Background: The combination of either pegylated liposomal doxorubicin (PLD) and bortezomib (BORT) or lenalidomide (LEN) and dexamethasone (DEX) have shown significant anti-MM activity. However, both regimens are associated with significant toxicity and produce response rates in only 40-60% of patients. We modified the doses of BORT (1 mg/m²) and PLD (5 mg/m²) and added intravenous (IV) DEX 40 mg with all 3 drugs administered on days 1, 4, 8, and 11 of a 28-day schedule for the treatment of MM patients in both the frontline and R/R setting, and have found this to be a highly effective regimen with reduced toxicities including peripheral neuropathy (PN), cytopenias, and hand-foot syndrome. Methods: This trial is an ongoing, single-arm, multi‑center, phase II study for R/R MM patients. Its objective is to evaluate the combination of IV 40 mg DEX, 1 mg/m² BORT, 4 mg/m² PLD on days 1, 4, 8, and 11, and a modified dose of LEN at 10 mg daily on days 1-14 of each 28-day cycle. Patients were treated to maximum response plus 2 additional cycles or to a maximum of 8 cycles of therapy without disease progression. Results: Thirty (of 40 planned) patients have been enrolled to date with data evaluable on 27 patients. Patients were heavily pretreated with a median of 3 (1-17) prior regimens. Nineteen patients (70%) have shown objective responses to the DVD‑R regimen, including 5 complete responses (19%), 4 very good partial responses (15%), 4 partial responses (15%), and 6 minimal responses (22%). An additional 6 patients showed stable disease and 2 progressed while on study. Fifteen patients experienced grade 3 or 4 adverse events, including: reversible neutropenia (n=3), pneumonia (n=4), reversible anemia (n=6), and thrombocytopenia (n=3) with only one patient experiencing a grade 4 reversible thrombocytopenia. Eight (27%) have developed PN with no cases of stomatitis or hand-foot syndrome. Conclusions: Thus, these results suggest that the DVD-R regimen is a well tolerated treatment that produces high response rates for heavily pretreated MM patients with R/R disease.