Objective To explore the efficacy and safety of dose adjustment daratumumab with dexamethasone, cyclophosphamide, etoposide, cisplatin (DA-DDCEP) regimen in the patients with multiple myeloma (MM) dual-refractory to bortezomib and lenalidomide. Methods From March in 2020 to September in 2022, a total of 17 patients from the department of hematology of our hospital were included in this retrospective study. The overall response rate(ORR), optimal response rate, progression-free survival (PFS), and overall survival (OS) time were statistically analyzed, and the effect of different treatment responses, Eastern Cooperative Oncology Group (ECOG) physical status, and whether accompanied by extramedullary diseases (EMD) on survival were eveluated. Hematologic and nonhematologic toxicity associated with treatment were observed. Results In 17 patients with a mean age of(63.2±10.0) years, eight（47%) were males and a median treatment line number was 5(3-8). After a median cycle of 4(2-14), the ORR and complete response (CR) rates were 65% and 18%. After median follow-up months of 26 (11-40）, the median PFS and OS time were 8 and 12 months, respectively. The response to the treatment had a significant impact on survival. Comparing response[≥(partial response, PR)] with non-response patients, PFS was 14 months vs. 2 months (P=0.000) and OS was 19 months vs. 7 months(P=0.05). The ECOG physical state has no impact on survival, comparing ECOG score ≤2 with >2 patients, PFS was 8 months vs. 7 months (P=0.863) and OS was 19 months vs. 10 months (P=0.615). Contrasting relapse with EMD or without EMD, PFS was 6 months vs. 14 months (P=0.009) and OS was 9 months vs. 19 months (P=0.187), respectively. Grade 3-4 adverse events included 8 case (47%) neutropenia, 8 case (47%) anemia, 9 case (53%) lymphocytopenia and 9 case (53%) thrombocytopenia. There were 5 cases (29%) of pulmonary infection, all of which were grade 2. In addition, hepatitis B reactivation occurred in two patients. Conclusions DA-DDCEP regimen is effective in myeloma patients dual-refractory to bortezomib and lenalidomide, and the patients with poor ECOG physical status can tolerate the treatment and benefit from it. The survival of patients with EMD still need to be improved. Overall safety is good, but hepatitis B virus should be monitored carefully.