Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study.
The combination of lenalidomide-dexamethasone is active in multiple myeloma (MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to lenalidomide and dexamethasone, providing the rationale for this Phase I, multicentre, single-arm study to assess the safety and determine the maximum-tolerated dose (MTD) of perifosine-lenalidomide-dexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50-100 mg daily and lenalidomide 15-25 mg once daily on days 1-21 of each 28-d cycle, plus dexamethasone 20-40 mg weekly thereafter, as indicated. Thirty-two patients were enrolled across four dose cohorts. MTD was not reached, with 31 patients evaluable for safety/tolerability. The most common all-causality grade 1-2 adverse events were fatigue (48%) and diarrhoea (45%), and grade 3-4 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57·5-89·2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression-free survival was 10·8 months and median overall survival 30·6 months. Response was associated with phospho-Akt in pharmacodynamic studies. Perifosine-lenalidomide-dexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM.
University of Michigan Cancer Center, Ann Arbor, MI, USA. ajakubowiak@medicine.bsd.uchicago.edu
Andrzej J
AJ
Jakubowiak
Paul G
PG
Richardson
Todd
T
Zimmerman
Melissa
M
Alsina
Jonathan L
JL
Kaufman
Malathi
M
Kandarpa
Stephanie
S
Kraftson
Charles W
CW
Ross
Colleen
C
Harvey
Teru
T
Hideshima
Peter
P
Sportelli
Enrique
E
Poradosu
Lesa
L
Gardner
Kathy
K
Giusti
Kenneth C
KC
Anderson
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012008:Recurrence; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome
D010767:Phosphorylcholine; C105905:perifosine; D013792:Thalidomide; D003907:Dexamethasone; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000077269:Lenalidomide