In patients with systemic amyloid light chain (AL) amyloidosis who are relapsed/refractory (R/R) to other treatments, the regimen of ixazomib + dexamethasone did not improve hematologic response but did improve multiple other outcomes in the phase 3 TOURMALINE-AL1 trial.
“Although the primary end point of hematologic response was not met, all clinically relevant time-to-event end point data favored ixazomib/dexamethasone versus physician’s choice,” Angela Dispenzieri, MD, reported.
Systemic AL amyloidosis is a clonal plasma cell disorder in which amyloid fibrils are deposited in tissues and organs, leading to multisystem organ dysfunction. The most frequently involved organs are the heart and the kidneys, and achievement of hematologic response results in improved organ function and better survival. Currently, no treatments have been approved for AL amyloidosis at any stage of the disease, but multiple myeloma treatment strategies are used. The oral proteasome inhibitor ixazomib is approved in combination with lenalidomide and dexamethasone for patients with myeloma who have received ≥1 prior therapies.
The randomized phase 3 TOURMALINE-AL1 trial enrolled 168 patients with primary systemic AL amyloidosis who were relapsed or refractory after 1 or 2 prior therapies. Most patients had cardiac and/or renal involvement at diagnosis. Patients were randomized to ixazomib + dexamethasone (n = 85) or physician’s choice of treatment (n = 83). The median time since diagnosis was 34.5 months in the experimental arm and 32.6 months in the physician’s choice arm, and prior therapies received were equally distributed between arms. The primary end points were overall hematologic response rate centrally adjudicated, and death or vital organ deterioration at 2 years.
The primary end point was not met: hematologic responses were seen in 45 (53%) patients in the ixazomib + dexamethasone arm and 42 (51%) patients in the arm treated with physician’s choice, which was not significantly different (P = .762). Higher rates of complete response, however, were achieved with the ixazomib regimen (26% vs 18%), and the median duration of hematologic response was substantially higher in the experimental arm.
Multiple other outcomes were also improved: overall survival, overall/hematologic/vital organ progression-free survival, time to vital organ deterioration/death, duration of response, time to treatment failure, and time to subsequent therapy data all favored the ixazomib arm. Importantly, vital organ response rates were 36% in the ixazomib + dexamethasone arm versus 11% with physician’s choice.
Overall survival data are immature, but demonstrate a trend in favor of ixazomib + dexamethasone over physician’s choice, she noted.
Continuous treatment with ixazomib + dexamethasone was generally well-tolerated, and no new safety signals were seen. Grade ≥3 adverse events (AEs) were seen in 62% versus 56% of patients, including 34% versus 41% with drug-related grade ≥3 AEs; 47% versus 33% had serious AEs, 26% versus 20% had AEs resulting in discontinuation, and 6% versus 5% died while on study in the ixazomib + dexamethasone and physician’s choice groups, respectively. However, because it was well-tolerated, patients in the experimental arm received treatment for twice as long as physician’s choice (median treatment duration of 11.7 months vs 5 months), and therefore had more time to experience AEs.
“TOURMALINE-AL1 is the first phase 3 trial in relapsed/refractory systemic AL amyloidosis to show significant outcome improvements, suggesting ixazomib/dexamethasone represents a new option for relapsed/refractory patients, who have limited access to therapies,” Dr Dispenzieri commented.
Dispenzieri A, et al. ASH Abstract 139. Session 653.
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