Hong, Wan‐Jen

Abstract Background: Real-world data (RWD) derived from electronic health records are becoming increasingly important for deriving insights from clinical practice to complement findings from clinical trials. Response to treatment in multiple myeloma (MM) is assessed using the International Myeloma Working Group (IMWG) response criteria based on MM-specific laboratory measures (i.e. monoclonal [M] protein in serum and urine, free light chain [FLC] levels), as well as radiological images and bone marrow (BM) investigations when appropriate. As healthcare providers do not routinely collect all the information required by the IMWG response criteria, RWD data are often incomplete. Here, we present a derived real-world response (dR) algorithm based on IMWG criteria that accounts for lab measures routinely collected in the clinical care of MM patients and evaluate its ability to accurately assess response to treatment using clinical trial patient-level data. Methods: Treatment response is assessed using a rule-based algorithm integrating longitudinal laboratory measures routinely captured in RWD (Xu et al. Pharmacoepidemiol Drug Saf 2021) as e.g. by the Flatiron MM database. The rules are based on 'relaxed' IMWG criteria, which entail exclusion of BM biopsies data and of imaging results, and reduction in either serum or urine M protein levels (rather than both) to assign partial response. This algorithm was applied to patient-level clinical trial data from the Bellini trial (Kumar et al. Lancet Oncol 2020) with response assignment made by an independent review committee (IRC) in the trial used as the 'ground truth'. Agreement between the IRC's and algorithm's assignments of response was estimated using Cohen's Kappa statistic. Differences in overall response rate (ORR) between treatment and placebo arms were calculated using stratified Cochran-Mantel-Haenszel tests based on strata at randomization with number of prior lines of therapy and previous proteasome inhibitor treatment status variables used for stratification. Results: The Bellini trial is a Phase 3 clinical trial with 2:1 design enrolling 194 and 97 patients in its treatment and placebo arms, respectively (291 patients in total). Regular assessments of M protein and FLC levels were performed (median 13 or 14 measurements), providing detailed trajectory of patient response (Table 1). Comparison between the IRC's and algorithm's assignments of responders classified as Partial Response or better (PR+) resulted in almost perfect agreement with Cohen's Kappa 0.82 (274/291 assignments in agreement). It is worth noting that the Cohen's Kappa between the IRC's and Investigator's assessments is 0.85, indicating that the algorithm's error is within some expected uncertainty. Due to the exclusion of BM information, agreement decreased to 0.56 when depths of response were considered separately as opposed to grouping PR+ patients together with most cases being overestimated as complete response (CR) or stringent CR. In assessing treatment effect, differences in ORR between the intervention and placebo arms in the trial based on IRC's assessment could be accurately recapitulated (68% [66/97] vs 71% [69/97] responders in the placebo arm and 82% [159/194] vs 87% [169/194] in the intervention arm for IRC's and algorithm's assessment, respectively). Based on these results, algorithm response assignment led to consistent conclusions about treatment efficacy in the Bellini trial. Implementation of criteria to characterize very good partial response or better (VGPR+) also led to a conclusion consistent with the Bellini trial IRC's assessment, while implementation of criteria of CR+ resulted in estimates of treatment efficacy that were higher, but directionally consonant (Table 2). Conclusions: We present a fully automated rule-based algorithm for response assessment in MM relying on longitudinal lab measurements during treatment. The algorithm uses 'relaxed' IMWG criteria to account for routine clinical practice settings and demonstrates very high agreement with the assessment of trained clinicians, while reliably reproducing the efficacy analysis in the Bellini trial when ORR and VGPR+ are considered. We envision that, if the concordance observed here is confirmed