The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function

BACKGROUND: In patients with multiple myeloma, renal impairment (RI) at the time of diagnosis is associated with poor survival. To the authors' knowledge, the current retrospective analysis presented is the first to assess the impact of various degrees of renal dysfunction on safety and efficacy outcomes in a large cohort of patients with relapsed and/or refractory multiple myeloma who received treatment with lenalidomide plus dexamethasone. METHODS: Three hundred fifty-three patients from 2 large phase 3 trials were randomized to receive lenalidomide (25 mg) plus dexamethasone (40 mg). For the purpose of this analysis, RI was defined according to the calculated creatinine clearance (CLCr) level as follows: mild or no RI (CLCr ≥ 60 mL/minute), moderate RI (CLCr from ≥ 30 mL/minute to <60 mL/minute), and severe RI (CLCr <30 mL/minute). RESULTS: The RI subgroups did not differ significantly in terms of the overall response rate (range, 50%-64%) or response quality (very good partial response or better, 27%-37%). In all RI subgroups, the time to progression and progression-free survival did not differ significantly compared with the mild or no RI group. Patients with RI experienced an increased incidence of thrombocytopenia, required more frequent lenalidomide dose reduction or interruption, and had shorter overall survival than patients with mild or no RI (P = .006). Lenalidomide plus dexamethasone led to improvement in renal function in the majority of patients. CONCLUSIONS: The results from this study indicated that, with careful monitoring of the CLCr level and adverse events as well as appropriate dose adjustments, lenalidomide plus dexamethasone is an effective and well tolerated treatment option for patients with multiple myeloma who have RI. Cancer 2010. © 2010 American Cancer Society.

RI is usually mild to moderate (ie, plasma creatinine >1.3 mg/dL and <2 mg/dL) in approximately 50% of patients; however, severe RI (plasma creatinine 2 mg/dL) may be observed in 15% to 20% of patients at diagnosis. 3,[5][6][7] Effective myeloma control and resultant reduction in urinary light-chain excretion can lead to improvement in RI in 50% to 60% of patients. 3,6,8,9 Although patients with MM who have persistent RI often have inferior survival, recovery of renal function, often made possible through novel drugs that better control the disease, is associated with an improvement in outcome. 4 In patients with RI, drugs known as nephrotoxic should be avoided whenever possible. Medications that are excreted renally typically need dose and/or schedule adjustment to reduce the risk of side effects. 10,11 Lenalidomide combined with dexamethasone is an effective treatment for MM that provides an overall response (OR) rate of 60% with a complete response (CR) rate of 15%, in patients with relapsed and/or refractory MM. 12,13 Two-thirds of lenalidomide is eliminated unchanged through urinary excretion. 14 To our knowledge, the retrospective analysis presented here is the first to assess the impact of various degrees of renal dysfunction on safety and efficacy outcomes with lenalidomide, such as OR, time to progression (TTP), progression-free survival (PFS), overall survival (OS), and improvements in renal function, in a large cohort of patients with relapsed and/or refractory MM who received lenalidomide.

MATERIALS AND METHODS
In total, 704 patients who met the entry criteria were enrolled in MM-009 and MM-010, 2 large, phase 3, randomized, multicenter clinical trials that compared treatment with lenalidomide (25 mg daily on Days 1-21 of each 28-day cycle) plus dexamethasone (40 mg on [9][10][11][12], and 17-20 every 28 days for 4 cycles and 40 mg on Days 1-4 every cycle thereafter) versus dexamethasone alone (identical schedule). 12,13 Treatment was continued until patients developed either unacceptable toxicity or disease progression. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0, as reported previously. 12,13 Three hundred fifty-three patients who were randomized to receive lenalidomide plus dexamethasone in these 2 trials 12,13 were included in the current subgroup analysis. Inclusion and exclusion criteria were published previously. 12,13 Entry criteria for renal function were based on serum creatinine levels. All patients were required to have a baseline serum creatinine level <2.5 mg/dL. Renal function was assessed throughout the course of the study by measuring serum creatinine levels. For the purpose of the present RI analysis, renal function was assessed by using the serum creatinine level to calculate creatinine clearance (CL Cr ) with the Cockroft-Gault equation. Then, patients were subdivided into RI subgroups based on their CL Cr values, defined as follows: mild or no RI, CL Cr 60 mL/minute; moderate RI, CL Cr 30 mL/minute and <60 mL/minute; or severe RI, CL Cr <30 mL/minute. 15 The objective of the current analysis was to evaluate the efficacy of therapy, safety, and tolerability with lenalidomide plus dexamethasone in patients who had mild or no RI compared with patients who had moderate and severe RI. Response to treatment was assessed according to the modified European Group for Blood and Marrow Transplantation criteria for CR and partial response (PR), according to criteria described by the International Myeloma Working Group for a very good PR (VGPR). 16,17 TTP was measured from the date of randomization to the date of the first assessment that identified disease progression. Patients who died or discontinued the study without evidence of disease progression were censored at the last evaluation for assessment of TTP. PFS was measured from the date of randomization to the date of the first assessment that identified disease progression or the date of death during treatment, whichever occurred first. Patients who were alive and discontinued study therapy without evidence of disease progression were censored at the last evaluation for assessment of PFS. OS was measured from the date of randomization to the date of death from any cause or was censored at the last follow-up.
Data on OR (CR þ VGPR þ PR), TTP, and PFS were assessed up to unblinding, which occurred in June 2005 for MM-009 and August 2005 for MM-010, for a median follow-up duration of 17.5 months. The cutoff for follow-up data on OS was January 2007, with a median follow-up duration of 31.3 months.
Differences in OR rates were analyzed using continuity-corrected Pearson chi-square tests. Time-to-event variables with censoring, including TTP, PFS, and OS, were estimated by using the Kaplan-Meier method. Twosided log-rank tests were used for comparisons of TTP, PFS, and OS.

