Assessment Of Drug Toxicity In Patients With and Without Renal Impairment Receiving Lenalidomide At a Large Academic Institution

Approximately 20-40% of multiple myeloma (MM) patients have renal impairment (RI) at diagnosis (Kyle et al. Mayo Clin Proc. 2003). Immediate initiation of interventions aimed at restoring renal function including but not limited to anti-MM chemotherapy is critical in such patients. Lenalidomide can be used in this context as a component of chemotherapy, but requires close monitoring and adherence to manufacturer recommendations to avoid toxicity given the impact of impaired renal function on lenalidomide pharmacokinetics (Chen et al. J Clin Pharmacol. 2007). The purpose of this study is to evaluate the impact of lenalidomide dosing on the agent’s toxicity profile in patients with and without RI.

The primary objective of this study is to assess the impact of initial lenalidomide dose administered to newly diagnosed and relapsed/refractory MM patients with and without RI, and to evaluate the incidence of dose reductions, temporary drug discontinuations, and adverse events in these two groups. The secondary objective is to assess patients’ anticoagulation use and the development of venous thromboembolic events (VTE).

Data was collected retrospectively on 62 myeloma patients who filled a prescription for lenalidomide at a single institution outpatient pharmacy from January 2010 to May 2012. Data collected included the initial dose and schedule of lenalidomide, dose reductions due to toxicities, types of toxicities and number of days of temporary discontinuations of lenalidomide. Renal impairment was defined as creatinine clearance (CrCl) less then 60ml/min. The manufacturer’s label recommends a dose of 25 mg for patients with CrCl ≥60ml/min QD, 10mg QD for those with CrCl 30 – 59 ml/min, and either 15 mg QOD or 5 mg QD for patients with CrCl <30. Patients who received the recommended dose based on RI were designated as renally dose-adjusted, whereas those who received more than the recommended dose were designated as non renally dose-adjusted.

Sixty two patients were included in this study, 40 of whom had normal CrCl and 22 who had RI. Thirty (48.4%) patients had newly diagnosed MM, 25 (40.3%) had relapsed/refractory disease and the remainder of patients (N=7) were on maintenance therapy either post transplant or post induction. Lenalidomide was most frequently partnered with dexamethasone (N=52; 84%) and/or bortezomib (N=24; 39%). Among the 22 patients with RI, 11 (50%) received a starting dose of lenalidomide that was greater than the manufacturer recommended one. Dose reductions and/or temporary discontinuation occurred in 49 (79%) of the 62 patients: 30 (75%) in the normal CrCl patients and 19 (86%) among those with RI (difference=11%, 95% CI:-11%, 31%). Amongst the RI patients, dose reductions and/or temporary discontinuation occurred in 72.7% (8/11) of patients in whom an initial dose adjustments was made for RI, and in 100% (11/11) of patients in whom dose adjustment of lenalidomide based on renal function was not made (difference=27%, 95% CI:-5%, 62%). The most common adverse events (any grade, according to CTCAE version 3) leading to dose reductions and/or temporary discontinuations included neutropenia (N=15), rash (N=10), worsening renal function (N=10), VTEs (N=9), GI intolerance (N=8), and thrombocytopenia (N=5). Among patients with RI, no difference in the type of adverse events was observed based on whether or not an initial dose adjustment for lenalidomide was made. Aspirin or warfarin was initiated as prophylaxis in 57 of the 62 (92%) patients evaluated. Nine (15%) patients had a documented thrombotic event, all of whom were receiving aspirin prophylaxis. As of data retrieval, 23 patients are still on lenalidomide either as treatment for relapsed disease or maintenance. For the remaining 39 patients who discontinued lenalidomide, the most common reason for lenalidomide discontinuation was progressive disease (16/39) or toxicities (9/39).

This analysis suggests that in the setting of RI, dose reductions and/or discontinuations were less common in patients who received the recommended renally-dose adjusted lenalidomide at time of treatment initiation. However, the type of adverse events leading to dose reduction and/or discontinuation were similar between the two groups. The rate of thrombotic events was higher than expected and thrombotic events occurred exclusively in patients receiving aspirin prophylaxis.

Richardson:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlossman:Celgene: Consultancy. Anderson:Celgene: Membership on an entity’s Board of Directors or advisory committees.