Pre-Apheresis Prediction of Toxicity and Response in Patients Receiving BCMA-Directed CAR-T for Relapsed/Refractory Multiple Myeloma

Introduction: Recent efforts have shed light on the clinical and laboratory factors associated with toxicity and response to BCMA-directed CAR-T therapy in patients with relapsed/refractory multiple myeloma (RRMM). However, a major limitation of current scoring systems lies in their assessment at time of lymphodepletion. Because they are not determined before apheresis, they are ill-equipped to guide patient selection, anticipate level-of-care, or plan pre-emptive toxicity management strategies. We therefore aimed to characterize early predictors of CAR-T toxicity and response.

Study Design: In this multicenter observational study, we examined demographic, clinical, and laboratory data across three distinct timepoints: indication (e.g., treatment decision), apheresis, and pre-lymphodepletion (LD). CRS and ICANS were graded according to ASTCT criteria. Hematotoxicity (ICAHT) was graded using EHA/EBMT criteria. Early infections (day 0-100) were defined based on microbiologic data or as a clinical infection syndrome, and graded per Hill et al, Blood 2018. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared by log-rank test. Cox proportional hazard models were applied to explore associations between pre-apheresis risk factors and key toxicity and survival outcomes. The CAR-HEMATOTOX (HT) score - encompassing markers of inflammation (e.g., CRP, ferritin) and marrow reserve (e.g., hemoglobin, ANC, platelet count) - was determined at each timepoint (Rejeski et al, Blood 2021).

Results: We included 530 RRMM patients treated with standard-of-care cilta-cel (n=184) or ide-cel (n=346) across nine centers. Median age was 65 (range 31-88), median ECOG was 1 (IQR 0-1), and patients received a median of 5 prior lines of therapy (IQR 4-7). The median time from indication to apheresis was 16 days (IQR 7-52), while the median time from apheresis to infusion was 56 days (IQR 46-69). The proportion of high-risk patients by HT score did not change between the pre-apheresis and LD timepoints (19% vs. 20%, p=0.82). Most patients stayed either low-risk (n=388, 73.2%) or high-risk (n=68, 12.8%). However, 35 patients (6.6%) shifted from high-to-low risk, while 39 patients (7.4%) progressed from low-to-high risk - reflecting their response to bridging therapies.

We noted considerable differences in morbidity and mortality based on the pre-apheresis HT score. Compared to their low-risk counterparts (score 0-2, n=427), high-risk patients (score ≥3, n=103) were hospitalized longer (12 vs. 15 days, p=0.009) and required more frequent ICU admissions (6% vs. 12%, p=0.05). They exhibited more severe early cytopenias (G3+: 8% vs. 25%, p<0.001) and late cytopenias (G3+: 7% vs. 21%, p<0.001), resulting in increased use of TPO agonists and stem cell boosts. Grade 3 or higher ICANS was also more common in HT^high patients (3% vs. 11%, p=0.006), as were severe infections (14% vs. 27%, p=0.007). We found increased non-relapsed mortality in HT^high patients (1-yr NRM 4.6% vs. 16.1%, p<0.001), but no significant difference in the occurrence of secondary malignancies (p>0.9).

With a median follow-up of 12.4 months, HT^high patients showed inferior PFS (1-yr PFS 29% vs. 63%, p<0.0001) and OS (1-yr OS 49% vs. 83%, p<0.0001). Transitioning from a low-to-high score was linked to poor survival (1-yr PFS 26%), while the shift from high-to-low risk was associated with favorable outcomes (1-yr PFS 51%). In a multivariable Cox regression model of pre-apheresis features, a high HT score (aHR 2.52, p<0.0001), prior anti-BCMA therapy (aHR 1.55, p=0.04), history of extramedullary disease (aHR 1.42, p=0.02), and penta-refractoriness (aHR 1.45, p=0.02) were independently associated with PFS. Notably, the presence of more than 3 of these high-risk features defined an ultra-high-risk cohort of 28 patients (5.3%) with particularly dismal survival (1-year PFS 15%).

Conclusions: Leveraging granular pre-apheresis data from a large international cohort, we identify early markers of toxicity and response in CAR-T-treated RRMM patients. The HT score - reflecting baseline inflammation and hematopoietic reserve - identified high-risk patients likely to benefit from pre-emptive toxicity mitigation strategies such as prophylactic stem cell collection. Most importantly, we characterize a small yet ultra-high-risk group of RRMM patients in need of more effective bridging and therapeutic options.

