Anti-CD38 monoclonal antibodies have been successfully combined with immunomodulatory agents, proteasome inhibitors (PIs), alkylators, and corticosteroids in newly diagnosed multiple myeloma (NDMM). We assessed a regimen of daratumumab, cyclophosphamide, thalidomide, and dexamethasone (Dara-CTD) for patients with NDMM eligible to autologous stem cell transplantation (ASCT). Patients received 4 28-day cycles of induction therapy with Dara-CTD followed by ASCT, 4 cycles of consolidation Dara-TD, and single-agent daratumumab maintenance until progression or limiting toxicity. The primary end point was the percentage of patients achieving at least a very good partial response (VGPR) after the second cycle of consolidation. A key secondary end point was progression-free survival (PFS). We enrolled 24 patients, with a median age of 59.5 years, 62.5% of whom were female. Patients received a median of 28 treatment cycles. The rate of VGPR or better was 75.0% (95% confidence interval, 68.3-98.7); of 18 responding patients, 3 had a complete and 15 had a VGPR. The response duration varied between 9.5 and 41.9 months (median not reached). The estimated PFS rate at 36 months was 65%, and the overall survival rate at 48 months was 70%. The most frequent toxicity was constipation, febrile neutropenia, lymphopenia, neutropenia, peripheral neuropathy, and stomatitis. There were 7 documented cases of coronavirus disease 2019, 2 of which fatal. Two patients had permanent treatment discontinuation due to toxicity, 1 case each attributed to cyclophosphamide and daratumumab. Dara-CTD is an active, PI-free, quadruplet regimen with an acceptable safety profile for patients with ASCT-eligible NDMM. This trial was registered at www.ClinicalTrials.gov as #NCT03792620 and in the Plataforma Brasil at https://plataformabrasil.saude.gov.br as #CAAE96591818.0.0000.0048.