Adverse event management in the TOURMALINE-MM3 study of post-transplant ixazomib maintenance in multiple myeloma

Abstract

The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) demonstrated improved progression-free survival with ixazomib maintenance versus placebo post autologous stem cell transplant (ASCT) in multiple myeloma patients. We report additional safety data from TOURMALINE-MM3 to inform adverse event (AE) management recommendations. Patients were randomized 3:2 to receive ixazomib (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles for ~ 2 years or until progressive disease/toxicity. The initial 3-mg ixazomib dose was escalated to 4 mg in cycle 5, if tolerated in cycles 1-4. Safety was a secondary endpoint assessed in all treated patients; AEs were graded using Common Terminology Criteria for AEs v4.03. The rate of grade ≥ 3 AEs was higher in the ixazomib arm (19%) than in the placebo arm (5%), but the rate of discontinuation due to AEs was similar (7% vs. 5%). For AEs of clinical interest, rates were higher with ixazomib versus placebo: nausea 39% versus 15%, vomiting 27% versus 11%, diarrhea 35% versus 24%, thrombocytopenia 13% versus 3%, and peripheral neuropathy 19% versus 15%. However, the majority of events were low-grade, manageable with supportive therapy or dose reduction, and reversible, and did not result in discontinuation. There was no evidence of cumulative, long-term, or late-onset toxicity with ixazomib maintenance. Ixazomib is an efficacious and tolerable option for post-ASCT maintenance. AEs associated with ixazomib maintenance can be managed in the context of routine post-ASCT supportive care due to the limited additional toxicity. ClinicalTrials.gov NCT02181413.

Keywords: Adverse events; Ixazomib; Maintenance therapy; Multiple myeloma; Safety.

Conflict of interest statement

MK: consulting/advisory relationship with Abbvie, Amgen, BMS, Celgene, GSK, Janssen, Karyopharm, and Takeda; research funding from Celgene and Janssen; honoraria from Celgene, Janssen, Amgen, and Takeda

MB: consulting/advisory relationship with Amgen, Takeda, Bristol Myers Squib, Janssen & Janssen, and Sanofi, and honoraria received indirectly through the institutions for these consultancies; scientific advisory boards with Amgen, Takeda, BMS, Janssen & Janssen, and Sanofi

NG: nothing to disclose

FS: consulting/advisory relationship with Mundipharma, GSK, Pfizer/BMS, Novartis, Amgen, Celgene, Takeda, Bayer, Adaptive, Janssen, Oncopeptides, and MSD, Sanofi; research funding from Celgene, Mundipharma, Amgen, Novartis, Takeda, and Janssen; honoraria from Amgen, Mundipharma, Celgene, Teva, BMS, Takeda, Abbvie, Janssen, Novartis, and SkyliteDX; ownership interests with Oncopeptides

RH: consulting/advisory relationship with Janssen, Amgen, Celgene, Abbvie, BMS, Novartis, Pharma Mar, and Takeda; research funding from Janssen, Amgen, Celgene, Abbvie, BMS, Novartis, and Takeda; honoraria from Janssen, Amgen, Celgene, Abbvie, BMS, Novartis, Pharma Mar, and Takeda

PM: consulting/advisory relationship with Takeda, Amgen, Celgene, Janssen, and Abbvie; honoraria from Takeda, Amgen, Celgene, Janssen, and Abbvie

FdA: honoraria from Celgene, Amgen, Janssen, and Takeda; scientific advisory board with Celgene, Amgen, and Janssen

M-VM: honoraria from Janssen, Celgene, Amgen, Takeda, Abbvie, GSK, Adaptive, EDO Mundipharma, Roche, and Seattle Genetics; scientific advisory board with Janssen, Celgene, Amgen, Takeda, Abbvie, GSK, Adaptive, EDO Mundipharma, Roche, and Seattle Genetics

SW: nothing to disclose

AS: nothing to disclose

SVR: nothing to disclose

KS: employee of Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

MC: employee of Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

CL: employee of and ownership interests in Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

ZT: employee of Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

RL: employee of Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

MAD: honoraria from Amgen, Janssen, Takeda, Celgene, and BMS; consulting or advisory role with Amgen, Janssen, Takeda, Celgene, and BMS

Figures

Fig. 1

CONSORT diagram. Reproduced with permission from Dimopoulos MA, Gay F, Schjesvold F et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019;393:253–264

Fig. 2

Cumulative incidence of new-onset thrombocytopenia (a) and median platelet counts (b) over time in the ixazomib and placebo groups, and actions taken for events of thrombocytopenia (c). Note: More than one action could be taken for a single event of thrombocytopenia

Fig. 3

Incidence rate by cycle (a) and cumulative incidence (b) of new-onset nausea. Only one patient in the ixazomib arm (< 1%) and no patients in the placebo arm had grade ≥ 3 nausea. Incidence rate is the number of events in a cycle divided by the sum of patient cycles at risk in a cycle. A patient with an ongoing AE could not be at risk of getting the same AE until it was resolved

Fig. 4

Incidence rate by cycle (a) and cumulative incidence (b) of new-onset vomiting. No patients in the placebo arm had grade ≥ 3 vomiting. Incidence rate is the number of events in a cycle divided by the sum of patient cycles at risk in a cycle. A patient with an ongoing AE could not be at risk of getting the same AE until it was resolved

Fig. 5

Incidence rate by cycle (a) and cumulative incidence (b) of new-onset diarrhea. Incidence rate is the number of events in a cycle divided by the sum of patient cycles at risk in a cycle. A patient with an ongoing AE could not be at risk of getting the same AE until it was resolved

Fig. 6

Cumulative incidence of new-onset PN. Only one patient in the ixazomib arm had grade 3 PN (