Abstract: BACKGROUND Lenalidomide (LEN) until progressive disease (PD) is an established treatment (Tx) in newly diagnosed and relapsed and/or refractory multiple myeloma (RRMM); thus, patients (pts) for whom the benefit of LEN has been exhausted are a clinically relevant population. However, LEN-refractory pts have typically been excluded from recent clinical trials investigating triplet regimens after ≤ 3 prior Tx lines. MM-014 (NCT01946477) is an ongoing phase 2 study that was designed to assess the safety and efficacy of pomalidomide (POM)-based Tx regimens in pts with RRMM and first- or second-line LEN Tx failure immediately before study entry. Earlier results from cohort A (POM + low-dose dexamethasone [LoDEX]) and cohort B (POM + LoDEX + daratumumab [DARA] ) indicate that POM-based Tx is safe and effective in this setting. Here we report updated results from cohort B. METHODS Eligible pts had RRMM, had 1 or 2 prior lines of Tx, received LEN-based Tx as their most recent Tx regimen, and had PD during or after their last line of Tx. Pts received POM 4 mg/day on days 1 through 21 + LoDEX 40 mg/day (20 mg/day if aged 〉 75 years) on days 1, 8, 15, and 22 and DARA 16 mg/kg intravenously on DEX dosing days of cycles 1 and 2, days 1 and 15 of cycles 3 through 6, then day 1 of cycle 7 and beyond. Each Tx cycle lasted 28 days. Thromboprophylaxis was mandatory. The primary endpoint for cohort B is overall response rate (ORR) by modified International Myeloma Working Group criteria. Secondary endpoints include time to response (TTR), progression-free survival (PFS), time to progression (TTP), and safety. RESULTS The intention-to-treat (ITT) population comprised 112 pts (median follow-up, 8.2 mos); data cutoff was April 30, 2018. Median age was 66.5 years, 67.9% of pts were male, and 111 (99.1%) had ECOG PS ≤ 1. A total of 34 pts discontinued Tx: 19 due to PD, 9 due to study withdrawal, 2 due to adverse events (AEs), and 4 due to other reasons. All pts received prior LEN, and 87 (77.7%) received prior bortezomib; 84 pts (75.0%) were refractory to LEN, while 28 (25.0%) relapsed after LEN-based Tx. Median duration of the most recent prior LEN-based Tx was 23.9 mos, with 36 pts (32.1%) receiving LEN 25 mg/day during their last LEN-based Tx. ORR was 77.7%, with 33.9% of pts achieving ≥ very good partial response. Median TTR was 1.0 mo. The clinical benefit rate (≥ minimal response [MR]) was 85.7%. ORR was 80.6% in the efficacy-evaluable population (n = 108; defined as all pts who received ≥ 1 dose of study drug and had ≥ 1 post-baseline response assessment), 75.0% in LEN-refractory pts, and 76.2% in pts with 2 prior lines of Tx (n = 42). The 9-mo PFS rate was 86.3% (range, 76.5%-92.2%); median PFS was not estimable (NE; Figure). The 9-mo TTP rate was 88.1% (range, 78.3%-93.6%); median TTP was NE. The most common grade 3/4 hematologic treatment-emergent AE (TEAE) in the safety population (n = 112) was neutropenia (61.6%; Table); pneumonia was the most common grade 3/4 nonhematologic TEAE (7.1%). POM dose reductions occurred in 31 pts (27.7%); per protocol, DARA dose reductions were not allowed. POM dose interruptions due to AEs were reported in 69 pts (61.6%) and DARA dose interruptions due to AEs were reported in 82 pts (73.2%). POM and DARA dose interruptions due to neutropenia were reported in 39 (34.8%) and 42 (37.5%) pts, respectively; 25 pts (22.3%) had DARA dose interruptions due to infusion-related reactions. Median durations of POM and DARA Tx were 6.0 mos (range, 0.3-17.7 mos) and 6.6 mos (range, 0.3-18.6 mos), respectively; among those who achieved ≥ MR, pts remained on POM Tx for a median of 7.4 mos (range, 0.9-17.7 mos) and on DARA Tx for a median of 7.5 mos (range, 0.9-18.6 mos). CONCLUSIONS LEN-refractory pts with RRMM are in need of effective Tx options. MM-014 is the first prospective clinical trial to investigate a POM-based doublet or triplet regimen immediately after LEN-based Tx failure. In the context of a relatively short follow-up, the 9-mo PFS rate (86.3%) is promising. The ORR (77.7%) was higher than that previously reported with this triplet combination in heavily pre-treated pts with RRMM (≥ 2 prior lines [median, 4]; ORR, 60%), and the rate of grade 3/4 neutropenia in the present study was lower (61.6% vs 77%). These updated res ults from cohort B continue to demonstrate that POM + LoDEX + DARA is safe and effective following first- or second-line LEN-based Tx failure and further support earlier use of POM-based Tx in pts with RRMM Disclosures Siegel: Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Berdeja:Bluebird: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Glenmark: Research Funding; Genentech: Research Funding; Amgen: Research Funding; Teva: Research Funding; Poseida Therapeutics, Inc.: Research Funding. Ganguly:Janssen: Consultancy; Seattle Genetics: Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Bar:Celgene: Consultancy. Quick:CTI BioPharma: Research Funding. Fonseca:Celgene: Speakers Bureau. Reece:Janssen: 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; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Agarwal:Celgene Corporation: Employment, Equity Ownership. Chung:Celgene Corporation: Employment, Equity Ownership. Zafar:Celgene: Employment. Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Abstract: Background: Venetoclax (Ven), a highly selective BCL-2 inhibitor, combined with azacitidine (Aza) suppresses oxidative phosphorylation, which selectively targets leukemia stem cells that drive initiation and perpetuation of acute myeloid leukemia (AML; Pollyea. Nat Med. 2018;24:1859), an aggressive malignancy most common in older adults. Safety and efficacy of Ven combined with the hypomethylating agents (HMA) Aza or decitabine (Dec) for the treatment of newly diagnosed AML in patients (pts) who are ineligible to receive intensive chemotherapy has been demonstrated (DiNardo. Blood. 2019;133:7; DiNardo. N Engl J Med. 2020;383:617). Phase 1 and Phase 3 studies initiated Ven + HMA in an inpatient setting due to the nature of the study design and concerns of tumor lysis syndrome (TLS) based on chronic lymphocytic leukemia treatment with Ven. Safety and efficacy of Ven + HMA treatment initiation in an exclusively outpatient setting is being evaluated in an ongoing Phase 3b, single-arm, multicenter, open-label study (NCT03941964). Here, we present pt baseline (BL) characteristics and safety during initial outpatient dose ramp-up of Ven + HMA. Methods: Pts with untreated AML with an ECOG performance status of 0-3 who were ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at BL, and deemed an appropriate candidate for outpatient initiation of Ven + HMA by the investigator were eligible. Enrolled pts received Ven (100 mg on Cycle [C] 1 Day [D] 1, 200 mg C1D2, 400 mg C1D3-D28, and 400 mg daily for each 28-day cycle thereafter) in combination with Aza (75 mg/m 2 intravenously [IV] or subcutaneously for 7 days) or Dec (20 mg/m 2 IV for 5 days), beginning on D1 of each cycle, as per institutional practice, for ≤6 cycles. After the study period ended, pts could continue receiving commercially acquired standard-of-care treatments with Ven and Aza or Dec. Ven dosing was modified for concomitant use with moderate and strong CYP3A inhibitors (CYP3Ai). Ven and HMA dosing adjustments were permitted for the management of adverse events (AEs). TLS prophylaxis was initiated in all pts before the first dose of study drug or first new escalated dose. Pts were screened for BL TLS markers. BL AML characteristics, such as blast count and cytogenetics, were examined. The incidence of TLS per Howard Criteria (Howard. N Engl J Med. 2011;364:1844) was assessed for 5 days starting after the first dose of Ven. Results: At the data cutoff (April 30, 2021), 53 pts were enrolled, with 27 receiving Ven + Aza and 26 receiving Ven + Dec (Table). Among all pts, the median age was 76 years (range, 66-94), 89% of pts had an ECOG performance status of 0-1, and 60% were ineligible for standard induction therapy due to age ≥75 years. Overall, 15% and 38% of pts were transfusion-dependent on platelets or red blood cells, respectively. Grade 4 neutropenia was present at BL in 51% of pts; renal and hepatic impairment were present at BL in 79% and 19%, respectively. Most pts had intermediate (47%) or poor (43%) cytogenetic risk. De novo AML was the most common type of disease (75%), followed by secondary (17%) and therapy-related AML (8%). Thirteen pts (25%) had ≥50% bone marrow blasts, and the median blast count was 30% (range, 0-90). In some pts, mutations in biomarkers of interest (FLT3, IDH1/2, NPM1, and TP53) were detected; an analysis will be presented. Nineteen pts (36%) received prophylactic anti-infective moderate or strong CYP3Ai. During Ven ramp-up, there were no cases of clinical TLS and 2 cases (4% of pts) of laboratory TLS; both pts were hospitalized and managed with dose interruption and medical intervention, and neither case led to treatment or study discontinuation. Three pts were hospitalized during Ven ramp-up for other serious AEs. Conclusion: In our study of pts receiving Ven + HMA in an outpatient setting at US community-based oncology centers, most had an ECOG performance status of 0-1 and were not platelet or red blood cell transfusion-dependent. Disease was primarily de novo AML, and 74% of pts had bone marrow blast counts & lt;50%. During ramp-up of Ven, & lt;10% of pts required hospitalization for any reason; 4% of pts met criteria for TLS, without requiring discontinuation. These results indicate that, with appropriate TLS prophylaxis and monitoring, pts with untreated AML can safely initiate Ven in an outpatient setting. Figure 1 Figure 1. Disclosures Manda: Genmab: Current equity holder in publicly-traded company; Morphosys: Honoraria. Benton: AbbVie: Consultancy; Karyopharm: Consultancy; Pharmaessentia: Consultancy. Yimer: Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Beigene: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Renshaw: Amgen: Speakers Bureau; SeaGen: Consultancy; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Texas Oncology: Current Employment. Geils: Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen Oncology: Honoraria, Speakers Bureau. Fanning: Sanofi: Speakers Bureau; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; BMS: Speakers Bureau. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Sharman: BMS: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy; BeiGene: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Kang: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Svensson: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Pai: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Abstract: 100 Background: Improving the value provided to patients and payers in our system of cancer care relies on reduction of avoidable hospital and emergency department (ED) utilization. Furthermore, recent payer pressures on community oncology practices (COPs) have resulted in an increased focus on improving care coordination (CC) under strict resource constraints. As part of the ASCO Quality Training Program, we tested several low-cost CC interventions, leveraging workflow redesign, already employed care team members, and technology already implemented, to reduce ED visits (EDV) in a single large COP clinic where more than 3,200 cancer patients were treated during 2016. Methods: Baseline EDV rates were obtained through nurse chart review during Jan.-Jun. 2016. The following CC interventions were implemented: Initiated after hours call process with access to EMR and patient access to bidirectional real-time messaging with care team members; Implemented new in-office process to “close the loop” on patient evaluations by creating follow up guidelines for symptomatic telephone triage and in-clinic patient evaluations; Implemented a standard 48 hour follow up process for all EDV and hospital admissions; Increased patient awareness of telephone triage services during and after clinic hours by: augmenting new patient education by staff, developing a magnetic reminder to call the office for non-emergent and emergency situations, and instructions for use of afterhours call system. Nurse chart reviews were conducted throughout implementation to observe effects of new CC processes on EDV. Results: We observed a 30% reduction in EDV from baseline measurement. No new FTEs added and no new technology licenses acquired for this initiative. Conclusions: Low-cost CC interventions can be implemented in COPs to avoid ED utilization. Limitations of this analysis included manual chart abstraction that could not account for EDV outside the partnering health system, illustrating data access for hospital utilization remains a major challenge for quality improvement efforts for COPs. Additional challenges have been experienced in expanding these process improvements from a single large clinic to the broader Tennessee Oncology network of more than 30 clinics.

Abstract: The combination of azacitidine with pracinostat does not improve outcomes in patients with higher‐risk myelodysplastic syndromes. Higher rates of treatment discontinuation may partially explain these results. See also pages 911‐4.

Abstract: Background: Venetoclax (VEN), a B-cell lymphoma 2 inhibitor, is an oral agent with demonstrated efficacy in patients (pts) with chronic lymphocytic leukemia (CLL). VEN treatment induces rapid tumor reduction, posing a risk for tumor lysis syndrome (TLS), particularly in pts with high tumor burden, and may require inpatient monitoring at the initiation of therapy. Agents such as obinutuzumab (G), ibrutinib, and bendamustine (B) have been used in clinical studies to debulk tumors prior to treatment with VEN. However, the benefits of these debulking regimens could not be established conclusively, as disease restaging was rarely performed. In the present study, disease restaging was performed every 2 cycles to evaluate the efficacy and safety of G, with or without B, as a debulking therapy in untreated pts with CLL, prior to VEN treatment in an outpatient community setting. Methods: This open-label, phase 3b trial (NCT03406156) enrolled adult pts with previously untreated CLL/small lymphocytic lymphoma (excluding those with 17p deletion) who had Eastern Cooperative Oncology Group performance status of ≤1 and medium (any lymph node [LN] 5 to & lt;10 cm or absolute lymphocyte count [ALC] ≥25 × 109/L) or high (any LN ≥10 cm or ALC ≥25 × 109/L and any LN ≥5 cm) tumor burden. Pts received at least 2 cycles of debulking therapy (G±B), which could be repeated for a maximum of six 28-day cycles until low tumor burden (ALC & lt;25 × 109/L and all LN & lt;5 cm) was achieved. B was administered at investigator discretion, with protocol recommendation for pts with LN & gt;10 cm or with del(11q) and LN & gt;5 cm. Restaging data were obtained after every 2 cycles of debulking therapy. When low tumor burden was achieved, VEN was administered (5-week ramp-up schedule) as combination therapy with G (VEN+G) for 5 months, and then as monotherapy (VEN mono) for a total of 1 year. Response assessments were scheduled at week 38 and week 65 post-VEN initiation. Adverse events (AEs) were monitored throughout the study. Primary endpoints were the reduction in tumor burden after debulking therapy and the complete remission (CR)/CR with incomplete marrow recovery (CRi) rates of pts subsequently treated with VEN. We report the results of a planned interim analysis when 50 pts had completed their week 38 disease assessment. Results: As of 3 Feb 2020, 117 pts were treated with study drug(s): 80 (68%) received G and 37 (32%) received G+B for debulking; 113 pts were active in study (7 in the debulking phase; 106 completed debulking therapy and initiated VEN, including 26 in posttreatment follow-up). Four pts discontinued study due to withdrawal by pt (n=2; 1 at debulking and 1 at VEN treatment phase) and physician decision (n=1; at VEN treatment phase) and other (n=1; at debulking). At baseline, 85% of pts had ALC ≥25 × 109/L, 9% had LN ≥10 cm, 23% had LN 5-10 cm; 74%/26% had medium/high TLS risk, respectively, per investigator assessment (1 pt with low TLS risk was enrolled and subsequently discontinued). After 2 cycles of debulking therapy, low tumor burden was achieved in 85% (89/105) of evaluable pts: 86% (63/73) with G and 81% (26/32) with G+B. Reductions by pt subgroups and genetic features are presented in Figure. For pts debulked with G, similar debulking efficacy was observed among the subgroups being explored (Figure). Of the 50 pts with a week 38 disease assessment, 17 pts had an initial response of partial remission and await confirmation per IWCLL criteria. Objective response rate was 96% (48/50) overall, with 95% (37/39) for those debulked with G and 100% (11/11) for those debulked with G+B. The rate of CR or CRi was 52% (26/50) overall, with 54% (21/39) achieving CR/CRi for those debulked with G and 45% (5/11) for those debulked with G+B (Figure). More grade ≥3 AEs were observed in pts receiving G+B than those receiving G: debulking, 62% vs 40%; VEN+G, 43% vs 34%; VEN mono, 41% vs 28%. Conclusions: Most pts (85%) achieved low tumor burden after 2 cycles of G±B. Similar debulking efficacy was observed across subgroups in pts debulked with G. In this early efficacy analysis, CR/CRi at week 38 was observed in 52% of pts treated with VEN after the debulking phase. Preliminary efficacy results from this study are consistent with other VEN studies in treatment-naive pts. Current study highlights the efficacy of the debulking strategy prior to treatment with VEN; this may allow more pts to have VEN ramp-up in outpatient setting. Figure Disclosures Flinn: Calithera Biosciences: Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; Merck: Research Funding; Curio Science: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Constellation Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; BeiGene: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Forty Seven: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Takeda: Consultancy, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; Agios: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Loxo: Research Funding; Genentech, Inc.: Research Funding. Andorsky:AstraZeneca: Research Funding; Celgene: Research Funding; AbbVie: Honoraria. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Anz:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Kolibaba:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Verastem: Honoraria; Cell Therapeutics: Research Funding; Celgene: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Atara Biotech: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Acerta: Research Funding; Compass Oncology: Ended employment in the past 24 months; McKesson Life Sciences: Consultancy; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: travel, accommodations, expenses, . Yimer:Sanofi: Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; TG Therapeutics: Consultancy; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Burke:Adaptive: Consultancy; Kura: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; Astra Zeneca: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy. Fanning:TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Courtright:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Islas-Ohlmayer:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Kambhampati:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Pesko:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Vizkelety:AbbVie: Current Employment, Other: may hold stock or stock options.. Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding.

Abstract: Background : Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US and EU for patients (pts) with CLL and allows for treatment without chemotherapy. Standard of care for first-line CLL in older pts or those with comorbidities includes single-agent ibr and chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As the addition of obinutuzumab (G) to clb provides superior efficacy over clb alone or rituximab-G, we investigated the potential for improved efficacy with addition of G to single-agent ibr vs clb-G in an international, open-label, randomized phase 3 study (PCYC-1130; iLLUMINATE) in first-line CLL/SLL. Methods : Eligible pts had previously untreated CLL/SLL requiring treatment per iwCLL criteria and were ≥65 years of age or were 〈 65 years old with coexisting conditions (Cumulative Illness Rating Scale score 〉 6, creatinine clearance 〈 70 mL/min, and/or del(17p) or TP53 mutation). Pts were randomized 1:1 to receive ibr (420 mg once daily continuously) combined with G (1000 mg on days 1/2, 8, and 15 of cycle 1, and day 1 of subsequent 28-day cycles, for a total of 6 cycles), or clb (0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles) combined with G (as above). Primary endpoint was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary endpoints included PFS in high-risk population (del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV), rate of undetectable minimal residual disease (MRD), overall response rate (ORR), overall survival (OS), and safety. Pts with IRC-confirmed progression on clb-G could cross over to next-line therapy with single-agent ibr. Results : A total of 229 pts were randomized to ibr-G (n=113) or clb-G (n=116). Median age was 71 years (range, 40-87) and 65% of pts had high-risk genomic features. At a median follow-up of 31.3 mo, ibr-G significantly prolonged IRC-assessed PFS compared with clb-G (median not reached [NR] vs 19.0 mo; HR 0.231; 95% CI, 0.145-0.367; P 〈 0.0001), with a 77% reduction in risk of progression or death (Figure 1). PFS rates at 30 mo were 79% and 31% with ibr-G and clb-G, respectively. Investigator (INV)-assessed PFS was also significantly improved with ibr-G vs clb-G (median NR vs 21.9 mo; HR 0.260; 95% CI, 0.163 to 0.415; P 〈 0.0001). PFS benefit with ibr-G was consistent across subgroups examined. Superior PFS with ibr-G vs clb-G was also seen in the high-risk population (median NR vs 14.7 mo; HR 0.154; 95% CI, 0.087-0.270; P 〈 0.0001), with an 85% reduction in risk of progression or death in this population (Figure 2). IRC-assessed ORR was 88% with ibr-G vs 73% with clb-G; complete response (CR/CRi) rate was also higher with ibr-G (19% vs 8%). INV-assessed ORR was 91% with ibr-G vs 81% with clb-G; CR/CRi rates were 41% and 16%, respectively. MRD was undetectable in blood and/or bone marrow ( 〈 10-4 by flow cytometry) for 35% of pts with ibr-G and 25% with clb-G. 30-mo OS rates were 86% and 85% in the ibr-G and clb-G arms, respectively, with 40% of pts randomized to clb-G receiving single-agent ibr as second-line therapy. Over a median follow-up of 31.3 mo, 4% in the ibr-G arm and 44% in the clb-G arm initiated subsequent therapy. Median treatment duration was 29.3 mo with ibr-G and 5.1 mo with clb-G. Most common (≥3%) serious adverse events (AEs) were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%) with ibr-G, and infusion-related reactions (IRRs; 7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%) with clb-G. IRRs were less frequent with ibr-G vs clb-G for both any grade (25% vs 58%) or grade ≥3 or serious IRRs (3% vs 9%). No pt discontinued G due to IRRs with ibr-G vs 7 pts (6%) with clb-G. AEs leading to discontinuation of ibr or clb occurred in 18 (16%) and 11 pts (9%), respectively; AEs leading to discontinuation of G occurred in 10 pts (9%) in ibr-G arm and 15 (13%) in clb-G arm. With ~3 yrs of follow-up, 70% of pts in the ibr-G arm remain on single-agent ibr. Conclusions : Ibr-G resulted in superior PFS regardless of high-risk genomic features, compared with clb-G, a standard CIT regimen. Response rates and depth of remission (CR and undetectable MRD) were also higher with ibr-G. Combination therapy with ibr-G was tolerable with no new safety signals identified and represents an effective chemotherapy-free treatment option for first-line CLL/SLL including the high-risk population. Disclosures Moreno: Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Greil:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Demirkan:Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Tedeschi:Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Simkovic:Roche/Genentech: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Novak:Amgen: Consultancy; Takeda: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Strugov:Beigene Ltd: Equity Ownership; Kite Pharma: Equity Ownership; Portola Pharmaceuticals Inc: Equity Ownership; Juno Therapeutics: Equity Ownership; TG Therapeutics Inc: Equity Ownership; Loxo Oncology Inc: Equity Ownership; Crispr Therapeutics AG: Equity Ownership; Intellia Therapeutics Inc: Equity Ownership; Editas Medicine Inc.: Equity Ownership; Ignyta Inc.: Equity Ownership; Astellas: Honoraria; AbbVie: Equity Ownership, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Janssen: Honoraria; ECO-SAFETY Medical Center: Employment; Aptose Biosciences Inc: Equity Ownership; Esperion Therapeutics Inc: Equity Ownership; Merck & Company: Other: TRAVEL, ACCOMODATIONS, EXPENSES. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Gribben:Roche: Honoraria; Abbvie: Honoraria; Kite: Honoraria; NIH: Research Funding; Wellcome Trust: Research Funding; Unum: Equity Ownership; Pharmacyclics: Honoraria; Acerta Pharma: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Cancer Research UK: Research Funding; Medical Research Council: Research Funding. Hsu:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Clow:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: LEADERSHIP; TRAVEL, ACCOMODATIONS, EXPENSES. James:AbbVie: Equity Ownership, Other: Spouse's employment and stocks, Patents & Royalties: AbbVie Patent Applications; Pharmacyclics LLC, an AbbVie Company: Employment. Styles:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Flinn:Genentech: Research Funding; Pharmacyclics: Research Funding; Trillium: Research Funding; Curis: Research Funding; Agios: Research Funding; Forty Seven: Research Funding; Kite: Research Funding; Janssen: Research Funding; ArQule: Research Funding; Gilead: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Forma: Research Funding; BeiGene: Research Funding; Merck: Research Funding; Portola: Research Funding.

Abstract: Background : Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US and EU for patients (pts) with CLL and allows for treatment without chemotherapy. Standard of care for first-line CLL in older pts or those with comorbidities includes single-agent ibr or chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As no data were available from phase 3 studies directly comparing single-agent ibr with CIT, we performed a cross-trial analysis using data from two phase 3 studies to assess single-agent ibr vs clb plus obinutuzumab (G) in first-line CLL. Methods : In the ongoing PCYC-1115/1116 (RESONATE-2), pts with previously untreated CLL/SLL aged ≥65 years without del(17p) were randomized to receive ibr (420 mg once daily continuously) or clb. In PCYC-1130 (iLLUMINATE), pts with untreated CLL/SLL aged ≥65 years or 〈 65 years with coexisting conditions or del17p/TP53 mutation were randomized to receive ibr plus 6 cycles of G or 6 cycles of clb-G. As pts with del(17p) were ineligible for RESONATE-2, pts with del(17p) in iLLUMINATE were excluded from cross-trial analyses. Primary analysis was investigator (INV)-assessed progression-free survival (PFS) with single-agent ibr in RESONATE-2 vs clb-G in iLLUMINATE; secondary analyses were PFS in the high-risk population (del(11)q, TP53 mutation, or unmutated IGHV), medical resource utilization in the first 6 mo, and safety (including time-matched analysis at 6 mo to account for different treatment durations). Additional exploratory analyses compared single-agent ibr in RESONATE-2 vs ibr-G in iLLUMINATE to evaluate lymphocytosis (≥50% increase in absolute lymphocyte count from baseline and ≥5 × 109/L), and overall response rate (ORR). Results : Primary analysis included 136 pts treated with single-agent ibr and 98 pts treated with clb-G. Median age was 73 years in both groups. High-risk genomic features were generally well balanced (54% and 58% of pts, respectively), including del(11q) (21% and 22%), TP53 mutations (9% and 5%), and unmutated IGHV (43% and 46%). Bulky disease (≥5 cm) was present in 40% and 37% of pts, respectively. Median follow-up was 48.8 mo for ibr and 31.3 mo for clb-G. Single-agent ibr significantly prolonged PFS compared with clb-G (median not reached [NR] vs 22.2 mo), with an 82% reduction in risk of progression or death (HR 0.184; P 〈 0.0001; Figure 1). PFS rates at 30 mo were 85% vs 40% for ibr vs clb-G. Superior PFS with ibr vs clb-G was also seen in the high-risk population (median NR vs 18.3 mo; HR 0.072; P 〈 0.0001), with a 93% reduction in risk of progression or death. PFS consistently favored ibr over clb-G across all subgroups examined. Median treatment duration was 46.9 mo for ibr and 5.1 mo for clb-G, resulting in an AE collection period that was 9 times longer for ibr. Hospitalizations were similar for ibr vs clb-G (26% vs 28% of pts), while use of blood supportive products (16% vs 20%) or growth factors (6% vs 41%) was lower for ibr. Most common grade ≥3 adverse events (AEs) are in Table 1. During the first 6 mo, AEs led to discontinuation (DC) of ibr in 7% and DC of clb-G in 18% of pts; over the entire AE reporting period, AEs led to DC of ibr in 26%, and DC of clb-G in 18% of pts; (Table 1). With ibr, AEs leading to ibr DC in ≥2 pts were atrial fibrillation (n = 4), palpitations, pneumonia, death, and CLL (n = 2 each). With clb-G, AEs leading to DC of either clb or G in ≥2 pts were infusion-related reaction (n = 6) and neutropenia (n = 4). Exploratory analyses included 136 pts treated with single-agent ibr and 99 pts treated with ibr-G. Median follow-up was 31.3 mo for ibr-G. ORR by INV was similar with ibr vs ibr-G (91% vs 92%), but complete response (CR/CRi) was higher for ibr-G (44% vs 27%; P=0.006). Lymphocytosis occurred in 57% vs 8% of pts with ibr vs ibr-G and resolved in 95% vs 100%; median duration of lymphocytosis was 12.4 vs 3.1 weeks, respectively. Conclusions : Despite limitations of this cross-trial analysis, results suggest that PFS with single-agent ibr was superior to clb-G, including, importantly, in patients with high-risk