Target antigen and plasma cell phenotype are critical factors for sensitivity to response-adapted daratumumab therapy.

In this response-adapted clinic trial with daratumumab monotherapy for elderly newly diagnosed multiple myeloma (MM), we identified target antigen expression, a plasma cell phenotype, and an activated immune microenvironment (iTME) as critical features associated with response to CD38 monoclonal antibody therapy. Here, patients achieving a partial response (PR) after 2 cycles continued daratumumab, otherwise lenalidomide or bortezomib was added. This strategy resulted in an overall response rate of 97% and low rates of adverse events, with 37% of patients able to continue daratumumab monotherapy. Importantly, we found that higher CD38 expression, plasma cell gene expression programming, and an activated iTME were associated with patients who were able to continue daratumumab therapy alone. In contrast, patients requiring the addition of lenalidomide or bortezomib had increased expression of adhesion, TNF signaling, KRAS signaling, and B cell programs as well as an immunosuppressed iTME. Tracking of clonal dynamics illustrated the selection of subclones enriched for de novo resistance gene expression programs after only two cycles of daratumumab monotherapy. Upon relapse, daratumumab refractory MM cells were characterized by the expansion of pre-existing minor subclones with mixed transcriptomic programs containing the plasma cell phenotype with decreased CD38 and maintenance of resistance programs, suggesting development of acquired resistance involves an uncoupling of transcriptional programs present in therapy naïve tumors. To our knowledge, this is the first study to demonstrate the effectiveness of response-adapted daratumumab treatment and describe critical biomarkers of single-agent daratumumab sensitivity in vulnerable, therapy naïve MM patients. NCT04151667.