Delayed Neurotoxicity after CAR-T in Multiple Myeloma: Results from a Global IMWG Registry

Background

Emerging evidence has demonstrated rare subacute to late neurological toxicities (NTs) after BCMA CAR T-cell therapy (CAR-T) in multiple myeloma (MM). These adverse events can be categorized as: 1) Parkinsonism (PD), 2) cranial nerve (CN) palsies, and 3) peripheral neuropathies/Guillan Barré syndrome (GBS). These toxicities can cause significant morbidity, but given their relative rarity in clinical trials, there is limited data regarding evaluation and treatment. To our knowledge, this is the largest and only global registry of delayed NTs after BCMA CAR-T.

Methods

We retrospectively established a registry of NTs via the Immune Therapy Working Committee of the International Myeloma Working Group (IMWG). We gathered data pertaining to demographics, MM characteristics, MM response, NT signs/symptoms, diagnostic workup, and treatment.

Result

A total of 52 patients with delayed neurotoxicity were included from 14 institutions and 6 countries; 92% received ciltacel, 4% idecel, and 4% investigational CAR-T. Median age at CAR-T infusion was 65 years; 69% were male and 88% were Caucasian. Median bone marrow plasma cell (PC) burden was 15% prior to CAR-T (range 0-95%). Patients received a median of 4 prior lines of therapy (LOT), with 67% progressing on last LOT. Seventeen percent had pre-existing neurological diagnoses (including stroke, epilepsy, migraines).

We identified sixteen cases of PD (94% with movement disorder, 69% with cognitive impairment, 75% with personality changes), occurring at a median of 26 days (range: 15-87) after CAR-T. Ninety four percent had CRS (grade (G)1 50%, G2 38%, G3 6%, G4 0%), while 19% had ICANS (G1 13%, G2 6%, G3-G4 0%). Median peak absolute lymphocyte count (ALC) was 9.5 x 10⁹/L, peak C-reactive protein (CRP) 60.9 mg/L, and peak ferritin 1893.5 ug/L within the first 30 days. Concurrently, 3 upper respiratory infections (URIs) and 2 low-level HHV7 in the cerebrospinal fluid (CSF) were detected. A median of 73% of T-cells in the CSF were CAR-T, based on a flow cytometry assay. Ten patients received steroids (median 19 days after symptoms, 70% partial response, 20% no response, 10% unknown), 2 received intrathecal (IT) methotrexate-based therapy (median 32 days after symptoms, 1 with no response, 1 unknown), 5 received intravenous (IV) cyclophosphamide (median 31 days after symptoms, 40% full response, 20% partial response, 40% no response), 4 received high-dose IVIG ≥1g/kg for one or more dose (50% partial response, 50% no response), and 6 received dopamine agonists.

There were 37 CN palsies (76% CN7, 15% CN6, 7% CN5, 2% CN3), occurring at a median of 37.5 days (range: 7-482) after CAR-T. Eighty one percent had CRS (G1 68%, G2 14%, G3-G4 0%); 11% had G1 ICANS (G2-G4 0%). Median peak ALC was 4.1 x 10⁹/L, CRP 25.4 mg/L, and ferritin 543 ug/L within the first 30 days. We identified 2 concurrent URIs, 4 CMV viremia (50% with viral load >1500 IU/mL), 1 HHV6 viremia, and 1 HSV in the CSF. Thirty-two (86%) received steroids for a median duration of 12 days, 50% with full response, 3% with no response, and 47% with partial response (of which 43% had later full recovery without further intervention). One received IT methotrexate and another received IV cyclophosphamide without response. Thirteen (41%) received IVIG, of which 38% was high-dose IVIG. Four patients with CN palsies developed peripheral neuropathy/GBS.

Eight patients (15%) in this cohort were not heavily pre-treated (≤1 prior LOT); 7 developed CN palsies (6 after ciltacel, 1 after investigational CAR-T) and 1 PD (after idecel). These patients had median <5% PC; none had extramedullary disease. Median ALC was 4.14 x 10⁹/L, CRP 33 mg/L, and ferritin 448.5 ug/L within the first 30 days.

Conclusions

Delayed NT requires prompt recognition, evaluation for alternative causes, and treatment. In our cohort, the majority of patients were male and Caucasian, suggesting that sex and race may impact the likelihood of developing NT. Individuals with PDs had greater inflammatory response (CRS, ALC, CRP, ferritin) compared to those with CN palsies. CN palsies responded to steroids and/or IVIG, whereas PD had at best partial response to steroids, prompting additional therapy. These toxicities notably did occur in less heavily pre-treated patients, perhaps driven by immune fitness and greater circulating T-cells rather than MM burden. At the time of the annual meeting, data will be updated with additional NTs from less heavily pre-treated patients.

Hashmi:Janssen: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Parrondo:AstraZeneca: Honoraria; Sanofi Aventis: Honoraria; Bristol Myers Squibb, GSK: Research Funding. Chhabra:Omeros: Speakers Bureau; GlaxoSmithKline, Sanofi: Honoraria; Bristol Myers Squibb, Amgen, Janssen, Novartis, Syndax, Ionis, Sanofi, and GlaxoSmithKline: Research Funding. Kortüm:AbbVie, BMS, GSK Janssen, Novartis, Pfizer, Sanofi, Takeda, Stemline: Consultancy; AbbVie, BMS, GSK Janssen, Novartis, Pfizer, Sanofi, Takeda, Stemline: Honoraria; University Hospital Wurzburg: Current Employment. Scheller:Swedish Orphan Biovitrum GmbH: Honoraria. Einsele:BMS: Honoraria; Sanofi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; BMS: Consultancy, Honoraria, Research Funding; PharmaMar: Consultancy, Honoraria; Novartis: Consultancy, Research Funding. Martinez Lopez:Pfizer: Honoraria. Biran:Amgen: Research Funding; Pfizer: Consultancy, Honoraria; Karyopharm: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy; Sanofi: Honoraria, Speakers Bureau. Fernández de Larrea:Cellectar Biosciences: Research Funding; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Expenses; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Honoraria, Research Funding. Abrahamsen:Janssen: Consultancy; Novartis: Consultancy; BMS: Consultancy; Janssen: Honoraria; Takeda: Honoraria. Harrison:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Haematologix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eusa: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Costello:BMS, Janssen, Karyopharm, Kite, Genentech, Pfizer: Honoraria; BMS; Genentech; Janssen; Karyopharm; Kite; and Pfizer: Consultancy; BMS; Harpoon; Janssen; Pfizer; Poseida; and Takeda: Research Funding. Costa:Janssen: Consultancy, Honoraria, Research Funding; Adaptive biotechnoligies: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Caribou: Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria. Wiita:Indapta Therapeutics, LLC: Current equity holder in private company; Sanofi: Honoraria; Protocol Intelligence, LLC: Current equity holder in private company. Martin:Pfizer: Honoraria; BMS: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Roche: Honoraria; GSK: Honoraria; AMGEN: Research Funding. Lin:Genentech: Consultancy; Legend: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Caribou: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees. Chari:Janssen: Research Funding; Abbvie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genetech/Roche, Glaxo Smith Klein, Janssen, Karyopharm, Millenium/Takeda, Sanofi/Genzyme: Consultancy.