Nelfinavir and Lenalidomide/Dexamethasone in Patients with Lenalidomide-Refractory Multiple Myeloma. A Phase I/II Trial — SAKK 39/10

Introduction

Nelfinavir (NFV) is an approved HIV protease inhibitor. In mammalian cells, NFV induces proteotoxic stress and activates the unfolded protein response (UPR) via an unknown mechanism. NFV in combination with bortezomib and dexamethasone (NeVd) is highly active in patients with advanced, proteasome inhibitor-refractory multiple myeloma (Driessen et al Blood 2016, 128(22), 487). We hypothesized that the addition of NFV to standard lenalidomide/dexamethasone (Rd) may overcome lenalidomide-resistance in myeloma patients (pts).

Methods

This multicenter, dose escalation phase I/II trial used a 3+3 design to identify the recommended dose of NFV. Pts having progressed during or within 60 days after termination of lenalidomide-containing therapy were eligible for this trial. Pts were treated with escalating doses of NFV (1250-2500 mg b.i.d) in combination with lenalidomide 25mg daily (d 1 - 21) and dexamethasone 40/20 mg (days 1, 8, 15, 22 every 4 weeks) for up to 4 cycles. In the phase II part a Simon's two stage design was used to investigate an objective response rate (ORR) ≤ 10% versus ORR ≥ 30% (alpha 5%, power 80%) requiring 29 pts. Pharmacodynamic parameters (proteasome activity, activation of the UPR and autophagy) were assessed from PBMC collected at baseline, d 8 and 15 in the phase I part from 7 pts (ClinicalTrials.gov NCT01555281).

Results

In phase I, 10 pts were analyzed for dose limiting toxicities (DLTs). 2 DLTs were observed: diarrhea grade 3 and thrombocytopenia grade 4 at dose level 1850 mg b.i.d. NFV 1250 mg b.i.d. was identified as the recommended dose for phase II. 29 pts including 6 pts from phase I with advanced, lenalidomide-refractory (IMWG criteria) myeloma were analyzed for phase II. 25 pts (86%) had undergone 2 or more prior lines of therapy, 18 pts (62%) had prior autologous stem cell transplantation, 8 pts (28%) had high risk cytogenetic features. 16 pts (55%) achieved an objective response (MR or better, 95% CI 36-74), VGPR was reached in 3 pts (10%), PR in 6 pts (21%), and MR in 7 pts (24%), SD in 4 pts (14%), PD in 7 pts (24%), 2 pts were not evaluable. Of 8 pts with high risk cytogenetics we observed 1 VGPR and 2 PR. The median duration of response was 4 months (95% CI 1.8-5.7) and median overall survival was 21.6 months (95% CI 13.0-50.1). 14/29 pts discontinued trial treatment due to: unacceptable toxicity (4 pts), progressive disease (8 pts), patient refusal (2 pts). Most frequently observed adverse events were grade 1 gastrointestinal symptoms (9 pts) and metabolic disorders (9 pts). Hematologic adverse events of grade 3 or more were anemia (7 pts), thrombocytopenia (6 pts) and neutropenia (7 pts, including 2 with febrile neutropenia). Non-hematologic adverse events of grade 3 or more occurring in > 1 patient were: dyspnea (3 pts), fatigue (3 pts), lung infection (3 pts) and bone pain (2 pts).

We performed quantitative pharmacodynamic monitoring of proteasome activity and of protein expression indicating an activation of the unfolded protein response (IRE1, CHOP) and autophagy (LC3). We observed a mean overall reduction of 45% (95% CI 40-51) of total proteasome activity in PBMC at days 8 or 15 during treatment with nelfinavir/lenalidomide/dexamethasone, compared to baseline.

Conclusion

The addition of NFV 1250 mg b.i.d. to Rd therapy is a safe and active oral combination for treatment of relapsed, lenalidomide-refractory myeloma. The proteasome-inhibiting activity of nelfinavir in combination with Rd is noteworthy and may be the basis for the clinical activity. Our data support the continued development of NFV as a myeloma drug. NFV is an oral, cost-effective drug to re-sensitize myeloma patients for lenalidomide therapy.