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.

1st Department of Medicine Department of Hematology 1st Faculty of Medicine Charles University and General Hospital Prague Czech Republic

Aeterna Zentaris Frankfurt Germany

Assuta Ashdod University Hospital Faculty of Health Sciences Ben Gurion University of the Negev Beer Sheba Israel

Cancer Care Northwest Spokane Washington USA

Chaim Sheba Medical Center Tel Hashomer Israel

CIUSSS de l'est de l'île de Montréal University of Montreal Montreal Canada

Department of Hematology Oncology Medical College of Wisconsin Milwaukee Wisconsin USA

Department of Hematooncology University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Internal Medicine Seoul National University College of Medicine Seoul South Korea

Greenebaum Comprehensive Cancer Center University of Maryland Baltimore Maryland USA

Hadassah University Hospital Jerusalem Israel

Hospital Universitario 12 de Octubre CNIO Complutense University Madrid Spain

Institute of Hematology Assuta Medical Centers Tel Aviv and Ariel University Ariel Israel

Jerome Lipper Center for Multiple Myeloma Research Dana Farber Cancer Institute Boston Massachusetts USA

Keryx Biopharmaceuticals Inc New York New York USA

Sungkyunkwan University School of Medicine Samsung Medical Center Seoul South Korea

TCM Groups Inc Berkeley Heights New Jersey USA

Tel Aviv Sourasky Medical Center Tel Aviv Israel

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