Pharmacokinetics and Safety of Elotuzumab Combined With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma and Various Levels of Renal Impairment: Results of a Phase Ib Study

Abstract

Introduction: The present study evaluated the pharmacokinetics and safety of elotuzumab, a humanized IgG1 monoclonal antibody against signaling lymphocyte activation molecule-F7, combined with lenalidomide and dexamethasone, in patients with multiple myeloma (MM) and renal impairment.

Patients and methods: Patients with MM and normal renal function (NRF) (creatinine clearance [CrCl] ≥ 90 mL/min), severe renal impairment (SRI) (CrCl < 30 mL/min, not requiring dialysis), or end-stage renal disease (ESRD) (requiring dialysis) were enrolled in this open-label, phase Ib study. Elotuzumab (10 mg/kg), lenalidomide (5-25 mg), and dexamethasone (40 mg) were administered in 28-day cycles until disease progression or unacceptable toxicity developed. The primary endpoint was single-dose elotuzumab pharmacokinetics.

Results: A total of 26 patients (median age, 63 years) were treated (NRF, n = 8; SRI, n = 9; ESRD, n = 9). The median baseline CrCl was 105 mL/min (range, 84-146 mL/min) for those with NRF and 26 mL/min (range, 15-33 mL/min) for those with SRI. Twenty-three patients (89%) had received previous therapy (median, 2 regimens; range, 1-7). Treatment was discontinued in 6 patients with NRF, 4 with SRI, and 5 with ESRD, primarily because of disease progression. The mean elotuzumab serum concentrations were comparable across groups (n = 23). No statistically significant differences were observed in the maximum observed serum concentration, area under the concentration-time curve from time 0 to the last quantifiable serum concentration, or area under the concentration-time curve from time 0 to infinity when the SRI and ESRD groups were compared with the NRF group (P > .05). All patients had ≥ 1 adverse event (AE). Of the 8 patients with NRF, 9 with SRI, and 9 with ESRD, 7, 8, and 7 experienced grade 3 to 4 AEs. The overall response rates were 75% in the NRF, 67% in the SRI, and 56% in the ESRD groups.

Conclusion: The results of the present study support the use of elotuzumab for the treatment of patients with MM and renal dysfunction without dose adjustment.

Keywords: Creatinine clearance; End-stage renal disease; Glomerular filtration rate; Monoclonal antibody; SLAMF7.

Figure 1

Study Design Showing the Number of Patients Planned for Enrollment. ^aPremedication With an H1 Blocker (Diphenhydramine, 25–50 mg, or Equivalent), an H2 Blocker (Ranitidine, 50 mg, Adjusted for Renal Failure, or Equivalent), and Acetaminophen (650–1000 mg) Was Required 30–90 Minutes Before Elotuzumab Administration. ^bIn All Patients, Lenalidomide Was Given Daily for 21 Days of a 28-day Cycle: Normal Renal Function (NRF), 25 mg Orally (p.o.) Once Daily; Severe Renal Impairment (SRI), 15 mg p.o. Every 48 Hours; End-Stage Renal Disease (ESRD), 5 mg p.o. Once Daily. ^cWeeks Without Elotuzumab: 40 mg p.o.; Weeks With Elotuzumab 8 mg Intravenously (I.V.) Plus 28 mg p.o. Abbreviation: IMWG = International Myeloma Working Group.

Figure 2

Patient Disposition Flow Diagram. Nine Patients Did Not Enter the Treatment Period After Enrollment for the Following Reasons: Platelet Count Too Low, No Longer Met Criteria for Severe Renal Impairment (SRI), Ineligibility, Best Response Achieved Was Not at Least a Partial Response, Progression With Previous Lenalidomide Therapy, Previous Lenalidomide Exposure Was Discontinued Because of a Grade 3 Adverse Event (AE), Lenalidomide Was Discontinued Because of a Grade 3 AE, Creatinine Clearance of 52 mL/min, and at the Decision of the Investigator (n = 1 for All) Abbreviations: ESRD = end-stage renal disease; NRF = normal renal function.

Figure 3

Elotuzumab Pharmacokinetics (PK) Values Stratified by Renal Function^a: (A) Elotuzumab Serum Concentration Profiles Over Time From Initial Elotuzumab Dose^b; (B) Maximum Observed Serum Concentration (C_max); (C) Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC_(INF)]. ^aThree Patients Were Excluded From the PK Summary Statistics Because of a Dosing Error (End-Stage Renal Disease [ESRD] Group, n = 1), Estimated Glomerular Filtration Rate (eGFR) Outside the Value Limit Range (Severe Renal Impairment [SRI] Group, n = 1), and Limited Samples or Biologically Implausible Time Corresponding to C_max (T_max) at 672 Hours (SRI Group, n = 1). ^bMean 48-hour Dialysis Values Were Excluded in 1 Patient Abbreviations: NRF = normal renal function; SD = standard deviation.