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Daratumumab is approved for patients with multiple myeloma (MM) and high-risk smoldering MM (HR-SMM). However, HR-SMM is often as genomically complex as MM, suggesting it may be too advanced for single-agent intervention. We report on a Phase II trial of single-agent daratumumab in patients with earlier-stage disease, including high-risk monoclonal gammopathy of undetermined significance and low-risk SMM, to test if earlier treatment can induce deep responses and prevent progression to MM (D-PRISM/NCT03236428, n = 41). As primary outcome, the rate of Very Good Partial Response or better is 17% (95% CI: 7-32), which is comparable to what was observed in HR-SMM and does not meet the study's primary endpoint. The overall response rate is 54%, with two patients developing MM and 51% biochemical progression. Grade 3 or higher toxicities include hypertension (7%), diarrhea (2%), flu-like symptoms (2%), and headache (2%). Genomic and immune variables associated with biochemical progression are identified in exploratory analyses leveraging whole-genome and single-cell RNA-sequencing. This study demonstrates that, although less effective than expected, daratumumab is safe and can induce deep responses in certain early-stage patients, highlighting the importance of adopting genomic and immune profiling to improve patient selection and maximize the benefit/risk ratio in trials of early intervention.