Abstract 725: An mRNA-based predictor of response to daratumumab in multiple myeloma

Abstract The purpose of this study was to develop a predictor of response to treatment with daratumumab in multiple myeloma. Daratumumab has considerably improved outcomes for myeloma patients. However, the treatment is expensive and not all myeloma patients benefit from treatment. Therefore, a predictor of daratumumab benefit would focus on treating patients with high likelihood of responding, and avoid treating those who are unlikely to respond or benefit. Daratumumab is a monoclonal antibody that binds to CD38, causing apoptosis via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDCC). ADCC requires the presence of natural killer cells, and can be measured in vitro with a calcein release assay using multiple myeloma cell lines in the presence of natural killer cells. Measuring the baseline gene expression in the cell lines makes it possible to identify mechanisms of resistance or sensitivity to daratumumab induced ADCC in vitro. We used published data of lysis of 19 multiple myeloma cell lines and B-cell non-Hodgkin’s lymphoma cell lines in the presence of daratumumab and natural killer cells from peripheral blood mononuclear cells. Correlating the sensitivity to ADCC with the baseline gene expression of these cell lines, we identified 27 genes correlated to sensitivity and 26 genes correlated to resistance. Among these are genes previously associated with sensitivity to daratumumab, glucocorticoid response, the proteasome, natural killer cell resistance, nuclear transport, myeloma risk classification, and myeloma cancer drivers. The 53 genes collectively constitute a daratumumab drug response predictor (DRP), and a single score of predicted sensitivity to daratumumab can be calculated as the difference between the mean of the positively correlated genes and the mean of the negatively correlated genes. We used published single-cell RNAseq data from the KYDAR trial of multiple myeloma patients treated with daratumumab, carfilzomib, lenalidomide and dexamethasone, to test the 53 gene DRP on clinical samples. The KYDAR trial enrolled 41 newly diagnosed MM patients who either failed to respond, or experienced early relapse, after a bortezomib-containing induction regimen. Baseline single-cell RNA sequencing data and overall response information was available for 17 subjects. The overall response to treatment correlated with the DRP score: Pearson correlation coefficient 0.26 (95% CI 0.15 - 0.83). A cutoff can be applied to separate responding patients from nonresponding patients. These results provide proof-of-concept for an mRNA-based predictor of response in multiple myeloma that warrants further clinical validation in multiple myeloma. When combined with our previously published response signatures for other cancer treatments used in myeloma, a map of predicted sensitivities can be provided for each patient based on a bone marrow sample. Citation Format: Steen Knudsen, Peter Gimsing, Henrik Stender, Thomas Jensen, Jeremy R. Graff. An mRNA-based predictor of response to daratumumab in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 725.