Results of an interim analysis of the phase 3 TOURMALINE-AL1 study (ClinicalTrials.gov Identifier: NCT01659658), comparing ixazomib and dexamethasone vs physician’s choice of treatment in relapsed or refractory systemic light chain (AL) amyloidosis, were recently reported in the journal Leukemia. Although ixazomib and dexamethasone did not significantly increase overall hematologic response rate relative to physician’s choice and thus did not meet the first primary endpoint, all time-to-event data favored ixazomib with dexamethasone.
Adult patients (N=168) with relapsed/refractory AL amyloidosis and major organ (cardiac and/or renal) involvement after 1 to 2 prior lines of therapy were enrolled at 68 sites across 19 countries in Europe, North America, Latin America, and Asia-Pacific. Patients could have prior exposure to proteasome inhibitor therapy but were ineligible if refractory to it.
Patients were randomly assigned (1:1) to receive oral ixazomib (4 mg; days 1, 8, 15) plus dexamethasone (20 mg; days 1, 8, 15, 22; n=85) or physician’s choice (dexamethasone with or without melphalan, cyclophosphamide, thalidomide, or lenalidomide; n=83) in 28-day cycles until progression or toxicity. The first primary endpoint, hematologic response rate, was the only endpoint formally tested for the interim analysis. The second primary endpoint was 2-year vital organ deterioration or mortality rate.
Best hematologic response rate was 53% in the ixazomib–dexamethasone arm compared with 51% in the physician’s choice arm (P =.76). Complete response rate was 26% with ixazomib and dexamethasone and 18% with physician’s choice (P =.22). Median duration of hematologic response was 46.5 months with ixazomib and dexamethasone compared with 20.2 months with physician’s choice (HR, 0.55; 95% CI, 0.26-1.18; P=.12). Median time to vital organ deterioration or mortality was prolonged with ixazomib–dexamethasone relative to physician’s choice (34.8 vs 26.1 months; HR, 0.53; 95% CI, 0.32-0.87; P =.01).
Median treatment duration was more than twice as long with ixazomib and dexamethasone than with physician’s choice (11.7 vs 5.0 months; HR, 0.46; 95% CI, 0.32-0.67). The safety population included all patients receiving ixazomib and dexamethasone and 81 patients receiving physician’s choice. Grade ≥3 adverse events (AEs) occurred in 62% of patients (53/85) in the ixazomib and dexamethasone arm and 56% of patients (45/81) in the physician’s choice arm. Grade ≥3 AEs occurring in over 5% of patients were fatigue (9% in both arms), anemia (2% vs 11%), cardiac failure (6% vs 4%) and dyspnea (6% vs 4%). Any-grade AEs of clinical importance included diarrhea (34% vs 30%), rash (33% vs 20%), cardiac arrhythmias (26% vs 15%), nausea (24% vs 14%), pneumonia (21% vs 16%), and peripheral neuropathy (19% vs 15%).
“Treatment with ixazomib–dexamethasone was generally well tolerated, enabling patients to receive treatment for twice as long as physician’s choice. The time-to-
event data suggest that ixazomib–dexamethasone may benefit patients with relapsed/refractory AL amyloidosis who have limited treatment options,” the authors wrote.
Disclosure: This research was supported by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Please see the original reference for a full list of disclosures.
Dispenzieri A, Kastritis E, Wechalekar AD, et al. A randomized phase 3 study of ixazomib-dexamethasone versus physician’s choice in relapsed or refractory AL amyloidosis. Leukemia. Published online June 24, 2021. doi:10.1038/s41375-021-01317-y