Enhancing the safety of ciltacabtagene autoleucel in relapsed multiple myeloma (MM): Identification of potentially modifiable risk-factors associated with delayed neurotoxicity and non-relapse mortality
Abstract
Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors associated with DNT and NRM may help with risk mitigation by aiding the development of interventions for potentially modifiable risk factors and also help with clinical decision making. Methods: In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM were evaluated in by univariable and multivariable analysis. Any NRM events occurring after disease progression were censored for NRM evaluation. Results: The median age of the cohort was 65 years old (range: 30-88), median prior lines of therapy (pLoT) were 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLOT) in 16% (n=120) patients. High-risk cytogenetics [del 17p, t(14;16) or t(4;14)] were present in 39%, with extramedullary disease (EMD) in 27% and R-ISS stage III in 18% of patients, respectively. Majority of patients (86%) received bridging therapy with response to bridging (≥ partial response, PR) seen in 33% of patients, respectively. Median follow up was 10.1 months, with response rate of 92% and CR rate of 70%. DNT was seen in 10% (n=75) of patients, with distribution as follows: Parkinsonism in 2.9% (n=22), cranial nerve palsy in 4.6% (n=35) and other DNT in 2.4% (n=18), with some patients manifesting more than one type of DNT. Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, both p<0.05) Of the 22 cases of Parkinsonism, 21 patients (95%) did not respond to bridging, even though they achieved a post CAR-T response with ORR of 91% and ≥ CR in 68%. Absolute lymphocyte count (ALC), a surrogate measure of CAR expansion was higher in patients who developed DNT, particularly Parkinsonism, including ALC at days 7,14,21,28 and as peak ALC in the first month post cilta-cel (p<0.05 for all). Median peak ALC for patients with vs without Parkinsonism was: 5.88 vs 1.17/uL (p<0.001). We evaluated risk of Parkinsonism with various thresholds of peak ALC expansion. Amongst patients who developed Parkinsonism vs. not, peak ALC was as follows, > 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19% and > 3000/uL: 68% vs 14% (all p<0.001). The absolute risk of Parkinsonism with ALC > 3000 vs ≤ 3000/uL was 12% vs 1%, p<0.001; for ALC 2500 vs ≤ 2500uL was 9% vs 1%, p<0.001. On multivariable analysis, peak ALC > 3000/uL (OR: 12.7, p<0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) were independent risk factors for developing Parkinsonism after cilta-cel. After cilta-cel, 1 and 2 year NRM estimates were 9% and 10%, respectively. Amongst 63 (8%) patients experiencing NRM events, the most common cause of NRM was infectious complications (35, 56%), followed by acute immune-mediated adverse events (AEs) like CRS, ICANS, IEC-HS in 14 (22%), delayed immune mediated AEs like DNT and colitis in 6 (9.5%), second cancers in 5 (8%) and other causes in 3 (5%) patients, respectively. When evaluating the timing of NRM events, the risk of infection related mortality remained relatively stable in the first year, though immune mediated toxicty deaths were uncommon after 6 months, while SPMs were uncommon within the first 6 months. On multivariable analysis, non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics and age ≥ 70 years were independent predictors for NRM. Conclusion: In a large cohort of over 750 patients receiving cilta-cel, we identified potentially modifiable risk factors for Parkinsonism and NRM. Non-response to bridging therapy and peak ALC > 3000/uL were independent predictors of developing Parkinsonism. Peak ALC of > 2500/uL and > 3000/uL were associated with 9% and 12% absolute risk of Parkinsonism. This indicates that peak ALC of 2500/uL or 3000/uL in the first month after cilta-cel may be a potential biomarker to identify patients for pre-emptive interventions such as steroids that can suppress rapid CAR expansion and perhaps decrease the risk of Parkinsonism. In addition, we need to focus on effective bridging strategies to further decrease the risk of Parkinsonism, as well as NRM with cilta-cel.
Article Details
Authors (66)
Surbhi Sidana
Stanford University School of Medicine, Palo Alto, CA
Brett Reid
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Danai Dima
Fred Hutchinson Cancer Center, Seattle, Washington, United States
Lauren Peres
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Mahmoud Gaballa
4The University of Texas MD Anderson Cancer Center, Houston, United States
Rahul Banerjee
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.
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
Masooma Rana
8Stanford University School of Medicine, Stanford, United States
Hitomi Hosoya
Lekha Mikkilineni
Stanford University School of Medicine, Palo Alto, California, United States
Vanna Hovanky
Saurabh Zanwar
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
Omar Alexis Castaneda Puglianini
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Gabriel De Avila
H Lee Moffitt Cancer Center, Tampa, Florida, United States
Christian Gordillo
10Herbert Irving Comprehensive Cancer Center at Columbia University, New york, United States
Eli Zolotov
11Hackensack Meridian Health, Hackensack, United States
Ariel Grajales-Cruz
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, 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
Jeries Kort
1The University of Kansas Cancer Center, Kansas City, United States
Raffaella Cassano
6Fred 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
Zhuoer Xie
Moffitt Cancer Center, Tampa, Florida, 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
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
Saurabh Dahiya
Frederick Locke
1H. Lee Moffitt Cancer Center, Hematology and Oncology, Tampa, United States
David Miklos
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
Yi Lin
Krina Patel
4The University of Texas MD Anderson Cancer Center, Houston, United States
Doris Hansen
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States