Jiye Liu, PhD, on Multiple Myeloma: Genome-Wide CRISPR-Cas9 Screening Identifies KDM6A as a Modulator of Daratumumab Sensitivity
2022 ASH Annual Meeting and Exposition
Jiye Liu, PhD, of Dana-Farber Cancer Institute, discusses study findings that demonstrate KDM6A regulates CD38 and CD48 expression in multiple myeloma. Dr. Liu’s team validated combination treatment with an FDA-approved EZH2 inhibitor plus daratumumab, which can overcome daratumumab resistance in preclinical multiple myeloma models, providing the rationale for combination clinical trials to improve patient outcome (Abstract 148).
Transcript
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
We know that daratumumab is the first in class humanize the monoclonal antibody to target CD38 on myeloma cells. So the daratumumab triggers myeloma cell toxicity through the different molecular mechanisms including ADCC, ADCP and CDC, and the direct killing. And several clinical trials recently using the daratumumab alone and in combination with other agent to treat the newly diagnosed and the relapse, and the refractory myeloma cells then show the high efficacy. However, the relapse of the disease is commonly observed due to the daratumumab resistance. So we are seeking for the molecular mechanism of the daratumumab resistance in our project. We performed the genome-scale CRISPR screening in myeloma cells and find the genes named the KDM6A is most enriched in our daratumumab, positively select the gene list. And we found that the KDM6A is a histone 3 lysine 27 demethylase which activating the gene transcription.
Then we found that we knock out the KDM6A in the myeloma cells and can significantly downregulate the CD38 expression level on the myeloma cells. And associated with the increased H3K27me3 level on the CD38 promote area. We found that the KDM-60 knockout cells showed resistance to the DARAmediated ADCC in vitro and the in vivo mass model. Also by analyzing the [inaudible 00:01:55] in the KDM-60 knockout cells, we found that the KDM-60 also regulate CD48 expression, which is thought to be an NK-activating ligand in myeloma cells. So we knock out the CD48 in myeloma cells, attenuate the DARAmediated ADCC. So this data suggests that the KDM6A mediate ADCC not only by regulating CD38, but also modulate NK activity by the CD48 regulation. So how we can overcome the resistance induced by the KDM6A?
We know the KDM6A and EZH2 mediate the H3K27me3 level together in the cells and balance the genes transcription in the myeloma cells. So it is challenging to elevate the KDM-60 level in the myeloma patient cells. So we hypothesize that whether we can inhibit EZH2 to restore the CD38 or the CD48 expression level in the myeloma cells. So we used the one that FDA approved, the EZH2 inhibitor, to treat the KDM-60 knockout cells and find the CD38 and the CD48 expression level for restore also enhanced DARAmediated ADCC in these KDM-60 knockout cells. Our funding here identify a novel mechanism underlying the daratumumab sensitivity. This funding provided that the EZH2 inhibitor combined with the daratumumab to overcome the daratumumab resistance and for the translation to the clinical trial and improve the myeloma patient outcome.
The ASCO Post Staff
Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, discusses preliminary results from the dose-expansion phase of the CC-92480-MM-001 Trial, which showed promising efficacy in patients with relapsed and refractory multiple myeloma, including those with prior BCMA-targeted therapies. Patients in these two groups had an overall response rate of 40% and 50%, respectively. The results support the development of mezigdomide, currently being evaluated in combination with standard therapies in multiple myeloma as part of a large, ongoing phase I/II trial (NCT03989414) and planned phase III studies (Abstract 568).
The ASCO Post Staff
Tomohiro Aoki, MD, PhD, of the University of British Columbia and the Centre for Lymphoid Cancer at BC Cancer, discusses a novel prognostic model applicable to patients with relapsed or refractory classical Hodgkin lymphoma who were treated with autologous stem cell transplantation. The model has shown the interaction between the biomarker CXCR5 on HRS cells (Hodgkin and Reed/Sternberg cells, hallmarks of Hodgkin lymphoma) with specific follicular T helper cells and macrophages, a prominent crosstalk axis in relapsed disease. This insight opens new avenues to developing predictive biomarkers (Abstract 71).
The ASCO Post Staff
Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center, discusses the outcomes of patients newly diagnosed with acute myeloid leukemia (AML) who were treated with cytarabine plus daunorubicin plus gemtuzumab ozogamicin (GO). These patients experienced higher rates of measurable residual disease–negative complete remission and complete remission with incomplete count recovery, compared to those treated with cytarabine plus idarubicin daunorubicin alone. Although adding GO was not associated with improved overall survival, longer follow-up is warranted to determine an absolute survival advantage of this regimen (Abstract 58).
The ASCO Post Staff
Joseph Schroers-Martin, MD, of Stanford University, discusses immunogenomic features reflecting divergent biology in posttransplant lymphoproliferative disorders (PTLD). These include evidence of mismatch repair defects in Epstein-Barr virus–positive PTLD, tumor microenvironment depletion, and MYC pathway enrichment in certain patients (Abstract 72).
The ASCO Post Staff
Jorge E. Cortes, MD, of Georgia Cancer Center at Augusta University, discusses new findings on vodobatinib, which was administered to patients with chronic-phase Philadelphia chromosome–positive chronic myeloid leukemia (CML) and appeared to be efficacious and safe in people who had received therapy with two or three prior tyrosine kinase inhibitors (TKIs). Vodobatinib remains a potential option for these highly refractory patients. A phase II study (NCT02629692) of vodobatinib is ongoing in CML patients whose disease has failed to respond to three or more TKIs, including ponatinib (Abstract 84).