Safety Results of a Phase 2 Multicenter, Open-Label Study of Pomalidomide (CC-4047) Plus Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) and Renal Impairment
Authors: Weisel Katja , Dimopoulos Meletios A , van de Donk Niels W.C.J. , Ramasamy Karthik , Gamberi Barbara , Streetly Matthew , Offidani Massimo , Bridoux Frank , de la Rubia Javier , Kueenburg Elisabeth , Lersch Frederik , Rosettani Barbara , Bacon Pamela , Sonneveld Pieter 
Published: October 2019

Abstract
Background: Renal failure is a common complication for patients (pts) with MM. The incidence of renal failure increases during the course of the disease. Renal insufficiency is associated with poor prognosis in MM; however, the introduction of novel agents has led to improved survival. This trial evaluates safety, efficacy, and pharmacokinetics of pomalidomide (POM) plus dexamethasone (DEX) in pts with myeloma-related renal impairment and an eGFR < 45 mL/min/1.73m2as well as in pts on hemodialysis.
Aims:The aim of this analysis is to summarize the safety profile of POM and DEX in pts with RRMM and renal impairment, including pts on hemodialysis.
Methods: This interventional phase 2, open-label, multicenter study enrolled 3 cohorts of pts with RRMM and differing degrees of renal impairment. Cohort A included pts with moderate renal impairment (eGFR between 30 and 45 mL/min/1.73m2), cohort B included pts with severe renal impairment (eGFR ≤ 30 mL/min/1.73m2) not requiring hemodialysis, and cohort C included pts with severe renal impairment requiring hemodialysis. Enrollment occurred in parallel, and all pts received treatment with starting doses of POM 4 mg and DEX 40 mg (20 mg for pts aged > 75 years). All pts continued study treatment until disease progression or unacceptable toxicity. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs v4.0. Supportive care, such as hematopoietic growth factors, was allowed; thromboembolic prophylaxis was required for all pts not on hemodialysis.
Results: As of June 2016, 78 pts (30 in cohort A, 34 in cohort B, 14 in cohort C) across 19 institutions in 8 European countries were enrolled in the trial. At the time of this abstract, there were 28 pts still on treatment (15, 11, and 2 in cohorts A, B, and C, respectively). During the study, 27 pts (34.6%) discontinued treatment due to progressive disease (33.3% [n = 10/30], 41.2% [n = 14/34], and 21.4% [n = 3/14] in cohorts A, B, and C, respectively), 8 pts (10.3%) due to AEs (6.7% [n = 2/30], 8.8% [n = 3/34], and 21.4% [n = 3/14]), and 15 pts (19.2%) due to other reasons.
The safety population consisted of 76 pts (29, 34, and 13 in cohorts A, B, and C, respectively). Median treatment duration was 3.8 months (range, 0.5-17.5 months) overall (4.1 months [range, 0.9-17.5 months], 4.1 months [range, 0.5-13.4 months], and 2.1 months [range, 0.5-9.2 months] in cohorts A, B, and C, respectively), and the median average daily POM dose was 4 mg/day for all cohorts. Dose reductions occurred in 12 pts (15.8%) overall (13.8% [n = 4/29], 17.6% [n = 6/34], and 15.4% [n = 2/13] in cohorts A, B, and C, respectively). Occurrence of ≥ 1 grade 3/4 AE was similar between cohorts (75.9%, 76.5%, and 76.9% in cohorts A, B, and C, respectively). In cohorts A, B, and C, the occurrence of serious AEs was 48.3%, 52.9%, and 76.9%, respectively. Overall, the most frequently reported AEs of any grade were neutropenia in 46 (60.5%) pts (69.0%, 52.9%, and 61.5% in cohorts A, B, and C, respectively) and thrombocytopenia in 32 (42.1%) pts, (48.3%, 35.3%, and 46.2% in cohorts A, B, and C, respectively). Neutropenia did not translate into febrile neutropenia, which occurred in only 1 pt each in cohorts A and B. Overall, infections were reported in 41 (53.9%) pts (55.2%, 58.8%, and 38.5% in cohorts A, B, and C, respectively), including 11 pts (14.5%) who had pneumonia (20.7%, 5.9%, and 23.1%). Rates of asthenia (20.7%, 11.8%, and 30.8% in cohorts A, B, and C, respectively) and fatigue (20.7%, 17.6%, and 30.8%) were slightly higher in pts on hemodialysis compared with pts with moderate renal impairment or severe renal impairment without hemodialysis, representative of the poor performance status and anemia (at baseline, 41.4%, 41.2%, and 61.5% in cohorts A, B, and C, respectively) noted in these pts.
Conclusions: Results of this study investigating POM in combination with DEX in pts with RRMM and renal impairment show a similar AE profile as previously reported in pts without renal insufficiency. Compared with pts not on hemodialysis, slightly more non-hematologic AEs were reported in pts on hemodialysis, who have a poor performance status in comparison with other cohorts. Updated data will be presented at the meeting.

Disclosures
Weisel: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Onyx: Consultancy; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Honoraria. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk:Celgene: Research Funding; BMS: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Ramasamy:Celgene: Honoraria, Research Funding. Streetly:Guys and St. Thomas' NHS Trust: Honoraria. Offidani:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Bridoux:Celgene, Roche, Amgen, Janssen, Baxte: Honoraria, Research Funding. de la Rubia:Janssen: Consultancy; Amgen,: Consultancy; Celgene: Consultancy; Bristol Myers: Consultancy. Kueenburg:Celgene International Sarl: Consultancy, Honoraria. Lersch:Celgene: Employment. Bacon:Celgene: Employment, Equity Ownership. Sonneveld:Celgene: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding.