Post-CAR-T Driving Restrictions after Week 4 Appear Unnecessary: Data from the United States Myeloma Immunotherapy Consortium

Background: The FDA package inserts for all approved chimeric antigen receptor T-cell (CAR-T) therapies state that patients should universally refrain from driving for 8 weeks following infusion. However, there are no clear data to support this recommendation, particularly in multiple myeloma (MM) which all CAR-T therapies use 4-1BB as opposed to CD28 costimulatory domains. Specifically, no seizures were reported in the KarMMa, KarMMa-3, CARTITUDE-1, or CARTITUDE-4 trials. Because patients typically return to their referring oncologists after Day (D) +28 following CAR-T infusion, an additional month of driving restrictions can create confusion for referring oncologists, impose significant burdens for patients and caregivers, and potentially even affect the choice of MM therapy for patients living in remote areas.

Methods: We conducted a two-part study within the US MM Immunotherapy Consortium. Firstly, we analyzed data from commercial idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) recipients (leukapheresis cutoff December 31, 2023) to identify the prevalence of CRS, ICANS, or death between Weeks 5-8 (D+29 to D+56) following CAR-T (Day 0). Patients with index hospital stays lasting over 4 weeks and patients with <8 weeks of post-CAR-T follow-up were excluded. Secondly, we surveyed Consortium members about the prevalence of impaired driving risk (defined as “anything that could impair a patient's ability to drive safely, e.g. seizures, altered mental status, blindness, etc.”) and used 1-5 Likert scales to gauge the perceived importance of driving restrictions (assuming no FDA guidance existed) during Weeks 0-4 vs 5-8. This anonymous IRB-exempted survey was distributed via email to 63 CAR-T-prescribing physicians within the Consortium.

Results: Of 553 analyzed patients, 41% (n=224) had received cilta-cel and 59% (n=329) ide-cel. The median age was 64 (IQR 58-70), 42% (n=231) were female, 78% White (n=434), 13% (n=72) Black, and 9% (n=51) Hispanic. ECOG PS at infusion was ≥2 in 11% (n=63) of patients, and 5% (n=28) had had previous CNS co-morbidities such as prior strokes. One patient (0.2%) developed Grade 2 CRS during Weeks 5-8 (onset D+47, resolution one day later); no patients had de novo ICANS after D+28. There were 16 cases of non-ICANS neurotoxicity (including 2 cases of Parkinsonism) diagnosed a median of 24 days after CAR-T (range: 17-147 days), of which 3 cases (all non-Parkinsonian) were first diagnosed during Weeks 5-8. There were 10 deaths (2%) during Weeks 5-8, one due to infection and the remainder from progressive MM.

The survey was completed by 45 oncologists (71% response rate), 41 of whom had managed both >5 ide-cel and >5 cilta-cel recipients. Regarding impaired driving during Weeks 0-4, 20% of physicians felt this was never a risk, 36% a risk for 1-2% of patients, 29% a risk for 3-10% of patients, and 16% a risk for >10% of patients. The distribution was significantly different (p < 0.01) for Weeks 5-8: 49% never a risk, 36% a risk for 1-2% of patients, 16% a risk for 3-10% of patients, while no respondents felt this remained a risk for >10% of patients. For Weeks 0-4, 73% agreed that patients should be advised not to drive while 9% disagreed. In contrast, for Weeks 5-8, 14% of physicians agreed with driving restrictions while 78% disagreed (p < 0.01 compared to Weeks 0-4).

Discussion: Our two-part study demonstrates that driving restrictions following Week 4 after CAR-T therapy in MM may not be required. The incidence of de novo CRS or any-type neurotoxicity being diagnosed during Weeks 5-8 was <1%, and - if such toxicities developed - patients and physicians could be expected to set appropriate restrictions at that juncture. While 73% of CAR-T-prescribing oncologists agreed that patients should refrain from driving during Weeks 0-4, 78% disagreed with this recommendation during Weeks 5-8. These findings complement other real-world studies (Wesson, Dima, et al, TCT 2024; Ahmed et al, Blood Advances 2024) reporting the rarity of CRS and ICANS after the first month in both MM and lymphoma. Our study is limited by a lack of patient-reported data, which was done intentionally to avoid asking patients about activities undertaken against medical advice. Nevertheless, we believe that narrowing universal driving restrictions to Weeks 0-4 following CAR-T therapy would constitute an evidence-based modification to the package inserts for ide-cel and cilta-cel.

Banerjee:Abbvie; JNJ; Novartis; Pack Health; Prothena; Sanofi: Research Funding; Adaptive; BMS; Caribou Biosciences; Genentech; GSK; JNJ / Janssen; Karyopharm; Legend Biotech; Pfizer; Sanofi; SparkCures: Consultancy. Khouri:GPCR Therapeutics: Honoraria; Legend Biotech: Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Janakiram:JANNSEN: Honoraria, Research Funding; BMS: Honoraria, Research Funding; LEGEND: Honoraria, Research Funding; FATE THERAPEUTICS: Research Funding. Cicero:BMS, Novartis: Research Funding. Shune:BMS: Membership on an entity's Board of Directors or advisory committees; Norvatis: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Jain:Bristol Myers Squibb, Incyte, Abbvie, CTI, Kite, Cogent Biosciences, Blueprint Medicine, Telios pharma, Protagonist therapeutics, Galapagos, Tscan therapeutics, Karyopharm, Morphosys: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma, Kartos therapeutics, Incyte, Bristol Myers Squibb: Research Funding. Afrough:Sanofi: Honoraria, Other; Karyopharm Therapeutics: Honoraria, Other; Bristol-Myers Squibb: Honoraria, Other; K36 Therapeutics: Research Funding; Adaptive Biotech: Research Funding; Abbvie: Research Funding. Ferreri:Janssen: Consultancy; Affimed: Current holder of stock options in a privately-held company. Mikkilineni:BiolineRx: Consultancy, Other: advisory board at ASH December 2023; Legend Biotech: Consultancy, Other: advisory board at ASH December 2023. Peres:Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding. Freeman:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Sanofi: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Research Funding; ONK therapeutics: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Roche/Genentech: Research Funding. Midha:Pfizer: Consultancy; Janssen: Consultancy. Beitinjaneh:Lyell: Research Funding; CRISPOR: Research Funding; Atara: Research Funding; Autolus: Consultancy, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Tessa: Research Funding. Davis:Janssen Biotech: Speakers Bureau. Wagner:Jazz: Research Funding; Pfizer: Consultancy. Forsberg:Colorado Blood Cancer Institute: Current Employment; Karyopharm: Research Funding; Johnson and Johnson, BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; University of Colorado: Ended employment in the past 24 months. Sborov:Paraxel: Other: Independent review committee; Celgene: Honoraria; Amgen, Celgene, and Janssen, GlaxoSmithKline, Abbvie, Pfizer, Astra Zeneca, Bioline, Sanofi, and Genentech: Consultancy; Pfizer: Research Funding; Janssen, Karyopharm: Membership on an entity's Board of Directors or advisory committees. Richard:Heidelberg Pharma: Research Funding; C4 Therapeutics: Research Funding; Gracell Therapeutics: Other: Steering Committee, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reshef:Cabaletta: Research Funding; TScan: Consultancy, Research Funding; Orca Bio: Consultancy; BMS: Research Funding; Takeda: Research Funding; Synthekine: Research Funding; CareDx: Research Funding; Incyte: Consultancy, Research Funding; TCR2: Research Funding; Sana Biotechnology: Consultancy; Quell Biotherapeutics: Consultancy; Autolus: Consultancy; Bayer: Consultancy; Atara Biotherapeutics: Research Funding; Sanofi: Research Funding; Immatics: Research Funding; Abbvie: Research Funding; J&J: Research Funding; Genentech: Research Funding; Precision Biosciences: Research Funding; Gilead Sciences: Consultancy, Research Funding; Allogene: Consultancy. Dhakal:Acrellx: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Research Funding; Carsgen: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Karyopharm: Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria; C4 therapeutics: Research Funding; Medical College of Wisconsin: Current Employment. Bachanova:Citius: Research Funding; Incyte: Research Funding. McGuirk:NEKTAR therapeutics: Consultancy; Legend biotech: Consultancy; Sana technologies: Consultancy; Autolus: Consultancy; Envision: Consultancy; CRISPR therapeutics: Consultancy; Caribou bio: Consultancy; Novartis: Consultancy; Allo Vir: Consultancy; Kite: Consultancy; BMS: Consultancy. Voorhees:AstraZeneca: Consultancy; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lava Therapeutics: Consultancy; GSK: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Lin:Sanofi: Consultancy; Regeneron: Consultancy; Caribou: Membership on an entity's Board of Directors or advisory committees; Legend: Consultancy; NexImmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy. Martin:Janssen: Research Funding; Poseida: Research Funding; GSK, Pfizer, Roche: Honoraria; BMS: Research Funding; Sanofi: Research Funding. Sidana:Abbvie: Consultancy; BMS: Consultancy, Research Funding; BiolineRx: Consultancy; Janssen: Consultancy, Research Funding; Regeneron: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Legend: Consultancy; Novartis: Research Funding; Kite, A Gilead company: Consultancy; Oncopeptides: Consultancy. Patel:Johnson & Johnson (Janssen): Consultancy; AstraZeneca: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; BMS: Consultancy, Other: chair of scientific advisory board ; Merck: Consultancy; Kite, A Gilead company: Consultancy, Other: scientific advisory board; Genentech: Consultancy; Poseida: Consultancy; Abbvie: Consultancy; Caribou Sciences: Consultancy; Oricel: Consultancy, Other: Chair of scientific board. Hansen:Pfizer: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Cowan:HopeAI: Consultancy, Current holder of stock options in a privately-held company; Harpoon: Research Funding; Caelum: Research Funding; Sanofi: Consultancy, Research Funding; Regeneron: Research Funding; IgM biosciences: Research Funding; Nektar: Research Funding; Juno/Celgene: Research Funding; BMS: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sebia: Consultancy. Kaur:Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Arcellx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Cellectar Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.