ABSTRACT
Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is evaluating cilta-cel safety and efficacy in pts with MM who received 1-3 prior LOT and were len-refractory - a difficult- to-treat population with poor prognosis. We present updated results. Methods: Pts had progressive MM after 1-3 prior LOT, including a PI and IMiD, were len-refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) was given post lymphodepletion. Safety and efficacy were assessed, and the primary endpoint was MRD negativity at 10-5. Management strategies were implemented to minimize risk of movement/neurocognitive AEs (MNTs). Pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood) are being conducted, as well as analyses of levels of CRS-related cytokines (eg, IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with ICANS, and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow- up [MFU] 17.1 mo [range 3.3-23.1]), 20 pts (65% male;median age 60 y [range 38-75]) received cilta-cel. Pts received a median of 2 (range 1-3) prior LOT, and a median of 3.5 y (range 0.7-8.0) since MM diagnosis. 95% were refractory to last LOT, and 40% were triple-class refractory. ORR was 95%, 90% achieved CR or better, and 95% had ≥VGPR. Median times to first and best response were 1.0 mo (range 0.7-3.3) and 2.6 mo (range 0.9-13.6), respectively. 16 pts were MRDevaluable, all of whom achieved MRD negativity at 10-5. Median DOR was not reached and 12-mo event-free rate was 79%. The 12-mo PFS rate was 75%. Median time to onset of CRS was 7 d (range 5-9) and occurred in 95% of pts (gr 3/4: 10%), with median duration of 3 d (range 2-12). Neurotoxicity occurred in 30% of pts (5 gr 1/2;1 gr 3/4). 3 pts (15%) had ICANS (all gr 1/2);1 pt had gr 2 facial paralysis. No MNTs were seen. 1 death occurred due to COVID-19 (assessed as tx-related by the investigator), 2 due to progressive disease, and 1 due to sepsis (not related to tx). Preliminary PK analyses indicate that peak expansion of CAR-T cells occurred at d 10.5 (range 8.7-42.9) and median persistence was 153.5 d (range 57.1-336.8). Conclusions: At a longer MFU of 17.1 mo, a single cilta-cel infusion led to deepening and durable responses in pts with MM who had 1-3 prior LOT and were lenrefractory. Follow-up is ongoing. Updated and in-depth PK, cytokine, and CAR-T subset analyses and clinical correlation will be presented and provide novel insights into biological correlates of efficacy and safety in this pt population. This pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827), which has concluded enrollment.
ABSTRACT
Objectives: Cilta-cel is a CAR-T cell therapy that expresses 2 BCMA-targeting single-domain antibodies, designed to confer avidity. In the multicohort, phase 2 CARTITUDE-2 study (NCT04133636), the safety and efficacy of cilta-cel in various clinical settings and suitability of outpatient administration was explored in patients with multiple myeloma. Material and methods: Patients enrolled in Cohort A had progressive MM after 1–3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and were naïve to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75 × 106 CAR+ viable T cells/kg) was given 5–7 days after start of lymphodepletion (daily cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 days). The primary outcome was minimal residual disease (MRD) 10-5 negativity. Secondary outcomes were response rates (per IMWG criteria) and safety (per CTCAE;CRS and ICANS by ASTCT). Results: As of the February 2021 data cutoff (median follow-up: 5.8 months [2.5–9.8]), 20 patients (65% male;median age 60 years [38–75]) received cilta-cel;1 patient was treated in an outpatient setting. Patients (n = 12: <3 prior LOT;n = 8: 3 prior LOT) received a median of 2 (1–3) prior LOT. All patients were exposed to PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. The majority (95%) were refractory to the last LOT;40% were triple-class refractory. Overall response rate was 95% (95% CI: 75–100), 75% (95% CI: 51–91) achieved stringent CR/CR, and 85% (95% CI: 62–97) achieved ≥VGPR. Median time to first response was 1.0 month (0.7–3.3);median time to best response was 1.9 month (0.9–5.1). Median duration of response was not reached. All patients (n = 4) with MRD-evaluable samples at 10-5 at data cutoff were MRD-negative. Hematologic AEs ≥20% were neutropenia (95%;grade 3/4: 90%), thrombocytopenia (80%;grade 3/4: 35%), anemia (65%;grade 3/4: 40%), lymphopenia (60%;grade 3/4: 55%), and leukopenia (55%;all grade 3/4). 