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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.

SUBMITTER: Richardson PG

PROVIDER: S-EPMC9175725 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Richardson Paul G PG Nagler Arnon A Ben-Yehuda Dina D Badros Ashraf A Hari Parameswaran N PN Hajek Roman R Spicka Ivan I Kaya Hakan H LeBlanc Richard R Yoon Sung-Soo SS Kim Kihyun K Martinez-Lopez Joaquin J Mittelman Moshe M Shpilberg Ofer O Blake Paul P Hideshima Teru T Colson Kathleen K Laubach Jacob P JP Ghobrial Irene M IM Leiba Merav M Gatt Moshe E ME Sportelli Peter P Chen Michael M Anderson Kenneth C KC

EJHaem 20200406 1

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 r ...[more]

PMID: 35847734

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Project description:Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562 .

Dataset Information

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

Publications

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

Similar Datasets

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