Reduced ALDH1A1 expression in multiple myeloma cells increases resistance to daratumumab via downregulation of retinoic acid

Multiple myeloma (MM) remains challenging in relapsed/refractory cases due to resistance to therapies like the proteosome inhibitors or anti-CD38 antibody daratumumab (Dara). This study investigates the dual role of ALDH1A1, an aldehyde dehydrogenase implicated in drug resistance, especially in modulating daratumumab efficacy. Clinical samples from newly diagnosed multiple myeloma (NDMM) patients and in vitro studies demonstrated that ALDH1A1 expression increases consistently with the development of drug resistance to proteasome inhibitor-based chemotherapy. However, paradoxically, daratumumab-resistant non-responder relapsed/refractory MM (nrRRMM) patients showed lower ALDH1A1 expression compared to responder RRMM (rRRMM) patients. Mechanistically, ALDH1A1 enhanced CD38 expression by upregulating retinoic acid (RA), which activated the retinoid acid receptor (RAR) signaling pathway. Knockdown of ALDH1A1 in MM cell lines (H929, RPMI 8226) reduced CD38 levels, impaired daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC), and suppressed NK (natural killer) cell activity (perforin/granzyme B secretion). In contrast, RA supplement reversed declined CD38 expression caused by knocking down ALDH1A1, thereby restoring antibody-dependent cellular cytotoxicity (ADCC) efficacy. In vivo, ALDH1A1 inhibition diminished daratumumab's antitumor effects in xenograft models, while RA co-administration reversed this resistance. These findings highlight ALDH1A1 as a context-dependent regulator: promoting chemotherapy resistance but enhancing daratumumab sensitivity via RA-CD38 axis activation. This study identifies ALDH1A1 as a predictive biomarker and proposes therapeutic strategies combining RA or ALDH1A1 modulation to overcome daratumumab resistance in RRMM.