A phase 3, two-stage, randomized study of mezigdomide, carfilzomib, and dexamethasone (MeziKd) versus carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): SUCCESSOR-2.
Bibliographic record
Abstract
TPS8070 Background: Mezigdomide (MEZI), a novel oral cereblon E3 ligase modulator (CELMoD), induces maximal degradation of Ikaros/Aiolos leading to increased MM cell apoptosis and immune-stimulatory effects. MeziKd has shown potent synergistic antiproliferative activity in MM cell lines resistant to lenalidomide (LEN), and in a phase 1/2 study showed promising preliminary efficacy and safety in RRMM. The SUCCESSOR-2 phase 3 trial (NCT05552976) will compare the efficacy and safety of MeziKd vs Kd in patients (pts) with RRMM. Methods: This multicenter, open-label study comprises 2 stages. In Stage 1, ≥ 128 pts will be randomized 3:3:3:2 to 1 of 3 MEZI doses (1.0, 0.6, or 0.3 mg) + Kd, or to the Kd arm to select the optimal MEZI dose in combination with Kd for Stage 2. In Stage 2, ≈ 397 additional pts will be randomized 3:2 to MeziKd at the selected MEZI dose or to Kd, for efficacy and safety analyses (Stage 1 pts in the selected MeziKd dose cohort and Kd arm will also be included in these analyses). Pts will be stratified by age (≤ 70 vs > 70 y), number of prior lines of treatment (Tx; ≤ 2 vs > 2), and ISS stage at screening (I vs II vs III). MEZI dose selection will be based on Stage 1 efficacy, safety, pharmacokinetic and pharmacodynamic data, and exposure–response analyses. Primary efficacy endpoint is progression-free survival (PFS). Assuming a decrease in PFS risk by 33.3% (HR = 0.667) with MeziKd, under exponential distribution assumption of PFS (1-sided α = 0.025) and adjusted for 3 interim analyses, ≥ 273 PFS events will have ≈ 89% power to detect improvement in Tx effect. The planned interim analyses are for: MEZI dose selection at end of Stage 1, and to examine PFS futility and superiority when ≈ 82 (30%) and ≈ 205 (75%) events, respectively, have been accumulated. Secondary endpoints include determination of the recommended MEZI dose plus Kd (Stage 1 only), and assessment of overall survival, overall response rate, time to response, duration of response, time to progression, safety, and quality of life. MeziKd arm Tx consists of 28-day (D) cycles (C) with MEZI on D1–21; 20 mg/m2 intravenous (IV) carfilzomib (CFZ) on D1 of C1, then 56 mg/m2 on D8 and 15 of C1, on D1, 8, and 15 of C2–12, and on D1 and 15 of ≥ C13; and 40 mg oral/IV DEX (20 mg optional in certain pt groups) on D1, 8, 15, and 22. Tx in the Kd arm consists of 28-D cycles with 20 mg/m2 IV CFZ on D1 and 2 of C1, then 56 mg/m2 on D8, 9, 15, and 16 of C1, and on D1, 2, 8, 9, 15, and 16 of ≥ C2; and 20 mg oral/IV DEX (10 mg optional in certain pt groups) on D1, 2, 8, 9, 15, 16, 22, and 23. Tx will continue until progressive disease (PD) or unacceptable toxicity. Key eligibility criteria include age ≥ 18 y, ≥ 1 prior line of anti-MM Tx including LEN and an anti-CD38 monoclonal antibody, minimal response or better to ≥ 1 prior Tx, documented PD during or after last regimen, and no prior CFZ Tx. Enrollment began in October 2022 and is ongoing. Clinical trial information: NCT05552976 .
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Randomized trial | low |
| gpt | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Randomized trial | low |
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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.008 | 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, unvalidatedLabeled directly by 2 models reading the full record.
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".