Background: High-risk multiple myeloma (MM) is often defined based on cytogenetic abnormalities (ie, t[4;14], t[14;16], and/or del17p); however, pts who relapse early (12-18 months) after initial therapy are considered a functional high-risk group that is also associated with poor prognosis. DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with standard-of-care regimens for MM. In the phase 3 CASTOR and POLLUX studies, D-Vd and D-Rd significantly improved progression-free survival (PFS), regardless of cytogenetic risk, and achieved higher rates of complete response or better (≥CR) and minimal residual disease (MRD)–negativity vs Vd or Rd alone in pts with RRMM. Post hoc analyses of CASTOR and POLLUX evaluated D-Vd vs Vd and D-Rd vs Rd in pt subgroups with 1 prior line of therapy based on timing of relapse (early or late) after initiation of the first line of therapy. Methods: In CASTOR and POLLUX, pts with RRMM and ≥1 prior line of therapy were randomized to D-Vd/Vd or D-Rd/Rd, respectively. The primary endpoint was PFS. In this analysis, the early relapse subgroup included pts with 1 prior line of therapy who relapsed <18 months after initiating their first line of therapy; pts with 1 prior line of therapy who relapsed ≥18 months after initiating their first line of therapy were included in the late relapse subgroup. Results: 49 and 186 pts from CASTOR and 99 and 196 pts from POLLUX were included in the early relapse and late relapse subgroups, respectively. Median follow-up was 72.6 months (CASTOR) and 79.7 months (POLLUX). PFS consistently favored the DARA-containing regimens across subgroups (Table). In CASTOR, ≥CR rates were higher with D-Vd vs Vd in the early relapse (21% vs 17%; P = 0.7360) and late relapse (51% vs 14%; P<0.0001) subgroups. In POLLUX, ≥CR rates were higher with D-Rd vs Rd in the early relapse (53% vs 12%; P<0.0001) and late relapse (62% vs 38%; P = 0.0012) subgroups. MRD-negativity rates (10^–5) were higher with D-Vd/D-Rd vs Vd/Rd regardless of relapse timing (CASTOR: early, 13% vs 0%; P = 0.1476; late, 23% vs 3%; P<0.0001; POLLUX: early, 30% vs 4%; P = 0.0006; late, 34% vs 14%; P = 0.0009). Conclusions: These post hoc analyses of CASTOR and POLLUX showed PFS and depth of response benefits of DARA-containing regimens in patients with 1 prior line of therapy, regardless of relapse timing (early or late). Our results support the use of D-Vd and D-Rd in RRMM, including in pts who are considered functional high risk. Clinical trial information: NCT02136134 and NCT02076009.