Nelfinavir and lenalidomide/dexamethasone in patients with lenalidomide-refractory multiple myeloma. A phase I/II Trial (SAKK 39/10)

Abstract

The antiretroviral agent nelfinavir has antimyeloma activity and can overcome resistance to bortezomib. Our phase I/II trial investigated whether adding nelfinavir to lenalidomide-dexamethasone can overcome lenalidomide resistance in lenalidomide-refractory multiple myeloma (MM). Twenty-nine patients were included (high-risk cytogenetic aberrations 31%; ≥2 prior therapy lines 93%; lenalidomide-bortezomib double-refractory 34%). Twenty-four patients (83%) had prior bortezomib and 10 (34%) were lenalidomide-bortezomib double-refractory. They received four cycles of nelfinavir 2500 mg/day with standard-dose lenalidomide (25 mg days 1-21) and dexamethasone (40/20 mg days 1, 8, 15, 22). Minor response or better was achieved in 16 patients (55%; 95% CI 36-74%), including 40% of those who were lenalidomide-bortezomib double-refractory, and partial response or better in nine patients (31%; 95% CI 15-51%). Median progression-free survival was 3.4 (95% CI 2.0-4.9) months and median overall survival 21.6 (13.0-50.1) months. Lenalidomide-related pneumonitis, pneumonia, and neutropenic fever occurred, but there were no unexpected adverse events. Peripheral blood mononuclear cells showed a 45% (95% CI 40-51%) reduction in total proteasome activity from baseline and significant induction of unfolded protein response and autophagy. Thus, nelfinavir-lenalidomide-dexamethasone is an active oral combination in lenalidomide-refractory MM.

Fig. 1. Proteasome activity in PBMC.

a Maximum change from baseline in proteasome activity on days 8 or 15 (β2/2i, β1/1i, 5/5i proteasome subunits and global proteasome activity), mean of all patients. b Comparison of β2/2i/β1/1i, 5/5i ratio versus clinical response. c Active site labeling days 0 (baseline), 8, and 15 (n = 2 patients) and its densitometric evaluation of the bands

Fig. 2. UPR and autophagy in PBMC.

a Comparison of phospho-IRE1α expression versus clinical response. b Maximum change from baseline in UPR, western blots densitometric evaluation (phospho-IRE1α, CHOP), and autophagy (LC3A) [mean of all patients]. c Western blots for ER stress proteins (phospho-IRE1α, CHOP) and densitometric evaluation on days 0, 8, and 15 from two representative patients