https://orcid.org/0000-0003-3781-5441
TO THE EDITOR:
Chimeric antigen receptor T-cell (CAR-T) therapies, such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have dramatically improved the outcomes for patients with relapsed/refractory multiple myeloma (MM). However, these therapies require significant time investments from patients and caregivers to complete a multimonth process that encompasses T-cell collection, manufacturing, lymphodepletion, CAR-T infusion, and subsequent monitoring for toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) thus require patients to stay in geographic proximity to their treatment center for 4 weeks following infusion.1-4
A lesser-discussed provision in both the FDA and EMA guidelines is the recommendation that patients refrain from driving or operating heavy machinery for 8 weeks following infusion. This text is printed almost identically in all CAR-T product inserts regardless of disease, target, costimulatory domain, or drug-specific toxicity profiles. The historic rationale for universal driving restrictions is the theoretical risk for high-grade neurotoxicity (most notably sudden-onset seizures) that have primarily been reported with axicabtagene ciloleucel in lymphoma.5-7 In contrast, none of the registrational CAR-T trials in MM have reported seizures as adverse events (AEs).8-11
To better understand the risk for driving impairments following CAR-T therapy in MM, we conducted a 2-part study within the US MM Immunotherapy Consortium. All consortium centers obtained institutional review board approval for participation, and methods for the development of this retrospective real-world database have been described previously.12,13 For this analysis, we first investigated data from commercial ide-cel and cilta-cel recipients (apheresis cutoff, 31 December 2022; data cutoff, 22 July 2024) to identify potential driving-relevant AEs (drAEs), defined a priori as CRS, ICANS, movement and neurocognitive treatment-emergent AEs (MNTs),14,15 or any fatal AEs that developed after hospital discharge. Toxicities were categorized by onset with an emphasis on weeks 5 to 8 (days +29 through +56) to reflect the gap between CRS-related and driving-related regulatory guidance. Second, we separately surveyed 64 US-based oncologists within the consortium (details in supplemental Table 1; instrument in supplemental Table 2) about safety-related restrictions following CAR-T therapy in MM.
Of 586 CAR-T recipients, 40.3% (n = 236) received cilta-cel and 59.7% (n = 350) received ide-cel. The median age was 64.5 years (range, 30-90 years), and 42.5% (n = 249) were female. The median hospital length of stay was 11 days with an interquartile range of 8 to 15 days (supplemental Figure 1). De novo drAEs during weeks 5 to 8 were rare (Table 1) and included CRS at a rate of 0.2% (n = 1), ICANS at 0.3% (n = 2, neither of which involved seizures), MNT at 0.9%, and fatal AEs at 0.4% (n = 2, both owing to infections). Of the 5 cases of MNTs, there was 1 case of parkinsonism diagnosed during the sixth week of a 10-week hospitalization that began with CAR-T infusion. Only 5 unique patients (0.9% of all patients) developed de novo drAEs between weeks 5 and 8 (Figure 1). The cumulative incidence of drAEs rose rapidly to 76.3% by the end of week 2 and incrementally thereafter to 79.6% by week 16.
drAEs following CAR-T therapy in MM
| AE | Week 1 | Week 2 | Weeks 3-4 | Weeks 5-8 | Weeks 9+ | Never |
|---|---|---|---|---|---|---|
| CRS∗ | 372 (63.5%) | 86 (14.7%) | 2 (0.3%) | 1 (0.2%) | 0 (0%) | 125 (21.3%) |
| ICANS† | 82 (14.0%) | 19 (3.2%) | 7 (1.2%) | 2 (0.3%) | 0 (0%) | 476 (81.2%) |
| MNT‡ | 1 (0.2%) | 1 (0.2%) | 12 (2.1%) | 5 (0.9%) | 4 (0.7%) | 563 (96.1%) |
| Fatal AE§ | 0 (0%) | 1 (0.2%) | 2 (0.3%) | 2 (0.3%) | 53 (9.0%) | 528 (90.1%) |
| AE | Week 1 | Week 2 | Weeks 3-4 | Weeks 5-8 | Weeks 9+ | Never |
|---|---|---|---|---|---|---|
| CRS∗ | 372 (63.5%) | 86 (14.7%) | 2 (0.3%) | 1 (0.2%) | 0 (0%) | 125 (21.3%) |
| ICANS† | 82 (14.0%) | 19 (3.2%) | 7 (1.2%) | 2 (0.3%) | 0 (0%) | 476 (81.2%) |
| MNT‡ | 1 (0.2%) | 1 (0.2%) | 12 (2.1%) | 5 (0.9%) | 4 (0.7%) | 563 (96.1%) |
| Fatal AE§ | 0 (0%) | 1 (0.2%) | 2 (0.3%) | 2 (0.3%) | 53 (9.0%) | 528 (90.1%) |
Some patients had >1 AE in a given period.
