Oral Abstract Session - Session Chairs: Natalie Callander/Merav Leiba
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OAB-012 - Depth of response and MRD in newly diagnosed ultra high-risk myeloma and plasma cell leukemia treated with Dara-CVRd and V-MEL ASCT: results of the molecularly stratified UK OPTIMUM/MUKnine trial
Martin Kaiser, Andrew Hall, Katrina Walker, et al.
Conclusions: We report here high response and MRD-negativity rates with Dara-CVRd quintuplet induction and augmented ASCT in difficult-to-treat UHiR NDMM and PCL patients, with good tolerability and all- oral/subcutaneous deliverability. However, some early progressors highlight the ongoing need for innovation in UHiR MM and PCL.
OAB-013 - Iberdomide (IBER) in combination with dexamethasone (DEX) and daratumumab (DARA), bortezomib (BORT), or carfilzomib (CFZ) in patients (pts) with relapsed/ refractory multiple myeloma (RRMM)
Sagar Lonial, Paul G. Richardson, Rakesh Popat, et al.
Conclusions: In pts with heavily pretreated RRMM, IberDd, IberVd, and IberKd showed a tolerable safety profile and promising efficacy. These results support further development of IBER-based regimens in MM, including the initiation of phase 3 combination studies. Previously published in Lonial S, et al. HemaSphere 2021;5(S2):49.
OAB-014 - Newly diagnosed Multiple Myeloma patients with high levels of circulating tumor cells are distinguished by increased bone marrow plasma cell proliferation
OAB-015 - Minimal residual disease following autologous stem cell transplant for myeloma patients in the Myeloma XI trial: prognostic significance and the impact of lenalidomide maintenance and molecular risk
Ruth De Tute, Charlotte Pawlyn, David Cairns, et al.
Conclusions: In patients with multiple myeloma, MRD status at both ASCT+3 and ASCT+9 is a powerful predictor of PFS and OS. At both time points, regardless of MRD status, lenalidomide maintenance was associated with improved PFS and OS, whilst high-risk molecular features were associated with adverse outcomes.
OAB-016 - Treatment pathways for patients with multiple myeloma: a real-life study based on the French National Claim database from 2014 to 2019
Aurore Perrot, Vincent Augusto, Marie Pierres, et al.
Conclusions: This study shows the flow of patients from frontline to L4+ and their survival rates. The study also showed that real-world data are a powerful tool to study treatment lines at a national scale and lead the way to more precise analyses of optimal therapeutic sequences, including their impact on the overall survival.
Oral Abstract Session - Session Chairs: Enrique Ocio/Annemeik Brojil
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OAB-017 - Attenuation of T cell cytotoxicity mediated by CD200 expression on multiple myeloma cells
Pooja Shah, Thorsten Stühmer, Daniela Brünnert, et al.
Conclusions: CD200 expression on MM cell lines leads to attenuated cytotoxicity from primary healthy donor CD3+ T cells. Here, we provide evidence that this inhibitory mechanism in CD3+ T cells is mediated via DOK2.
OAB-018 - A BCL2L1 armoured BCMA-targeting CAR T cells to overcome exhaustion and enhance persistence in multiple myeloma
Ranjan Maity, Sacha Benaoudia, Holly Lee, et al.
