Citations

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.

7029 Background: CBP501, a synthetic duodecapeptide, enhances the cytotoxicity of cisplatin in cell lines and xenografts, including NCI-H226 human mesothelioma. CBP501 increases cisplatin influx into tumor cells through an interaction with calmodulin, and inhibits cell cycle progression by abrogating DNA repair at the G2 checkpoint. Phase I clinical trials combining CBP501 with cisplatin alone or with pemetrexed showed acceptable safety profiles and suggested activity. The most common toxicity of CBP501 is infusion-related urticaria, which is easily managed with diphenhydramine. Methods: Chemotherapy-naive patients with unresectable MPM were stratified by histology (epithelioid vs other) and performance status (PS 0-1 vs 2) and randomized 2:1 to Arm A: pemetrexed/cisplatin plus CBP501 25 mg/m2 IV (42 pts planned), or Arm B: pemetrexed/cisplatin alone at standard doses (21 pts planned). Patients continued on treatment until progression or intolerance; no maintenance therapy was delivered. The primary endpoint is progression free survival (PFS) in Arm A; if > 23 of the 42 patients remain free of progression more than 4 months, the combination will be deemed worthy of further study. In addition to standard CT imaging to assess response and PFS, PET scans, pulmonary function tests, and mesothelin levels were performed. Results: Enrollment was completed in October 2011. 65 pts from 14 institutions were randomized, and 63 were treated. Patient characteristics in the two arms were similar and as follows: median age 65, 82% male, 71% epithelioid histology, 8% PS2. Grade 3/4 treatment-related toxicities were uncommon, no different than expected from standard chemotherapy, and comparable in the two arms. 70% of patients treated with CBP501 had infusion reactions, all grade 1-2. The best overall response rate in evaluable patients (modified RECIST, investigator assessed) was 12/37 (32%) (95% CI 18-50) in Arm A, and 3/22 (14%) (95% CI 3-35) in Arm B. The median number of chemotherapy cycles was 5.5 in Arm A, 5 in Arm B. Conclusions: Data on the primary endpoint of PFS in Arm A are maturing and will be presented at the meeting.

TPS10592 Background: Angiosarcomas (ASs) are rare, aggressive, malignant endothelial cell tumors that constitute 1% to 2% of all soft tissue sarcomas with 5-year survival of 35%. Cytotoxic agents have demonstrated response rates of about 15%. Gene-array data from MSKCC has revealed up-regulation of endothelial associated genes, including active members of the angiopoietin system e.g., Tie2 and Angiopoietin 2 (Ang2). Trebananib (AMG386) is a novel agent that targets Ang1 and Ang2. We hypothesize that inhibition of angiopoietin 2 with trebananib will be an effective therapy in patients (pts) with AS. Methods: This CTEP sponsored, investigator initiated, multi-center phase II study uses trebananib, in pts with AS having metastatic/unresectable AS and conducted through the Alliance for Clinical Trials in Oncology (Alliance A091103). Pts must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are treated with trebananib 30mg/kg d1, 8, 15, and 22 every 28 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR) via RECIST v1.1. Secondary endpoints include the evaluation of progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with i. baseline and post-treatment expression of Ang2 and Tie2 by immunohistochemistry (IHC), ii. serum levels of Ang1 and Ang2, iii. baseline and post-treatment phospho-receptor tyrosine kinase (p-RTK) status of Tie2, VEGFR-2, PI3K, MEK and MAPK, and iv. mutational status of VEGFR-2 and amplification of MYC/FLT4. A Simon Optimal two-stage phase II study design is used and one confirmed response in the first 12 pts expands enrollment to 25. Pre- and post-treatment biopsies will be performed in up to 10 pts treated at MSKCC. Enrollment began in July 2012. As of January 2013, 7 pts have been recruited. Clinicaltrials.gov#: NCT01623869. Funded by the Alliance Clinical Trials in Oncology. NIH Grant CA-25224. Clinical trial information: NCT01623869.

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.

10088 Background: The ability of the immune system to recover its components after autologous stem cell transplantation (ASCT) is known to predict survival in patients with different types of neoplasms. Also, our previous work showed that polyclonal immunoglobulin can be used to improve T cell diversity and, consequently, T cell function in animal models. The aim of this retrospective study was to understand if the recovery of the polyclonal compartment of immunoglobulin in patients with multiple myeloma (MM) at day 100 (± 40d) after ASCT is a predictor factor for survival in MM patients who were subject to ASCT. Methods: From294 patients with IgG-MM subject to ASCT at the Mayo Clinic, Rochester, MN since October, 1993 until June, 2004, 143 patients were studied. The rational to select this group of patients was the fact that they had levels of serum IgM collected at day 100 ± 40 after ASCT recorded. Progression free survival (PFS) was assessed from the day of the transplant. PFS was studied using Kaplan-Meier curves and the univariate and multivariate analysis were done using age-adjusted proportional Cox. The prognostic variables in the multivariate model were: recovered of IgM at day 100, B2 microglobulin, age, conditioning regimen and disease status at the time of transplant. Results: There were 59 females in the study. The median age of the cohort was 58 y (33–75). The median follow up of the study was 26 mo (range, 2-111). PFS was significantly higher in the group who recovered normal serum levels of IgM at D100 compared to the pts who did not. This corresponds to a survival that is 1.5 longer in the group of patients who recovered normal levels of IgM at day100 after ASCT versus the patients who did not (median: 34 to 23 mo, respectively; p=0.05). By univariate analysis, those who did not recover normal serum levels polyclonal immunoglobulin by day 100 after ASCT had a risk of relapse 65% higher than the risk of the patients who recovered. Multivariate analysis suggests that recover the normal levels of polyclonal immunoglobulin after ASCT is an independent prognostic factor for PFS for MM patients after ASCT. Conclusions: These results suggest that polyclonal immunoglobulin is a major factor promoting immunity after ASCT. No significant financial relationships to disclose.

