Background: Lenalidomide (LEN) is typically a frontline therapy for newly diagnosed MM. Patients (pts) with MM refractory to LEN are less likely to repond to other IMiDs and represent a signification area of unmet medical need. In the BOSTON study in the ITT population, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. Methods: The BOSTON trial (NCT03110562) is a Phase 3 randomized, controlled, open-label study of once weekly XVd vs twice weekly Vd in pts with MM and 1-3 prior therapies. We performed post-hoc analyses on two different subgroups to compare outcomes based on refractory status to LEN and immunomodulatory drug (IMiD) therapy. These post hoc analyses evaluated if PFS, overall response rate (ORR), time to next treatment (TTNT) and safety was influenced by prior treatment with LEN when comparing XVd with Vd. Results: Amongst the 402 pts in BOSTON, 160 had MM refractory to any IMiD (XVd = 74, Vd = 86). Of those, 106 were documented to be refractory to LEN (XVd = 53, Vd = 53) and 296 were not refractory to LEN (XVd = 142, Vd = 154). Baseline characteristics were generally well balanced between subgroups. In these subgroups based on refractory status to IMiD or LEN, median PFS was significantly longer in the XVd arm as compared to Vd (IMiD refractory, 13.9 vs. 8.4 months (mo), p = 0.005; LEN refractory, 10.2 vs. 7.1 mo, p = 0.012; not LEN refractory, 15.4 vs 9.6 mo, p = 0.014). Significant increases in TTNT were observed with XVd treatment in pts that were IMiD refractory (14.8 vs. 10.2 mo, p = 0.003), LEN refractory (13.0 vs. 7.6 mo, p = 0.015), and not refractory to LEN (19.1 vs 12.9 mo, p = 0.005). ORR was improved with XVd compared to Vd regardless of refractory status (IMiD refractory, 68.9% vs 55.8%, p = 0.045; LEN refractory, 67.9% vs. 47.2%, p = 0.016; and not refractory to LEN, 79.6% vs 67.5%, p = 0.010). The most common treatment-emergent AEs for the XVd/Vd arms for all subgroups were thrombocytopenia (66.2/30.6%; 71.7/40.4%; 55.6/22.4%), nausea (48.6/11.8%; 50.9/11.5%; 50.0/9.2%), and fatigue (40.5/20.0%; 45.3/21.2%; 40.8/17.1%) for IMiD, LEN, and not LEN refractory, respectively. Incidence of PN AEs of any grade were reduced compared to pts treated with Vd (IMiD refractory, 27% vs. 42.4%; LEN refractory, 30.2% vs 36.5%; not refractory, LEN 33.1% vs 50.7%). Conclusions: In pts with previously treated MM, PFS, ORR, and TTNT were significantly improved regardless of documented refractory status to any IMiD or to LEN-specifically. These analyses support the use of the XVd combination for pts with disease refractory to LEN and likely to any IMiD. Clinical trial information: NCT03110562