Rejeski:Pierre-Fabre: Other: Travel Support; BMS/CELGENE: Consultancy, Honoraria; Novartis: Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel Support, Research Funding. Hansen:Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Research Funding. Castaneda:BMS: Consultancy; Legend Biotech: Consultancy; Janssen: Consultancy. Alsdorf:Immatics: Consultancy, Other: Travel costs, accommodations, expenses, assistance in medical writing; Janssen: Consultancy, Honoraria, Other: Travel costs, accommodations, expenses, assistance in medical writing; GSK: Honoraria; Astellas: Honoraria; AstraZeneca: Honoraria; Biontech: Other: Travel costs, accommodations, expenses, assistance in medical writing, Research Funding; Affimed: Research Funding. Frenking:Janssen-Cilag: Other: Travel and congress participation grants; BMS, Stemline: Honoraria. Freeman:Janssen: Consultancy, Research Funding; Roche/Genentech: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy; ONK therapeutics: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. Gaballa:GLG: Consultancy; Guidepoint: Consultancy; Boxer Capital, LLC: Consultancy; Bristol Myers Squibb: Consultancy. Hwa:GSK: Honoraria; Janssen: Honoraria; MultiMedia Medical, LLC: Consultancy; Shield Therapeutics: Honoraria; Pfizer: Other: Consulting fee located to Mayo Research fund. Jain:Kite/Gilead: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Incyte: Research Funding; Loxo: Research Funding. Parrondo:Sanofi Aventis: Honoraria; Bristol Myers Squibb, GSK: Research Funding; AstraZeneca: Honoraria. Bassermann:BMS, Janssen: Honoraria. Raab:Heidelberg Pharma: Research Funding; Pfizer: Consultancy, 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, Other: travel expenses, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Oncopeptides: Consultancy, Honoraria, Other: travel expenses; Takeda: Consultancy, 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. Weisel:Janssen: Consultancy, Honoraria, Other: Research grant to institution; GlaxoSmithKline: Consultancy, Honoraria, Other: Research grant to institution; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Other: Research grant to institution; Amgen: Consultancy, Honoraria, Other: Research grant to institution; AbbVie: Other: Research grant to institution; Sanofi: Consultancy, Honoraria, Other: Research grant to institution; Adaptive Biotechnologies: Consultancy, Honoraria; AstraZeneca: Honoraria; BeiGene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche Pharma: Consultancy, Honoraria; Stemline: Honoraria; Takeda: Consultancy, Honoraria; Regeneron: Consultancy. Locke:Clinical Care Options Oncology: Honoraria; Gilead Company: Consultancy; Communications CARE Education: Honoraria; Aptitude Health: Honoraria; BMS: Consultancy, Research Funding; Sana: Consultancy; Leukemia and Lymphoma Society Scholar in Clinical Research: Research Funding; Celgene: Consultancy; Janssen: Consultancy; Iovance: Consultancy; Gerson Lehrman Group (GLG): Consultancy; Cowen: Consultancy; Cellular Biomedicine Group: Consultancy; Society for Immunotherapy of Cancer: Honoraria; Legend Biotech: Consultancy; Amgen: Consultancy; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; ASH: Honoraria, Other: Travel support; ecoR1: Consultancy; Calibr: Consultancy; GammaDelta Therapeutics: Consultancy; Caribou: Consultancy; iMedX: Honoraria; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BioPharma: Honoraria; Pfizer: Consultancy; Emerging Therapy Solutions Gerson Lehman Group: Consultancy; Umoja: Consultancy; Wugen: Consultancy; Moffit Cancer Center: Patents & Royalties: cellular immunotherapy; Allogene: Consultancy, Research Funding; CERo Therapeutics: Research Funding; 2SeventyBio: Research Funding; National Cancer Institute: Research Funding; A2: Consultancy; Aptitude Health: Honoraria. Subklewe:AstraZeneca, BMS, Gilead/Kite, GSK, Janssen, LAWG, Novartis, Pfizer, Roche, Springer Healthcare: Speakers Bureau; AbbVie, Amgen, Autolus, AvenCell, BMS, CanCell Therapeutics, Genmab US, Gilead, Ichnos Sciences, Incyte Biosciences, Interius BioTherapeutics, Janssen, Miltenyi Biomedicine, Molecular Partners, Nektar Therapeutics, Novartis, Orbital Therapeutics, Pfizer,: Honoraria; Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi Biotec, Molecular Partners, Novartis, Roche, Seagen, Takeda: Research Funding. Patel:Genentech: Consultancy; Merck: Consultancy; Oricel: Consultancy, Other: Chair of scientific board; Takeda: Consultancy; BMS: Consultancy, Other: chair of scientific advisory board ; Poseida: Consultancy; Johnson & Johnson (Janssen): Consultancy; Caribou Sciences: Consultancy; AstraZeneca: Consultancy; Kite, A Gilead company: Consultancy, Other: scientific advisory board; Pfizer: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy. Lin:Janssen: Consultancy, Research Funding; Legend: Consultancy; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; NexImmune: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding; Caribou: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy.