Effect of Renal and Hepatic Function on Pomalidomide Dose in Patients with Relapsed/Refractory Multiple Myeloma

Abstract

Background: Pomalidomide is the newest IMiD approved for the treatment of patients with relapsed/refractory multiple myeloma (MM). Pomalidomide undergoes hepatic metabolism, and as such is not expected to accumulate as its predecessor lenalidomide, in patients with impaired renal function. Renal insufficiency is common in patients with myeloma, and is generally associated with poor outcomes. Previous studies have shown that renal dysfunction is not associated with increased toxicity in these patients. Here we evaluate the impact of renal and hepatic function on dose level of pomalidomide in our cohort of patients receiving ClaPD (clarithromycin, pomalidomide, dexamethasone).Methods: One hundred twenty patients with relapsed/refractory MM were enrolled in a phase II trial of ClaPD: clarithromycin 500mg PO BID, pomalidomide 4mg PO daily, dexamethasone 40mg PO weekly. We evaluated renal and hepatic function, as well as bone marrow involvement in all patients at baseline and throughout the study, and evaluated how this correlated with dose reduction requirement.Results: Renal function was evaluated based on creatinine clearance. Hepatic function was evaluated by albumin, bilirubin, and transaminases. At baseline renal dysfunction was seen in 37 (31%) patients, and hepatic dysfunction was seen in 7 (6%) patients. Neither was significantly associated with pomalidomide dose reductions. Treatment emergent cytopenias and dose reduction were not associated with baseline neutropenia. However, thrombocytopenia at baseline did correlate significantly with dose reduction (p<0.03). Patients with renal dysfunction were 5.3 times more likely to have concurrent thrombocytopenia at baseline (p<0.0003).Discussion: Lenalidomide is excreted by the kidneys largely unchanged, and renal dysfunction has been shown to result in elevated circulating levels producing greater myelotoxicity [BJH, 138: 640–643]. Pomalidomide is a newer generation IMID, which undergoes extensive hepatic metabolism by CYP1A2 and CYP3A4, and thus is predicted not to accumulate due to renal insufficiency. In our cohort of 120 patients, pomalidomide dose reductions were required for cytopenias, however baseline hepatic and renal dysfunction were not predictive. Coincident baseline renal dysfunction and thrombocytopenia likely represent patients with greater disease burden. Pomalidomide is now a standard for patients with relapsed/refractory MM, and dosing should not be limited by renal or hepatic dysfunction. Prospective studies evaluating the safety and efficacy of pomalidomide in special populations are warranted and ongoing.TableBaseline evaluation renal, hepatic and hematopoietic function by dose reductionClaPd TrialBaselineNo Dose reductionsDose ReductionNeutropeniaGrade III/IV43/81 (53%)31/39 (79%)Thrombocytopenia Grade III/IV20/81 (25%)24/39 (62%)Creatine Clearance < 6041/81 (51%)22/39 (56%)Abumin <340/81 (49% )15/39 (38%)Bilirubin >26/81 (7%)1/39 (2.5%)AST > ULL x24/81 (5%)4/39 (10%)ALT > ULL x26/81 (7%)6/39(15%) DisclosuresRossi:millenium: Speakers Bureau; celgene: Speakers Bureau. Mark:Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Pekle:Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Perry:celgene: Speakers Bureau. Coleman:Onyx: Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.