Pristimerin and bortezomib are synergistically cytotoxic to myeloma cells across a broad range of concentrations. Human myeloma cell lines (A-E) were cotreated treated with pristimerin (IC₀-IC₁₀₀) and/or bortezomib (IC₀-IC₁₀₀) and viability (normalized to untreated cells) was determined by MTT assay at 72 hours. The bortezomib dose-response curve for each myeloma line is shown, with left-shifted bortezomib IC₅₀ at each concentration of pristimerin illustrated as a vertical dashed arrow. Pristimerin and bortezomib uniformly chemosensitized myeloma cells to each other, reducing the effective concentrations required to induce 50% lethality (IC₅₀) and causing synergistic cell death across a wide concentration spectrum. Similar results were obtained for t(11;14)–positive SKMM2 (A) or KMS12PE (B) cells; for t(4;14)–positive JJN3 (C) or H929 (D) cells; and for t(14;16)–positive OCI-MY5 (E); thus bortezomib-pristimerin synergy is not limited to a single molecular subgroup of tumor. (F) The synergistic, independent or antagonistic cytotoxic effects of combining pristimerin at 200, 400, 600, 800, or 1000 nM, with bortezomib at 1 nM or 2 nM, against 5 myeloma tumor lines, were evaluated using a score of Bliss independence³⁷  (BI) and are plotted as a histogram. Negative values (plotted upward) suggest synergistic cytotoxicity from the combination of pristimerin and bortezomib that is more than that predicted by the product of effects of the agents acting independently (“more than additive” cytotoxicity). BI values are log₂ based; therefore, the fold difference between the observed and expected viability resulting from combining both drugs is 2^BI. Pristimerin and bortezomib commonly combine at active concentrations to produce synergistic myeloma cell cytotoxicity more than 2- to 3-fold greater than that expected from the product of effects of both drugs used independently of one another.