P868: MEZIGDOMIDE (MEZI) PLUS DEXAMETHASONE (DEX) IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): RESULTS FROM THE DOSE-EXPANSION PHASE OF THE CC-92480-MM-001 TRIAL
Bibliographic record
Abstract
Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: MEZI, a novel oral cereblon E3 ligase modulator (CELMoD™) with enhanced tumoricidal and immune-stimulatory effects compared with IMiD® agents, induces maximal Ikaros/Aiolos degradation, leading to increased apoptosis in MM cells. Preclinically, MEZI demonstrated potent synergy with DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs). In phase 1 of CC-92480-MM-001 (NCT03374085), the recommended phase 2 dose (RP2D) of MEZI + DEX (Mezi-d) was selected at 1 mg once daily for 21/28 days. Aims: To report results from the Mezi-d dose-expansion cohort in pts with heavily pretreated RRMM. Methods: Eligible pts had: RRMM; ≥3 prior lines of therapy; refractoriness to lenalidomide (LEN)/pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb; disease progression in ≤60 days of last myeloma therapy. MEZI 1 mg was given on days 1–21 of each 28-day cycle, with weekly DEX (40 mg; 20 mg if >75 years of age). Primary objective was to evaluate efficacy by overall response rate (ORR); secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. Results: As of September 16, 2022, 101 pts had received MEZI-d at the RP2D. Median age was 67 (range 42–85) years, median time since initial diagnosis was 7.4 (1.1–37.0) years, and 20.8% of pts had ISS stage III at study entry. Plasmacytomas were present in 39.6% of pts and 37/101 pts had high-risk cytogenetics (56/101 pts not evaluable). Median number of prior regimens was 6 (range 3–15). Prior therapies included stem cell transplantation (77.2%) and anti-B-cell maturation antigen (BCMA) therapy (29.7%). All pts were refractory to last myeloma regimen and triple-class refractory, and 39.6% of pts were refractory to LEN, POM, ≥ 2 PIs, and an anti-CD38 mAb. Median follow-up was 7.46 (range 0.5–21.9) months, with a median number of 4 (1–20) cycles received; 10 (9.9%) pts continued treatment, with the main reason for discontinuation being progressive disease (60.4%). ORR was 40.6% in all pts (Table). While data are not yet mature, median progression-free survival (PFS) was 4.4 (95% confidence interval [CI] 3.0–5.5) months and median duration of response was 7.6 (95% CI 5.4–9.5) months. In pts with plasmacytomas, ORR was 30.0% (n=40) and median PFS was 3.0 (95% CI 2.1–4.9) months. In pts with prior anti-BCMA therapy, ORR was 50.0% (n=30) and median PFS was 5.4 (95% CI 2.1–9.4) months. Grade (Gr) 3/4 treatment-emergent adverse events (TEAEs) were reported in 92 (91.1%) pts. Most frequent (≥20% pts) hematologic Gr 3/4 TEAEs were neutropenia (75.2%, with 14.9% febrile neutropenia), anemia (35.6%), and thrombocytopenia (27.7%). Gr 3/4 infections were seen in 34.7% of pts, including Gr 3/4 pneumonia (15.9%) and COVID-19 (7.0%). Other Gr 3/4 non-hematologic TEAEs were generally low, including gastrointestinal disorders (5.9%), fatigue (5.0%), and rash (1.0%). Due to TEAEs, 76 (75.2%) pts and 29 (28.7%) pts had MEZI dose interruptions and reductions, respectively. MEZI induced substrate degradation and increases in activated and proliferating T cells in all pts, including in pts refractory to POM-containing therapies, demonstrating the efficacy of MEZI in this heavily pretreated population. Summary/Conclusion: MEZI-d had a manageable safety profile with encouraging efficacy in pts with triple-class refractory RRMM, including pts with prior BCMA-targeted therapies. These results support the development of MEZI in MM. MEZI is being evaluated in combination with standard therapies in MM in an ongoing phase 1/2 trial (NCT03989414); phase 3 trials in combination with PIs are planned.Keywords: Clinical data, Multiple myeloma, Immunomodulation
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".