Renal impairment is a frequent complication in patients with MM, and its incidence increases in patients with recurrent disease and as the disease becomes refractory to treatment.1
Two large, prospective randomized trials, MM-009 and MM-010, established the significant activity of combination lenalidomide plus dexamethasone in patients with relapsed and/or refractory MM.12,13
Although lenalidomide is excreted renally, many patients with advanced myeloma and RI may not have any other treatment option. This frequent clinical complication prompted a retrospective analysis of data from MM-009 and MM-010 to evaluate the effects of RI on patient outcomes. The results from the current subgroup analysis demonstrate that the combination of lenalidomide plus dexamethasone is effective in patients with all degrees of renal dysfunction. Renal impairment at the time of diagnosis is associated with poor survival in patients with MM.6,9
Persistent renal failure is associated with an increased risk of morbidity and early mortality.18,19
In 1 study, the median survival was an additional 6 months for patients who had reversible renal failure compared with patients who had irreversible renal injury, indicating that renal improvement may be associated with improved long-term survival.6
Thus, the reversibility of renal failure may be an important prognostic factor, perhaps as important as quality of response to therapy, for patients with RI.6,9
The improvement in RI to a near-normal range (CLCr
≥60 mL/minute) observed in the majority of patients in the current study suggests that lenalidomide plus dexamethasone may be a particularly useful therapy in this setting.
In the current study, TTP and PFS did not differ significantly between patients who had mild or no RI compared with patients who had RI. However, patients who had severe RI (CLCr <30 mL/minute) tended to have shorter PFS and a trend toward shorter TTP. Patients who had moderate or severe RI had significantly shorter OS (29.0 months and 18.4 months, respectively) compared with patients who had mild or no RI (38.9 months; P = .006 for both). Furthermore, more patients who had severe RI discontinued therapy because of adverse events (predominantly cytopenias). These differences may be associated with treatment schedule: Patients with moderate RI received a median daily dose of 25 mg, similar to patients with mild or no RI, and patients with severe RI received a median daily dose of 15 mg; thus, patients with severe RI may have received longer treatment and greater benefit at a lower starting and treatment dose, consistent with the recent dosing adjustment recommendations for this patient population (Table ).
Recommendations for Lenalidomide Dosing in Patients With Multiple Myeloma Who Have Renal Impairmenta
The time to dose reduction appeared to be shorter for patients who had RI compared with patients who had mild or no RI, and those who had moderate or severe RI required significantly more frequent intervention because of anemia and thrombocytopenia than those with mild or no RI. Although thrombocytopenia was more pronounced, there were no bleeding events. Other adverse events generally occurred with similar frequencies in patients with and without RI.
The current study highlights the limitations of using the serum creatinine level as a measure of patient renal function, because a subset of eligible patients (serum creatinine <2.5 mg/dL) had severe RI (CLCr
<30 mL/minute) and a greater frequency of certain treatment-related adverse events. Because renal clearance may be reduced by 35% to 50% without evidence of renal disease in elderly patients, dosage adjustments are necessary for renally excreted drugs. In addition, because creatinine production is lower in elderly individuals due to decreased muscle mass and because serum creatinine may be normal despite impaired CLCr
, it is recommended to base dosage adjustments on CLCr
instead of serum creatinine (Table ).20
By using CLCr
as a guide for dosing patients with MM who have RI, Chen and colleagues14
studied the effect of RI on the pharmacokinetics of lenalidomide after a single 25-mg oral dose (patients aged 39-76 years) in patients without cancer. Those authors demonstrated that, in study participants who had increased baseline RI, renal lenalidomide clearance decreased substantially, prolonging its half-life by approximately 6 to 12 hours.14
An 80% decrease in lenalidomide clearance was observed in patients with RI compared with healthy individuals, and that decrease corresponded to the primary renal route of drug excretion.14
Since this analysis, adjustments to the initial dose of lenalidomide have been recommended in patients with moderate RI (CLCr
≥30 mL/minute and <60 mL/minute) or severe RI (CLCr
<30 mL/minute not requiring dialysis) and end-stage renal failure (CLCr
≥30 mL/minute and <60 mL/minute requiring dialysis). On the basis of a pharmacokinetic study in patients who had RI caused by nonmalignant conditions, the recommendations for the starting dose of lenalidomide in patients with MM who have RI to maintain appropriate exposure are shown in Table .20,21
In conclusion, lenalidomide plus dexamethasone led to improvement in RI in the majority of patients in the current analysis. With careful monitoring of CLCr levels and adverse events and with appropriate dose adjustments, lenalidomide plus dexamethasone is a highly effective treatment and is well tolerated in patients with MM who have RI. Platelet counts also should be monitored carefully, because we observed more marked thrombocytopenia in patients who had a CLCr <30 mL/minute, although there did not appear to be any increased incidence of bleeding in the 16 patients in the current study. Formal studies confirming the efficacy of lenalidomide in patients with renal failure are warranted and ongoing. Currently, 2 trials are recruiting for the study of lenalidomide treatment in patients with MM who have RI. These include a study of the pharmacokinetics of lenalidomide in patients with MM who have RI (National Clinical Trial [NCT] 00779922) and a phase 1/2 trial of lenalidomide plus low-dose dexamethasone in patients with relapsed and/or refractory MM and RI (NCT00790842). For future studies and therapy with lenalidomide, it is important to convert serum creatinine to CLCr and to use CLCr for dosage adjustments, as recommended in Table , for patients with RI.