Association between cilta-cel dose and efficacy and toxicity outcomes for patients with Relapsed/Refractory multiple myeloma (RRMM): A real-world analysis from the US multiple myeloma immunotherapy consortium
Abstract
Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) is a highly effective BCMA-redirected CAR T-cell therapy for RRMM. While the pivotal CARTITUDE-1 trial established a target dose of 0.75 x 10^6 CAR+ viable T-cells/kg, the approved cell dose is 0.5-1.0 x 10^6 and the optimal dosing strategy to balance efficacy and toxicity remains unclear. This question is of interest given that a dose-response association has been demonstrated for idecabtagene vicleucel (a related BCMA-directed CAR T product). It has also been hypothesized that lower doses of cilta-cel may be associated with reduced toxicity. This study aims to evaluate the association between cilta-cel dose and key efficacy and toxicity outcomes using a large, real-world dataset from the US Multiple Myeloma Immunotherapy Consortium. Methods: We conducted a multicenter, retrospective analysis of 751 RRMM patients treated with commercial cilta-cel across 15 US academic centers. The administered cilta-cel dose (million cells/kg) was categorized into four groups: low (<0.5), standard-low (0.5 to <0.6), standard (0.6 to <0.8), and standard-high (0.8 to 1.0). We compared incidence rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity (DNT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) across these dose categories using logistic regression. Best response rates and progression-free survival (PFS), estimated using the Kaplan-Meier method, were also compared, with differences assessed using the log-rank test for the latter. Results presented are derived from multivariable models adjusting for extramedullary disease, ECOG status, penta-refractory disease and receipt of bridging therapy. Results: Among 751 infused patients, the dose distribution was: <0.5 (n=33), 0.5 to <0.6 (n=131), 0.6 to <0.8 (n=550), and 0.8 to 1.0 (n=37). The four dose groups were well-balanced in terms of baseline patient and disease characteristics, including age, high-risk cytogenetics, and extramedullary disease, with the exception of t(14;16), which was more common in the standard-low and standard dose groups (p=0.006). There were no statistically significant differences in the rates of any grade CRS (p=0.11), any grade ICANS (p=0.84), grade ≥3 ICANS (p=0.36), duration of CRS (p=0.18) or ICANS (p=0.64), or IEC-HS (p=0.16) across the four dose categories. Time to onset of CRS was shorter for the standard-high dose compared to the low dose (6 days vs. 8 days; p=0.08). Importantly, there was no significant difference in the rate of DNT (3.0%, 9.2%, 8.8%, 5.4%; p=0.24). Similarly, there was no significant difference in overall response rates (97%, 96%, 96%, 88%; p=0.50) or complete response rates (75%, 65%, 75%, 66%; p=0.10) by dose. The median follow-up was 12.3 months (IQR: 6.9, 20.5). For patients who received a standard-low dose (0.5, 0.6), the median PFS was 17.5 (IQR: 13.5, NR) months. For the standard dose range of (0.6, 0.8), the median PFS was 28.7 (95% CI: 19.8, NR) months, while the median PFS for the standard-high dose (0.8, 1.0) was not reached. For the low dose range of <0.5, the median follow up was only 8.7 months, which did not allow reliable estimation of the median PFS. While the overall difference in PFS among the groups did not reach statistical significance by the log rank test, there was a clear trend toward improved PFS with higher cell doses in the multivariable model, with outcomes clearly ordered in the same direction as the cell dose categories. A similar trend was also evident in the rates of 12-month PFS which showed an improvement with increasing dose (62% ,67%, 73%, 80%). Conclusions: In this large, real-world cohort of RRMM patients treated with cilta-cel, a lower cell dose was not associated with reduced incidence or severity of CRS, ICANS, DNT, or IEC-HS. Conversely, a dose-response correlation with PFS was observed, with higher doses trending toward longer median and 12-month PFS. It remains unknown if a lower cell dose in the commercial setting reflects poor T cell quality, yet these findings suggest that dose reduction of cilta-cel may not be an effective strategy to mitigate toxicities and might be associated with a trend toward lower efficacy. Therefore, the standard target dose should be utilized to maximize patient outcomes and further prospective dose exploration is warranted.
Article Details
Authors (68)
Ran Reshef
13Division of Hematology/Oncology, Blood and Marrow Transplantation and Cell Therapy Program, Columbia University Irving Medical Center, New York, NY
Alexandria Jensen
Christian Gordillo
10Herbert Irving Comprehensive Cancer Center at Columbia University, New york, United States
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 Puglianini
3Moffitt Cancer Center, Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, United States
Gabriel De Avila
H Lee Moffitt Cancer Center, Tampa, Florida, United States
Eli Zolotov
11Hackensack Meridian Health, Hackensack, United States
Evguenia Bhurtel
1The University of Kansas Cancer Center, Kansas City, 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
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
Surbhi Sidana
Stanford University School of Medicine, Palo Alto, CA