Comprehensive Characterization of Prolonged Unexplained Cytopenias in Relapsed/Refractory Multiple Myeloma Patients Following BCMA-Directed CAR-T Cell Therapy

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) directed against B-cell maturation antigen (BCMA) is a highly effective treatment for patients with relapsed/refractory multiple myeloma (RRMM). Prolonged cytopenias following CAR-T for lymphoid malignancies are common (PMID 33928266) and often preclude patients who progress after CAR-T from participating in clinical trials. However, there is limited understanding of the prevalence, severity and underlying mechanism of cytopenias following BCMA-directed CAR-T in RRMM. We here study the pattern of hematologic recovery and associated factors in this population. Methods: We retrospectively reviewed laboratory data for 90 RRMM patients from our institution who received a BCMA-directed CAR-T product as part of a clinical trial between 2017 hematologic recovery, as defined above, was considered to be "poor" in 22 (28%) and "adequate" in the remaining 56 (72%). A comparison of baseline clinical & bone marrow characteristics for these two groups is shown in Table 1. Patients in the "poor" hematologic recovery group were older (median age at CAR-T infusion 67 vs 60 years, p=0.01), more heavily pre-treated (median number of prior lines of therapy 6 vs 4, p=0.004), and more likely to have received ≥1 prior autologous stem cell transplant (ASCT) (37 vs 13%, p=0.04). In a multivariate logistic regression model, having >3 prior lines of therapy had the strongest association with "poor" hematologic recovery at four months (multivariate odds ratio OR 8.3, 95% CI 1.5-76, p=0.03). Type of CAR-T construct and type of bridging chemotherapy were not associated with significant differences in time to hematologic recovery. Bone marrow findings at baseline were grossly comparable between the two groups, including plasma cell percentage & myeloid-related cytogenetic/genomic abnormalities. A considerably higher proportion of patients in the "poor" hematologic recovery group was subsequently diagnosed with myelodysplastic syndrome (27 vs 16%), but the difference did not reach statistical significance. Conclusion: To our knowledge, this is the largest and most comprehensive characterization of prolonged, unexplained cytopenias in RRMM patients treated with BCMA-directed CAR-T. Roughly one third of patients had an ongoing ≥G3 cytopenia four months after infusion, but the majority recovered at one year (prevalence <10%). We found older age, higher number of prior lines of therapy, and prior history of ≥1 ASCT to be significantly correlated with poor hematologic recovery at four months post-CART, suggesting that T-cell redirection in RRMM patients with reduced bone marrow reserve due to aging and/or treatment-related toxicity may contribute to the decline of hematopoietic function by an unknown mechanism. Further research is needed to elucidate the biological basis for post-CART cytopenias in RRMM patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal