ALBERT

Description: Introduction The advent of new therapies for the treatment of multiple myeloma (MM) has resulted in improved clinical outcomes and patient (pt) survival. However, the best combination of agents from different drug classes and subsequent therapeutic strategies for pts with newly diagnosed MM (NDMM), while investigated, has not yet been established. The goal of the Connect(R) MM registry is to provide insight into the disease and explore the management and outcomes of pts with NDMM who are treated at community and academic sites in the United States. This analysis aims to describe the combinations used in NDMM outside the interventional clinical trial setting and the activity and outcome response to different regimens by class of therapeutic agents in clinical practice. Methods Connect MM is an ongoing prospective, longitudinal, observational registry of NDMM pts. This multicenter US pt registry was initiated in 2009. Pts who were newly diagnosed with symptomatic MM within 2 months of enrollment were eligible to participate. Data were collected at baseline and every 3 months. Pts who had response data 12 months after enrollment, met CRAB criteria, and received treatment were eligible for this analysis. Treated pts were stratified according to SCT status. Data on baseline demographic and clinical characteristics, and initial therapies (proteasome inhibitors [PI], IMiD(R) immunomodulating agents, alkylating agents [AA], corticosteroids, and combinations) were collected. The overall response rate (ORR), as assessed by the site investigator, was defined as the best response during the course of initial therapy and is presented as cumulative ORR over 3, 6, and 12 months. Results As of the data cutoff (April 15, 2013), 1494 pts were enrolled in the registry; 1312 pts met CRAB criteria and received treatment. Of these, 439 received SCT or were anticipated to receive (had undergone a stem cell harvest) SCT and 873 would not receive SCT (non-SCT). Mean (SD) age for SCT and non-SCT pts was 58.9 years (8.7) and 69.8 years (10.7), respectively. Majority of pts in both groups were male (62.0% vs 56.5%) and Caucasian (85.4% vs 81.4%). Among SCT pts, ISS stages were: I/II (55.1%), III (25.3%), and unknown (19.6%) and ECOG performance status (PS) was 0/1 (63.1.%), 2/3 (7.1%), and unknown (29.8%). Among non-SCT pts, ISS stages were: I/II (42.0.%), III (32.2%), and unknown (25.8%) and ECOG PS was 0/1 (56.6%), 2/3/4 (14.7%), and unknown (28.8%). ORR to initial therapy and 1-year survival for the 5 most commonly used regimens are presented in the Table. A triplet regimen is 2 times more likely to be selected for SCT pts than for non-SCT pts, suggesting investigator bias in selecting more aggressive therapy for younger pts. For the 5 most commonly used regimens, 1-year survival was 97.9% for SCT pts and 83.3% for non-SCT pts. Conclusion Outside an interventional clinical trial setting, the most commonly used initial treatment regimens for NDMM were IMiD + PI + steroid for SCT pts and PI + steroid for non-SCT pts. Response rates were higher among SCT pts regardless of regimen. The investigator-assessed response rates were similar across the various combinations including 2 vs 3 drug combinations in SCT pts. Disclosures: Abonour: Celgene: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Off Label Use: This abstract will report on an observational study. There is no pre-specified use of drugs; treating physicians determined what drugs to use and some could be off-label. Shah:Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Durie:Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Terebelo:Amgen: Honoraria; Millennium: Honoraria. Gasparetto:Celgene ( 2012): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium (2012): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Consultancy. Sullivan:Celgene: Employment. Srinivasan:Celgene: Employment. Nagarwala:Celgene: Employment. Rifkin:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Description: Abstract 2081 Poster Board II-58 AZD6244 is an orally bioavailable small molecule inhibitor of the MEK kinase. MEK is downstream of the RAS/RAF pathway, which is activated by mutations occurring in RAS as well as mutations and/or overexpression of upstream receptor tyrosine kinases such as FLT3 and c-KIT in AML. In addition, elevated levels of phosphorylated-ERK (p-ERK), the only known substrate of MEK, have been demonstrated in 〉75% of patients(pts) with AML, and MEK inhibition of primary AML cells in vitro results in growth arrest. AZD6244 was well tolerated in phase I trials in advanced solid tumors and had a favorable pharmacokinetic profile; the recommended phase II dose was 100mg twice daily. We hypothesized that in AML, a MEK inhibitor would lead to inhibition of RAS-mediated signal transduction, with subsequent antiproliferative effects and inhibition of the leukemia clone. We report our experience with the first clinical trial utilizing a MEK inhibitor in advanced AML. Methods: 47 pts were enrolled on a Phase II multicenter study of AZD6244 in relapsed/refractory AML. Median age was 69 years (range, 26-83 yrs) with 57% males. ECOG performance status at baseline was 0, 1 and 2, respectively, in 12, 27 and 8 pts. 14 pts (30%) were previously untreated for AML and 〉60 yrs; 11 of these pts had received prior therapy for an antecedent hematologic disorder (AHD); 1 had therapy-related AML (t-AML) and only 2 pts (4%) had previously untreated de novo AML. 6 pts (13%) had AML in first relapse, 14 (30%) had AML beyond first relapse, and 13 (27%) had primary refractory disease. 4% had good risk cytogenetics, 28% intermediate risk, 49% poor risk, and 19% had other or unknown cytogenetics. Overall, 53% had AML that had evolved from an AHD and/or t-AML. Ten pts had a FLT3 ITD or TKD, 36 had no FLT3 mutation detected, and FLT3 mutational status was unknown in 1. Median number of prior therapies for AML and/or MDS was 2 (range, 0-6). AZD6244 was given at 100mg twice daily without interruption; cycles were repeated every 28 days. Dose modifications and/or delays occurred for grade 3&4 non-hematologic toxicities, or prolonged grade1&2 toxicities. Peripheral blood and/or marrow samples were obtained at baseline for mutational analysis (RAS/c-KIT/FLT3), and at serial time points to measure p-ERK. Results: Daily AZD6244 was tolerable. 42 pts are evaluable for efficacy and safety. Median number of cycles administered was 1 (range, 1-9). 19 pts (40%) received ≥2 cycles. 4 pts required dose reduction. The most common drug-related toxicities were grade 1&2 diarrhea, nausea, fatigue and vomiting, occurring in 43%, 36%, 31% and 24%, respectively. Grade 3&4 adverse events possibly related to AZD6244 included fatigue, nausea and dehydration, occurring in 7%, 5% and 5%, respectively. 4 pts had a minor response (defined as 〉50% decline in peripheral blood and/or marrow blasts lasting 4 weeks). 2 additional patients also had 〉50% decline in marrow blasts but did not have a follow up confirmatory biopsy. In 1 of these pts, the decline in blasts was associated with sustained improvement in platelets (〉100K/uL) lasting 4 months. 6 additional pts had evidence of disease stabilization, lasting a median of 34 days (range, 21-222+ days). Analysis of p-ERK by flow cytometry has just been intiated, and in the first 3 pts analyzed, baseline p-ERK levels were low, and none of these pts responded. In contrast, p-mTOR levels (downstream of the PI3 Kinase pathway) were significantly elevated in these same pts. Conclusions: Administration of the oral MEK inhibitor AZD6244 is feasible in AML. Modest evidence of antileukemic activity has been observed, consistent with the predicted cytostatic activity of this class of drugs. Analysis of the effect of AZD6244 on p-ERK and signaling intermediates of the PI3 Kinase pathway such as p-mTOR is ongoing. Given its modest toxicity profile, AZD6244 should be investigated further in combination with drugs that target other critical signaling pathways and/or dysregulated transcriptional pathways in AML. Sponsored by NCI grant NO1-CM-62201 Disclosures: No relevant conflicts of interest to declare.

Description: Background: MM treatment (Tx) advances have greatly improved clinical outcomes for patients (pts). A recent study demonstrated improved survival in MM through the past decade attributable to the impact of initial therapy with lenalidomide, bortezomib, and thalidomide. The greatest impact was observed in older pts (Kumar, et al. Leukemia, 2014). Connect MM, the first and largest prospective, observational, US-based, multicenter registry was designed to characterize pts, Tx patterns, and outcomes in newly diagnosed MM (NDMM). Methods: This ongoing registry was initiated in September 2009. Eligible pts with NDMM (diagnosis must have occurred within 2 mos of study entry) were enrolled at 234 US sites. Data were collected at baseline and each subsequent quarter using an electronic case report form. The initial enrollment includes all pts who had provided informed consent as of November 1, 2012 (N = 1493). The data cutoff for this analysis was Dec 10, 2013. A total of 1444 pts were treated and were included in overall survival (OS) analyses. Survival was examined for all treated pts adjusting for pt and Tx characteristics including age, autologous stem cell transplant (ASCT) status, gender, race, disease risk factors (International Myeloma Working Group [IMWG] high risk vs. non-high risk), and therapy received (triplet vs. non-triplet) among others. Triplet therapy was defined as any combination of 3 or more drugs during the first Tx regimen. OS was estimated using Kaplan-Meier methods and comparisons across groups were assessed used the log-rank test. Results: At the time of data cutoff, 1493 pts were enrolled with 1444 having received Tx. Of the treated pts 253 pts (18%) had IMWG high-risk disease and 108 pts (7%) had del(17p) at baseline. Median age was 67 y (range, 24-94 y), 57.2% were male, and 81.9% were white. Median follow-up was 29 mos (0-49.4 mos). The median OS for all treated pts was 44.4 mos. When assessed by age group, OS was significantly different (log-rank P 〈 .0001) with a median of 47.6 mos for pts aged 〈 65 y (n = 632), 45.0 mos for those aged 65 to 〈 75 y (n = 443), and 33.7 mos for those aged ≥ 75 y (n = 369). OS was significantly longer for pts with ASCT vs. no ASCT (P 〈 .0001), but not different by gender (P = .962) or race (Caucasian vs. African American vs. other; P = .250). Three-year OS probabilities by subgroup are listed in Table 1. When considering risk factors, IMWG risk was borderline significant (high vs. non-high; P = .106), and presence of del(17p) by cytogenetics and FISH was associated with significantly shortened OS (P = .005; Figure 1A). Interestingly, use of triplet therapy vs. non-triplet therapy was associated with significantly prolonged OS regardless of IMWG risk (non-high: P 〈 .0001; high: P = .003; Figure 1B). However, no improvement was noted for triplet vs. non-triplet therapy in pts with del(17p). By multivariate analysis, the significant (P 〈 .05) factors impacting OS were age (in 10-yr increments), International Staging System (ISS) disease stage, ECOG performance status, history of diabetes, anemia, renal function, and platelet count. Conclusions: This interim analysis based on initially treated pts demonstrated that age, ISS stage, and co-morbidities impact OS irrespective of IMWG cytogenetic risk. Triplet Tx was associated with significantly longer OS in pts regardless of IMWG risk status. This is the largest prospective pt cohort with high-risk disease including del(17p). Pts with high-risk disease did not have significantly lower OS vs. pts without high-risk features. Pts with del(17p) (p53 deletion) continue to have shorter OS approaching 3 y and increased survival with use of triplet therapy. Table 1. Kaplan-Meier Estimated 3-Y OS Probability Patients 3-y OS Probability (%) (95% CI) All (N = 1444) 62.6 (59.5-65.8) 〈 65 y (n = 632) 69.8 (65.2-74.3) 65 to 〈 75 y (n = 443) 65.0 (59.4-70.6) ≥ 75 y (n = 369) 47.2 (40.7-53.8) Gender Male (n = 831) 62.1 (57.9-66.3) Female (n = 613) 63.4 (58.7-68.2) Race Caucasian (n = 1191) 61.8 (58.3-65.3) African American (n = 183) 64.4 (55.4-73.5) Other (n = 27) 77.6 (57.3-98.0) ASCT Yes (n = 494) 77.1 (72.5-81.7) No (n = 950) 54.2 (50.0-58.3) Triplet therapy Yes (n = 778) 69.3 (65.3-73.3) No (n = 666) 54.8 (49.9-59.6) IMWG risk High (n = 253) 59.0 (51.6-66.4) Standard (n = 566) 66.3 (61.4-71.2) Low (n = 86) 75.7 (63.6-87.8) del(17p) Present (n = 108) 52.7 (41.8-63.6) Absent (n = 1336) 63.4 (60.1-66.7) Figure 1 Figure 1. Disclosures Shah: Celgene Corp: Consultancy, Research Funding. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Durie:Celgene Corp: Export Board Committee Other, Membership on an entity's Board of Directors or advisory committees; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Rifkin:Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy.

