An open-label rollover study to assess the long-term safety of ixazomib
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".