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Antiretroviral Agent Makes Strong Showing in Refractory Multiple Myeloma



The objective response rate of 65% observed in this very advanced, heavily pretreated, mostly dual-refractory patient population is exceptional. Nelfinavir plus bortezomib/dexamethasone has the potential to become a fully generic, affordable, active therapy option for proteasome inhibitor–refractory patients.
— Christoph Driessen, MD, PhD

An antiretroviral drug that is used for human immunodeficiency virus (HIV) demonstrated strong activity when combined with bortezomib (Velcade) in patients with relapsed/refractory multiple myeloma in a small multicenter phase II study presented at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition.1 Two-thirds of patients refractory to bortezomib responded to nelfinavir (Viracept), given with bortezomib and dexamethasone, including patients with high-risk cytogenetics, reported Christoph Driessen, MD, PhD, of Kantonsspital St. Gallen in Switzerland.

“Nelfinavir plus bortezomib/dexamethasone has substantial activity in advanced, proteasome inhibitor–refractory multiple myeloma,” Dr. Driessen said. “The activity of nelfinavir/dexamethasone was preserved in proteasome inhibitor-plus-[immunomodulatory drug] double-refractory patients as well as poor-risk cytogenetic patients, and the toxicity profile was similar to bortezomib/dexamethasone in heavily pretreated patients.”

“The objective response rate of 65% observed in this very advanced, heavily pretreated, mostly dual-refractory patient population is exceptional,” said Dr. Driessen, who advocated for further development of nelfinavir, which has gone off patent, as a sensitizing agent in proteasome inhibitor–based therapy.

Dr. Driessen suggested that nelfinavir may “universally boost” the cytotoxic activity of proteasome inhibitors. “With future generic bortezomib, nelfinavir plus bortezomib/dexamethasone has the potential to become a fully generic, affordable, active therapy option for proteasome inhibitor–refractory patients.”

Despite encouraging outcomes in patients with poor prognosis, future development of this therapy remains uncertain, he acknowledged. Since nelfinavir is no longer patented, the manufacturer may have little incentive for this. Also, patients with relapsed/refractory disease interested in a clinical trial have many experimental options already, and the appropriate comparator in a phase III trial of nelfinavir is also unclear, Dr. Driessen added.

Rationale for Nelfinavir

About 30% of proteasome inhibitor–refractory patients respond to currently available drugs. Activity of the unfolded protein response and high expression of IRE1/XBP1 correlate with sensitivity to bortezomib, whereas IRE1/XBP1 downregulation is associated with proteasome inhibitor resistance. Nelfinavir induces activation of unfolded protein response and IRE1/XBP1 expression and overcomes proteasome inhibitor resistance in vitro, explained Dr. Driessen.

Preclinical studies of protease inhibitors, including nelfinavir, have demonstrated antitumor activity by mechanisms that include proteasome inhibition, suggesting potential activity in myeloma. And in a phase I clinical trial, treatment with nelfinavir led to induction of unfolded protein response and IRE1/XBP1 in peripheral blood mononuclear cells. Responses in five of six patients with myeloma refractory to bortezomib and lenalidomide (Revlimid) led to this phase II study.

Study Details

The open-label study enrolled 34 patients with proteasome inhibitor–refractory myeloma, who had received a median of 5 prior regimens. Three-fourths of the patients had undergone stem cell transplantation, and 13 patients (38%) had poor-risk cytogenetic profiles. All of the patients had prior exposure to bortezomib and lenalidomide, and almost half had received pomalidomide (Pomalyst).

Patients received six cycles of nelfinavir in combination with standard doses of bortezomib and dexamethasone. The primary endpoint was response rate. A response rate of ≤ 15% was considered inadequate to consider for further investigation, whereas a response rate ≥ 30% indicated the treatment is worth pursuing in a larger study, he said.

Key Findings

Responses were observed in 22 patients (65%) on the nelfinavir-containing regimen. These were very good partial responses in 5 patients (15%) and partial responses in 17 patients (50%). Additionally, 3 patients (9%) had minor responses, and 4 others (12%) had stable disease, resulting in a clinical benefit rate of 86%. The benefits were consistent across the population’s spectrum of prior therapy, Dr. Driessen reported.

Nelfinavir in Multiple Myeloma

  • The antiretroviral drug nelfinavir showed strong activity in relapsed/refractory multiple myeloma, according to a small phase II trial of 34 patients.
  • The response rate was 65%, including a 15% rate of very good partial responses or better. In patients with high-risk cytogenetics, the response rate was 77%.
  • The development of this potential treatment, however, is uncertain, given the fact that nelfinavir has gone off patent.

Of the 13 patients with high-risk cytogenetics, 10 (77%) achieved at least a partial response. The median time to new antimyeloma therapy or death was 16 weeks. Dr. Driessen said 13 patients had confirmed disease progression during treatment, and 5 others had unconfirmed disease progression.

Patients were likely to respond to therapy regardless of prior drug treatment. Response rates were 65% in bortezomib-refractory patients; 65% in patients who were refractory to bortezomib and lenalidomide; 56% in patients refractory to bortezomib, lenalidomide, and pomalidomide; and 50% in those refractory to bortezomib, lenalidomide and carfilzomib (Kyprolis).

The most frequent grade ≥ 3 adverse events were anemia (n = 10), thrombocytopenia (n = 8), lung infections (n = 8), hypertension (n = 6), hyperglycemia (n = 6), hyponatremia (n = 5), and fatigue (n = 5), as well as 3 fatal cases of sepsis.

Although these findings are encouraging, Dr. Driessen commented: “I do think these results need to be confirmed in a larger cohort.”

Additional Comments

Shaji Kumar, MD

Shaji Kumar, MD

Shaji Kumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota, told The ASCO Post that he found the findings for nelfinavir “quite fascinating” and “would love to see more data” for nelfinavir/bortezomib/dexamethasone. He predicted that whether this potential treatment can move forward in multiple myeloma “will depend on whether they can get funding for a phase III trial.” Repurposing of existing generic drugs can go a long way toward containing the cost of care. ■

Disclosure: Dr. Driessen has received honoraria from and served as an advisor to Mundipharma EDO GmbH as well as served as a consultant for Celgene and Janssen.

Reference

1. Driessen C, Müller R, Novak U, et al: The HIV protease inhibitor nelfinavir in combination with bortezomib and dexamethasone has excellent activity in patients with advanced, proteasome inhibitor–refractory multiple myeloma: A multicenter phase II trial (SAKK 39/13). 2016 ASH Annual Meeting. Abstract 487. Presented December 4, 2016.



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