title: Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma.
abstract: The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/d) and prednisone (20 mg/d). At the MTD (n = 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands.
authors.forename: Inger S
authors.initials: IS
authors.lastname: Nijhof
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands.
authors.forename: Laurens E
authors.initials: LE
authors.lastname: Franssen
authors.affiliation: Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands.
authors.forename: Mark-David
authors.initials: MD
authors.lastname: Levin
authors.affiliation: Department of Hematology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Gerard M J
authors.initials: GMJ
authors.lastname: Bos
authors.affiliation: Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Annemiek
authors.initials: A
authors.lastname: Broijl
authors.affiliation: Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands.
authors.forename: Saskia K
authors.initials: SK
authors.lastname: Klein
authors.affiliation: Department of Hematology, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Koene
authors.affiliation: Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Andries C
authors.initials: AC
authors.lastname: Bloem
authors.affiliation: Department of Internal Medicine, Spaarne Hospital, Hoofddorp, The Netherlands.
authors.forename: Aart
authors.initials: A
authors.lastname: Beeker
authors.affiliation: Department of Internal Medicine, Rode Kruis Hospital, Beverwijk, The Netherlands.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Faber
authors.affiliation: Department of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: van der Spek
authors.affiliation: Department of Internal Medicine, HagaZiekenhuis, Den Haag, The Netherlands; and.
authors.forename: Paula F
authors.initials: PF
authors.lastname: Ypma
authors.affiliation: Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands.
authors.forename: Reinier
authors.initials: R
authors.lastname: Raymakers
authors.affiliation: Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Dick-Johan
authors.initials: DJ
authors.lastname: van Spronsen
authors.affiliation: Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Westerweel
authors.affiliation: Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands.
authors.forename: Rimke
authors.initials: R
authors.lastname: Oostvogels
authors.affiliation: Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Velzen
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Berris
authors.initials: B
authors.lastname: van Kessel
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
authors.affiliation: Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sonja
authors.initials: S
authors.lastname: Zweegman
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Lokhorst
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Niels W C J
authors.initials: NWCJ
authors.lastname: van de Donk
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use*; D011379:Prognosis; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D013792:Thalidomide; D003520:Cyclophosphamide; D000077269:Lenalidomide; D011241:Prednisone