Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide.
Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.
Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Andrew J
AJ
Yee
Parameswaran
P
Hari
Raffaella
R
Marcheselli
Anuj K
AK
Mahindra
Diana D
DD
Cirstea
Tyler A
TA
Scullen
Jill N
JN
Burke
Scott J
SJ
Rodig
Teru
T
Hideshima
Jacob P
JP
Laubach
Irene M
IM
Ghobrial
Robert L
RL
Schlossman
Nikhil C
NC
Munshi
Kenneth C
KC
Anderson
Edie A
EA
Weller
Paul G
PG
Richardson
Noopur S
NS
Raje
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068338:Everolimus; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome
D013792:Thalidomide; D000068338:Everolimus; D000077269:Lenalidomide; D020123:Sirolimus
everolimus; lenalidomide; mTOR inhibitor; multiple myeloma; phase I clinical trial