SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.
According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.
In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.
Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.
Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.
High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.
Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.
“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.
So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.
In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.
Three patients achieved a partial response (PR) and 3 a minor response (MR).
The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.
Study design
Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:
- Nelfinavir at 2 x 2500 mg orally on days 1–14
- Bortezomib at 1.3 mg/m2 intravenously or subcutaneously on days 1, 4, 8, and 11
- Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.
Trial therapy lasted for a maximum of 6 cycles (18 weeks).
Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”
The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.
Investigators considered a 30% or higher response rate promising.
Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.
Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.
Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.
Patient population
Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.
They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.
The time from last dose of prior therapy to enrollment on the study was a median of 27 days.
“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.
All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.
Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.
“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.
Efficacy
Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).
Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.
Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).
Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.
Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.
In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.
Efficacy by prior therapy
Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.
For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.
For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.
And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.
Adverse events
“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.
“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”
Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).
Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”
The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.
