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Abstract Response to daratumumab in patients with relapsed/refractory multiple myeloma is heterogeneous, and a reliable biomarker of response is lacking. We aimed to develop a method that identifies response to daratumumab therapy. Patient‐derived MM cells were collected before start of daratumumab treatment and were cultured in a hydrogel‐based culture system. The extent of antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity in vitro was associated with both clinical response and progression‐free survival in corresponding patients. Together, our results demonstrate that in vitro sensitivity to daratumumab therapy in a hydrogel culture with primary MM cells might be used to identify patients most likely to benefit from treatment.