophosphamide, 30 mg/m2 fludarabine daily for 3 d). The primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (RP2D; phase 1b), and evaluate efficacy (phase 2). Cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by CTCAE, v5.0 (in phase 1b). CRS and ICANS were graded by ASTCT criteria (in phase 2). Here, Lee et al and CTCAE v5.0 were mapped to ASTCT for CRS and ICANS, respectively. Results: As of Sept 1, 2020, 97 pts with a median of 6 prior lines received cilta-cel. Overall response rate per independent review committee (primary endpoint) was 97% (95% CI, 91–99), with 67% achieving stringent complete response (sCR). Median time to first response was 1 month (range, 1–9), and median time to CR or better was 2 months (range, 1–15). Responses deepened over time, and median duration of response was not reached. Of 57 pts evaluable for minimal residual disease (MRD) assessment, 93% were MRD-negative at 10-5. The 12-month progression-free survival (PFS) and overall survival rates (95% CI) were 77% (66–84) and 89% (80–94), respectively; median PFS was not reached. Grade 3/4 hematologic AEs ≥20% included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). CRS occurred in 95% of pts (4% grade 3/4), with median time to onset of 7 d (range, 1–12), and median duration of 4 d (range, 1–14, excluding 1 pt with 97-d duration). CRS resolved in all but one with grade 5 CRS/haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 21% of pts (grade ≥3, 10%). Fourteen deaths occurred during the study after cilta-cel infusion: none within the first 30 days, 2 within 100 days; and 12 more than 100 days post infusion, of which 5 were due to disease progression, and 4 due to treatment-related AEs. Conclusions: A single infusion of cilta-cel yielded early, deep, and durable responses in heavily pretreated pts with MM, with a manageable safety profile at the RP2D. Cilta-cel is under further investigation in other MM populations in earlier lines of therapy and in outpatient settings. Clinical trial information: NCT03548207.