Background
Phase III, open-label, randomized trial (CANOVA). 263 adults with t(11;14)-positive RRMM who had received ≥2 prior lines of therapy. BCL-2 is overexpressed in t(11;14) MM, providing biologic rationale for venetoclax. t(11;14) confirmed by FISH/karyotype. Randomized 1:1; crossover not permitted at progression.
Interventions and follow up
Arm A: Venetoclax 800 mg daily + dexamethasone 40 mg weekly (continuous)
Arm B: Pomalidomide 4 mg D1–21 + dexamethasone 40 mg weekly (28-day cycles)
Primary endpoint: IRC-assessed PFS
mFollow up: NR (mature analysis)
Arm B: Pomalidomide 4 mg D1–21 + dexamethasone 40 mg weekly (28-day cycles)
Primary endpoint: IRC-assessed PFS
mFollow up: NR (mature analysis)
Results
PFS: 9.9 vs 5.8 months, HR 0.823, 95% CI 0.596–1.136, P=.24 — primary endpoint NOT MET
ORR: 62% (venetoclax-dex) vs 35% (pomalidomide-dex)
VGPR or better: 39% vs 14%
MRD negativity (10−5): 8% vs 0%
OS: 32.4 vs 26.9 months, HR 0.856, 95% CI 0.612–1.197 — not significant
ORR: 62% (venetoclax-dex) vs 35% (pomalidomide-dex)
VGPR or better: 39% vs 14%
MRD negativity (10−5): 8% vs 0%
OS: 32.4 vs 26.9 months, HR 0.856, 95% CI 0.612–1.197 — not significant
Adverse events
Overall toxicity: Grade ≥3 TEAEs 67% (venetoclax-dex) vs 83% (pomalidomide-dex); treatment-emergent deaths 12% vs 6%
By system: Infections more common with venetoclax-dexamethasone, consistent with BCL-2 inhibitor class effects; hematologic toxicity more common with pomalidomide
By system: Infections more common with venetoclax-dexamethasone, consistent with BCL-2 inhibitor class effects; hematologic toxicity more common with pomalidomide
Conclusions
CANOVA did not meet its primary PFS endpoint, but venetoclax-dexamethasone demonstrated numerically longer PFS and OS, markedly higher response rates, and MRD negativity compared to pomalidomide-dexamethasone in t(11;14) RRMM. The study was likely underpowered.
Key Limitations
Trial did not meet its primary endpoint. The doublet comparator (pomalidomide-dex) is not the current standard of care for most RRMM patients — triplet regimens are preferred, limiting the clinical utility of this comparison. Higher infection-related deaths with venetoclax-dex (12% vs 6%) is a meaningful concern. MRD negativity rate (8%) is low compared with anti-CD38-based triplets.
Clinical Context
Despite missing the primary endpoint, CANOVA demonstrates clinically meaningful activity of venetoclax-dex in t(11;14) RRMM. Venetoclax is currently used off-label in this biomarker-selected population. More relevant comparisons with venetoclax-based triplets (e.g., daratumumab-venetoclax-dex) are ongoing. The t(11;14) translocation accounts for ~15–20% of MM patients.