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1032 Ciltacabtagene Autoleucel (Cilta-cel) Vs Standard of Care (SoC) in Patients with Lenalidomide (Len)-Refractory Multiple Myeloma (MM) after 1–3 Lines of Therapy: Minimal Residual Disease (MRD) Negativity in the Phase 3 Cartitude-4 Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 655. Multiple Myeloma: Cellular Therapies: Unleashing Cell Therapies Against Myeloma
Hematology Disease Topics & Pathways:
Chimeric Antigen Receptor (CAR)-T Cell Therapies, Plasma Cell Disorders, Diseases, Biological therapies, Treatment Considerations, Lymphoid Malignancies, Measurable Residual Disease
Monday, December 9, 2024: 5:45 PM

Rakesh Popat, MBBS, PhD1, Albert Oriol2*, Michele Cavo, MD3*, Lionel Karlin4*, Irit Avivi Mazza5*, Wilfried Roeloffzen6*, Seok Jin Kim, MD, PhD7, Brea Lipe, MD8, Noffar Bar, MD9, Noemi Horvath10, Andrew Spencer, MBBS11*, Chang-Ki Min12*, Diana Chen13*, Quanlin Li14*, Katherine Li15*, Ana Slaughter16*, Carolina Lonardi17*, Nina Benachour18*, Arnab Ghosh19*, Martin Vogel20*, Nikoletta Lendvai19*, Tamar Lengil21*, Nitin Patel22*, Octavio Costa Filho22*, Erika Florendo22* and Yi Lin, MD, PhD23

1University College London Hospitals, NHS Foundation Trust, London, United Kingdom
2Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Baldona, Barcelona, Spain
3IRCCS Azienda Ospedaliero-Universitaria di Bologna, Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
4Centre Hospitalier Lyon Sud, Pierre-Bénite, France
5Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
6Department of Hematology, University Medical Center Groningen, Groningen, NLD
7Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of (South)
8University of Rochester Medical Center, Rochester, NY
9Yale Cancer Center, Yale University, New Haven, CT
10Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, Australia
11School of Translational Medicine, Alfred Health-Monash University, Melbourne, VIC, Australia
12Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea, Republic of (South)
13Janssen Research & Development, Shanghai, China
14Janssen Research & Development, Apex, NC
15Janssen Research & Development, Spring House, PA
16Cilag GmbH International, Zug, Switzerland
17Janssen, Buenos Aires, Argentina
18Janssen Research & Development, Beerse, Belgium
19Janssen Research & Development, Raritan, NJ
20Janssen Research & Development, Neuss, Germany
21Janssen Global Services, Raritan, NJ
22Legend Biotech USA Inc., Somerset, NJ
23Division of Hematology, Mayo Clinic, Rochester, MN

Introduction: Cilta-cel is approved in the US and EU for the treatment (tx) of patients (pts) with len-refractory MM after ≥1 line based on the randomized, phase 3 CARTITUDE-4 trial (NCT04181827). At the first interim analysis (15.9-month [mo] median follow-up), cilta-cel significantly improved progression-free survival (PFS) vs SoC (hazard ratio [HR], 0.26 [protocol-specified weighted analysis]; P<0.0001). At the second interim analysis, overall survival (OS) was significantly improved with cilta-cel vs SoC (HR, 0.55; P=0.0009). MRD negativity is a prognostic marker of prolonged survival outcomes for pts with MM. We report MRD negativity, including overall and sustained MRD negativity, overall MRD-negative complete response or better (≥CR), and MRD-negative ≥CR at mo 12, from the prespecified second interim analysis of CARTITUDE-4.

Methods: Eligibility criteria were previously described. Pts were assigned 1:1 to cilta-cel or SoC (pomalidomide, bortezomib, and dexamethasone [PVd]/daratumumab, pomalidomide, and dexamethasone [DPd]). Pts in the cilta-cel arm underwent apheresis, received bridging therapy (PVd/DPd), and then a single cilta-cel infusion (target dose, 0.75×106 CAR+ viable T cells/kg) 5–7 days (d) after the start of lymphodepletion. PFS was the primary endpoint; ≥CR rate, overall response rate, overall MRD-negativity rate, and OS were key secondary endpoints. MRD was assessed centrally via next-generation sequencing (clonoSEQ v2.0; Adaptive Biotechnologies). MRD was evaluated at d 56 post infusion in the cilta-cel arm; and in both arms at suspected ≥CR and at 6, 12, 18, and 24 mo post infusion (cilta-cel arm) or cycle 1 d 1 (SoC arm), as well as yearly until progression/start of subsequent therapy in pts in ≥CR. Sustained MRD negativity (10−5) was defined as confirmed MRD negativity ≥12 mo apart and without MRD positivity in between. Pts were evaluable for sustained MRD negativity if they achieved MRD negativity and had ≥1 evaluable MRD sample ≥12 mo after the first negative result or progressed/died/started subsequent tx <12 mo after the first negative result.