One patient developed new-onset grade 2 CRS (no previous CRS) on day +37 with resolution after 2 days.
Two patients developed ICANS between weeks 5 and 8 (beginning on days +35 and +53, respectively), neither of which involved seizures.
Five patients developed MNTs during weeks 5 to 8, 4 of which were nonparkinsonian in nature (beginning on days +31, +31, +35, and +51, respectively). One patient developed parkinsonism at day +36 following cilta-cel while still hospitalized (total hospital length of stay 69 days following CAR-T infusion); this patient ultimately passed away from MNT-related complications on day +162.
Two patients had postdischarge fatal AEs during weeks 5 to 8, in 1 case because of COVID-19 and 1 case because of bacterial sepsis.
Cumulative incidence of drAEs. drAEs were defined as CRS, ICANS, MNTs, or any postdischarge fatal AE following CAR-T for MM. Of note, 86 patients (14.7% of all patients) never developed any drAEs during follow-up (median follow-up, 12.8 months).
Cumulative incidence of drAEs. drAEs were defined as CRS, ICANS, MNTs, or any postdischarge fatal AE following CAR-T for MM. Of note, 86 patients (14.7% of all patients) never developed any drAEs during follow-up (median follow-up, 12.8 months).
Our survey was completed by 47 physicians (74% response rate), most of whom had cared for >10 individual patients who received ide-cel (64%, n = 30) or cilta-cel (70%, n = 33). As shown in supplemental Table 3, >80% of respondents (n = 40) stated that the risk for impaired driving was present in <2% of the patients during weeks 5 to 8. In terms of universal driving restrictions, 72% (n = 34) agreed or strongly agreed with the rationale during weeks 1 to 4, whereas 77% (n = 36) disagreed or strongly disagreed with the restrictions during weeks 5 to 8. Similarly, dichotomous distributions (P < .01 for all questions) in physician agreement were noted for weeks 1 to 4 when compared with weeks 5 to 8 in terms of the safety-related rationales for geographic proximity and continuous caregiver support.
Taken together, our analysis demonstrated that driving restrictions following week 4 after CAR-T therapy in MM do not seem to be universally indicated. Although the FDA’s and EMA’s 8-week restrictions are echoed in the current International Myeloma Working Group guidance,16 expert opinions in our study favored universal driving restrictions through week 4 but not through week 8. Even with an expansive definition of drAEs well beyond actual seizures (which did not occur in our cohort), only 1% of ambulatory patients developed any drAEs during weeks 5 to 8. Importantly, not all drAEs would immediately jeopardize a patient’s ability to drive safely, such as transient CRS or mild Bell palsy. Even if treatment-related parkinsonism occurred, this AE would likely be diagnosed before frank impairment of driving ability. Furthermore, 8-week driving restrictions do not capture all such cases regardless.12,14 All in all, decisions about operating vehicles or heavy machinery can likely be made on a case-by-case basis with the treating physician and/or a neurology consultant in such scenarios.
