An open-label rollover study to assess the long-term safety of ixazomib

Abstract Introduction: Long-term parenteral proteasome inhibitor (PI)-based therapy can prove challenging due to the burden of administration. Ixazomib, an oral PI, allows prolonged PI-based therapy, whilst maintaining a tolerable safety profile in patients (pts) with multiple myeloma. Ixazomib has also been studied in pts with amyloidosis and lymphoma. The purpose of this study was to continue to provide ixazomib with/without other combinational study drugs to pts who had previously received and tolerated treatment for the above indications, and to evaluate the long-term safety profile of ixazomib. Methods: This was an open-label, multicenter, rollover study (NCT02924272). Pts who had received and tolerated ixazomib for the treatment of multiple myeloma, amyloidosis, or lymphoma in a prior study, and who had no further means to access the study treatment, but in the investigator's opinion could benefit from continued therapy, were eligible for inclusion. Pts entered the study on the same ixazomib dose that they were receiving at the time of rollover from their prior study, or according to the required dose modification from their prior study. The primary endpoint was safety of ixazomib as assessed by the incidence of treatment-emergent adverse events (TEAEs) coded using the Medical Dictionary for Regulatory Activities version 27.0; TEAE severity was summarized using the National Cancer Institute Common Terminology Criteria for adverse events (AEs), version 5.0. All results are reported descriptively; no statistical testing was conducted. Results: Between Dec 2016 and Jan 2022, a total of 32 pts were enrolled at 19 centers across 10 countries. Overall, 23 pts (71.9%) received ixazomib monotherapy and 9 (28.1%) received ixazomib in combination with one or more of dexamethasone, lenalidomide, or cyclophosphamide. The median (range) age was 74 (47–84) years and half of the pts were male. A higher proportion of pts receiving ixazomib monotherapy were aged ≥75 years (60.9%) compared with pts receiving ixazomib in combination (11.1%). At the data cut-off date (Jul 2024), all pts had discontinued study treatment. The most common reason for discontinuation was progressive disease (n=19; 59.4%). Other reasons were: study terminated by the sponsor (n=5; 15.6%); AEs (n=3; 9.4%); withdrawal by the pt (n=2; 6.3%); and clinical deterioration, death, or other (n=1 each; 3.1%). The median (range) number of treatment cycles with ixazomib (for the rollover period) was 25.5 (1–120) cycles (monotherapy: 25.0 [1–120] cycles; combination: 26.0 [2–85] cycles). The median (range) treatment duration was 718.5 (15–2587) days (monotherapy: 687.0 [15–2587] days; combination: 841.0 [36–2381] days). Median (range) dose taken (rollover period) was 245.7 (12.0–1126.0) mg (monotherapy: 276.0 [12.0–1126.0] mg; combination: 220.0 [12.0–996.0] mg). Among pts who received ixazomib monotherapy, 4 (17.4%) had a dose reduction and 3 (13.0%) had a dose increase; no pts who received ixazomib in combination had an ixazomib dose modification. Overall, 22 pts (68.8%) experienced ≥1 TEAE (monotherapy: 65.2%; combination: 77.8%). TEAEs that occurred in ≥10% of pts overall were: pneumonia (n=6; 18.8%); upper respiratory tract infection (n=6; 18.8%); anemia (n=4; 12.5%); and hypertension (n=4; 12.5%). Eighteen pts (56.3%) experienced a grade ≥3 TEAE (monotherapy: 56.5%; combination: 55.6%); these were considered treatment-related in 6 pts (18.8%). Sixteen pts (50.0%) experienced ≥1 serious AE (monotherapy: 52.2%; combination: 44.4%). In total, 2 pts (8.7%) who received ixazomib monotherapy experienced grade ≥2 peripheral neuropathy. Four pts (12.5%) experienced ≥1 new primary malignancy (monotherapy: 13.0%; combination: 11.1%). One pt (4.3%) who received ixazomib monotherapy died during the study due to a TEAE (craniocerebral injury); the event was not considered to be related to study treatment. Conclusion: No evidence of cumulative or long-term/late-onset toxicity was observed when ixazomib was continued as monotherapy or in combination with dexamethasone, lenalidomide, or cyclophosphamide. These data support the overall safety profile of ixazomib, indicating that ixazomib as monotherapy and ixazomib in combination remain well-tolerated in the long-term after initial treatment.