Efficacy of venetoclax-dexamethasone (VenDex) v pomalidomide-dexamethasone (PomDex) in patients (Pts) with t(11;14)-positive relapsed/refractory multiple myeloma [t(11;14)+ RRMM]: Phase 3 CANOVA study biomarker subgroup analysis.

person Nizar J. Bahlis Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada info_outline Nizar J. Bahlis, Rakesh Popat, Meral Beksac, Meletios Athanasios Dimopoulos, Moshe E. Gatt, Francesca Gay, Jae-Cheol Jo, Prashant Kapoor, Martin Kortüm, Silvia Ling, Chandramouli Nagarajan, Kenshi Suzuki, Maika Onishi, Monique Dail, Emily Rossi, Xizhi (Adam) Luo, Emma Louise Arriola, Orlando Felix Bueno, Jeremy A. Ross, Maria-Victoria Mateos

Authors person Nizar J. Bahlis Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada info_outline Nizar J. Bahlis, Rakesh Popat, Meral Beksac, Meletios Athanasios Dimopoulos, Moshe E. Gatt, Francesca Gay, Jae-Cheol Jo, Prashant Kapoor, Martin Kortüm, Silvia Ling, Chandramouli Nagarajan, Kenshi Suzuki, Maika Onishi, Monique Dail, Emily Rossi, Xizhi (Adam) Luo, Emma Louise Arriola, Orlando Felix Bueno, Jeremy A. Ross, Maria-Victoria Mateos Organizations Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada, University College London Hospitals, NHS Foundation Trust, London, United Kingdom, Istinye University Ankara Liv Hospital, Ankara, Turkey, Alexandra Hospital - University of Athens, Medical School, Athens, Greece, Hadassah Hebrew University Medical Center, Jerusalem, Israel, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea, Mayo Clinic Rochester, Rochester, MN, Würzburg University Hospital, University of Würzburg, Würzburg, Germany, Liverpool Hospital, Sydney, New South Wales, Australia, Singapore General Hospital and SingHealth Duke NUS Blood Cancer Center, Singapore, Singapore, Myeloma/Amyloidosis Center, Japanese Red Cross Medical Center, Tokyo, Japan, Genentech, Inc, South San Francisco, CA, AbbVie Inc., North Chicago, IL, AbbVie, Maidenhead, United Kingdom, University Hospital of Salamanca, Instituto de Investigación Biomédica de Salamanca and Institute of Cancer Molecular and Cellular Biology and CIBERONC, Salamanca, Spain Abstract Disclosures Research Funding AbbVie and Genentech/Roche Background: The randomized Phase 3 CANOVA study’s (NCT03539744) primary analysis showed multiple numerically improved efficacy endpoints with VenDex v PomDex, but the primary endpoint of mPFS by IRC was not statistically significant. Here, we report correlative biomarker analyses from CANOVA. Methods: CANOVA is a randomized, global, open-label Phase 3 study of VenDex v PomDex in pts with t(11;14)+ RRMM and ≥2 prior lines of therapy (LOTs). The primary endpoint was mPFS by IRC. Key secondary endpoints included ORR, ≥VGPR, mOS, and MRD negativity (<10 -5 ). In post hoc mPFS sensitivity analysis, disease progression, death, and start of next LOT were defined as events. BCL2 gene expression by RNAseq (3.7 log2 FPKM prespecified median cutoff for BCL2 high v BCL2 low ) and chr1q abnormalities by whole-exome sequencing (normal, gain, or amp) were assessed centrally from pretreatment, CD138-enriched BM aspirates. Results: mPFS, post hoc mPFS, and mOS in the VenDex arm were similar by BCL2 status, with numerically higher ORR, ≥VGPR, and MRD negativity rates in the BCL2 high subgroup. In contrast, mPFS and mOS within the PomDex arm were numerically longer in the BCL2 low subgroup, despite equal ORR in both subgroups (Table). Presence of 1q abnormalities was evenly distributed across BCL2 high v BCL2 low subgroups in the VenDex arm (51% v 45%) but not in the PomDex arm (59% v 31%). Normal 1q and gain(1q) subgroups had numerically improved mPFS, mOS, ORR, ≥VGPR, and MRD negativity with VenDex; pts with amp(1q) had poor outcomes regardless of treatment, albeit the sample size was small. Conclusions: Pts with BCL2 high or gain(1q) had numerically improved clinical efficacy with VenDex v PomDex. Clinical benefit was consistent across BCL2 subgroups ( BCL2 high or BCL2 low ) with VenDex but not PomDex. Pts with amp(1q) fared poorly irrespective of treatment arm. Clinical trial information: NCT03539744. Efficacy Outcomes. All Pts (VenDex, n=133 v PomDex, n=130) BCL2 high (VenDex, n=54 v PomDex, n=45) BCL2 low (VenDex, n=45 v PomDex, n=53) amp(1q) (VenDex, n=11 v PomDex, n=6) gain(1q) (VenDex, n=35 v PomDex, n=29) Normal 1q (VenDex, n=43 v PomDex, n=47) mPFS, mo HR (95% CI) 9.9 v 5.8 0.82 (0.60–1.14) 9.4 v 3.8 0.64 (0.38–1.06) 10.4 v 7.4 0.89 (0.52–1.55) 2.1 v 2.8 1.66 (0.30–9.10) 9.4 v 3.8 0.47 (0.24–0.91) 12.3 v 7.4 0.63 (0.36–1.11) Post hoc mPFS, mo HR (95% CI) 9.4 v 4.0 0.65 (0.49–0.87) 7.4 v 3.2 0.50 (0.31–0.80) 8.5 v 5.6 0.70 (0.44–1.13) 1.9 v 1.1 0.48 (0.14–1.69) 7.4 v 2.8 0.37 (0.21–0.68) 10.4 v 5.6 0.49 (0.30–0.82) mOS, mo HR (95% CI) 32.4 v 24.5 0.70 (0.47–1.03) 32.4 v 19.0 0.63 (0.35–1.12) 28.7 v 30.0 0.88 (0.46–1.68) 9.2 v 14.8 1.03 (0.27–3.94) 39.2 v 16.0 0.51 (0.24–1.07) 32.4 v 27.9 0.61 (0.31–1.23) ORR (≥VGPR), % 62 (39) v 35 (14) 69 (48) v 36 (13) 58 (31) v 36 (13) 27 (18) v 17 (17) 63 (43) v 24 (7) 72 (40) v 43 (15) MRD negativity (10 -5 ), % 8 v 0 15 v 0 2 v 0 0 v 0 11 v 0 12 v 0

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