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79 Previous HDM/ASCT Adversely Impacts PFS with BCMA-Directed CAR T-Cell Therapy in Multiple MyelomaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Multiple Myeloma: Clinical and Epidemiological: Decluttering Responses and Dynamic Risk: How Can We Improve Prognostication in Multiple Myeloma?
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research, Plasma Cell Disorders, Diseases, Therapy sequence, Treatment Considerations, Lymphoid Malignancies
Saturday, December 7, 2024: 9:30 AM

Joshua Gustine, MD1*, Diana Cirstea, MD2*, Andrew R. Branagan, MD3, Andrew J. Yee, MD1, Marcela Maus, MD4, Matthew J. Frigault, MD1* and Noopur Raje, MD5

1Massachusetts General Hospital, Boston, MA
2Center for Multiple Myeloma, Massachusetts General Hospital, Boston, MA
3Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, MA
4Massachusetts General Hospital, Harvard Medical School, Boston, MA
5Center for Multiple Myeloma, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Background: Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) is highly effective in patients with multiple myeloma (MM). The clinical activity of autologous CAR-T is impacted by the functional capacity of the patient’s endogenous T-cells. MM patients commonly have received high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) before BCMA-directed CAR-T, but HDM/ASCT can confer an exhausted and senescent T-cell phenotype (Chung Cancer Immunol Res 2016; Lucas Biol Blood Marrow Transplant 2020; Minnie Blood 2018). Whether a previous HDM/ASCT impacts clinical outcomes to BCMA-directed CAR-T in MM is unknown.

Methods: We identified consecutive MM patients treated with a BCMA-directed CAR-T at our institution from 2017-2023. Treatment responses and progression-free survival (PFS) were assessed per the International Myeloma Working Group. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy guidelines. Time-to-event outcomes were estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. The Cox-proportional hazard regression method was used to fit univariate and multivariate models; the outcome measure was hazard ratio (HR) with a 95% confidence interval (CI). Calculations were made using R software (R Foundation for Statistical Computing, Vienna, Austria).

Results: A total of 104 patients were included, of whom 54 (52%) had received HDM/ASCT before CAR-T. The median time from HDM/ASCT to CAR-T infusion was 5.2 years (range, 0.7-13.2). Patients who had received a previous HDM/ASCT were significantly younger at the time of CAR-T (64 vs. 69 years; p=0.005), and had a trend for a longer time between MM diagnosis and CAR-T (6.5 vs. 5.4 years; p=0.06). There was no difference in the number of prior lines of treatment before CAR-T (p=0.80). A previous HDM/SCT was not associated with the best categorial response attainment, including complete responses (p=0.42). However, patients who had received a previous HDM/ASCT had a significantly shorter median PFS with CAR-T (9.5 vs. 21 months; p=0.01). On multivariate analysis, a previous HDM/ASCT was independently associated with a significantly shorter PFS with CAR-T (HR 2.17, 95% CI 1.25-3.74; p=0.006) after adjusting for extramedullary disease, high-risk cytogenetics, R-ISS stage, LDH, and ferritin level. In a separate multivariate analysis, a previous HDM/ASCT remained associated with shorter PFS with CAR-T (HR 1.85, 95% CI 1.08-3.19; p=0.03) after adjusting for all types of previous treatment (i.e., bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab). The time between HDM/ASCT and CAR-T did not appear to be associated with PFS. Patients who received HDM/ASCT <5 and >5 years before CAR-T had a similar median PFS (9.5 vs 9.2 months, respectively). A previous HDM/ASCT was also not associated with OS (p=0.13) or the incidence of CRS (p=0.20) and ICANS (p=0.99) after CAR-T.

Conclusion: Patients with MM who had received a previous HDM/ASCT had significantly shorter PFS with BCMA-directed CAR-T. These findings may have implications for treatment sequencing in MM.

Disclosures: Branagan: Adapative: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Genzyme: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding. Yee: AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy; BMS: Consultancy; GSK: Consultancy; Janssen: Consultancy; Oncopeptides: Consultancy; Prothena: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Frigault: Oncternal Therapeutics: Current equity holder in publicly-traded company, Honoraria. Raje: K36 Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; GlaxoKlineSmith: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Caribou Biosciences: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Immuneel: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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*signifies non-member of ASH