Results of the TOURMALINE-AL1 Phase 3 Study in Patients with Relapsed or Refractory Systemic Light Chain Amyloidosis

Presently, there are no specific therapeutic options available for patients with relapsed/refractory light chain amyloidosis (RRAL) with multiorgan dysfunction; therefore, off-label treatment strategies are often utilized. Giampaolo Merlini, MD, of the University of Pavia, Pavia, Italy, and colleagues investigated the use of continuous ixazomib plus dexamethasone in patients with relapsed or refractory systemic light chain amyloidosis (AL).

TOURMALINE-AL1, a phase 3 clinical trial, was designed to investigate the impact of treatment on patients with AL who have cardiac and/or renal involvement, and have become relapsed or refractory after 1 to 2 prior therapies. In total, 168 patients were included in the trial. Participants were randomized (1:1) to receive either ixazomib 4 mg on days 1, 8, and 15, plus dexamethasone 20 mg on days 1, 8, 15, and 22, or physician’s choice of dexamethasone alone, melphalan plus dexamethasone, cyclophosphamide plus dexamethasone, thalidomide plus dexamethasone, or lenalidomide plus dexamethasone in 28-day cycles until disease progression or unacceptable toxicity.

Baseline patient demographic and disease characteristics were generally well-balanced between arms. In the ixazomib plus dexamethasone (N = 85) and physician’s choice (N = 83) arms, the median age of patients was 65 years and 66 years, respectively. In the ixazomib plus dexamethasone group, 60% of patients were male compared with 55% male for the physician’s choice group. The median number of sites of amyloid involvement at diagnosis was 2 for both groups. Similarly, cardiac risk stage at baseline for class I, II, and III were 32%, 48%, 20% in the ixazomib plus dexamethasone group and 31%, 52%, 17% for the physician’s choice group. Prior therapies received by participants were also equally distributed between arms.

Although the first primary end point of overall hematologic response rate was not met, hematologic complete response rate was higher and duration of response was longer in the ixazomib plus dexamethasone arm. Vital organ response was improved with ixazomib plus dexamethasone when compared with the physician’s choice (36% compared with 11% of patients). Most remarkably, from time of randomization, there was a 90% improvement in time to vital organ deterioration or death with ixazomib plus dexamethasone compared with physician’s choice, with a median 34.8 months in the ixazomib plus dexamethasone group, compared with 26.1 months for the physician’s choice group.

Ixazomib plus dexamethasone was well-tolerated with no unexpected adverse events (AEs). AEs of clinical importance occurring in ≥30% of patients in either arm (ixazomib plus dexamethasone, physician’s choice) included fatigue (45%, 43%), peripheral edema (46%, 32%), and diarrhea (34%, 30%). Overall, grade ≥3 AEs were seen in both arms, with the ixazomib plus dexamethasone group having a slightly higher rate (62%) than the physician’s choice group (56%). Drug-related grade ≥3 AEs occurred in 34% of patients in the ixazomib plus dexamethasone group compared with 41% of patients in the physician’s choice group. The ixazomib plus dexamethasone group also experienced a higher rate of AEs resulting in discontinuation of study drug (26% vs 20%).

TOURMALINE-AL1 is the first phase 3 trial in RRAL and demonstrates improvements in clinical outcomes. The data suggest that ixazomib plus dexamethasone may be an important treatment option for these patients who have limited treatment options. Treatment with ixazomib plus dexamethasone prolonged time to vital organ deterioration or death, progression-free survival, and time to subsequent therapy compared with physician’s choice. Continuous ixazomib plus dexamethasone was generally well-tolerated, which enabled patients to receive treatment for twice as long as those receiving physician’s choice.

Reference

Merlini G, Kastritis E, Wechalekar AD, et al. Ixazomib-dexamethasone versus physician’s choice in relapsed/refractory systemic AL amyloidosis: results from the phase 3 TOURMALINE-AL1 Trial. Presented at: 2020 International Symposium on Amyloidosis; September 14-18, 2020. Abstract OP36.

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