Downregulation of the unfolded protein response mediates
proteasome inhibitor resistance in
multiple myeloma. The Human Immunodeficieny Virus
protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of
nelfinavir in combination with the
proteasome inhibitor bortezomib. Twelve patients with advanced
hematologic malignancies were treated with
nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and
bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with
nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of
nelfinavir in the presence or absence of concomittant
bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response,
proteasome activity, toxicity and response to trial treatment.
Nelfinavir 2×2500 mg was the recommended phase II dose identified.
Nelfinavir alone significantly up-regulated expression of
proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited
proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed,
bortezomib-refractory,
lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of
nelfinavir with
bortezomib is safe and shows promising activity in advanced,
bortezomib-refractory
multiple myeloma. Induction of the unfolded protein response by
nelfinavir may overcome the biological features of
proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).