Our finding align with several other studies that reported the rarity of CRS and ICANS after 14 days.12,13,17-19 Although the risk for drAEs is demonstrably low after week 2 (and even more so after week 4), the potential hardships for patients owing to continued universal driving restrictions is high. With the current CRS-related requirements, all CAR-T recipients already require caregiver assistance for 4 weeks following infusion. Beyond that timepoint, an additional month of caregiver assistance or hired help (eg, with grocery procurement or transportation to/from appointments) may create hardships for patients. Indeed, the ability to drive is important not only for healthcare-related interactions but also for basic life-related activities. Given the known disparities in CAR-T access among patients who live remotely or who do not have the means to pay for hired help,20,21 this requirement may even prompt some patients to opt for other options instead (eg, bispecific antibodies) even if CAR-T therapy is deemed to be the best option for them.22
Our study has several limitations inherent to real-world data, including the possibility of drAEs not being reported to study centers. Based on the analyses of the FDA AE Reporting System, ∼20 seizures have been reported to the FDA following any CAR-T infusion in MM between 2019 and 2023.23,24 However, FDA AE Reporting System data lack denominators and also do not identify when and why these seizures occurred. Specific neurologic assessments (as can be done in Parkinson disease to assess driving abilities)25 and comprehensive eye examinations are the gold standards to assess driving risk but were not conducted as part of standard-of-care assessments for our patients. As CAR-T treatment patterns in MM evolve and new products gain regulatory approval, prospective data collection regarding drAEs will be important. Although our survey of physicians had a high response rate and included many oncologists with extensive CAR-T experience, response bias might have impacted our findings. Finally, to avoid asking patients about activities taken specifically against medical advice, we intentionally did not incorporate a patient-facing survey as a component of this study.
In conclusion, we propose changes to the FDA and EMA guidelines that encourage the individualization of post–CAR-T driving restrictions beyond week 4. For patients with prolonged hospitalizations or concerning MNTs, such as parkinsonism, continuing to refrain from driving until neurology consultation or further follow-up evaluation may be prudent. However, for most patients, our 2-part study using real-world data and expert consensus strongly suggests that universal driving restrictions seem unnecessary after the first month. Shortening the recommended timeframe for universal driving restrictions to 4 weeks would thus constitute an evidence-based modification to the package inserts for ide-cel and cilta-cel.
Acknowledgments: The authors acknowledge the patients who contributed data, as well as the research personnel at all study sites.
The use of Research Electronic Data Capture through the University of Washington Institute of Translational Health Sciences was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant UL1 TR002319. D.K.H. and L.C.P. were supported by National Cancer Institute grant R01CA281756-01A1 and the Pentecost Family Myeloma Research Center.
Contribution: R.B., A.R., and G.K. analyzed the data and wrote the first draft of the manuscript; and all authors contributed patients to this analysis, provided critical feedback, and approved the final manuscript.
Conflict-of-interest disclosure: R.B. reports serving as a consultant for Adaptive Biotech, Bristol Myers Squibb, Caribou Biosciences, Genentech, Gilead/Kite, Janssen, Karyopharm, Legend Biotech, Pfizer, Poseida Therapeutics, Sanofi, and SparkCures, and receiving research funding from AbbVie, Bristol Myers Squibb, Janssen, Novartis, Pack Health, Prothena, and Sanofi. S.M. reports serving as a consultant for Janssen and Pfizer; receiving honoraria from Pfizer; and owning stock in AbbVie. A.A. reports serving as a consultant for Bristol Myers Squibb, Karyopharm, Johnson & Johnson, and Sanofi, and receiving research funding from AbbVie, Adaptive, Johnson & Johnson, and K36 Therapeutics. F.A. reports serving as a consult or in an advisory role for Bristol Myers Squibb, Celgene, and Caribou Biosciences, and receiving research funding from Allogene Therapeutics, Celgene, GlaxoSmithKline, Bristol Myers Squibb, and Caribou Biosciences. S.A. reports receiving honoraria from Janssen and research funding from GlaxoSmithKline, Amgen, Karyopharm Therapeutics, Janssen, and Bristol Myers Squibb. O.C.P. reports serving as a consultant or in an advisory role for Bristol Myers Squibb, Janssen, and Legend Biotech. S.C. reports receiving honoraria from Sanofi, Sobi, and Ascentage Pharma, and receiving institutional research funding from AbbVie, C4 Therapeutics, CARsgen, AstraZeneca, and Johnson & Johnson. K.I.C. reports receiving research funding from Bristol Myers Squibb and Novartis and serving as a consultant for Prothena and Johnson & Johnson. J.A.D. reports serving as a consultant for Bristol Myers Squibb and Janssen and serving on the speakers’ bureau for Janssen. B.D. reports serving as a consultant or in advisory role for Bristol Myers Squibb, Janssen, Genentech, Kite Pharma, Pfizer, Arcellx, Karyopharm, ECor1, Takeda, and Natera, and receiving research funding from Bristol Myers Squibb, Janssen, Arcellx, CARsgen, C4 Therapeutics, and Sanofi. C.J.F. reports serving as a consultant for Janssen; receiving research funding from Janssen and Regeneron; and owning publicly traded stock of Affimed. P.A.F. reports serving as a consultant for Janssen and Sanofi and receiving research funding from Karyopharm. C.L.F. reports receiving honoraria from or serving as a consultant for Bristol Myers Squibb, Seattle Genetics, Celgene, AbbVie, Sanofi, Incyte, Amgen, ONK Therapeutics, and Janssen, and receiving research funding from Bristol Myers Squibb, Janssen, and Roche/Genentech. T.J. reports receiving institutional research support from CTI BioPharma, Kartos Therapeutics, Incyte, Bristol Myers Squibb, and TScan, and serving on an advisory board for Bristol Myers Squibb, Incyte, AbbVie, CTI BioPharma, Kite Pharma, Cogent Biosciences, Blueprint Medicine, Telios Pharma, Protagonist Therapeutics, Galapagos, TScan Therapeutics, Karyopharm, MorphoSys, and IN8bio. M.J. reports serving as a consultant or in an advisory role for Bristol Myers Squibb, Janssen, and Legend Biotech, and receiving research funding from Bristol Myers Squibb, Janssen, and Fate Therapeutics. J.K. reports serving as a consultant for GPCR Therapeutics, Janssen, Prothena, and Legend Biotech, and receiving research funding from Prothena, Ascentage, Janssen, Karyopharm, and GPCR Therapeutics. Y.L. reports servings as a consultant for Opna Bio. F.L. reports serving as a consultant for A2, Allogene, Amgen, bluebird bio, Bristol Myers Squibb, Calibr, Caribou Biosciences, EcoR1, Gerson Lehrman Group, Iovance, Kite Pharma, Janssen, Legend Biotech, Novartis, Sana, and Pfizer; serving on the data safety monitoring board for the National Cancer Institute Safety Oversight CAR T-cell Therapies Committee; receiving research funding from Kite Pharma (Institutional), Allogene (Institutional), 2SeventyBio (Institutional), Bristol Myers Squibb (Institutional), and Leukemia and Lymphoma Society Scholar in Clinical Research (PI: Locke); and having patents, receiving royalties, and owning other intellectual property in the field of cellular immunotherapy. J.P.M. reports receiving honoraria from Kite Pharma, Juno Therapeutics, AlloVir, Magenta Therapeutics, and EcoR1 Capital; serving on the speakers’ bureau for Kite/Gilead; receiving research funding from Novartis, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Novartis, Gamida Cell, Pluristem Therapeutics, Kite Pharma, and AlloVir; receiving honoraria from Kite