Purpose A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximally tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B cell malignancies (multiple myeloma, indolent and mantle cell lymphoma). Experimental Design Patients received bortezomib by IV push on days 1, 4, 8 and 11. Patients also received alvocidib on days 1 and 8 by 30 min bolus infusion followed by a 4 hour continuous infusion. Treatment was on a 21 day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3+3 design until the MTD was identified based upon DLTs. Pharmacokinetic studies and pharmacodynamic studies were performed. Results Sixteen patients were treated. The MTD was established as 1.3 mg/m2 for bortezomib and 30 mg/m2 for alvocidib (both the 30 min bolus and 4 hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common non-hematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate 44%). Pharmacokinetic results were typical for alvocidib, and pharmacodynamic studies yielded variable results. Conclusions The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non-Hodgkin’s lymphoma, justifying phase II studies to determine the activity of this regimen more definitively.