Establishment and characterization of bortezomib-resistant Vk*MYC tumors. (A) M-spike levels (normalized to day 0) of 2 mice (2917 and 2777) treated with bortezomib at 0.5 mg/kg (gray and black lines) or 1 mouse (B763) at 1 mg/kg (dotted line) for 2 weeks (1 cycle). Arrowheads indicate the time of administration of 1 cycle of therapy, their color refers to the treated mouse and their size is proportional to the drug dosage (medium = 0.5 mg/kg, large = 1 mg/kg). (B) M-spike levels (normalized to day 0) of 3 mice (2825, B1165, and 3569) treated with continuous escalating doses of bortezomib. Arrowheads and their size indicate treatment: small = 0.16 mg/kg, medium = 0.25 mg/kg, large = 0.5 mg/kg, and their color refers to the treated mouse. (C-D) Response to single or combination treatment of 2 independent bortezomib-resistant Vk*MYC tumors (Vk12598 and Vk12653) propagated by serial transplantation into congenic wild-type (wt) mice. M-spike levels at day 14 normalized to day 0 are shown in log2 scale. Each dot represents a mouse. Bars show median day 14 M-spike levels normalized to day 0. The P value of active drugs compared with vehicle is shown. (E) SPEP performed on the Vk12598 line of bortezomib-resistant mice shows effective bortezomib + HDACi combination treatment but ineffective single-agent activity of these 2 drug. Arrows point to M-spikes.