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

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Multiple Myeloma: Clinical and Epidemiological: Exploring T Cell Redirecting Therapies, Mutation Profiles and Early Relapse
Hematology Disease Topics & Pathways:
Research, Adult, Plasma Cell Disorders, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Treatment Considerations, Biological therapies, Real-world evidence, Adverse Events, Lymphoid Malignancies, Study Population, Human
Monday, December 9, 2024: 2:45 PM

Kai Rejeski, MD1,2, Doris K. Hansen, MD3, David M. Cordas Dos Santos, MD4*, Andre De Menezes Silva Corraes, MD5*, Omar Castaneda, MD3, Christen M Dillard, MD6*, Winfried Alsdorf7*, Jan H. Frenking, MD8*, Anna Purcarea, MD9*, Saurabh Chhabra, MBBS10*, Ciara Louise Freeman, PhD, MSc, FRCPC, MRCP3, Mirco Julian Friedrich, MD, PhD8*, Mahmoud R. Gaballa, MD11, Rebecca Gonzalez, PharmD12*, Syed Hamza Bin Waqar, MD12*, Yi Lisa Hwa, APRN, DNP, CNP5, Michael D. Jain, MD, PhD13, Ricardo D. Parrondo, MD14, Oren Pasvolsky, MD15, Wajma Shahbaz, MD1*, Roni Shouval, MD, PhD2, Genevieve Spiess, PAC5*, Haily Stephens, PAC5*, Sebastian Theurich, MD1*, Florian Bassermann, MD16*, Judith S. Hecker, MD17*, Marc S. Raab8*, Katja C. Weisel, MD7, Frederick L. Locke, MD13, Marion Subklewe, MD18, Krina K. Patel, MD, MSc19 and Yi Lin, MD, PhD5

1Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
2Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
4Dana-Farber Cancer Institute, Boston, MA
5Division of Hematology, Mayo Clinic, Rochester, MN
6Department of Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, TX
7University Medical Center Hamburg-Eppendorf, Hamburg, Germany
8Heidelberg Myeloma Center, Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
9Department of Medicine III and Center for Translational Cancer Research, Technical University of Munich (TUM), School of Medicine and Health, Munich, Germany
10Division of Hematology/Oncology, Mayo Clinic Arizona, Phoenix, AZ
11Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
12Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL
13Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL
14Division of Hematology-Oncology, Mayo Clinic-Florida, Jacksonville, FL
15Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
16Hospital Rechts der Isar, Internal Medicine III - Hematology and Oncology, Technical University of Munich, Munich, Germany
17Department of Medicine III, Hematology and Oncology, Technical University of Munich (TUM), School of Medicine and Health, Munich, Germany
18Department of Medicine III, LMU University Hospital, Munich, Germany
19M.D. Anderson Cancer Center, MD Anderson Cancer Center, Houston, TX

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 HThigh patients (3% vs. 11%, p=0.006), as were severe infections (14% vs. 27%, p=0.007). We found increased non-relapsed mortality in HThigh 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, HThigh 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.

Disclosures: 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.

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