Arriola, Emma

PURPOSE Venetoclax, an oral BCL-2 inhibitor, has efficacy in t(11;14)-positive relapsed/refractory multiple myeloma (RRMM), which is enhanced by dexamethasone, which promotes BCL-2 dependency. METHODS The randomized, open-label, phase III CANOVA study (ClinicalTrials.gov identifier: NCT03539744 ) enrolled adults with t(11;14)-positive RRMM who had received ≥2 previous lines of therapy. Patients were randomly assigned (1:1) to venetoclax-dexamethasone or pomalidomide-dexamethasone until progression or intolerable toxicity. The primary end point was independent review committee assessed–progression-free survival (PFS) in the intention-to-treat population analyzed by stratified log-rank test (two-sided type I error rate, α = .05), with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazard model. Secondary end points included response rates, overall survival (OS), minimal residual disease (MRD) negativity rate (<10 –5 ), and safety. RESULTS Overall, 263 patients were randomly assigned (venetoclax-dexamethasone, n = 133; pomalidomide-dexamethasone, n = 130). Median PFS was 9.9 months (95% CI, 6.9 to 12.6) with venetoclax-dexamethasone versus 5.8 months (95% CI, 3.8 to 9.2) with pomalidomide-dexamethasone (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24). Overall response and very good partial response or better rates were 62% and 39%, respectively, with venetoclax-dexamethasone versus 35% and 14% with pomalidomide-dexamethasone. MRD negativity rate was 8% with venetoclax-dexamethasone and 0% with pomalidomide-dexamethasone. Median OS was 32.4 months (95% CI, 26.4 to 40.7) with venetoclax-dexamethasone and 26.9 months (95% CI, 20.4 to 38.9) with pomalidomide-dexamethasone (HR, 0.856 [95% CI, 0.612 to 1.197]). Grade ≥3 treatment-emergent adverse event rates were 67% with venetoclax-dexamethasone versus 83% with pomalidomide-dexamethasone. There were 16 (12%) treatment-emergent deaths with venetoclax-dexamethasone versus 8 (6%) with pomalidomide-dexamethasone. CONCLUSION The primary end point of PFS was not met. PFS and OS were numerically longer with venetoclax-dexamethasone versus pomalidomide-dexamethasone in t(11;14)-positive RRMM. Consistent with previous studies, infections were associated with venetoclax-dexamethasone; no new safety signals were observed.

Abstract Background B-cell maturation antigen (BCMA)-targeting immunotherapies represent a promising class of treatment for the management of immunoglobulin light chain (AL) amyloidosis, a disease that is related to clonal plasma cells. Etentamig is a 2nd generation, off-the-shelf, fully human BMCA X CD3 bispecific antibody with bivalent BCMA domain and low CD3 affinity that targets both BCMA-expressing plasma cells and CD3-expressing T cells. Etentamig monotherapy is being studied in multiple myeloma (MM) in an ongoing phase 3 study (NCT06158841). Here, we report the first safety and efficacy results from M24-209, an open-label phase 1/2 study evaluating etentamig monotherapy in patients (pts) with relapsed/refractory (RR) AL amyloidosis from dose level 1 (DL1). Methods The phase 1 dose escalation (ESC) portion of the study (NCT06158854) with etentamig enrolled pts with RR AL amyloidosis with ≥1 prior lines of therapy (LOT), including a proteasome inhibitor and an anti-CD38 monoclonal antibody with no prior BCMA exposure. Eligible pts were required to have a difference in involved and uninvolved serum free light chain (dFLC) of ≥50 mg/L, and pts with Mayo Clinic 2004 cardiac risk stage IIIb with NT-proBNP ≥8500 pg/ml were excluded. Three dose groups were explored in dose ESC (etentamig dose levels [DL] 1, 2, and 3). In all cohorts, pts will receive up to 24 cycles of treatment and will be followed until disease progression. In dose ESC, the primary objectives are to determine safety/tolerability, pharmacokinetic/pharmacodynamic, and recommended phase 2 dose. The secondary objectives include evaluation of efficacy as measured by hematologic response and organ response. Responses are investigator assessed per consensus guidelines (Comenzo, et al. Leukemia. 2012. 26[11]:2317-25; Palladini G, et al. Amyloid. 2021 [Epub];28[1]:1-2). Results As of 17 July 2025, all DLs in dose ESC have been fully enrolled, and 12 pts have been treated with etentamig at DL1. Due to short follow-up, this initial report only includes data from DL1, with further follow-up data from ESC to be included at the time of presentation. Median duration of follow up in DL1 was 9.4 months (8.3–13.8) with 83% of pts continuing treatment. Median age for pts was 72 years (range, 56–85 years). Median number of prior LOT was 2 (range, 1–6), and median time from initial diagnosis was 3.6 years. Thirty-three percent have received a prior stem cell transplant and 50% previously received the regimen of daratumumab with cyclophosphamide, bortezomib, and dexamethasone in combination. Median dFLC at study baseline was 110. 5 mg/L (range, 56.6–617.5). At baseline, 83% of pts had cardiac involvement, 25% had renal involvement, and 8% had hepatic involvement. Eighty-three percent of pts had lambda AL amyloidosis. Treatment-emergent adverse events were reported in 100% (42% Grade ≥3) of pts at DL1. Cytokine release syndrome (CRS) occurred in 2 pts (17%, all Grade 1), with no instances of any grade immune effector cell-associated neurotoxicity syndrome (ICANS). CRS occurring after the first dose had median time to onset of 6.8 hours (range, 6.7–6.9). Grade ≥3 infections occurred in 1 pt (8%, all Grade 3). Grade ≥3 neutropenia also occurred in 1 pt (8%, all Grade 3), and no Grade ≥3 events of thrombocytopenia or anemia occurred. No Grade 5 events have occurred. Within the dose ESC DL1 cohort, the overall hematologic response rate was 100%, with all pts achieving ≥VGPR and 83% of pts achieving complete response (CR). The median time to CR was 0.9 months (0.3–9.3). The median duration of response has not yet been reached and 100% of pts remain in their best overall response by investigator assessment. To date, no pts have experienced hematologic progression on study. Cardiac response was observed in 30% of evaluable pts. Renal response was seen in 67% of evaluable pts. Conclusions In the DL1 cohort, etentamig showed a manageable safety profile in AL amyloidosis with low incidence and severity of CRS, no ICANS, and limited Grade ≥3 cytopenia events. Deep and rapid hematologic responses were observed with 100% ≥VGPR rate and 83% hematologic CR rate. Additional dose-level data will be presented at the time of the meeting. All pts remain in ongoing follow-up and evaluation, and the study will begin the dose expansion (EXP) portion after dose selection.

7510 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 BCL2high v BCL2low) 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 BCL2highsubgroup. In contrast, mPFS and mOS within the PomDex arm were numerically longer in the BCL2lowsubgroup, despite equal ORR in both subgroups (Table). Presence of 1q abnormalities was evenly distributed across BCL2high v BCL2low 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 BCL2high or gain(1q) had numerically improved clinical efficacy with VenDex v PomDex. Clinical benefit was consistent across BCL2 subgroups ( BCL2high or BCL2low) with VenDex but not PomDex. Pts with amp(1q) fared poorly irrespective of treatment arm. Clinical trial information: NCT03539744 . [Table: see text]

Abstract Background: Initial studies with venetoclax, a BCL-2 inhibitor, alone or in combination with either dexamethasone or bortezomib and dexamethasone has shown considerable anti-tumor activity in t(11;14) MM with relapsed disease. Based on preclinical studies suggesting synergy when combined with bortezomib and phase 1 data showing efficacy for venetoclax, this combination was compared with bortezomib and dexamethasone (BortDex) in relapsed MM. While the BELLINI (NCT02755597) trial did demonstrate improved PFS with the combination, there were limited number of patients with t(11;14) treated with BortDex. The objective of this study was to assess real-world effectiveness of BortDex in patients with t(11;14) positive relapsed/refractory MM. Patients and methods: This non-interventional, retrospective observational cohort study included patients with t(11;14) MM from the International Myeloma Working Group (IMWG) retrospective study of t(11;14) MM. From the overall cohort, patients with t(11;14) MM receiving BortDex in ≥2 nd and ≤4 th line were initially selected. The cohort was further limited to patients with no evidence of allogeneic SCT within 16 weeks or autologous SCT within 12 weeks prior to BortDex initiation. Finally, patients non-refractory to prior PI regimen and not receiving BortDex regimen as part of a clinical trial were included in the study. Patient demographic and clinical characteristics along with real-world effectiveness outcomes including best response, overall survival (OS), and time to next therapy (TTNT) as a surrogate measure for progression-free survival (PFS) were assessed. All analyses were descriptive in nature and were conducted using the SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Results: Overall, 144 patients who met the inclusion criteria were analyzed. Median age was 62.5 years, 62% were male. Patients had a median of 1 prior line (range 1-3) at start of BortDex, at a median of 18.4 months (range, 1-100) from diagnosis; 29% had a prior transplant. A PR or better was observed in 53% of patients with BortDex. The median TTNT for this cohort was 8.4 months and median OS was 46.1 months. Conclusions: This retrospective study of non-trial patients with t(11;14) MM provides a benchmark for newer therapies in this patient population for comparison with both venetoclax dexamethasone as well as combinations using the -BortDex backbone. Disclosures Emechebe: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Pharmaceutical/Biotech Companies: Current holder of stock options in a privately-held company. Kumar: Tenebio: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Goldschmidt: Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant. Mateos: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Kim: Janssen, BMS: Research Funding. Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Ludwig: Janssen, Celgene-BMS, Sanofi, Seattle Genetics: Consultancy, Speakers Bureau; Amgen, Takeda: Consultancy, Research Funding, Speakers Bureau. Handa: Kyowa Kirin: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Janssen: Honoraria; BMS: Honoraria; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Takeda: Honoraria, Research Funding. Fernandez de Larrea: Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; GSK: Honoraria; Sanofi: Consultancy. Reece: Amgen: Consultancy, Honoraria; GSK: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Millennium: Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Arriola: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

Abstract Background: Treatment of multiple myeloma (MM) commonly encompasses combination of drugs within the three drug classes including proteasome inhibitors (PIs), immunomodulators and (IMiDs), and monoclonal antibodies, both for newly diagnosed and relapsed disease. With increasing appreciation of disease heterogeneity based on underlying genetic abnormality, and demonstration of efficacy of venetoclax in patients with t(11;14) MM, the outcomes with commonly used MM regimens among the different cytogenetic subgroups are of great interest. Venetoclax, a BCL-2 inhibitor, is being studied in t(11;14) positive MM patients who have received at least two prior lines of treatment (NCT03539744; CANOVA). However, outcomes in previously treated t(11;14) MM patients using standard of care approaches in the real-world setting is limited. Patients and methods: This non-interventional, retrospective observational cohort study included patients with t(11;14) MM from the International Myeloma Working Group (IMWG) retrospective study of t(11;14) MM. From the overall cohort, patients with t(11;14) MM receiving pomalidomide + dexamethasone (PomDex) in ≥3 rd line were selected, similar to those being enrolled in the ongoing CANOVA trial. Patients were also required to have prior exposure to lenalidomide and a PI without a history of transplant within 16 weeks prior to PomDex initiation. Patients enrolled in a clinical trial were excluded. Overall best response, time to next therapy (TTNT) as a surrogate measure for progression-free survival (PFS) and overall survival (OS) were assessed after initiation of PomDex. All analyses were descriptive in nature and were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Results: Fifty-two patients who met the inclusion criteria were analyzed. Median age was 63 years, 60% were male. Patients had a median of 3 prior lines at start of PomDex, at a median of 4.3 years from diagnosis; 52% had a prior transplant. A PR or better was observed in 34% of patients with PomDex. The median TTNT for this cohort was 6.1 months and median OS was 19.2 months. Conclusion: This retrospective study of non-trial patients with t(11;14) MM provides a benchmark for newer therapies in this patient population for comparison with both venetoclax dexamethasone in the ongoing CANOVA study as well as combinations using the pomalidomide backbone. Disclosures Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Kumar: Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Gonzalez De La Calle: Celgene-BMS, Janssen, Amgen: Honoraria. Mangiacavalli: GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria. Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Esteves: AbbVie: Consultancy; BMS: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Delforge: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee: Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; GSK: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Sanofi: Consultancy. Arriola: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Manthena: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services .

TPS8554 Background: BCL-2 is an anti-apoptotic protein important for myeloma cell survival. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor, that has shown promise in clinical studies as monotherapy or in combination with other agents in patients with t(11;14)-positive relapsed/refractory multiple myeloma (RRMM; Kumar et al. Blood. 2017; Costa et al. ASH 2018. Abstr. #303; Harrison et al. ASH 2019. Abstr. #142; Bahlis et al. ASH 2019. Abstr. #925; Kaufman et al. ASH 2019. Abstr. #926). Notably, t(11;14)-positive MM is more dependent on BCL-2 for cell survival, which, together with these clinical data, suggests that Ven combined with dexamethasone (Dex) may provide greater clinical benefit versus standard therapies, like pomalidomide (Pom), in this biomarker-defined patient population. This ongoing Phase 3 study (CANOVA; NCT03539744) aims to evaluate the safety and efficacy of VenDex vs PomDex in t(11;14)-positive RRMM. Methods: Eligible patients (≥18 years) must have t(11;14)-positive RRMM per central lab, an ECOG performance status ≤2, received ≥2 prior lines of therapy, previously received a proteasome inhibitor, and must be refractory to lenalidomide and last line of therapy. Patients cannot have history of treatment with Ven, Pom, or other BCL-2 inhibitors. Patients will be randomized 1:1 to Ven (800 mg orally, once-daily) or Pom (4 mg orally, once-daily on days 1-21 of 28-day cycles). Patients in both groups will receive 40 mg Dex (20 mg for patients ≥75 years) once weekly. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal from study. Patients will be stratified based on age at randomization ( < 65 vs ≥65 years), prior lines of therapy (2 to 3 vs ≥4), and International Staging System stage at screening (I vs II vs III). The primary endpoint is progression-free survival (PFS) per independent review committee (IRC) assessment based on International Myeloma Working Group criteria. The final PFS analysis will be performed when approximately 147 PFS events per IRC are observed. Secondary endpoints are response rate, patient-reported outcomes, overall survival, duration of response, times to response and progression, minimal residual disease negativity rate, safety, and Ven pharmacokinetics. Approximately 244 patients will be enrolled; as of January 21, 2020, 28 patients have been randomized (from 19 sites in 12 countries) and enrollment is ongoing. Clinical trial information: NCT03539744 .