Session: 652. Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: New Approaches to MRD Assessment
Hematology Disease Topics & Pathways:
Research, Biological therapies, adult, Translational Research, Clinical Research, Plasma Cell Disorders, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Therapies, Lymphoid Malignancies, computational biology, Technology and Procedures, profiling, Study Population, Human, omics technologies
We extracted plasma cells from single-cell sequencing data and integrated it with the bulk sequencing data and compared the single MM cells between responders and non-responders at screening. Unsupervised clustering of plasma cells showed a distinct separation between non-responders and responders at screening. Differentially expressed genes significantly (FDR < 0.01) clustered within the chromosome 1q and chromosome 17p regions, which are regions frequently altered in MM. Although BCMAexpression was similar at screening between responders and non-responders, non-responders had upregulated expression of genes involved in oxidative phosphorylation and proteosome degradation and downregulated apoptosis-related genes. Non-responders also had significantly higher expression of CD38, SLAMF7, Bcl-2 and FGFR3 (FDR < 0.01), which could be potential therapeutic targets for combination therapies. Comparing plasma cells between screening and relapse in patients that initially responded to treatment, we observed the acquisition of features similar to non-responder MM cells including the enrichment of oxidative phosphorylation, DNA damage and downregulation of programmed cell death. BCMA expression was also significantly downregulated at relapse.
Using bulk WGS, we found a monoallelic loss of BCMAin 4% of pre-treatment samples, which increased to 12% at relapse, with 6% having a bi-allelic loss of BCMA at relapse.
We next evaluated the immune microenvironment and observed that the overall T cell %, CD4/CD8 ratio and CD4/CD8 sub-group frequency were similar between all groups at screening. However, at relapse in the patients who initially responded to treatment, the microenvironmental cells had changed relative to screening. For example, there were fewer CD4+ and CD8+ effector and central memory cells, and genes related to T cell activation were significantly downregulated. In addition, the other components of BM microenvironmental cells (T and NK cells and monocytes/macrophages) showed similar frequencies, phenotypes and functional characteristics between responders and non-responders at screening. However, in NK cells, the NK cell–mediated cytotoxicity pathway was significantly downregulated between responder and non-responders, with a further downregulation in cells at relapse.
Overall, our data suggest that the baseline characteristics of plasma cells impact the initial response to CAR T-cell therapy. Moreover, the similarities observed in immune cell populations between responders and non-responders suggest that initial resistance is not associated with a dysfunctional immune system or its immediate influence on CAR T cells. In terms of survival outcomes, our data suggest that changes in both the tumor and immune cells during and/or after treatment affect survival, with the most impactful events likely being antigen mutation, increased proliferative signal for tumor cells, loss of T cell activation and loss of NK cell cytotoxicity. Developing strategies to overcome these effects will lead to improving progression-free survival.
Disclosures: Martin: Bristol-Myers Squibb: Current Employment. Thompson: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kaiser: Bristol Myers Squibb: Current Employment. Munshi: Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda Oncology: Consultancy; GSK: Consultancy; Amgen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Pfizer: Consultancy; Legend: Consultancy; Celgene: Consultancy.
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