Results: 419 pts were randomized (intent-to-treat [ITT] set; cilta-cel, n=208; SoC, n=211); 176 pts in the cilta-cel arm received cilta-cel as study tx. As of May 1, 2024, median follow-up for the study was 33.6 mo. At the 10−5 threshold, 145 pts in the cilta-cel arm and 103 in the SoC arm were evaluable for MRD. MRD-negativity rates (10−5) in the ITT set and the MRD-evaluable subset were higher with cilta-cel vs SoC (ITT, 62% vs 18%; MRD evaluable, 89% vs 38%; both P<0.0001). Across subgroups, cilta-cel vs SoC consistently increased overall MRD-negativity rates (10−5). In the ITT set, 48% of the cilta-cel arm achieved MRD negativity (10−5) by d 56, with the MRD-negative rate rising to 60% by 6 mo post cilta-cel infusion. Overall MRD-negativity rates at the 10−6 threshold in the ITT set were higher with cilta-cel vs SoC (57% vs 9%; P<0.0001). In the cilta-cel arm, 119 (57%) pts vs 26 (12%) in the SoC arm achieved overall MRD-negative (10−5) ≥CR (P<0.0001). At the 12-mo MRD assessment, 92 (44%) pts in the cilta-cel arm vs 17 (8%) in the SoC arm (P<0.0001) had MRD-negative (10−5) ≥CR. In pts with MRD-negative (10−5) ≥CR at mo 12, median PFS was not reached (NR; 95% CI, not estimable [NE]–NE) with cilta-cel and 37.8 mo (95% CI, 25.0–NE) with SoC; median OS was NR (95% CI, NE–NE) and NR (95% CI, 37.8 mo–NE), respectively. Sustained MRD-negativity rates (10−5) in the ITT set were 40% in the cilta-cel arm vs 6% in the SoC arm (P<0.0001); among 110 and 26 evaluable pts for sustained MRD, sustained MRD-negativity rates were 75% vs 50% (P=0.0159). Among the 176 pts who received cilta-cel as study tx, overall MRD negativity at 10−5 was achieved by 129 (73%) pts (89% of 145 evaluable pts).

Conclusions: At 33.6-mo median follow-up in CARTITUDE-4, cilta-cel vs SoC significantly increased overall MRD-negativity rates >3-fold in the ITT set, with pts achieving MRD negativity rapidly post cilta-cel. The prognostic value of MRD-negative ≥CR at mo 12 was shown, as median PFS was >3 years in pts with MRD-negative ≥CR at mo 12, regardless of tx. These data further underscore the benefit of cilta-cel, which led to significant >3-fold increases vs SoC in rates of MRD-negative ≥CR at any time and at mo 12, and sustained MRD negativity. Our MRD data demonstrate higher rates of deep and sustained MRD negativity achieved with cilta-cel vs SoC in tx of len-refractory MM as early as first relapse.

Disclosures: Popat: BMS: Honoraria; Abbvie: Honoraria; Janssen: Honoraria, Speakers Bureau; Sanofi: Honoraria; GSK: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau. Oriol: Bristol Myers Squibb/Celgene: Honoraria, Speakers Bureau; Pfizer, Amgen, Oncopeptides: Honoraria; Sanofi: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Johnson & Johnson, Janssen: Honoraria, Speakers Bureau. Karlin: AbbVie, Amgen, Celgene, Janssen, Sanofi, Takeda: Honoraria; Amgen, Celgene, GSK, Janssen, and Takeda: Other: Advisory role. Avivi Mazza: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Roeloffzen: Abbvie: Other: Travel expenses; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Other: Travel expenses, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Lipe: Janssen, karyopharm, bms, Sanofi, Pfizer, and abbvie: Consultancy, Honoraria; Janssen and amgen: Research Funding. Spencer: F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding. Li: Janssen R&D: Current Employment, Current equity holder in publicly-traded company. Slaughter: Johnson & Johnson Innovative Medicine: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Lonardi: J&J Innovative Medicine: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Benachour: Johnson & Johnson: Current Employment. Ghosh: Janssen: Current Employment, Current equity holder in publicly-traded company. Vogel: Janssen: Current Employment, Current equity holder in publicly-traded company. Lendvai: Johnson and Johnson Innovative Medicine: Current Employment, Current equity holder in publicly-traded company. Lengil: Janssen: Current Employment, Current equity holder in publicly-traded company. Patel: Legend Biotech, GSK, Freeline, BMS (spouse), AbbVie (spouse): Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Costa Filho: Legend Biotech: Current Employment. Florendo: Legend Biotech: Current Employment. Lin: Legend: Consultancy; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; Janssen: Consultancy, Research Funding; Genentech: Consultancy.

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