Pharmacokinetics and Safety of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma and Various Levels of Renal Function: Results of a Phase 1b Study
Authors: Berdeja Jesus , Jagannath Sundar , Zonder Jeffrey , Badros Ashraf , Kaufman Jonathan L. , Manges Robert , Lynch Mark , Bleickardt Eric , Paliwal Prashni , Vij Ravi 
Published: October 2019

Abstract
INTRODUCTION
Renal impairment affects more than a third of patients with relapsed multiple myeloma (MM). Renal impairment predicts poor outcome with conventional treatments, while reversal of renal function is associated with improved outcome.1,2 Better therapies for patients with MM and renal impairment are needed. Elotuzumab (Elo) is a humanized monoclonal antibody targeted against Signaling Lymphocytic Activation Molecule F7 (SLAMF7; also called CS1). Through both direct activation and engagement of natural killer cells, Elo selectively kills SLAMF7-expressing myeloma cells and, in combination with lenalidomide (Len) and dexamethasone (dex), has shown objective responses in clinical trials.3 This study evaluated the pharmacokinetics (PK) and safety of Elo in combination with Len/dex in renally impaired patients with MM.
METHODS
This multicenter, open-label, Phase Ib trial (NCT01393964) enrolled patients with symptomatic newly diagnosed or relapsed/refractory 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). Elo was given in 28-day cycles until disease progression or unacceptable toxicity. Intravenous Elo (10 mg/kg) dosing occurred on Day 1 of the first cycle, weekly in cycles 2 and 3, and biweekly in subsequent cycles. Len (5–25 mg, depending on renal function) was given on Days 1–21 of each cycle and dex (40 mg) was given weekly. The primary endpoint was single-dose Elo PK. Other endpoints were safety and efficacy. Treatment responses were based on International Myeloma Working Group criteria.
RESULTS
A total of 26 patients were treated, 8 with NRF (median age 60 years), 9 with SRI (median age 75 years), and 9 with ESRD (median age 56 years). Median (range) baseline CrCl values were 105 (84–146) mL/min and 26 (15–33) mL/min for the NRF and SRI groups, respectively. One patient (CrCl 33 mL/min; SRI group) was excluded from the PK analysis. The majority (46%) had International Staging System stage III disease. Twenty-three patients (89%) had received prior therapy (median 2 regimens, range 1–7). Prior bortezomib, thalidomide, or Len treatment occurred in 21 (81%), 11 (42%), and 9 (35%) patients, respectively. Differences in baseline characteristics for race were seen between the NRF (8/8 white) and ESRD groups (1/9 white). Median Elo treatment duration for the NRF, SRI, and ESRD groups was 5, 15, and 8 months, respectively. Treatment discontinuation occurred in 6 (75%) NRF, 4 (44%) SRI, and 5 (56%) ESRD patients, primarily due to disease progression. Preliminary mean Elo PK values were calculated in 5 patients (1 NRF, 2 SRI, 2 ESRD). Maximum serum concentrations were 219, 214, and 203 µg/mL in the NRF, SRI, and ESRD groups, respectively. AUC0-Twas 46762, 52806, and 40357 h.µg/mL in the NRF, SRI, and ESRD groups, respectively. Half-life was 19, 13, and 8 days in the NRF, SRI, and ESRD groups, respectively. Total body clearance was 0.14, 0.15, and 0.29 mL/h/kg in the NRF, SRI, and ESRD groups, respectively. Adverse events are summarized in the table. No deaths or second primary malignancies were reported. Infusion reactions (Grade 2) were seen in 3 patients. Objective response rates (ORRs) were 75% (NRF, 6/8), 67% (SRI, 6/9), and 56% (ESRD, 5/9). Thirty-eight percent (3/8) of NRF, 56% (5/9) of SRI, and 11% (1/9) of ESRD patients had a very good partial response or better.
Table: Adverse events Adverse event NRF(n=8) SRI(n=9) ESRD(n=9) Any AE (any grade) 8 9 9 Most common AEs (occurred in >25% of patients) Fatigue 6 4 6 Diarrhea 2 5 4 Back pain 3 3 4 Anemia 2 5 3 Constipation 6 3 1 Pyrexia 4 1 4 Peripheral edema 1 4 4 Hyperglycemia 3 3 2 Thrombocytopenia 1 4 3 Rash 2 4 1 Hypokalemia 1 3 3 Cough 4 2 1 Dyspnea 3 2 2 Any Grade 3–4 AE 7 8 7
CONCLUSIONS
Elo, in combination with Len/dex, was well tolerated by patients with MM regardless of renal function. Updated PK assessments will be provided at the time of presentation. Responses were observed in all 3 renal function groups and ORR in patients with NRF was consistent with previous studies.
1. San Miguel JF, et al. Leukemia. 2008;22:842-9.
2. Knudsen LM et al. Eur J Haematol.2000;65:175-81.
3. Lonial S, et al. J Clin Oncol. 2012;30:1953-9.
This study is being funded by Bristol-Myers Squibb.
Professional medical writing and editorial assistance was provided by Matthew Thomas at Caudex Medical and was funded by Bristol-Myers Squibb.

Disclosures
Off Label Use: Elotuzumab is an investigational agent being studied for the treatment of multiple myeloma. Jagannath:Celgene; Bristol-Myers Squibb; Sanofi-Aventis: Honoraria. Zonder:Bristol-Myers Squibb: Advisory board Other. Kaufman:Millennium; Celgene; Novartis; Onyx; Janssen; Spectrum: Honoraria; Novartis; Onyx; Merck; Celgene: Research Funding; Millennium; Celgene; Novartis; Onyx; Janssen; Spectrum: Consultancy. Lynch:Bristol-Myers Squibb: Employment. Bleickardt:Bristol-Myers Squibb: Employment. Paliwal:Bristol-Myers Squibb: Employment. Vij:Array: Honoraria; Millennium: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.