Dose escalation demonstrates significant growth inhibition resulting from the combination of bortezomib and lonafarnib that is sequence dependent in myeloma cell lines. (A) MM.1S cells were plated in 96-well plates in triplicate and were treated with bortezomib at nanomolar concentrations for 48 hours. MTT assay was performed after 48 hours, and proliferation is represented as percent growth inhibition. (B) MM.1S cells were plated as in panel A and treated with lonafarnib in micromolar concentrations, and cell proliferation was assessed using an MTT assay. (C) MM.1S cells were plated as in panel A and treated concurrently with bortezomib (8 nm) and lonafarnib (increasing 1-5 μM), and cell proliferation was assessed using an MTT assay. (D) RPMI8226 cells were treated with bortezomib and lonafarnib either concurrently (C) or in sequence first with bortezomib followed by lonafarnib (B → L) or lonafarnib followed by bortezomib (L → B) after 9 hours. MTT assay was performed after 72 hours. C indicates concurrent; B, bortezomib; and L, lonafarnib.