Pharma, AlloVir, Juno Therapeutics, and Magenta Therapeutics; and claiming travel, accommodations, and expenses from Kite Pharma. L.M. reports serving as a consultant or in an advisory role for Legend Biotech and BioLineRx. O.N. reports serving as a consultant or in an advisory role for Bristol Myers Squibb, Janssen, Takeda, Sanofi, Pfizer, and GPCR Therapeutics; receiving research funding from Bristol Myers Squibb, Janssen, and Takeda; and receiving honoraria from Pfizer. L.C.P. reports receiving research funding from Bristol Myers Squibb and Karyopharm. R.R. reports serving as a consultant or in an advisory role for Allogene, Gilead Sciences, Incyte, TScan, Orca Bio, Quell Biotherapeutics, Sana Biotechnology, and Autolus; serving as an expert witness for Bayer; and receiving research funding from Atara Biotherapeutics, Incyte, Sanofi, Immatics, AbbVie, TCR2, Takeda, Gilead Sciences, CareDx, TScan, Cabaletta, Synthekine, Bristol Myers Squibb, Johnson & Johnson, Genentech, and Precision Biosciences. S.R. reports serving as a consultant for Pfizer and Prothena Biosciences and receiving research funding from Nexcella Inc, Poseida Therapeutics, and Janssen. D.W.S. reports serving in an advisory role or as consultant for Janssen, Bristol Myers Squibb, GlaxoSmithKline, Sanofi, Legend Biotech, Opna Bio, Pfizer, AbbVie, AstraZeneca, and Genentech, and receiving research support from Pfizer. L.S. reports serving as a consultant for Bristol Myers Squibb. S.S. reports receiving research support from Magenta Therapeutics, Bristol Myers Squibb, Allogene, Janssen, Novartis, and AbbVie, and serving on the advisory board or as a consultant for Bristol Myers Squibb, Janssen, Sanofi, Oncopeptides, Takeda, Regeneron, AbbVie, Pfizer, BioLineRx, Legend, and Kite Pharma. K.K.P. reports serving as a consultant for Bristol Myers Squibb, Janssen, AstraZeneca, Legend Biotech, Kite Pharma, Genentech, AbbVie, Sanofi, Caribou Biosciences, Takeda, Regeneron, and Poseida. D.K.H. reports receiving research funding from Bristol Myers Squibb, Janssen, Karyopharm, Kite Pharma, and Adaptive Biotech, and serving as a consultant for Bristol Myers Squibb, Janssen, Legend Biotech, Pfizer, Kite Pharma, AstraZeneca, and Karyopharm. Y.L. reports serving as a consultant for Janssen, Legend, Celgene, Sanofi, Bristol Myers Squibb, Pfizer, Regeneron, Genentech, NexImmune, and Caribou Biosciences, and receiving research funding from Janssen, Celgene, and Bristol Myers Squibb. T.G.M. reports receiving research funding from Sanofi, Amgen, and Janssen Oncology, and serving as a consultant or in an advisory role for GlaxoSmithKline and Legend Biotech. P.M.V. reports serving as a consultant or in an advisory role for AbbVie, AstraZeneca, Karyopharm Therapeutics, Bristol Myers Squibb, Lava Therapeutics, Sanofi, Janssen, and GlaxoSmithKline; receiving research funding from AbbVie, Janssen, GlaxoSmithKline, and TeneoBio; and claiming travel, accommodation, and expenses costs from Sanofi. L.D.A. Jr reports serving as a consultant for Janssen, Celgene, Bristol Myers Squibb, Amgen, GlaxoSmithKline, AbbVie, BeiGene, Cellectar, Sanofi, and Prothena, and receiving research support from Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, and AbbVie. A.J.C. reports serving as a consultant for AbbVie, Adaptive, Bristol Myers Squibb, Hope AI, Janssen, Sebia, and Sanofi, and receiving research support from AbbVie, Adaptive Biotechnologies, Caelum, Harpoon, Nektar, Bristol Myers Squibb, Janssen, Sanofi, Opna Bio, IGM Biosciences, and Regeneron. G.K. reports serving as a consultant for Bristol Myers Squibb, Arcellx, Sanofi, Janssen, Kite Pharma, Prothena, Cellectar, Pfizer, and Kedrion, and receiving research funding from Bristol Myers Squibb, Janssen, Arcellx, and AbbVie. The remaining authors declare no competing financial interests.
Correspondence: Rahul Banerjee, Division of Medical Oncology, Department of Medicine, Fred Hutchinson Cancer Center, 825 Eastlake Ave E, LG-650, Seattle, WA 98109; email: [email protected].
