Predictors of early relapse following ciltacabtagene autoleucel: Informing risk-adapted therapy in relapsed/refractory multiple myeloma
Abstract
Abstract Introduction Ciltacabtagene autoleucel (cilta-cel) has demonstrated unprecedented response rates and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM), but a proportion of patients experience early relapse. Identifying these patients is essential to guide future therapeutic strategies, such as enhanced bridging therapy or consolidation, while avoiding overtreatment in those likely to achieve durable disease control. Methods We conducted a multi-center study of patients treated with cilta-cel at 15 U.S. academic centers. Outcomes were evaluated based on high-risk (HR) features, including functional HR disease (FHR; relapse within 18 months of first-line therapy initiation), true extramedullary disease (EMD), traditional HR cytogenetics as defined in CARTITUDE-1 [deletion 17p, t(4;14), t(14;16)], and a 2024 IMS-IMWG-adapted HR definition (deletion 17p; t(4;14) or t(14;16) with gain 1q or deletion 1p; and gain 1q with deletion 1p). Multivariable Cox regression was used to examine the association of HR features (FHR, adapted IMS-IMWG HR, and EMD, individually and collectively) with PFS while adjusting for baseline ferritin, prior BCMA, and ECOG performance status (PS ≥2). Among patients with ≥18 months of follow-up, we evaluated predictors of early relapse (≤18 months post infusion) using logistic regression. Results Our cohort included 598 patients treated with cilta-cel between 5/2022 and 12/2024 who had available data on all HR features. The median age was 65 years (range 33-83), and the median prior lines of therapy (pLOT) was 5 (range: 1-18, 84% with >3 pLOT); 8% had received prior BCMA-directed therapy, and 27% were penta-refractory. Most patients (88%) received bridging therapy and 30% achieved ≥ partial response. In our cohort, 33% (n=195) had FHR, 43% (n=258) had traditional HR cytogenetics, 42% (n=253) had adapted IMS-IMWG HR disease, and 11% (n=64) had EMD. Median follow up was 10.6 months (range 0.4-34.1). Overall response rate (ORR) and complete response (CR) rates were lower in patients with vs without HR features: FHR (ORR: 89% vs 94%, CR: 61% vs 75%), traditional HR (ORR: 90% vs 94%, CR: 65% vs 74%), adapted IMS-IMWG HR (ORR: 91% vs 94%, CR: 64% vs 75%) and EMD (ORR: 77% vs 94%, CR: 61% vs 71%). Corresponding 12-month PFS was also lower in patients with vs without HR features: FHR (55% vs 79%), traditional HR (63% vs 78%), adapted IMS-IMWG HR (61% vs 80%) and EMD (59% vs 73%). ORR, CR rate, and 12-month PFS in patients without any HR features compared to those with ≥1 HR feature were 96% vs 90%, 81% vs 64%, and 83% vs 65%, respectively. In multivariable models, each HR feature (FHR, adapted IMS-IMWG HR, and EMD) was independently associated with inferior PFS after adjusting for baseline ferritin, prior BCMA, and ECOG PS ≥ 2. However, because early relapse cannot always be identified a priori based on traditional risk factors, we sought to identify predictors of relapse within 18 months of cilta-cel in a subset of patients with ≥18 months of follow-up (N=247; infused by 12/2023). Notably, while FHR (OR=3.04, 95% CI=1.59-5.89) and adapted IMS-IMWG HR (OR=2.07, 95% CI=1.10-3.89) were independently associated with odds of relapse within 18 months, EMD was not (OR=0.90, 95% CI=0.32, 2.40) when accounting for prior BCMA, ECOG PS ≥ 2, and baseline ferritin. We also used a time-varying Cox model to examine each HR feature associated with PFS at two time periods, <18 and ≥18 months, while adjusting for baseline ferritin, ECOG PS, and prior BCMA. We confirmed that FHR and adapted IMS-IMWG HR were both associated with relapse <18 months (HR=2.05, 95% CI=1.48-2.83 and HR=1.56, 95% CI=1.11-2.19) but not in the ≥18-month time period (HR=0.70, 95% CI=0.19-2.59 and HR=0.76, 95% CI=0.24-2.40). The magnitude of the association for EMD with PFS was similar across both time periods (<18 months HR=1.67, 95% CI=1.09-2.57 and ≥18 months HR=2.17, 95% CI=0.45-10.40). Conclusion While cilta-cel leads to high response rates and durable PFS in RRMM, a subset of patients with FHR and adapted IMS-IMWG HR remains at increased risk for early relapse. In this large multi-center cohort, we describe PFS outcomes across high-risk subgroups and identify key predictors of relapse within 18 months of cilta-cel. These findings inform risk-adapted therapeutic strategies and interventional trials, including bridging, consolidation, or maintenance approaches, to improve outcomes in the highest-risk RRMM patients.