583 Background: Lapatinib is an orally bioavailable reversible, dual tyrosine kinase ErbB1 and ErbB2 inhibitor. Trastuzumab, an ErbB2 inhibitor, has been associated with cardiotoxicity. Methods: Left ventricular ejection fraction (LVEF) was monitored every 8 weeks using MUGA or echocardiogram. Cardiac risk factors including age, underlying cardiovascular disease, previous exposure to AC, trastuzumab, or mediastinal/left sided radiation (XRT) were also collected. LVEF data were evaluated for ≥ NCI CTC grade 3, or ≥ 20% decline relative to baseline (& below institutional LLN). Results: 1.3%, 37 of the 2812 subjects who have received lapatinib in all trials to date have experienced decreased LVEF. 22 of 37 patients received lapatinib monotherapy, the remaining 15 received lapatinib in combination with other chemotherapeutic agents. 68% (25/37) of patients were female, median age was 59 years. Decreased LVEF occurred within 9 weeks of treatment onset in 68% of cases. The event resolved/improved in 57% of cases: in 50% of these, lapatinib treatment was continued. Average event duration was 5 weeks. Four of 37 patients were symptomatic (0.1% incidence). Most symptomatic events responded promptly to standard CHF therapy. The majority of patients (92%, 34/37) had confounding factors that may have contributed to the event, including previous exposure to AC, trastuzumab or XRT, and/or medical history. 8 of 34 patients had a positive lapatinib dechallenge (LVEF recovered): 3 were symptomatic (signs of CHF) and 5 asymptomatic. 3 patients had no contributing factors: 1 experienced symptomatic decreased LVEF, the remaining 2 died due to disease progression whilst LVEF decrease was ongoing. 16 of 1307 patients participating in placebo controlled studies experienced decreased LVEF. Of these 8 are known to have received lapatinib, giving an incidence of 1.2% (8/654). Conclusions: Lapatinib-associated LVEF decrease is rarely symptomatic and generally reversible/non-progressive. Incidence was 1.3% in our population, less than the 3–6% incidence of asymptomatic LVEF decreases observed in the general population. Pharmacogenetic studies are ongoing to determine whether there is a link between ErbB2 polymorphisms and lapatinib cardiotoxicity. [Table: see text]

Abstract Purpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental Design: Matched case–control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1−/− T47D breast cancer cell line. Conclusions: This matched case–control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.

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 >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<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<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.

Background. Candida tropicalis is a virulent fungal pathogen for which echinocandins are the primary therapy. Emergence of resistance to echinocandins of C. tropicalis carries potentially ominous therapeutic implications. Methods. We describe herein two patients with breakthrough C. tropicalis fungemia during echinocandin therapy, characterize their molecular mechanism of resistance, and systematically review 13 previously reported cases of echinocandin-resistant C. tropicalis bloodstream infections (BSIs) and other diseases. Results. Among these 15 patients with echinocandin-resistant C. tropicalis infections, the median age was 61 years (ages 28–84 years) and 13 (86%) were immunocompromised. Thirteen (86%) of all patients had a history of pervious or concurrent exposure to echinocandins. Isolates of C. tropicalis from 11 cases, including the two index cases, underwent DNA sequencing of the FKS1 gene for mutations known to confer echinocandin resistance. The amino acid substitution Ser654Pro was shown in four cases, while other FKS1 mutations encoded Ser80S/Pro, Phe641Leu, Phe641Ser, Ser80S/Pro substitutions. These mutational events were not associated with collateral increases in minimum inhibitory concentrations to antifungal triazoles and amphotericin B. Overall mortality in patients with echinocandin-resistant C. tropicalis infections was 40%. Among those six patients who died, two received monotherapy with voriconazole, one was treated with fluconazole, one remained on caspofungin, and two were switched to liposomal amphotericin B. Nine patients (60%) survived after being treated with an antifungal agent other than an echinocandin. Conclusions. Emergence of resistance to echinocandins by C. tropicalis, occurs during antifungal therapy, is associated with high mortality, is mediated by a diverse range of FKS1 mutations, retains in vitro susceptibility to triazoles and amphotericin B, and constitutes an emerging threat to patients with hematological malignancies.