genomic characteristics or bulky disease. In a time-matched analysis, AE profile with single-agent ibr appeared favorable to clb-G. In comparing ibr and ibr-G, lymphocytosis was more common with ibr than ibr-G but resolved in almost all pts, and ORR was similar for ibr and ibr-G. While CR rate was higher for ibr-G vs ibr, CR was not needed to achieve long-term PFS benefit with single-agent ibr. Disclosures Tedeschi: AbbVie: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Astra Zeneca: 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; Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; BMS: 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; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding. Demirkan:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Robak:Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy. Moreno:AbbVie: Consultancy; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barr:AbbVie, Gilead: Consultancy. Simpson:Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Gaidano:Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Bairey:Jansen: Research Funding; AbbVie: Consultancy; ROCHE: Research Funding. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Flinn:Takeda: Research Funding; Calithera: Research Funding; Agios: Research Funding; Forma: Research Funding; Trillium: Research Funding; Infinity: Research Funding; ArQule: Research Funding; Gilead: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Kite: Research Funding; Curis: Research Funding; Portola: Research Funding; Novartis: Research Funding; Verastem: Consultancy, Research Funding; Merck: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Seattle Genetics: Research Funding. Kipps:Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lin:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Webb:Janssen: Employment; Johnson & Johnson: Equity Ownership. Fedorov:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Styles:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Gribben:TG Therapeutics: Honoraria; Pharmacyclics: Honoraria; NIH: Research Funding; Novartis: Honoraria; Acerta Pharma: Honoraria, Research Funding; Abbvie: Honoraria; Kite: Honoraria; Roche: Honoraria; Unum: Equity Ownership; Wellcome Trust: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Cancer Research UK: Research Funding; Medical Research Council: Research Funding.

Abstract: 8025 Background: Treatment (Tx) of RRMM is complex and requires evaluation of disease and patient (pt) factors to maximize efficacy and minimize toxicity. HRQoL has become an important aspect of MM Tx, as survival has improved with therapeutic advances. Results of the ongoing phase 2 MM-014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low-dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in RRMM pts after first- or second-line lenalidomide (LEN)-based Tx failure. Here we report the impact of this regimen on HRQoL. Methods: RRMM pts with 1 to 2 prior Tx lines, LEN-based Tx as their most recent regimen, and progressive disease during or after their last Tx line received POM + LoDEX + DARA in 28-day cycles (MM-014 cohort B). HRQoL, an exploratory endpoint for cohort B, was assessed via EuroQol’s EQ-5D. Results: As of October 15, 2018, 108 pts were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ-5D completion rates for each cycle (1-6) were ≥ 88%. Mean change from baseline in the EQ-5D index and VAS health score was stable through 6 Tx cycles. At cycle 6, 28.8% and 39.0% of pts achieved minimum clinically important improvement in the EQ-5D index (≥ 0.1) and VAS health score (≥ 6), respectively. EQ-5D index values were stable, with a trend toward improvement in usual activities, pain/discomfort, and anxiety/depression (Table). Conclusions: In RRMM pts with early-line LEN Tx failure, HRQoL was maintained or trended toward improvement with POM + LoDEX + DARA, despite the combination of 3 drugs with distinct toxicities. These findings further support the earlier use of POM-based Tx in RRMM immediately after LEN failure. Clinical trial information: NCT01946477. [Table: see text]