85% of patients had CRS;10% were grade 3/4. Median time to CRS onset was 7 days (5–9), with a median duration of 3.5 days (2–11). CAR-T cell neurotoxicity occurred in 20% of patients (all grade 1/2). Three patients had ICANS (n = 1: grade 1;n = 2: grade 2);median time to onset was 8 days (7–11) and median duration was 2 days (1–2). One patient had grade 2 facial paralysis;time to onset was 29 days with a duration of 51 days. One death occurred due to Covid-19 (assessed as treatment-related by investigator). The safety profile was manageable in the patient who was treated in an outpatient setting. Discussion: Updated efficacy and safety findings will inform suitability of outpatient treatment in this and other cohorts of CARTITUDE-2 as well as the CARTITUDE-4 study. Conclusion: A single cilta-cel infusion at the recommended phase 2 dose led to early and deep responses with a manageable safety profile in patients with MM who had 1–3 prior LOT.
ABSTRACT
Background: Cilta-cel is a CAR T-cell therapy expressing two BCMA-targeting, single-domain antibodies designed to confer avidity. The multicohort, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating cilta-cel safety and efficacy in various clinical settings for patients (pts) with MM and exploring suitability of outpatient administration. Here, we present initial results from Cohort A. Methods: Cohort A pts had progressive MM after 1-3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) was given 5-7 days (d) after start of lymphodepletion (daily cyclophosphamide [300 mg/m2 ] and fludarabine [30 mg/m2 ] for 3 d). The primary objective was minimal residual disease (MRD) 10 negativity. Secondary outcomes were response rates (IMWG) and safety (per CTCAE;CRS and ICANS by ASTCT). Results: As of Feb 2021 data cutoff (median follow-up: 5.8 months [mo];range: 2.5-9.8 mos), 20 pts (65% male;median age 60 years [38-75]) received cilta-cel;1 pt was treated in an outpatient setting. Pts received a median of 2 prior LOT (1-3);12 pts received < 3 prior lines and 8 received 3 prior LOT. All pts were exposed to PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. The majority (95%) were refractory to the last LOT;40% were triple refractory. Overall response rate was 95% (95% CI: 75-100), 75% (95% CI: 51-91) achieved stringent CR/CR, and 85% (95% CI: 62-97) achieved ≥VGPR. Median time to first response was 1.0 mo (0.7-3.3);median time to best response was 1.9 mo (0.9-5.1). Median duration of response was not reached. All pts (n = 4) with MRD-evaluable samples at 10 at data cutoff were MRD-negative. Hematologic AEs ≥20% were neutropenia (95%;gr 3/4: 90%), thrombocytopenia (80%;gr 3/4: 35%), anemia (65%;gr 3/4: 40%), lymphopenia (60%;gr 3/4: 55%), and leukopenia (55%;all gr 3/4). CRS occurred in 85% of pts;10% were gr 3/4. Median time to CRS onset was 7 d (5-9), with a median duration of 3.5 d (2-11). CAR T-cell neurotoxicity occurred in 20% of pts (all gr 1/2). Three pts had ICANS (1 gr 1;2 gr 2);median time to onset was 8 d (7-11) and median duration was 2 d (1-2). One pt had gr 2 facial paralysis;time to onset was 29 d with a duration of 51 d. One death occurred due to COVID-19 (assessed as treatment (tx)-related by investigator). Safety profile was manageable in the pt treated in an outpatient setting. Conclusions: A single cilta-cel infusion at the recommended phase 2 dose led to early and deep responses with a manageable safety profile in pts with MM who had 1-3 prior LOT. Updated efficacy and safety findings will inform suitability of outpatient tx in this and other cohorts of CARTITUDE-2 as well as the CARTITUDE-4 study.