Multiomic Perspective on CD38 Regulation and Targeting Offers New Insights for Treatment With Daratumumab, Isatuximab

Multiple myeloma (MM) is a common hematologic malignancy marked by the overproduction of B lymphocytes, which impairs normal cell function and leads to severe complications such as brittle bones, renal insufficiency, immune system suppression, and organ dysfunction. Although MM remains incurable, advancements in treatments leveraging the immune system have significantly improved patient outcomes and extended survival. Research published in Blood Neoplasia suggests that CD38 density on tumor cells is a key predictor of the effectiveness of monoclonal antibody treatments. This may lead to the development of strategies aimed at increasing CD38 expression to potentially enhance the efficacy of CD38-targeting immunotherapies.^1,2

In a study conducted by researchers at the University of California, San Francisco, a comprehensive approach was used to investigate the regulation of surface CD38 in MM cells. Image Credit: © anamejia18 - stock.adobe.com

In MM, the presence of highly expressed surface proteins such as BCMA, GPRC5D, and CD38 has enabled the creation of targeted therapies with improved efficacy and reduced toxicity. Monoclonal antibodies, bispecific antibodies, and combination therapies are particularly noteworthy, as they harness these surface proteins to specifically detect and eliminate malignant cells. These advances underscore the connection between protein expression and the proliferation of malignant cells in MM.^1,2

CD38, a glycoprotein overexpressed on the surface of MM cells, can interfere with treatment responses and contribute to enhanced malignant cell proliferation. Key monoclonal antibodies daratumumab (Darzalex; Janssen Biotech, Inc and Genmab A/S) and isatuximab (Sarclisa; Sanofi-aventis) target CD38 and work by inducing cell death through mechanisms such as increasing cytotoxicity via recruitment of natural killer cells, macrophages, and complement proteins. Despite promising clinical trial results, resistance to these therapies is common and appears to result from complex factors, including alterations in surface antigens and dysfunction of the tumor immune microenvironment.³

Preclinical and clinical studies suggest that the density of CD38 surface antigens before treatment correlates with the efficacy of monoclonal antibody therapies. Increasing the surface expression of CD38 on tumor cells can improve treatment outcomes, as observed with all-trans retinoic acid (ATRA), which has shown efficacy in raising CD38 levels on MM cells. This increase provides more targets for monoclonal antibodies, potentially enhancing their ability to bind to and eliminate these cells.³

In a study conducted by researchers at the University of California, San Francisco, a comprehensive approach was used to investigate the regulation of surface CD38 in MM cells. The study employed CRISPR interference (CRISPRi)-based functional genomic screens, cell surface proteomics, epigenetic analyses, and phosphoproteomics to gain a multiomic perspective on CD38 regulation and the consequences of targeting CD38.³

The study identified XBP1 and SPI1 as critical regulators of CD38 expression, revealing a distinct regulatory mechanism compared with prior research on BCMA. While earlier studies on BCMA emphasized the importance of post-transcriptional mechanisms, this study highlights that CD38 regulation is primarily controlled at the transcriptional level.³

Proteomic analyses further indicated that reducing CD38 expression does not significantly alter the overall composition of the cell surface proteins, known as the "surfaceome." The findings also demonstrated that ATRA specifically upregulates CD38, whereas azacytidine (Vidaza; Bristol Myers Squibb) and panobinostat (Farydak; Novartis Pharmaceuticals) have broader effects on the surface protein profile. Additionally, the study revealed that daratumumab inhibits MAP kinase pathway signaling, which may affect key signaling pathways involved in cell growth and proliferation.³

This research provides valuable insights into the genetic and pharmacologic regulation of CD38, offering new strategies to enhance CD38-targeted therapies in MM. The findings underscore the potential for improving treatment efficacy through targeted manipulation of CD38 levels and the need for continued exploration of therapeutic strategies.

REFERENCES

1. Mapping the proteogenomic landscape of multiple myeloma: implications for targeted therapy. Pharmacy Times. July 8, 2024. Accessed August 6, 2024. https://www.pharmacytimes.com/view/mapping-the-proteogenomic-landscape-of-multiple-myeloma-implications-for-targeted-therapy
2. Daratumumab treatment advancements in newly diagnosed multiple myeloma. Pharmacy Times. June 3, 2024. Accessed August 6, 2024. https://www.pharmacytimes.com/view/daratumumab-treatment-advancements-in-newly-diagnosed-multiple-myeloma
3. Choudhry P, Kasap C, Patiño-Escobar B, et al. Functional multiomics reveals genetic and pharmacologic regulation of surface CD38 in multiple myeloma. Blood Neoplasia. July 2, 2024. doi:10.1016/j.bneo.2024.100025