Gasparetto, Cristina

SummaryAlthough new multiple myeloma (MM) therapies are effective in alleviating some disease‐associated symptoms (e.g. bone pain, fatigue, functional decline), they can result in additional toxicities, further impacting health‐related quality of life (HRQoL). Here, we compared HRQoL and safety of lenalidomide‐bortezomib‐dexamethasone [RVd (n = 445)], bortezomib‐melphalan‐prednisone [VMP (n = 77)] and Vd or VMP (n = 588) in patients with newly diagnosed MM (NDMM) from the Connect® MM Registry, a large, USA, multicentre, prospective observational cohort study. Functional Assessment of Cancer Therapy‐Multiple Myeloma subscale, EuroQol‐5D overall score and Bone Pain Inventory HRQoL scores were significantly improved with RVd versus Vd/VMP. Serious adverse event rates were similar in all groups. Treatment with RVd maintained HRQoL in this real‐world, largely community‐based population of patients with NDMM.

8521 Background: Several clinical and molecular prognostic factors (e.g, International Staging System [ISS] stage, plasma cell labeling index, genomic models) exist for multiple myeloma (MM). We hypothesized that exploiting gene signatures representative of oncogenic pathway deregulation (i.e., Ras, Myc, etc.), would improve MM prognostication and also aid with the identification of novel therapeutic targets. Methods: Using a discovery cohort (n=47) of patients with MM and corresponding gene expression data, we built upon current molecular risk-stratification and devised a Bayesian genomic (“metagene”) model for prognosis. We validated that model in an independent patient cohort (n=207). Finally, we incorporated ISS staging and clinical variables to construct a combined Clinico-Genomic Risk Stratification System. We further validated the combined model in a separate cohort (n=72), in a blinded manner. Results: Using gene signatures predictive of oncogenic pathway activation in the discovery cohort, we identified specific patterns (metagenes) of signaling pathway activation with prognostic relevance. In an independent validation cohort, this metagene-based model accurately predicted event free survival (EFS) independently of ISS (multivariate hazard ratio [HR] 3.4 for ISS stage, and 5.4 for the metagene model, p=0.002). Using multivariate risk modeling, we incorporated ISS staging and the metagene model into a Clinico-Genomic System and successfully stratified the validation cohort into three groups (low, intermediate, and high risk) with markedly different EFS (HR 4.2 for intermediate risk and 14.0 for high risk vs. the low risk cohort, p<0.0001). In an additional blinded validation, the Clinico-Genomic System again accurately predicted median overall survival (68.7 [low risk] vs 24.7 [intermediate risk] vs 18.7 months [high risk], p<0.0001); more accurately than either ISS or other reported genomic models. Conclusions: A combined Clinico-Genomic Risk Stratification System, building on patterns of oncogenic pathway activation and ISS staging system, improves upon current prognostic models in MM and identifies novel pathway targets for future therapeutic consideration. No significant financial relationships to disclose.

BackgroundStudies have reported racial disparities in access to and use of multiple myeloma (MM) treatments between African American (AA) and White patients. Although AA patients demonstrate longer disease‐specific survival, this has not uniformly translated into improved survival over time. The association between race and treatment patterns and survival outcomes was analyzed using data from the Connect MM Registry.MethodsThe Connect MM Registry is a large US, multicenter, prospective observational cohort study of patients with newly diagnosed MM. Patients who received first‐line (1L) stem cell transplantation (SCT) or who did not receive SCT (non‐SCT or non–stem cell transplantation [NSCT]) were grouped by raceEffects of race and transplantation status on the use of triplet treatment were estimated using logistic regression.ResultsTreatment patterns in 1L (types and duration of induction, posttransplantation maintenance) were similar between AA and White patients. SCT rates in 1L (32% vs 36%) and triplet treatment use (AA: 44% for NSCT patients and 72% for SCT patients; and White: 48% for NSCT patients and 72% for SCT patients) during first induction were similar. No significant effect of race or transplantation status on 1L triplet treatment use was observed. Race was not found to be associated with survival outcomes among patients who underwent NSCT; however, AA patients who received SCT had significantly longer overall survival compared with White patients who underwent SCT (not reached vs 88.2 months; hazard ratio, 0.56; 95% CI, 0.35‐0.89 [P = .0141]).ConclusionsAA and White patients were found to have similar treatment patterns in the Connect MM Registry, suggesting that both groups had equal access to health care. In this real‐world setting, AA patients received standard‐of‐care treatment, which might have contributed to better MM‐specific survival compared with White patients.

8518 Background: Patients (pts) with newly diagnosed multiple myeloma (NDMM) and renal impairment (RI) are often excluded from clinical trials. Data are limited on the effects of induction treatment in these pts, who may also be ineligible for autologous stem cell transplant (SCT) due to severity of RI. This analysis investigated the impact of RVd induction on renal function in transplant eligible (TE) and noneligible (TNE) pts from the Connect MM Registry, a US, multicenter, prospective, observational study. Methods: Eligible pts were ≥ 18 y and had symptomatic MM diagnosed ≤ 2 mos prior to enrollment, as defined by the International Myeloma Working Group criteria. For this analysis, pts that received front-line RVd for ≥ 3 cycles were grouped per transplant eligibility and renal function at baseline (BL; creatinine clearance [CrCl] < 30, 30-50, > 50-80, and > 80). Pts with progressive disease at BL were excluded. Renal function at 3 mos was measured. Median unadjusted progression-free survival (PFS) was calculated from start of regimen in TE and TNE populations, with pts grouped by CrCl (≤ 60 or > 60) at BL. Results: As of 7/23/19, 421 TE and 212 TNE pts received RVd for ≥ 3 cycles. TE and TNE pts were grouped by BL CrCl of < 30 (20 and 16 pts), 30-50 (36 and 50 pts), > 50-80 (117 and 63 pts), and > 80 (248 and 83 pts). Renal function improvement was observed in all pts receiving RVd, including those with moderate (30-50 CrCl) and severe (< 30 CrCl) RI at BL (Table). In pts with > 60 CrCl and ≤ 60 CrCl at BL, median PFS in TE pts was 48.6 mos and 43.2 mos, respectively. In TNE pts, median PFS was 36.4 mos and 30.6 mos, respectively. Conclusions: The results from the Connect MM Registry indicate that pts with NDMM and RI (including moderate and severe) who receive front-line RVd for ≥ 3 cycles may see improvement in renal function at 3 mos, regardless of transplant eligibility. RVd therefore can potentially be used in pts with RI. This analysis provides real-world data that support further investigation of RVd treatment in pts with moderate or severe RI. Clinical trial information: NCT01081028 . [Table: see text]

8509 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor. In the Phase 3 BELLINI trial, addition of Ven to bortezomib (B) + dexamethasone (d) significantly improved response rates and progression-free survival (PFS) vs placebo (Pbo) and showed significant efficacy in patients (pts) with either t(11;14) or BCL2high gene expression. Here we present updated safety and efficacy data from the prespecified second interim overall survival (OS) analysis. Methods: In this multicenter, randomized, double-blind study (NCT02755597), pts with relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo in combination with B (1.3 mg/m2) and d (20 mg). The primary endpoint was PFS; key secondary endpoints included overall response and overall survival (OS). Results: 291 pts were randomized; 194 to Ven, 97 to Pbo. Pt characteristics were well balanced among arms. In the Ven arm, median age was 66, 17% had high-risk cytogenetics, 11% had t(11;14), and 34% had BCL2high gene expression. As of 13 Sept 2019, 59 pts were still on study, 45 (23%) Ven vs 14 (14%) Pbo. At a median follow-up of 28.6 months, there were 64 (33%) deaths in the Ven arm vs 24 (25%) in Pbo. At the initial data cutoff (26 Nov 2018), PFS HR was 0.63 (0.44,0.90) and OS HR was 2.03 (1.04,3.95). Table shows updated PFS and OS. Most common treatment-emergent adverse events (TEAEs) with Ven were diarrhea (59%), nausea (37%), and constipation (35%). Most common grade 3/4 AEs (Ven/Pbo) were neutropenia (21%/8%), thrombocytopenia (15%/30%), anemia (16%/15%), diarrhea (15%/12%), and pneumonia (18%/13%). Serious AEs occurred in 54% Ven and 52% Pbo pts. 24% discontinued Ven due to AEs vs 12% Pbo. There were 14 treatment-emergent deaths in the Ven arm and 1 in Pbo. Conclusions: The addition of Ven to Bd significantly improves PFS but resulted in increased mortality vs Pbo in the total population. Greatest PFS improvement with Ven was observed in pts with t(11;14) or BCL2high gene expression, where Ven shows a favorable benefit-risk profile. The study continues for final OS analysis. Clinical trial information: NCT02755597 . [Table: see text]

8032 Background: The impact of t(11;14) (16%–24% of MM pts) on prognosis is not fully understood. Consensus is lacking on the effects of induction treatment (tx) on outcomes with t(11;14). The Connect MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with NDMM designed to examine real-world diagnostic patterns, treatment (tx) patterns, clinical outcomes, and HRQoL pt-reported outcomes in pts with NDMM. The impact of t(11;14) on tx outcomes are reported. Methods: Analysis included data from pts from 250 community, academic, and government sites in cohort (C) 1 (9/2009–12/2011) and C2 (12/2012–4/2016), who completed first-line (1L; induction) tx and were tested for t(11;14) by FISH or cytogenetics. Primary end points (progression-free survival [PFS] and overall survival [OS]) were measured from start of 1L tx to earliest event (PFS, death or progression; OS, death), loss to follow-up, or data cutoff, adjusted for baseline (BL) risk factors. A sensitivity analysis excluding pts with concomitant cytogenetic abnormalities [del 17p, t(4;14), t(14;16), 1q+] was also performed. Results: By 1/2018, 3011 pts were enrolled; 2938 were treated. Of 1574 enrolled pts tested for t(11;14), 378 were t(11;14)+ and 1196 were t(11;14)−. More pts in C2 vs C1 were t(11;14)+ (60% vs 40%). BL characteristics were similar between groups. t(11;14) status did not affect PFS ( P= NS) or OS ( P= NS; Table). Pts in C1 and C2 received similar 1L txs (IMiD agent + proteasome inhibitor [PI], 30% vs 42%; PI only, 42% vs 43%; IMiD agent only, 17% vs 11%). Results were similar when pts with concomitant abnormalities were excluded. Conclusions: Results of this analysis suggest that t(11;14) does not affect PFS and OS outcomes in NDMM pts. Clinical trial information: NCT01081028. [Table: see text]

8037 Background: Advances in the treatment of MM have greatly improved clinical outcomes for patients (pts). SPM occurrence has been observed in early and late stage MM as well as with increasing age. US SEER Cancer Registry reports a background incidence rate of SPM 2.1/100 person-yrs (PY) among persons ≥ 65 yrs of age. However, incidence of SPM in MM pts and the relationship to therapy still warrants further exploration. Methods: Connect MM is a US-based observational registry designed to characterize pts with newly diagnosed MM from 266 US sites. Initiated in Sep 2009, patient data were collected at baseline and each subsequent quarter with a standardized form. On Dec 14, 2011, Connect MM reached full enrollment at 1,500 pts. Results: As of Jan 13, 2012, preliminary retrospective SPM data is available for 1015 pts. Median age was 67 yrs, 56.8% male, and median follow-up was 10.6 mo (0.03-24.9 mo). 12 pts (7 male) with median age of 68.5 yrs developed SPM. Median time to SPM was 8.5 mo (0.8-17.7 mo) after treatment initiation. 11 invasive SPM were observed - 4 hematological (heme): 1 AML, 1 MDS, 1 CMML and 1 DLBCL, and 7 solid: 2 melanoma skin, 1 bronchus, 1 breast, 1 prostate, 1 tonsil, and 1 gastric carcinoid. Also, 1 pt had non-melanoma skin cancer (NMSC), and 1 pt with invasive skin cancer also had NMSC. Of the 4 pts developing heme SPM, 3 had bortezomib (BORT), 1 had thalidomide (THAL), 1 had lenalidomide (LEN), 2 had melphalan (MEL), and all 4 pts had steroids. Of the 7 pts who developed solid tumor SPM, 5 had BORT, 5 had LEN, 2 had doxorubicin, 1 had MEL, 5 had steroids, 1 had irradiation, and 1 had not received MM treatment. 2 pts with prior history of invasive malignancy developed solid tumor SPM (1 pt also developed NMSC).1 pt who received irradiation developed NMSC. Early overall incidence of invasive SPM was 1.21/100 PY (95% CI 0.60, 2.16) for all pts and 1.20/100 PY (95% CI 0.44,2.62) for pts ≥ 65 yrs of age. Conclusions: This preliminary analysis shows that SPM occurred at an expected rate in this disease specific registry of patients with NDMM and appeared to occur irrespective of MM treatment administered. Incidence rates of SPM may increase over time as patients receive transplantation and alkylators. Prospective observation will continue.

e18556 Background: Studies in the United States (US) have identified variation in incidence and survival of multiple myeloma (MM) patients of different races, and noted that MM is the most common hematologic cancer among African Americans. This analysis evaluated whether health-related quality of life (HRQOL) of patients in the US varies by race as they initiate treatment having been newly diagnosed with active, symptomatic MM. Methods: Data were collected in Connect MM, a prospective US observational registry begun in September 2009. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was reported by patients at enrollment within 2 months of diagnosis. Patients completed the Brief Pain Inventory (BPI), EQ-5D, and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Mean reported scores for BPI, EQ-5D and FACT-MM were analyzed by patient race. Statistical significance was ascertained by ANOVA using SAS 9.1. Results: Baseline HRQOL data were reported by 1144 patients (enrolled in 228 centers) of whom 82% were White, 13% Black, and 6% Other race. The cohorts did not differ statistically by ECOG status or by multiple myeloma stage (assessed by either the International Staging System or the Durie and Salmon system). Compared to non-Blacks, Black patients reported less anxiety/depression on the EQ-5D (p=0.030) and better emotional well-being on the FACT-MM (p=0.003). No other statistically significant differences were noted between cohorts on the BPI, other EQ-5D domains (mobility, self care, usual activities, pain/discomfort), or other FACT-MM domains (physical, social/family, functional, and MM-specific considerations). Conclusions: Initial results from the Connect MM Registry indicate that baseline HRQOL prior to initiation of treatment may vary by patient race with respect to emotional well-being, and specifically anxiety/depression. These results serve as a baseline reference for future analyses. As patients in the Connect MM Registry proceed through therapy, analyses should be conducted of patients by race, among other characteristics and factors, to determine whether it may be associated with subsequent clinical outcomes and HRQOL over time.

Background Venetoclax (Ven) is a selective, small molecule inhibitor of anti-apoptosis protein Bcl-2 that has antitumoral activity against multiple myeloma (MM), notably those with translocation t(11;14). Dexamethasone (d) has shown to enhance the expression of BCL-2 and pro-apoptotic protein Bim, shifting its binding towards Bcl-2 and sensitizing MM cells to Ven. This Phase 1/2 open-label trial is evaluating the safety and efficacy of the combination of Ven+d as a therapeutic approach to improve clinical outcomes in patients with t(11;14) Relapsed/Refractory (R/R) MM. Methods This ongoing study (NCT01794520) has 2 distinct phases. Phase 1 (P1) consisted of separate dose escalation, safety expansion, and Ven+d combination cohorts. The phase 2 (P2) portion is an expansion cohort of Ven+d to further evaluate its efficacy. The safety and efficacy of the Ven+d cohorts from P1 and P2 are reported here. Eligible patients (pts) were adults with t(11;14) R/R MM ≥18 years of age. Key eligibility criteria for the Ven+d cohort in P1 included prior treatment with a proteasome inhibitor (PI) and an immunomodulatory drug (IMID), and an ECOG score ≤1. In P2, eligibility included an ECOG score ≤2, disease progression on or within 60 days from the last dose on previous treatment and having received at least two lines of therapy with a PI, IMID, daratumumab, and glucocorticoids. Additional inclusion criteria for both phases included measurable disease and adequate bone marrow function in all pts, and the presence of t(11;14) determined by fluorescence in-situ hybridization. In both phases, pts received oral Ven 800 mg/day + oral d 40 mg (20 mg for pts ≥75 years of age) on days 1, 8, and 15 of each 21-day cycle. In P1, preliminary efficacy was assessed as the overall response rate (ORR), time to progression (TTP), progression free survival (PFS), and duration of response (DOR) of Ven+d based on the 2011 International Uniform Response Criteria for MM. Efficacy in P2 further evaluated ORR, very good partial response (VGPR) or better, PFS, DOR, TTP, and overall survival (OS) using 2016 IMWG response criteria. Results In P1, as of 15thApril, 2019, 20 pts were enrolled (17 [85%] male; median age, 63 years [range, 46-77]). The median number of prior therapies received was 2.5 (range: 1-7). Nineteen pts (95%) discontinued the study (18 due to progressive disease and 1 underwent transplant). The treatment-emergent adverse events (TEAEs) are summarized in the Table. Most frequent TEAEs were insomnia (45%), hypophosphatemia (40%), hyperglycemia (35%), diarrhea (35%), and thrombocytopenia (30%). Predominant Grade 3 or 4 TEAEs included neutropenia (21%), lymphopenia (29%), and hypophosphatemia (20%). The most common serious TEAE was tumor lysis syndrome (TLS) (10%). No deaths were reported in the treatment-emergent period. ORR was achieved by 13 (65%) and ≥VGPR was achieved by 6 (30%) pts respectively. Partial response (PR) was observed in 7 (35%) pts and stable disease (SD) in 4 (20%) pts. Median time to first response was 1.4 mos (95% CI: 0.7, 2.8). The DOR was 13.1 mos (95% CI: 10.9, 21.9). Median PFS and TTP were both 12.4 mos (95% CI 3.6, 20.9). In P2, as of March 18, 2019, 31 pts were enrolled (18 [58%] male; median age, 65 years [range, 48-80]). The median number of prior therapies received were 5 (range: 1-9). Eight (26%) pts discontinued the study (6 deaths, 1 withdrew consent, 1 due to physician's decision). The most frequent TEAEs reported were diarrhea (32%), nausea (26%) and lymphopenia (32%). The most frequent Grade 3 or 4 TEAEs were lymphopenia (32%), thrombocytopenia (11%), and hypertension (10%). Most common serious TEAE was sepsis (10%). Six (19%) deaths were reported (5 due to progressive disease and 1 due to adverse event). In the intention to treat population, the median TTR was 0.7 mos (range: 0.6-1.5). ORR was achieved by 14 (45%) and &gt;VGPR was observed in 8 (26%) pts. PR was observed in 6 (13%) pts and SD in 8 (26%) pts. Median PFS, DOR, and OS were not reached at the time of data analysis. The 9-mo estimates for PFS, DOR, and OS were 57% (95% CI: 19% 82%), 66% (95% CI: 16%, 91%), and 71% (95% CI: 44%, 87%) respectively. Conclusion In both phases of this study, Ven+d was efficacious and demonstrated tolerable safety in pts with t(11;14) R/R MM. These results support further investigation of Ven combinations in this pt population. This combination is also being investigated in the ongoing Phase 3 trial M13-494 (CANOVA) in t(11;14) positive R/R MM. Disclosures Kaufman: Takeda: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; TG Therapeutics: Consultancy. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Schjesvold:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria. Moreau:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Boise:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding. Alzate:AbbVie Inc: Employment, Other: Stock/stock options. Macartney:AbbVie Inc: Employment, Other: Stock/stock options. Pesko:AbbVie: Employment, Other: Stock/stock options. Salem:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Hong:Genentech Inc.: Employment, Equity Ownership; Roche: Equity Ownership. Maciag:AbbVie: Employment, Other: Stock/stock options. Pauff:AbbVie Inc: Employment, Other: may own stock or stock options. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in multiple myeloma, which is not an approved indication.

Background: Overexpression of the anti-apoptotic BCL-2 protein promotes multiple myeloma (MM) cell survival. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis and has shown synergistic activity with bortezomib (B) and dexamethasone (d). Phase 1 studies in relapsed/refractory (RR) MM demonstrated encouraging clinical efficacy of Ven + d in t(11;14) MM and in a broader patient (pt) population in combination with Bd. Recent results from the Phase 3 BELLINI study of Ven vs placebo (Pbo) + Bd in pts with RRMM demonstrated that pts treated with Ven + Bd had improved clinical response rates and progression-free survival (PFS) vs Pbo, although the overall survival (OS) result was in favor of Pbo. Subgroup analyses showed different efficacy and survival outcomes based on tumor cytogenetics and BCL-2 expression. Results of pre-specified subgroup analyses and additional retrospective correlative biomarker analyses in the Phase 3 BELLINI study are described herein. Methods: BELLINI (NCT02755597) was a randomized, double-blind, multicenter Phase 3 study of Ven or Pbo + Bd in pts with RRMM who received 1-3 prior therapies and were either sensitive or naïve to PIs. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo + Bd. The following biomarker analyses were performed by central laboratory assessments of pre-treatment tumor samples: BCL-2 protein expression by immunohistochemistry (IHC) analysis of bone marrow (BM) core biopsies; BCL2 gene expression by quantitative PCR (qPCR) and cytogenetic abnormalities by interphase fluorescence in situ hybridization (FISH) analysis of CD138-enriched BM mononuclear cells. Correlation between BCL-2 (protein and gene) expression, cytogenetics, and outcomes were examined by Kruskal-Wallis tests and by hazard ratio (HR) using the Cox proportional hazard model. Results: As of the data cut-off of 18 Mar 2019, 291 pts were randomized, 194 to the Ven arm and 97 to the Pbo arm. Out of the 291 pts randomized, 177 pts (61%) were evaluable by IHC, 257 pts (88%) by qPCR, and 262 pts (90%) by FISH. A broad range of BCL2 gene expression was observed (median 2-DCt: 0.212 [range: 0-5.21]), which strongly correlated with protein expression (median 2-DCt 0.115 in BCL-2 IHC Low vs 0.277 in BCL-2 IHC High, p=0.0021). t(11;14) MM had the highest levels of BCL-2 expression (23/23 BCL-2 High by IHC; median 2-DCt 0.406 vs 0.212 in t(11;14) negative, p=0.0132), however high BCL-2 expression was not limited to the t(11;14) subgroup. Univariate analyses showed higher BCL2 expression in pt tumor samples with del(13q) (median 2-DCt 0.333 vs 0.159 in pts without del(13q), p=0.0008) and gain(1q) (median 2-DCt 0. 295 vs 0.180 in pts without gain(1q), p=0.0059). Bootstrapping and aggregating thresholds from trees (BATTing) was used retrospectively to identify an estimated threshold value for BCL2 expression (2-DCt ≥0.323) that could provide optimum selection of pts with maximum improvement in PFS when treated with Ven+Bd. Biomarker subgroups with the greatest PFS improvement were t(11;14) (HR=0.10; 95% CI: 0.02-0.46, p=0.003) and High BCL2 by qPCR (HR=0.26; 95% CI: 0.13-0.51, p&lt;0.001; Table 1). Since the t(11;14) and High BCL2 patient populations do not completely overlap (20% of High BCL2 pts were t(11;14) and 54% of t(11;14) were High BCL2), a combined subgroup analysis was performed. For pts with t(11;14) or High BCL2, the median PFS was not reached in the Ven arm vs 9.9 mo in Pbo (HR=0.26, 95% CI: 0.14-0.48, p&lt;0.001; Table 1). Higher overall response (ORR, 88% vs 70%), very good partial response or better (≥VGPR, 73% vs 33%), and complete response or better (≥CR, 42% vs 3%) rates were observed in the Ven vs Pbo arm (Table 2). Minimal residual disease negativity (MRD-, 10-5) rate was also higher for t(11;14) or High BCL2 pts in the Ven vs Pbo arm (19% vs 0%). Median overall survival (OS) was not reached in either arm but was similar between treatment arms for the combined group with t(11;14) or High BCL2 pts (HR=0.92, 95% CI=0.39-2.16, p=0.85). In contrast, in the t(11;14) negative and Low BCL2 pts, OS favored Pbo (HR=3.13, 95% CI=1.2-8.13, p=0.019; Table 1). Conclusions: Adding Ven to Bd demonstrates significant efficacy in pts with RRMM harboring either t(11;14) or tumor cells expressing high levels of BCL2. The benefit-risk profile appears to be favorable in these subsets of pts and additional studies to gain further safety and efficacy information are warranted. Disclosures Harrison: GSK: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. De La Rubia:AMGEN: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Other: travel, accommodations, expenses. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Hungria:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender:Amgen: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Takeda: Honoraria, Other: Travel or accommodations. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Spencer:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Specialised Therapeutics Australia: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; GlycoMimetics Inc: Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garg:Janssen: Honoraria; Novartis, Janssen: Research Funding; Janssen, Takeda, Novartis: Other: Travel expenses. Punnoose:Roche: Other: Stock/stock options; Genentech, Inc.: Employment. Jalaluddin:AbbVie: Employment, Other: Stock/stock options. Jia:AbbVie: Employment, Other: Stock/stock options. Yang:AbbVie: Employment, Other: Stock/stock options. Sun:AbbVie: Employment, Other: Stock/stock options. Ward:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.