San Diego, CA—Nelfinavir (Viracept), a drug used for HIV, led to a surprisingly high response rate when added to bortezomib (Velcade) in patients with proteasome inhibitor–refractory multiple myeloma, according to a phase 2 study reported by Christoph Driessen, MD, myeloma specialist, Kantonsspital St. Gallen, Switzerland, at the 2016 American Society of Hematology meeting.
Approximately 65% of patients responded to the combination of nelfinavir, bortezomib, and dexamethasone. The addition of bortezomib did not add significantly to adverse effects associated with this protease inhibitor, said Dr Driessen.
“The combination of nelfinavir and bortezomib has substantial activity in advanced proteasome inhibitor–refractory multiple myeloma,” said Dr Driessen. “The activity was preserved in patients with proteasome inhibitor–immunomodulatory drug double-refractory disease, as well as in patients with poor-risk cytogenetics.”
Whether the activity is limited to its use in combination with bortezomib remains to be determined, but Dr Driessen did not rule out the possibility that “nelfinavir may universally boost the cytotoxic activity of proteasome inhibitors.”
Nelfinavir has a long history of effective treatment as a component of multidrug regimens for patients with HIV. The rationale for the clinical evaluation of nelfinavir in multiple myeloma came from preclinical studies showing that protease inhibitors, including nelfinavir, effected antitumor activity by mechanisms that include proteasome inhibition. In addition, nelfinavir has been shown to induce the upregulation of IRE1 and XBP1 genes, which is associated with the restoration of multiple myeloma cells’ sensitivity to proteasome inhibitors.
In a phase 1 clinical trial, 5 of 6 patients with bortezomib- and lenalidomide (Revlimid)-refractory multiple myeloma derived clinical benefit from nelfinavir therapy (Driessen C, et al. Haematologica. 2016;101:346-355). The benefit was associated with the induction of unfolded protein response and IRE1 and XBP1 genes in peripheral blood mononuclear cells, which was previously shown to be associated with bortezomib sensitivity.
The phase 2 clinical trial included 34 patients (median age, 67 years) with a median treatment history of 5 systemic regimens; 75% had undergone autologous stem-cell transplantation.
All patients had bortezomib-refractory disease, and 27 patients had lenalidomide-refractory disease. Nearly 50% of patients had exposure to pomalidomide (Pomalyst), and all but 1 patient had pomalidomide-refractory disease.
The patients received a median of 4.5 cycles of nelfinavir in combination with bortezomib therapy. Overall, 17 patients had partial response, and 5 patients had very good partial response, resulting in an objective response rate of 65%. Minor responses were reported in 3 (9%) patients. The clinical benefit rate (ie, very good partial response plus partial response plus minimal response) was 74%. An additional 4 (12%) patients had stable disease as best response.
In addition, 10 of the 13 patients with poor-risk cytogenetics responded to the combination therapy, reported Dr Driessen. An analysis of response by previous treatment showed that 22 (65%) patients with bortezomib-refractory disease responded to the combination therapy, as did 19 of 27 (70%) patients whose disease was also refractory to lenalidomide, and 9 of 15 (60%) patients with disease refractory to bortezomib, lenalidomide, and pomalidomide.
The median time to the next multiple myeloma therapy or death was 16 weeks. Overall, 13 patients had confirmed disease progression, and 5 patients had unconfirmed disease progression.
The most common grade ≥3 adverse events included thrombocytopenia, anemia, lung infection, hypertension, and hyperglycemia. Overall, 4 patients died during the study: 1 patient from febrile neutropenia and 3 patients from sepsis.
“With future availability of generic bortezomib, this combination has the potential to become a fully generic, affordable, active therapy option for protease inhibitor–refractory patients,” said Dr Driessen.
Although the results warrant evaluation in a phase 3 clinical trial, financial support for such study remains problematic, he said, noting that investigators had to apply for a grant to cover the cost of nelfinavir for the phase 2 study.