Conclusions: Cognizant of the role BclxL plays in T cells survival in response to CD28 co- stimulatory signaling, we postulated that increasing BclxL expression is a feasible strategy to enhance CAR T cell resistant to AICD, improve their persistence and anti- BCMA reactivity. To this goal, we designed a 2nd generation lentiviral CAR construct where the anti-BCAM scFV-41BBz CAR and the BCL2L1 cDNA were linked with self-cleaving 2A sequence. The efficiency in eradicating MM cells of this BclxL armored CAR (BCL2L1_CAR) was compared to that of non- unarmored CAR (BCMA_CAR) in vitro and in vivo studies. While BCL2L1_CAR and BCMA_CAR were equally cytotoxic to OPM2 MM cells, in MM cell lines expressing the FAS death receptor ligand FASLG (MM1S, OCMY5 and H929) BCL2L1_CAR viability and cytotoxic activity was significantly superior to that of unarmored BCMA_CAR. Of note, the expression of FASLG was upregulated in H929 cells when co-cultured with CAR T cells. Importantly, under chronic antigenic stimulation conditions, where CAR T cells were stimulated every 2 days over a 28 days period with irradiated OPM2 cells, we found no phenotypic difference between BCL2L1_CAR and BCMA_CAR with respect to the composition of Tem cells (CCR7−CD45RO+CD45RA−) or Tcm cells (CCR7+CD45RO+CD45RA−). However, under these chronic antigenic stimulation conditions, the CAR T cells viability, proliferation and anti-MM cytotoxic activities of the BCMA_CAR were dramatically reduced compared to that of the BCL2L1 armored CAR. Therefore BCL2L1 blockade of AICD not only enhanced the viability and cytotoxicity of CAR-T cells but surprisingly also reduced their functional exhaustion. Our findings provide a novel approach for CAR-T optimization and overcoming relapse resulting from lack of persistence.
OAB-019 - CRISPR screens with single-cell transcriptome readout reveal potential mechanisms of response to natural killer cell treatment in multiple myeloma
Sara Gandolfi, Olli Dufva, Jani Huuhtanen, et al.
Conclusions: Our data shed light on mechanisms of response to NK cells in MM and identify potential therapeutic targets for combination treatment. Furthermore, patient data correlation highlights subgroups that might have an increased susceptibility to NK cell treatment, highlighting the potential of such studies in the identification of predictive biomarkers.
OAB-020 - The Role of Checkpoint inhibitor PD-1H/VISTA in Multiple Myeloma Bone Disease
Jing Fu, Shirong Li, Huihui Ma, et al.
Conclusions: Taken together, our study, for the first time, reveals that checkpoint inhibitor PD- 1H/VISTA is the critical receptor for MMP-13 in osteoclasts, thereby mediating MMP-13- induced osteoclast fusion, activation, and bone resorption. MM-induced trabecular bone loss was significantly lower in Pd-1h-/- mice, demonstrating that PD-1H/VISTA plays a critical role in MMP-13-induced MM bone disease. Given the checkpoint role of PD- 1H/VISTA in cancer immunosuppression, we further posit that targeting the interaction of MMP-13 and PD-1H may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment.
OAB-021 - BCMA-specific ADC MEDI2228 and Daratumumab induce synergistic myeloma cytotoxicity via enhanced IFN-driven innate immune responses and expression of CD38 and NKG2D ligands
Lijie Xing, Su Wang, Jiye Liu, et al.
Conclusions: Taken together, our data showed that MEDI2228 restored MM sensitivity to CD38 targeting by Dara without depleting NK cells and potentiated immunogenic cell death of MM cells. These results therefore provide the mechanistic rationale for clinical evaluation of combination CD38- and BCMA-directed immunotherapies to further improve patient outcome in MM.
OAB-022 - Monoallelic Deletion of BCMA Locus is a Frequent Feature in MM and is Associated with Increased Genomic Loss
Mehmet K Samur, Anil Aktas-Samur, Romain Lannes, et a.
Conclusions: Our data from large scale copy number profiles showed that even without treatment pressure, monoallelic BCMA deletions are frequent events.Moreover, patients with these events show increased genomic loss.Such behavior potentially make these cells vulnerable for biallelic loss of other genes.Our results highlight that by looking at mRNA or protein expressions at bulk sample would not directly indicate the presence or absence of cells with target loss and therefore evaluating single cell level data are necessary.These results suggest the need to study del16p in patients being targeted for BCMA-directed therapy and its association with del17p raises question about the role of BCMA targeted therapy in high-risk myeloma.