Conference Correspondent

Ixazomib Monotherapy in RRMM Patients with Severe Renal Impairment or Those Requiring Hemodialysis

Conference Correspondent 

Available pharmacokinetic (PK) evidence indicates that the novel oral proteasome inhibitor ixazomib does not require dose modification in patients with mild or moderate renal impairment (RI; defined by creatinine clearance [CrCl] ≥30 mL/min); however, its PK in patients with severe RI or end-stage renal disease (ESRD) requiring hemodialysis is unknown.1 In this study, Gupta and colleagues sought to evaluate the single-dose PK of ixazomib in patients with relapsed/refractory multiple myeloma (RRMM) or advanced malignant solid tumors who had severe RI or ESRD requiring hemodialysis, characterize the safety and tolerability of oral ixazomib in these patient populations, and determine the overall response rate (ORR) and duration of response (DOR) in patients with RRMM.2

In this 2-part study, 41 eligible patients were enrolled in 3 renal function groups: normal (CrCl ≥90 mL/min; n = 20), severe RI (CrCl <30 mL/min; n = 14), and ESRD requiring hemodialysis (n = 7); patients received a single dose of ixazomib 3 mg. Of these, 37 patients had RRMM, and 4 had advanced solid tumors. In part A of the study, blood samples were collected predose, after single-dose ixazomib and at multiple times over 15 days; for patients with ESRD, pre- and post-dialysis plasma samples were also collected hourly during the first 4-hour dialysis session 24 to 28 hours after dosing. In part B of the study, patients went on to receive ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, plus low-dose dexamethasone at the investigator’s discretion.

PK analysis found that ixazomib was rapidly absorbed in all 3 renal function groups following the initial 3-mg dose, with a median Tmax of 1.0 to 1.25 hours. Nearly all (99%) ixazomib was bound to plasma proteins, and to a similar extent in all 3 groups. Unbound systemic exposures (areas under the curve) of ixazomib were 38% higher in patients with severe RI or ESRD compared with those with normal renal function, indicating the need for a lower starting dose in this population. There was no difference in ixazomib concentrations in pre- and post-dialysis samples collected hourly from ESRD patients, suggesting that it can be administered at any point during dialysis.

In the overall safety population, the majority (95%) of patients experienced at least 1 adverse event (AE), which included diarrhea (45%), nausea (35%), fatigue (25%), vomiting (30%), and anemia (5%). There was no difference in incidence of all-grade AEs among renal function groups, except anemia, which occurred more frequently in the severe (43%) and ESRD (29%) groups compared with the normal (5%) group. By contrast, the incidence of grade 3/4 AEs was greater in the severe (79%) and ESRD (43%) groups versus the normal (35%) group, as were the incidences of serious AEs (43% and 57% vs 10%, respectively).

In part B of the study, 25 RRMM patients with measurable disease at baseline, and of these, 18 were response evaluable (3 with normal renal function, 11 with severe RI, and 4 with ESRD). AEs resulting in dose reductions (43% vs 30%) and discontinuations (29% vs 10%) occurred more commonly in the severe RI group compared with the normal renal function group. There were 3 on-study deaths; 1 death (patient with MM and severe renal impairment) due to acute hypoxemic respiratory failure was deemed treatment-related. The ORR in these patients was 28%, including complete remissions, partial remissions, and very good partial remissions. Among the 5 patients with partial remissions, the median DOR was 117 days. Based on these results, it was concluded that a reduced starting dose of 3 mg was recommended for MM patients with severe RI or ESRD requiring dialysis.

  1. Gupta N, et al. Br J Clin Pharmacol. 2015;79(5):789-800.
  2. Gupta N, et al. ASH 2015. Abstract 4227.

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