Venetoclax in Combination with Daratumumab and Dexamethasone Elicits Deep, Durable Responses in Patients with t(11;14) Relapsed/Refractory Multiple Myeloma: Updated Analyses of Minimal Residual Disease Negativity in Phase 1/2 Study
Bibliographic record
Abstract
Introduction: Venetoclax (Ven) is a potent and selective oral BCL-2 inhibitor with demonstrated anti-myeloma activity in patients with t(11;14)-positive relapsed/refractory multiple myeloma (RRMM). The combination of Ven with daratumumab (D) and dexamethasone (d) has shown a high overall response rate (ORR) and tolerable safety profile in the Phase 1/2 study ( Blood [2021] 138 [Supplement 1]: 817). Here, we report updated analyses of minimal residual disease (MRD) negativity from the Phase 1/2 trial of VenDd at 400 and 800 mg Ven dose levels, versus bortezomib plus Dd (DVd) in patients with t(11;14)-positive RRMM. Methods: Parts 1 (nonrandomized) and 3 (randomized among Ven [400 mg] Dd, Ven [800 mg] Dd and DVd arms) in this Phase 1/2 multicenter study evaluated VenDd versus DVd in patients with t(11;14)-positive RRMM (as determined by central lab plasma-cell enriched fluorescence in situ hybridization), who had ≥1 prior line of therapy (LOT), including proteasome inhibitor and immunomodulatory drug exposure (NCT03314181). Patients in the investigational arm (VenDd, 28 day cycles [C]) received oral Ven once daily (400 mg or 800 mg) with D (either 16 mg/kg intravenous [IV] or 1800 mg subcutaneous [C1-2: Days 1, 8, 15, 22; C3-6: Days 1 and 15; C7+: Day 1]) and d (40 mg weekly; oral/IV); patients in the DVd arm were dosed per label. MRD negativity (<10 −5) was assessed in bone marrow aspirates by next-generation sequencing (clonoSEQ®, Adaptive, Seattle, WA) at the time of suspected complete response (CR) / stringent CR (sCR), and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive. Results: As of March 10, 2023, Part 1 enrolled 5 patients (Ven [400 mg] Dd) and 19 patients (Ven [800 mg] Dd). Part 3 enrolled 21 patients (Ven [400 mg] Dd), 10 patients (Ven [800 mg] Dd), and 26 patients (DVd). A total of 80 patients were enrolled (Parts 1 and 3 combined); 55 patients received VenDd (24% high-risk cytogenetics, 53% 1 prior LOT, 2% prior anti-CD38 monoclonal antibody [mAb], 76% lenalidomide-refractory); and 26 received DVd (23% high-risk cytogenetics, 38% 1 prior LOT, 4% anti-CD38 mAb, 92% lenalidomide-refractory). Median (range) follow-up for survivors was longer with VenDd than DVd (28.2 months [1.0-55.7 months] with VenDd vs 16.9 months [0.0-34.1 months] with DVd). VenDd achieved 96% ORR, 93% ≥ very good partial response (VGPR), 67% ≥ CR, and median progression-free survival (PFS) not reached (95% confidence interval [CI]: 35.0- not estimable [NE]). DVd achieved 65% ORR, 39% ≥ VGPR, 19% ≥ CR, and median PFS 15.5 months (7.5-NE). The 33-month PFS rate was 73.4% (95% CI: 56.4-84.6) versus 38.8% (16.3-61.1) for VenDd versus DVd. MRD negativity rates were 38% with VenDd and 8% with DVd. MRD negativity rates in key subgroups, including number of prior LOTs, lenalidomide refractory status, and high-risk cytogenetics, were higher with VenDd compared to DVd (Table). Of 8 VenDd-treated patients assessed for duration of MRD negativity, 6 were MRD negative >6 months, of whom 2 achieved MRD negativity >12 months. No DVd-treated patients had durable MRD negativity >6 months (Figure). No new safety signals were observed. Conclusions: VenDd treatment showed higher rates of MRD-negativity and sustained MRD-negativity compared to DVd in patients with t(11;14)-positive RRMM, which was associated with longer PFS with VenDd.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".