Lenalidomide in renal insufficiency – balancing the risks and benefits

Lenalidomide is the most recent agent to be approved by the United States Food and Drug Administration for the treatment of multiple myeloma. This approval has extended the compendium of available and active agents against myeloma, a disease that is currently witnessing a renaissance both in terms of scientific advances and therapeutic options. As a result of this renaissance, the overall survival time of patients afflicted by myeloma is beginning to increase (Kristinsson et al, 2007). This increased clinical efficacy must, however, be balanced with the potential increased toxicity of a renally metabolized drug, which has a markedly different side-effect profile to its related compound, thalidomide. These differences offer significant benefits as well as challenges, in maximizing therapeutic effects as well as minimizing toxicities. Myelosuppression is a major toxicity associated with lenalidomide. The exact impact of renal impairment is not fully understood due to the exclusion of patients with significant renal insufficiency in many of the large clinical studies published to date. The two randomized, phase III trials of dexamethasone with or without lenalidomide for relapsed myeloma conducted in North America and Europe, excluded patients with serum creatinine levels >221 μmol/l (Weber et al, 2006). The recently reported phase III Eastern Cooperative Oncology Group trial (E4A03) of lenalidomide with high- or low-dose dexamethasone in untreated myeloma patients also had a serum creatinine level cut-off of 221 μmol/l (Rajkumar et al, 2006). However, renal insufficiency can be present in up to 29% of myeloma patients (Knudsen et al, 2000), where the overall impact of renally metabolized, myeloma-specific agents has significant implications in both the toxicity profile, as well as the disease response. As such, there is a paucity of information regarding the toxicity and efficacy of lenalidomide in this subset of myeloma patients. Niesvizky et al (2007) reported on lenalidomide-induced myelosuppression as related to renal function, studied in a subset of patients enroled in a clinical trial. Specifically, they observed that a creatinine clearance (CrCl) of 150 d. Secondly, it is unclear whether the lower dose was associated with reduced serum levels of the active drug, and/or whether this was associated with reduced anti-myeloma activity. A clear implication of these findings is that drug dosing must be adjusted in patients with renal impairment and that CrCl may be a more accurate criterion to utilize, compared with serum creatinine. A recent study presented at the American Society of Clinical Oncology (Chen et al, 2007) reported up to 240% increase in the area under the curve (AUC) of lenalidomide in patients with severe renal insufficiency (CrCl <0·5 ml/s but not on dialysis) and 360% in patients with end-stage renal disease. Based on these findings, a dose-reduction algorithm was proposed. However, this algorithm must be prospectively verified, in terms of both the toxicity profile and anti-myeloma efficacy, and correlated with AUC measurements of the drug before it can be broadly implemented. In summary, lenalidomide is a novel, renally metabolized agent with significant anti-myeloma activity. Clearly, impaired renal function is associated with increased toxicity. Is the increased AUC associated with a higher response-rate, or increased myelosuppression? The findings by Niesvizky et al (2007) point to the need for studies specifically designed to address the efficacy and toxicity of reduced-dose lenalidomide in patients with either end-stage renal disease, or several renal impairment (but not on dialysis) as these patients represent a significant subset of myeloma patients that will ultimately require lenalidomide at some point during the course of their disease.