Pharmacokinetics, safety, and efficacy of lenalidomide plus dexamethasone in patients with multiple myeloma and renal impairment.
OBJECTIVE
Renal impairment (RI) is a common comorbidity in multiple myeloma (MM). Current dose adjustments recommended for renally excreted lenalidomide are based on data from noncancer patients. This study evaluated the pharmacokinetics, safety, efficacy, and exposure-response for lenalidomide plus dexamethasone in patients with relapsed/refractory MM and stable RI using the recommended dose adjustments.


METHODS
This phase 2 multicenter, open-label study stratified patients into 5 groups based on creatinine clearance (CrCl) calculated by Cockcroft-Gault equation: normal renal function (CrCl > 80 mL/min), mild RI (50 ≤ CrCl ≤ 80 mL/min), moderate RI (30 ≤ CrCl < 50 mL/min), severe RI (CrCl < 30 mL/min), and end-stage renal disease requiring hemodialysis. Dosing was based on the lenalidomide label.


RESULTS
Among 38 patients, the median age was 68 (range 62-74) years, and poorer renal function was associated with older age, more advanced disease, and more lines of prior therapy. Lenalidomide clearance declined with decreased CrCl. Mean lenalidomide area under plasma concentration-time curve (AUC) was within ±25 % of the target AUC in each group. Overall response was 76 %, and safety profiles were similar across groups, with no exposure-dependent trend in efficacy or toxicity. Estimated glomerular filtration rates calculated using the simplified Modification of Diet in Renal Disease equation highly correlated with lenalidomide clearance and, in 87 % of patients, would lead to assigning the same starting dose of lenalidomide as CrCl.


CONCLUSIONS
In patients with stable renal function, the recommended dose adjustments achieved proper plasma exposure and similar safety and efficacy across renal groups.
Department of Nephrology, Hôpital Jean Bernard CHU Poitiers, 2, rue de la Milétrie 86021 Poitiers France and INSERM CIC 1402, University Hospital, University of Poitiers, Poitiers, France. f.bridoux@chu-poitiers.fr.|Centre national de reference amylose AL et autres maladies à depots d'immunoglobulines monoclonales, University Hospital, University of Poitiers, Poitiers, France. f.bridoux@chu-poitiers.fr.
Frank
F
Bridoux
Department of Clinical Pharmacology, Translational Development, Celgene, Summit, NJ, USA.
Nianhang
N
Chen
Centre national de reference amylose AL et autres maladies à depots d'immunoglobulines monoclonales, University Hospital, University of Poitiers, Poitiers, France.|Department of Clinical Hematology, University Hospital, University of Limoges, Limoges, France.
Stephane
S
Moreau
Department of Hematology and Immunology and EA 3963, Hôpital Saint Louis, Paris, France.
Bertrand
B
Arnulf
Department of Nephrology, Hôpital Jean Bernard CHU Poitiers, 2, rue de la Milétrie 86021 Poitiers France and INSERM CIC 1402, University Hospital, University of Poitiers, Poitiers, France.|Centre national de reference amylose AL et autres maladies à depots d'immunoglobulines monoclonales, University Hospital, University of Poitiers, Poitiers, France.
Eric
E
Moumas
Centre national de reference amylose AL et autres maladies à depots d'immunoglobulines monoclonales, University Hospital, University of Poitiers, Poitiers, France.|Department of Clinical Hematology, University Hospital, University of Limoges, Limoges, France.
Julie
J
Abraham
Department of Nephrology, Hôpital Jean Bernard CHU Poitiers, 2, rue de la Milétrie 86021 Poitiers France and INSERM CIC 1402, University Hospital, University of Poitiers, Poitiers, France.|Centre national de reference amylose AL et autres maladies à depots d'immunoglobulines monoclonales, University Hospital, University of Poitiers, Poitiers, France.
Estelle
E
Desport
Centre national de reference amylose AL et autres maladies à depots d'immunoglobulines monoclonales, University Hospital, University of Poitiers, Poitiers, France.|Department of Clinical Hematology, University Hospital, University of Limoges, Limoges, France.
Arnaud
A
Jaccard
Department of Hematology and Immunology and EA 3963, Hôpital Saint Louis, Paris, France.
Jean Paul
JP
Fermand
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D003404:Creatinine / Q000097:blood*; D003907:Dexamethasone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007677:Kidney Function Tests; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011446:Prospective Studies; D012008:Recurrence; D051437:Renal Insufficiency / Q000503:physiopathology*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
D013792:Thalidomide; D003907:Dexamethasone; D003404:Creatinine; D000077269:Lenalidomide
Estimated glomerular filtration rate; Lenalidomide; Pharmacokinetics; Relapsed/refractory multiple myeloma; Renal impairment