Abstract: Background: The combination of an immunomodulatory drug with the proteasome inhibitor (PI), bortezomib (BORT), and low-dose dexamethasone (LoDEX) has demonstrated preclinical synergy and considerable clinical activity in relapsed and refractory multiple myeloma (RRMM; Mitsiades et al Blood, 2002; Richardson et al Blood, 2014). Treatment (Tx) with the immunomodulatory drug pomalidomide (POM) + LoDEX has been shown to delay disease progression and extend survival in patients (pts) with myeloma previously treated with lenalidomide (LEN) and BORT (Richardson et al Blood, 2014; San Miguel et al Lancet Oncol, 2013). This approach was tested using POM + BORT + LoDEX (PVd) in MM-005; preliminary results showed that PVd was effective and well tolerated in LEN-refractory and BORT-exposed pts. Subcutaneous (SC) BORT was shown to be non-inferior to intravenous (IV) BORT and had an improved safety profile in RRMM (Moreau et al Lancet Oncol, 2011). In addition to a cohort of PVd with IV BORT, MM-005 included a cohort of PVd with SC BORT. Methods: In this phase 1 dose-escalation trial, pts must have received 1-4 lines of prior Tx, with ≥ 2 consecutive cycles of LEN plus a PI. Pts had to be PI exposed and refractory to LEN but not to BORT. A 3 + 3 design with 21-day cycles was used to determine the maximum tolerated dose (MTD). Cycles 1-8 of dose-escalation cohorts received POM (1-4 mg/day on days 1-14), IV or SC BORT (1-1.3 mg/m2 on days 1, 4, 8, and 11), and LoDEX (20 mg/day, or 10 mg/day for pts aged 〉 75 years, on days 1, 2, 4, 5, 8, 9, 11, and 12) until progressive disease (PD) or unacceptable adverse event (AE). After cycle 8, BORT was administered on days 1 and 8, and LoDEX was administered on days 1, 2, 8, and 9. The primary endpoint was MTD, and secondary endpoints included safety, overall response rate (ORR; ≥ partial response [PR]), duration of response (DOR), and time to response. Results: Of the 34 pts enrolled from March 2012 to August 2014, the median age was 58.5 years (range, 36-76 years) and 59% were male. The median number of prior antimyeloma Tx lines (PAMTL) was 2 (range, 1-4), the proportion of pts with ≥ 2 PAMTL was 56%, and the Eastern Cooperative Oncology Group performance status was ≤ 1 for all pts. All pts were refractory to LEN, and all were exposed to prior PI (33 pts [97%] received prior BORT and 2 pts [6%] received prior ixazomib). All pts discontinued Tx, most commonly due to PD (n = 23), but none due to Tx-related AEs. No dose-limiting toxicities were reported in the dose-escalation cohorts or at the maximum planned dose (MPD) of POM 4 mg, BORT 1.3 mg/m2, and LoDEX 20 mg (10 mg for pts aged 〉 75 years). The median number of Tx cycles received was 9 (range, 2-36) for all pts and was 11 (range, 2-19) vs 8 (range, 3-15) in the MPD with IV BORT (n = 10) vs SC BORT (n = 12) cohorts. The ORR for all pts was 65% (n = 22), with 2 complete responses (CRs), 1 stringent CR, 10 very good PRs (VGPRs), and 9 PRs; all pts achieved at least stable disease. The median DOR for the 22 responders was 7.4 months. Commonly reported grade 3/4 AEs were more frequent at the MPD level with IV BORT vs SC BORT (90% vs 75%), including neutropenia (60% vs 17%), thrombocytopenia (40% vs 8%), and pneumonia (30% vs 8%). There were no reports of grade 3/4 peripheral neuropathy (PN) or deep vein thrombosis (DVT) in any of the cohorts. Conclusions: PVd was effective, with an ORR of 65% in pts with LEN-refractory and PI-exposed myeloma. PVd was well tolerated, with no grade 3/4 PN or DVT and no Tx discontinuation due to Tx-related AE; toxicities were well managed. Moreover, AEs were generally less frequent with SC vs IV BORT. Thus, the favorable tolerability and efficacy of PVd, which could be a highly attractive therapeutic option in pts with RRMM, is under further evaluation in the large ongoing phase 3 trial MM-007. Disclosures Richardson: Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide in combination with bortezomib. Raje:BMS: Consultancy; Takeda: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Onyx: Consultancy; Eli Lilly: Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Acetylon: Research Funding. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding; Celgene Corporation: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Nooka:Spectrum Pharmaceuticals: Consultancy; Onyx: Consultancy. Zaki:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Li:Celgene Corporation: Employment, Equity Ownership. Shah:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Anderson:Oncocorp: Equity Ownership; Celgene Corporation: Consultancy; acetylon pharmaceuticals: Equity Ownership; Gilead: Consultancy; BMS: Consultancy; Millennium: Consultancy.