Background: POM + LoDEX + DARA in RRMM was approved in the US based on a phase 1b trial in heavily pretreated patients (pts; ≥ 2 prior lines [median, 4]; ORR, 60%). Data on the use of this regimen in earlier lines of Tx and immediately after LEN-based Tx are limited. Thus, MM-014 (NCT01946477) cohort B was initiated in pts with first- or second-line LEN-based Tx failures immediately before study entry to assess outcomes with POM + LoDEX + DARA sequenced earlier in Tx. Methods: Pts with RRMM after 1 or 2 prior lines who received a LEN-based Tx immediately before study and had progressive disease (PD) were eligible. In 28-d cycles (c), pts received POM 4 mg/d on d 1-21 + LoDEX 40 mg/d (20 mg/d if aged > 75 yrs) on d 1, 8, 15, and 22, and DARA 16 mg/kg IV on DEX dosing days of c 1 and 2, then d 1 and 15 of c 3-6, then d 1 of c 7+. Thromboprophylaxis was mandatory. The primary objective was ORR by modified IMWG criteria. Results: A total of 46 pts were in the ITT population (median follow-up, 7.8 mos). 13 pts discontinued Tx (PD, 7; AEs, 2; other reasons, 4). Pts were refractory to (n = 36; 78%) or had relapsed after (n = 10; 22%) LEN-based Tx. Median duration of prior LEN-based Tx was 23.6 mos; 20 pts (43%) received LEN 25 mg/d in their last LEN-based Tx. ORR was 76.7% in efficacy-evaluable pts (n = 43), 72.2% in LEN-refractory pts, and 75.0% in pts who received LEN 25 mg/d in their last LEN-based Tx. Efficacy and safety are shown in the Table. At baseline, 10 pts (21.7%) had grade ≥ 2 neutropenia. There was 1 each of grade 3/4 pulmonary embolism and peripheral neuropathy. Any-grade infusion-related reactions occurred in 13 pts. Neutropenia (POM and DARA) and infusion-related reactions (DARA only) were primary reasons for dose interruptions. Conclusions: These results underscore the importance of POM-based Tx in RRMM after LEN. POM + LoDEX + DARA was safe, with promising activity when sequenced in earlier lines immediately after LEN-based Tx failure. Clinical trial information: NCT01946477