We evaluated sequential bortezomib, liposomal doxorubicin and dexamethasone (BDD) followed by thalidomide and dexamethasone (TD) if ≥ partial response (PR) or bortezomib and TD (BTD) if < PR in untreated patients with multiple myeloma with International Staging System stage II/III or extramedullary disease. Of the 42 patients enrolled, two-thirds had cytogenetic abnormalities including high-risk findings [del(13q) by karyotype, t(4;14), loss of p53 or gain 1q] in one-third. After the planned three cycles of BDD, the overall response rate (ORR) was 81% with 40% ≥ very good partial response (VGPR), including 26% near complete and complete responses (nCR/CR). After the additional two cycles of TD or BTD, ORR was 83% with 60% ≥ VGPR including 43% nCR/CR, indicating deeper responses following sequential therapy (p = 0.008). Two-thirds of patients who presented with significant renal impairment had improved renal function. All patients undergoing stem cell harvest had a successful collection. BDD followed by TD or BTD is effective initial therapy for this population with higher-risk myeloma and results in rapid disease control and a high response rate.