Background: Recent trials of triple therapy in 2L and third-line (3L) Tx excluded pts refractory to LEN. This is not reflective of standard of care in first line and 2L where LEN is given until progressive disease (PD). MM-014 enrolled pts with RRMM and 2L LEN-based Tx failure. Here we report results only from cohort A of pts receiving POM + LoDEX. Cohort B will investigate POM + LoDEX + daratumumab. Methods: Adult pts with MM, 2 prior Tx lines, and PD after ≥ 2 cycles of 2L LEN-based Tx received POM + LoDEX. The primary endpoint was overall response rate (ORR). Other endpoints included time to response (TTR), PFS, second primary malignancies (SPMs), and biomarkers. Results: Of 51 pts in cohort A, 39 (76.5%) discontinued Tx. Most pts (88.2%) were refractory to their last LEN Tx, (median Tx duration 24.6 mos) and 72.5% had prior bortezomib. At a median follow-up of 13.6 mos, ORR was 29.4% (2.0% complete response, 9.8% very good partial response, and 17.6% partial response [PR]) and median TTR was 1.9 mos; 66% of pts had ongoing response at 1 yr. Minimal response [MR] was reached in 15.7%. Median PFS was 13.8 mos. Pts with ≥ MR had similar Tx durations as those achieving ≥ PR. Additional results in Table. Post-Tx T-cell populations were significantly higher vs baseline (CD3⁺, 72.6% vs 67.8%; CD3⁺/CD8⁺, 36.9% vs 32.1%). Relative changes from baseline were significantly greater in pts with response vs pts with no response (CD3⁺, 10.4 vs −0.8; CD3⁺/CD4⁺, 4.2 vs −3.5). Conclusions: This update confirms the safety and efficacy of POM + LoDEX following 2L LEN-based Tx failure in pts with RRMM. Hematologic adverse event (AE) rates improved and median PFS was longer with 3L use than previously reported with POM + LoDEX use in later Tx lines. In addition, achieving disease control of ≥ MR led to similar PFS rates as reaching ≥ PR. Clinical trial information: NCT01946477

^a Subject to survival biases.