Article Details
Authors (64)
Doris Hansen
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Lauren Peres
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Danai Dima
Fred Hutchinson Cancer Center, Seattle, Washington, United States
Saurabh Zanwar
Omar Alexis Castaneda Puglianini
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Alicia Richards
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Mahmoud Gaballa
4The University of Texas MD Anderson Cancer Center, Houston, United States
Oren Pasvolsky
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Aimaz Afrough
Myeloma, Waldenstrom’s, and Amyloidosis Program, Hematologic Malignancies and Cellular Therapy Program, Simmons Comprehensive Cancer Center (A.A.), University of Texas Southwestern Medical Center, Dallas, TX.
Brett Reid
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Ariel Grajales-Cruz
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Zhuoer Xie
Moffitt Cancer Center, Tampa, Florida, United States
Utkarsh Goel
6Cleveland Clinic Taussig Cancer Center, Cleveland, United States
Aishwarya Sannareddy
5UT Southwestern Harold C. Simmons Comprehensive Cancer Center, Dallas, United States
Christen Dillard
4The University of Texas MD Anderson Cancer Center, Houston, United States
Christopher Ferreri
7Atrium Health Levine Cancer Institute, Charlotte, United States
Shebli Atrash
Levine Cancer Institute–Atrium Health, Charlotte, NC
Cindy Varga
7Atrium Health Levine Cancer Institute, Charlotte, United States
Andrew Portuguese
2Fred Hutchinson Cancer Center, Seattle, United States
Hitomi Hosoya
Lekha Mikkilineni
Stanford University School of Medicine, Palo Alto, California, United States
Nilesh Kalariya
4The University of Texas MD Anderson Cancer Center, Houston, United States
Damian Mikulski
4The University of Texas MD Anderson Cancer Center, Houston, United States
Charlotte Wagner
Christopher Cahoon
9University of Utah Huntsman Cancer Institute, Salt lake City, United States
Peter Cheng
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Christian Gordillo
10Herbert Irving Comprehensive Cancer Center at Columbia University, New york, United States
Eli Zolotov
11Hackensack Meridian Health, Hackensack, United States
Evguenia Bhurtel
1The University of Kansas Cancer Center, Kansas City, United States
Jeries Kort
1The University of Kansas Cancer Center, Kansas City, United States
Raffaella Cassano Cassano
2Fred Hutchinson Cancer Center, Seattle, United States
Shonali Midha
13Dana-Farber Cancer Institute, Boston, United States
James Davis
Duke University School of Medicine, Durham, NC
Rebecca Gonzalez
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Megan Herr
15Roswell Park Comprehensive Cancer Center, Buffalo, United States
Hamza Hassan
7Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
Sneha Purvey
16Virginia Commonwealth University, Richmond, United States
Marcus Geer
17University of Michigan, Ann Arbor, United States
Kimberly Green
14Medical University of South Carolina, Charleston, United States
Fabiana Perna
Moffitt Cancer Center, Tampa, Florida, United States
Hien Liu
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Taiga Nishihori
Moffitt Cancer Center, Tampa, Florida, United States
Jack Khouri
1Cleveland Clinic Foundation, Department of Hematology and Medical Oncology, Cleveland, United States
Shahzad Raza
Taussig Cancer Institute, Cleveland Clinic, Cleveland
Faiz Anwer
Cleveland Clinic Foundation, Cleveland, Ohio, United States
Susan Bal
University of Alabama at Birmingham, Birmingham, Alabama, United States
Omar Nadeem
Ciara Louise Freeman
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Rahul Banerjee
Leyla Shune
Ran Reshef
13Division of Hematology/Oncology, Blood and Marrow Transplantation and Cell Therapy Program, Columbia University Irving Medical Center, New York, NY
Kenneth Shain
H. Lee Moffitt Cancer Center and Research Institute
Melissa Alsina
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Rachid Baz
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Douglas Sborov
9University of Utah Huntsman Cancer Institute, Salt lake City, United States
Peter Voorhees
Department of Materials Science and Engineering
Larry Anderson
5UT Southwestern Harold C. Simmons Comprehensive Cancer Center, Dallas, United States
Luciano Costa
42Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, United States
Noa Biran
11Hackensack Meridian Health, Hackensack, United States
Shaji Kumar
Frederick Locke
1H. Lee Moffitt Cancer Center, Hematology and Oncology, Tampa, United States
Yi Lin
Surbhi Sidana
Stanford University School of Medicine, Palo Alto, CA
Krina Patel
4The University of Texas MD Anderson Cancer Center, Houston, United States