in other independent cohorts, this algorithm can be used in the assessment of response in RWD and can facilitate response assessment when suboptimal amounts of data are available. Figure 1 Figure 1. Disclosures Tyanova: F. Hoffmann-La Roche: Current Employment. Xu: F. Hoffmann-La Roche AG: Current Employment. Williamson: Amgen: Current equity holder in publicly-traded company; Genentech: Current Employment, Current equity holder in publicly-traded company. Rocci: Novartis: Other: Wife is and employee of Novartis and holds Novartis stocks; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Received travel sponsorship ; Janssen-Cilag Ltd: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Other: Received travel sponsorship ; Owner of 100% stocks of Harlock Healthcare Consulting Ltd (UK privately-held company currently not active).: Current holder of individual stocks in a privately-held company; Roche: Current equity holder in publicly-traded company; Takeda: Consultancy, Honoraria, Other: Received travel sponsorship , Speakers Bureau; Sanofi: Consultancy; NHS: Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd.: Current Employment; AbbVie: Other: Received travel sponsorship . Hong: Imago BioSciences: Current Employment; Genentech, Inc.: Ended employment in the past 24 months; Stock options in Imago BioSciences: Current equity holder in publicly-traded company. Jin: Genentech Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Roose: Flatiron Health, Inc.: Current Employment; Roche: Current equity holder in publicly-traded company. Sawas: Seattle Genetics: Honoraria; Affimed: Research Funding; Roche: Current equity holder in publicly-traded company; Flat Iron Health: Current Employment; Acrotech: Honoraria; Daiichi-Sankyo: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau. Kumar: Antengene: Consultancy, Honoraria; Novartis: Research Funding; Adaptive: 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; Carsgen: Research Funding; Tenebio: Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Abstract Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

AbstractMultiple myeloma (MM) treatment options have evolved rapidly, but how new agents are incorporated into treatment decisions in current practice is not well understood. This study examined prescribing trends of physicians treating newly diagnosed MM and treatment outcomes in the United States. Electronic health record data from 6271 adult patients diagnosed with MM and receiving initial treatment between 1 January 2011 and 31 January 2020 were derived from the Flatiron Health electronic‐health record de‐identified database. The number/types of agents included in therapy regimens, time to next treatment (TTNT), and overall survival (OS) were assessed. Subgroups were analyzed by the International Staging System (ISS) disease stage at diagnosis, stem cell transplant eligibility and timing, and practice type. Exploratory prognostic models evaluated the association between baseline covariates and time‐to‐event outcomes. The proportion of patients receiving triplet therapies increased from 2011 (36%) to 2019 (72%) as those receiving initial monotherapy or doublet therapy decreased. Overall, the most prevalent triplet regimen consisted of an immunomodulatory drug (IMiD), a proteasome inhibitor, and a steroid. From 2017 to 2019, median TTNT from front‐line to second‐line was longer in patients with ISS stage I versus stages II/III, and in those receiving IMiD‐containing doublet or triplet therapies versus other combinations. Overall median OS was 56 months and increased from 2011 to 2014, after which median OS was not yet reached. Age, ISS stage, and high‐risk status were prognostic for both OS and TTNT, while sex, practice type, and ECOG status were prognostic for OS only.

AbstractVenetoclax (Ven) is a selective small‐molecule inhibitor of BCL‐2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open‐label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21–day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL‐2) and BCL2L1 (BCL‐XL) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow‐up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF‐kB. VenDex demonstrated efficacy and manageable safety in heavily‐pre‐treated patients with t(11;14) R/R MM.

Background: The FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Gilt) improves survival compared with standard salvage chemotherapy in relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML); however, relapses are common and long-term survival remains poor. Combination therapies of FLT3 tyrosine kinase inhibitors (TKIs) with agents that induce apoptosis have demonstrated preclinical synthetic lethality and enhanced cytotoxicity against FLT3mut+ clones. This may delay or prevent drug resistance. We present updated data from the dose-escalation and expansion cohorts of an ongoing, multicenter, open-label, Phase 1b trial (NCT03625505) of Gilt in combination with B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Ven) in patients (pts) with R/R FLT3mut+ AML. Methods: Pts with R/R AML with ≥1 prior line of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible. The expansion cohort required FLT3mut+ R/R AML at enrollment. Pts received the recommended Phase 2 dose (RP2D) of Ven 400 mg in combination with Gilt 120 mg daily in 28-day cycles, following a 3-day ramp-up of Ven. Pts with prior Gilt were excluded from expansion, and none were enrolled in dose escalation; prior Ven or other FLT3 inhibitor was permitted. Concurrent use of moderate or strong CYP3A4 inhibitor was allowed. Interruptions of Ven or both drugs simultaneously were permitted for management of adverse events (AEs), and subsequent cycles could include dose adjustments to minimize myelosuppression or other drug-related AEs. The primary endpoint was modified composite complete remission (mCRc; complete response [CR] + CR with incomplete platelet recovery [CRp] + CR with incomplete blood count recovery [CRi]) + morphologic leukemia-free state (MLFS). Responses were graded by the International Working Group (IWG) for AML criteria (with adapted CRi criteria as presented in the ADMIRAL trial) for comparison with composite CR (CRc) used in Gilt development. All criteria for response used by IWG were maintained in these response definitions. Secondary endpoints included CR + CR with partial hematologic recovery (CRh) and duration of response (DOR) of mCRc. Results: At data cutoff, April 15, 2020, 39 R/R pts started therapy at the RP2D (internal tandem duplications [ITD] only [n=32]; tyrosine kinase domain [TKD] mutation only [n=5]; both TKD and ITD [n=2]). Median age was 63 years (range 23-85) and the majority had an ECOG status of 1-2 (87.2%). Most pts (n=29; 74.4%) had received ≥2 prior lines of therapy, including ≥1 FLT3 TKI (n=25, 64.1%; midostaurin, n=19; sorafenib, n=5; crenolanib, n=1). Twelve pts (30.8%) had prior stem-cell transplant (SCT); 3 (7.7%) had received prior Ven. Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 37 pts (94.9%), and 28 (71.8%) reported serious AEs. The only Grade 3/4 nonhematologic TEAE reported in >20% of pts was febrile neutropenia (48.7%). Four pts (10.3%) experienced a fatal AE, including colitis, disease progression, multiple organ dysfunction syndrome, and bronchopulmonary aspergillosis (all n=1). AEs leading to Ven and Gilt interruptions occurred in 19 pts (48.7%) and 18 pts (46.2%), respectively, and AEs leading to dose reductions occurred in 2 pts (5.1%) for each treatment. Six pts (15.4 %) and 5 pts (12.8%) discontinued Ven and Gilt, respectively, owing to AEs. mCRc was achieved by 83.8% of pts (n=31/37; Table). With median duration of follow-up of 2.9 (range 0.8−11.0) months in all pts, median event-free survival was 5.1 (95% confidence interval: 2.8, 8.3) months but administrative censoring after short follow-up for a large number of recently enrolled patients limits interpretation; median DOR has not been reached. Eight pts (21.6%), all ITD only, proceeded to SCT. CR + CRh was achieved by 7 pts (18.9%). Conclusions: Ven plus Gilt achieved a very high overall rate of marrow and blood blast elimination and mCRc rate (84%) in this expansion cohort of heavily pretreated FLT3mut+ pts, the majority of whom had prior FLT3 TKI exposure. Using similar response assessment criteria, the high mCRc rate here suggests substantially greater antileukemic activity from Ven plus Gilt compared with single-agent Gilt. Cytopenias were prominent but manageable with dose interruption/modification on subsequent cycles. Nonhematologic toxicities were modest, and the combination was well tolerated. Disclosures Daver: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Altman:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Agios, Theradex, Abbvie: Other: Advisory Board; Astellas, Agios: Honoraria, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Patents & Royalties: Scientific Advisory Board - no payment accepted; Biosight: Other: No payment but was reimbursed for travel . Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Ritchie:Abbvie: Honoraria; Sierra Oncology: Honoraria; Incyte: Speakers Bureau; Novartis: Honoraria; Jazz pharmaceuticals: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. McCloskey:Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Smith:Abbvie: Other: Research Support, Research Funding; Sanofi: Honoraria; Astellas Pharma: Honoraria, Other: Research Support, Research Funding; FujiFilm: Other: Research support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria. Schiller:Johnson & Johnson: Current equity holder in publicly-traded company; Novartis: Consultancy, Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Genentech-Roche: Research Funding; Geron: Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Celator: Research Funding; FujiFilm: Research Funding; Ariad: Research Funding; Constellation: Research Funding; Cyclacel: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Astellas Pharma: Honoraria, Research Funding; Actinium: Research Funding; Gamida: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Daiichi Sankyo: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Forma: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Sanofi: Speakers Bureau. Bradley:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Qin:AbbVie: Current Employment, Other: may hold stock or other options. Dilley:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Perl:Leukemia & Lymphoma Society.: Other; AbbVie Inc, Astellas, Actinium, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo Inc, FUJIFILM Pharmaceuticals USA Inc: Research Funding; AbbVie Inc, Actinium Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc, FORMA Therapeutics, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, NewLink Genetics: Other; AbbVie Inc, Arog Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc: Consultancy; Astellas, AbbVie Inc, Daiichi Sankyo, Actinium, Forma, Syndax, Loxo: Consultancy, Honoraria. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test.

Introduction: MM is an incurable disease with risk categorizations by cytogenetic abnormalities. Prognostic implications of chromosome translocation t(11;14)+ are important to inform development of biomarker-targeted therapies such as the B-cell lymphoma-2 (BCL-2) pathway inhibitors. This study aims to evaluate MM treatment (Tx) patterns and outcomes of t(11;14)+ compared with other cytogenetic cohorts in US routine clinical practice. Methods: A retrospective observational cohort study of the Flatiron Health database, which comprises de-identified electronic health record-derived patient (pt)-level data from over 280 community and academic cancer clinics in the US. Pts aged ≥18 years who received a first-line (1L) induction Tx within ≤60 days of MM diagnosis from 1/1/2011 to 1/31/2020, and were not enrolled in a clinical trial were identified at the start of each Tx line (index date) and followed up (f/u) until 1/31/2020. Only cytogenetic results by fluorescence in situ hybridization (FISH) were used to stratify the cohort into: t(11;14)+; standard risk, excluding t(11;14)+ (SR); and high risk, (HR; del 17p, t(4;14), t(14;16), t(14;20), chromosome 1 abnormalities as a proxy for 1q gain; and t(11;14) where it co-occurs). Descriptive analyses of pt characteristics and Tx were conducted. Kaplan-Meier analyses were used to evaluate median time to next treatment (TTNT) and overall survival (OS) with log-rank test for significance. The cohort was stratified by age ≤70/>70 years (yrs) as a proxy for transplant eligibility. Results: Of 10,703 pts with MM in the database, 5982, 3059 and 1595 pts were eligible for 1L, second-line (2L), and third-line (3L) analysis, of which 76%, 84%, and 86%, respectively, had FISH test results before Tx initiation. 14% of pts with FISH test results were t(11;14)+, ~55% SR and ~35% HR. Included pts were predominately male (55%), ~90% treated in the community setting and ~16% African-American. Pts in the 3L cohort were younger at diagnosis with a median age (interquartile range) of 67 (59 ̶ 74) yrs compared with 69 (61 ̶ 76) yrs in both 1L and 2L. The 1L Tx pattern was consistent across cytogenetic cohorts with bortezomib (V), lenalidomide (R), dexamethasone (d) as the most common Tx (>42%). Together, VRd, Rd, Vd, and cyclophosphamide (Cy) in combination with Vd represented ≥90% of 1L Tx (Figure 1). Across 2L cytogenetic cohorts, the most common Tx regimens (≥25%) were VRd and Rd. The use of regimens containing carfilzomib (K) and daratumumab (D) was emerging in 2L: KRd in 8% of t(11;14)+ and HR and 5% in SR; Kd 5% in all groups; DRd in 4% of t(11;14)+ and 3% in SR and HR (Figure 1). 3L Tx pattern was fragmented with different Tx regimens. Rd was the most common 3L Tx option: 9% in t(11;14)+, 10% in SR and 7% in HR (Figure 1). Across all lines of Tx, t(11;14)+ had similar Tx outcomes to SR, and HR had poorest outcomes (Table 1). Pts TTNT shortened as they advanced to later lines of Tx (Table 1). Although TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts, especially in 1L where transplant in those ≤70 yrs vs >70 yrs at diagnosis was 44% vs 11% for t(11;14)+, 47% vs 10% for SR and 49% vs 9% for HR. Conclusions: This study identified cytogenetic subgroups across 1L to 3L in a predominately community setting in the US. MM t(11;14)+ pts had similar 1L and 2L Tx patterns to SR and HR. Across all lines of Tx, the outcomes of t(11;14)+ and SR pts were comparable and better than HR pts. TTNT was reduced as pts advanced to later lines of Tx. Pts continuing to 3L Tx were younger at diagnosis, but there was not a clear-cut standard of care. While TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts. This study sets the benchmark for novel treatment options, such as BCL-2 pathway inhibitors, primarily wherever available biomarker-driven therapy is considered appropriate. Disclosures Atrash: Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; BMS, Jansen oncology, Sanofi: Speakers Bureau; Amgen, GSK, Karyopharm.: Research Funding. Flahavan:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Roche Products Ltd.: Current Employment. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Karve:AbbVie: Current Employment, Current equity holder in publicly-traded company. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jirau-Lucca:Genentech, Inc.: Current Employment; AbbVie: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Nixon:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Ailawadhi:Takeda: Honoraria; Pharmacyclics: Research Funding; Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Phosplatin: Research Funding; Amgen: Research Funding; Celgene: Honoraria; Janssen: Research Funding.

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 .

8547 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor that has synergistic activity with bortezomib (B) and dexamethasone (d). In the Phase 3 BELLINI trial, addition of Ven to Bd significantly improved median progression-free survival (PFS) and response rates, including minimal residual disease (MRD) negativity, but resulted in increased mortality vs placebo (Pbo). Here, we determine whether MRD negativity was associated with longer PFS and OS in relapsed/refractory multiple myeloma (RRMM) patients treated with Ven+Bd in the BELLINI dataset. Methods: In BELLINI (NCT02755597), RRMM patients (pts) sensitive or naïve to proteasome inhibitors with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo plus B (1.3 mg/m2) and d (20 mg). Next-gen sequencing MRD assessments were done on bone marrow aspirates at the time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive. Evaluation of MRD in biomarker-defined subgroups (cytogenetics and BCL2 expression) was also performed and will be presented. Results: In total, 291 pts were randomized; 194 to Ven, 97 to Pbo. As of 13 Sep 2019, the median follow-up was 29 months. Ven + Bd demonstrated significantly higher MRD negativity rates ( < 10−5), including a higher proportion of pts achieving sustained MRD negativity (Table). In the Ven arm, the median (m)PFS was not reached for MRD negative pts vs 16.2 months for MRD positive pts (HR = 0.23, 95% CI: 0.10-0.54, p < 0.001). While the mOS was not reached in the Ven arm, OS was significantly longer for MRD negative vs MRD positive pts (HR = 0.25, 95% CI: 0.08-0.80, p = 0.0194). Conclusions: The addition of Ven to Bd resulted in deep and durable responses, including higher rates of MRD negativity. MRD negativity in the context of Ven was associated with prolonged survival in patients with RRMM, consistent with the broader MRD body of evidence with other therapies in MM. Clinical trial information: NCT02755597 . [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]

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.