Pharmacokinetics, safety, and efficacy of lenalidomide plus dexamethasone in patients with multiple myeloma and renal impairment.

PURPOSE: 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.

Fanconi syndrome and chronic kidney disease in paroxysmal nocturnal hemoglobinuria: effect of eculizumab therapy.

The association of Fanconi syndrome (FS) and chronic kidney disease (CKD) has been rarely described during the course of paroxysmal nocturnal hemoglobinuria (PNH). We report 2 patients with PNH and CKD associated with proximal tubule dysfunction, which manifested as full-blown FS in one case. In both patients, abnormal iron load within the kidneys was demonstrated by magnetic resonance imaging, which correlated with diffuse and numerous hemosiderin inclusions within proximal tubular cells. After 12 months, eculizumab treatment resulted in significant decrease in the kidney iron load in both cases. Glomerular filtration rate improved in one case and was stabilized in the other, in whom pretreatment kidney biopsy had shown severe extensive interstitial fibrosis. However, symptoms of proximal tubular dysfunction persisted in both patients. These data suggest that hemosiderin deposition in proximal tubules is probably an important mechanism involved in the development of FS, an under recognized and early manifestation of CKD in PNH. Prolonged treatment with eculizumab may improve long-term renal function in PNH patients with CKD.

[Current treatment of AL amyloidosis]. / Traitement actuel de l'amylose AL.

Systemic AL amyloidosis is a rare complication of monoclonal gammopathies. Renal manifestations are frequent, mostly characterized by heavy proteinuria, with nephrotic syndrome and renal failure in more than half of the patients at diagnosis. Without treatment, median survival does not exceed 12 months. Amyloid heart disease and diffusion of amyloid deposits are associated with reduced survival. Treatment of systemic AL amyloidosis has been profoundly modified with the introduction of international criteria for the definition of organ involvement and hematologic response, and with the use of sensitive tests for the measurement of serum-free light chain levels. Melphalan plus dexamethasone is now established as the gold standard for first line treatment of systemic AL, with similar efficacy and reduced treatment-related mortality compared to high-dose therapy. Modern chemotherapy regimens, based on the use of novel agents such as bortezomib and lenalidomide, might further improve patient survival.

[New insights in the treatment of myeloma with renal failure]. / Actualités dans le traitement du myélome avec insuffisance rénale.

Renal failure, mostly related to myeloma cast nephropathy (MCN), is a frequent complication of multiple myeloma (MM), which occurs in up to 50% of patients during the course of the disease. Persistent renal failure in MM is associated with poor survival. Treatment of MCN relies on urgent symptomatic measures (alkalinisation, rehydration, correction of hypercalcemia, and withdrawal of nephrotoxic drugs), with rapid introduction of chemotherapy to efficiently reduce the production of monoclonal light chains (LC). Recent studies suggest that, in patients with MM and severe renal failure due to MCN, rapid removal of circulating LC, through intensive hemodialysis sessions using a new generation high cut-off dialysis membrane, might result in dialysis withdrawal in most patients. If the development of intensive therapy and new efficient chemotherapy agents (thalidomide, bortezomib, lenalidomide) has transformed the care and prognosis of MM, the modalities and safety of these therapeutic regimens in patients with renal failure remain to be defined. The association of bortezomib with dexamethasone should be considered currently as first-line treatment in patients with MM and impaired renal function.