Baseline Characteristics
Of the 353 patients who were randomized to receive lenalidomide plus dexamethasone, baseline CL Cr data were available for 341 patients. Of these patients, 243 (71%) had mild or no RI (CL Cr 60 mL/minute), 82 (24%) had moderate RI (CL Cr 30 mL/minute and <60 mL/minute), and 16 (5%) had severe RI (CL Cr <30 mL/minute). According to protocol exclusion criteria, all patients who were included in this analysis had a relatively low serum creatinine level (<2.5 mg/dL), although 16 patients had severe RI. Patients who had RI were older, more likely to be women, and had higher serum b 2 -microglobulin levels compared with patients who did not have RI (all P < .05) ( Table 1). Besides this, renal function subgroups were balanced (Table 1).

Efficacy
There were no statistical differences in OR rates between the 3 subgroups (Table 2). Moreover, the quality of response did not differ by severity of RI. A VGPR or better was achieved in 34% of patients with mild or no RI, in 27% of patients with moderate RI, and in 38% of patients with severe RI (P ¼ not significant [NS] for both). The TTP was similar in patients with mild or no RI (median, 12.0 months) and patients with moderate RI (median, 11.1 months) ( Table 2). Patients who had severe RI had a shorter TTP; however, the difference was not significant compared with patients who had mild or no RI (median, 7.8 months; P ¼ NS). Similarly, PFS did not differ significantly between patients who had mild or no RI (median, 11.1 months) and patients who had moderate RI (median, 9.5 months; P ¼ NS) or severe RI (median, 7.8 months; P ¼ NS) ( Table 2, Fig. 1).
After a median follow-up of 31.3 months, OS was 38.9 months for patients who had mild or no RI ( Table  2). Patients who had moderate or severe RI tended to have shorter OS (29.0 months and 18.4 months, respectively), and this was significantly shorter compared with the OS of patients who had mild or no RI (P ¼ .006 for both) ( Table 2, Fig. 2).

Improvement in Renal Function
Improvement in CL Cr by at least 1 level (ie, mild or no RI, moderate RI, or severe RI as described above; see Materials and Methods) was experienced by 68 of 94 patients (72%) with moderate-to-severe RI who received lenalidomide plus dexamethasone; whereas, of all those who received lenalidomide plus dexamethasone, only 3 patients (1%) had a worsening CL Cr by at least 1 level (Table 3).

Safety
Neutropenia was the most common grade 3 or 4 hematologic adverse event, and the rates of neutropenia were similar across all subgroups of renal function (32%, 48%, and 38% of patients with mild or no RI, moderate RI, and severe RI, respectively) ( Table 4). Renal impairment was not associated with a higher incidence of fever or infections during neutropenia. However, there was an increased incidence of pneumonia unrelated to neutropenia in the limited number of patients with severe RI (Table 4). Thrombocytopenia was significantly more common in patients with severe RI (38%; P < .05) and moderate RI (22%; P < .05) than in patients with mild or no RI (9%). Grade 3 or 4 thrombotic events occurred in patients with mild or no RI (13%), moderate RI (15%), and severe RI (6%) ( Table 4). All patients received a starting lenalidomide dose of 25 mg. The median dose of lenalidomide was 25 mg for patients with moderate or better RI and 15 mg for patients with severe RI (Table 5). Significantly more

DISCUSSION
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 (CL Cr 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 (CL Cr <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 ¼ .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 6).
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 (CL Cr <30 mL/ minute) and a greater frequency of certain treatmentrelated 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 CL Cr , it is recommended to base dosage adjustments on CL Cr instead of serum creatinine (Table  6). 20 Table 6. 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 CL Cr 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 CL Cr <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 CL Cr and to use CL Cr for dosage adjustments, as recommended in Table  6, for patients with RI.