Randomized, placebo‐controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib

Abstract

Perifosine, an investigational, oral, synthetic alkylphospholipid, inhibits signal transduction pathways of relevance in multiple myeloma (MM) including PI3K/Akt. Perifosine demonstrated anti‐MM activity in preclinical studies and encouraging early‐phase clinical activity in combination with bortezomib. A randomized, double‐blind, placebo‐controlled phase 3 study was conducted to evaluate addition of perifosine to bortezomib‐dexamethasone in MM patients with one to four prior therapies who had relapsed following previous bortezomib‐based therapy. The primary endpoint was progression‐free survival (PFS). The study was discontinued at planned interim analysis, with 135 patients enrolled. Median PFS was 22.7 weeks (95% confidence interval 16·0–45·4) in the perifosine arm and 39.0 weeks (18.3–50.1) in the placebo arm (hazard ratio 1.269 [0.817–1.969]; P = .287); overall response rates were 20% and 27%, respectively. Conversely, median overall survival (OS) was 141.9 weeks and 83.3 weeks (hazard ratio 0.734 [0.380–1.419]; P = .356). Overall, 61% and 55% of patients in the perifosine and placebo arms reported grade 3/4 adverse events, including thrombocytopenia (26% vs 14%), anemia (7% vs 8%), hyponatremia (6% vs 8%), and pneumonia (9% vs 3%). These findings demonstrate no PFS benefit from the addition of perifosine to bortezomib‐dexamethasone in this study of relapsed/refractory MM, but comparable safety and OS.

Where We Stand With Precision Therapeutics in Myeloma: Prosperity, Promises, and Pipedreams

“…A phase I study of perifosine, lenalidomide, and dexamethasone in RRMM produced an encouraging 73% ORR and found that responders had higher baseline bone marrow phospho-Akt levels, identifying another potential biomarker for agents targeting the PI3K/AKT pathway ( 44 ). A more recent phase III study, however, randomized patients to bortezomib and dexamethasone with or without perifosine but found no signal towards improved response rates or progression-free survival (PFS) at the first interim analysis and was discontinued ( 45 ). The pan-Akt inhibitor afuresertib has also been clinically tested in multiple myeloma, with initial monotherapy trials discontinued due to limited single agent activity ( 46 ).…”

Future Developments in the Treatment of AL Amyloidosis

“…A few clinical trials have assessed the efficacy of perifosine, an AKT-inhibitor, as monotherapy or in combination regimens with mixed results [84,85], while a phase III trial that evaluated the combination of perifosine with bortezomib and dexamethasone was stopped at the interim analysis due to lack of efficacy in terms of ORR and PFS in the perifosine arm compared to the placebo arm [86].…”

Pathway-Directed Therapy in Multiple Myeloma

“…Another phase I/II-trial testing perifosine in combination with bortezomib and dexamethasone showed a response rate (≥minor remission (MR)) of 41% in patients relapsed or refractory to bortezomib, however, with a PFS of only 6.8 months [ 80 ]. A phase III trial (ClinicalTrials.gov Identifier: NCT01002248) further evaluating this combination was stopped at the first interim analysis due to a lack of benefit in responses (ORR ≥ PR 20% vs. 27 %) and PFS (22.7 weeks (95% CI 16.0–45.4) in the perifosine arm and 39.0 weeks (18.3–50.1) in the placebo arm) [ 81 ].…”