The therapeutic landscape of relapsed multiple myeloma (MM) is constantly evolving. To date, a large proportion of patients present with lenalidomide refractory disease at the time of first or second relapse. In this context, few efficient options are currently available. Carfilzomib and daratumumab are approved in the relapse setting. Recently, Phase Ib and Phase III trials evaluated the triplet drug combination daratumumab–carfilzomib–dexamethasone in the relapse setting and demonstrated strong clinical efficacy, especially in lenalidomide refractory patients. Based on these results, this combination has been approved by the US FDA for relapsed MM patients. The present review discusses the safety and efficacy of daratumumab–carfilzomib–dexamethasone in MM.