Description: Background: Increased rates of SPM have been observed as newer cancer treatments have improved survival over the past 2 decades (Fraumeni et al. NCI, 2006). Higher incidence of specific types of hematologic SPM following MM, especially acute myeloid leukemia and myelodysplastic syndromes, have been reported relative to the general population (Dores et al. NCI, 2006; Mailankody et al. Blood, 2011; Ravazi et al. Blood, 2011; Landgren and Mailankody. Leukemia, 2014). A complex interplay between myeloma-, host-, environmental-, and treatment-related factors likely contributes to the increased incidence of SPM in MM. Connect MM is the first and largest prospective, observational, US-based, multicenter registry designed to characterize patients (pts), treatment patterns, and outcomes in newly diagnosed MM (NDMM) pts. Methods: Between September 2009 and November 2012,a total of 1493 NDMM pts were enrolled from 234 US sites within 2 mos of the first diagnosis of MM. Patient data were collected at baseline and each subsequent quarter using a standardized form. Invasive SPM included hematologic and solid tumor second cancers and non-invasive SPM were defined as non-melanoma skin cancers (NMSC). SPM incidence and incidence rate (IR; number of pts with SPM per 100 patient-yrs [PY]) were calculated for all pts and by exposure to specific treatments, including lenalidomide (LEN). PYs were calculated as the observation period from the start of treatment until the detection of the first reported SPM (per category), death, or end of follow-up (pt lost or data cutoff). Results: As of Dec 10, 2013, SPM data were available for 1493 NDMM pts. The median age was 67 yrs (range, 24-94 yrs), 82% of patients were white and 57% were male. Median follow-up was 29.0 mos (0-49 mos). The median OS of treated pts was 44.4 mos. Fifty pts did not receive treatment and had no SPM reported. A total of 74 of the 1443 treated pts (5.1%) reported SPM. Invasive SPM were observed in 51 pts (3.5%): 37 pts (2.6%) with solid tumors and 14 pts (1.0%) with hematologic SPM. Lung/bronchus and myelodysplastic syndromes were the most frequently reported solid tumor and hematologic SPM respectively. NMSC were reported for 26 pts (1.8%). 3 pts had both an invasive SPM and NMSC. The IRs for invasive, hematologic, and solid tumor SPM by LEN exposure are listed in Table 1. By multivariate analysis, the only significant risk factor for the occurrence of SPM was prior history of invasive malignancy. Demographics (including age, ethnicity, race, and gender), International Staging System stage, family history of myeloma or other cancers, history of smoldering MM or monoclonal gammopathy of unknown significance, or prior radiation therapy were not associated with the occurrence of SPM. Conclusions: This analysis shows that there was no increased risk of invasive SPM in this disease-specific registry of pts with NDMM. The risk of SPM for LEN exposed pts was not greater than that for pts not exposed to LEN. In addition, multivariate analysis indicated the only significant risk factor for SPM was prior history of invasive malignancy. As additional agents are approved for the treatment of MM and the length of pt survival increases, longer prospective observation with expanded enrollment on the registry will better characterize the occurrence of SPM in this pt population. Correlations with risk factors including age, pre-existing MDS, risk status, as well as type and duration of therapy will continue to be investigated. Table 1. Incidence rates (per 100 PYa) by treatment exposure IR per 100 PY (95% CI) SPM LEN-Exposed (n = 977) Non–LEN Exposed (n = 466) Invasive 0.85 (0.61-1.19) 1.16 (0.72-1.86) Hematologic 0.17 (0.08-0.36) 0.47 (0.22-0.99) Solid tumor 0.67 (0.46-0.98) 0.68 (0.36-1.26) NMSC 0.50 (0.32-0.77) 0.41 (0.18-0.91) a PY of exposure is the sum of exposure of all pts. Disclosures Rifkin: Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Shah:Celgene Corp: Consultancy, Research Funding. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Lu:Celgene Corp: Employment. Kenvin:Celgene Corp: Employment. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Durie:Celgene Corp: Expert Board Committee Other; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees.

Description: Background: mTOR inhibitors, including temsirolimus (TEM), have demonstrated activity in patients (pts) with relapsed/refractory (rel/ref) lymphomas (J Clin Oncol 2010;28(31):4740). Lenalidomide (LEN) is an immunomodulatory agent with activity in a number of lymphoma subtypes with potential additive or synergistic effects. We previously reported phase I results of TEM/LEN in patients with relapsed/refractory lymphomas and showed good tolerability and evidence of clinical activity (J Clin Oncol 2012;30 suppl; abstract 8075). Recommended phase II doses of TEM 25 mg weekly and LEN 20 mg daily (D1-21, q28D) were tested in 3 histology-based cohorts with final results presented here. Methods: Pts with rel/ref lymphomas having received 〉 1 cytotoxic regimen were eligible. Other criteria included ANC 〉 1000/uL, platelets 〉 75,000/uL, and normal renal and hepatic function. Pts were enrolled into 3 cohorts: DLBCL (cohort A), FL (cohort B), and other lymphomas (cohort C). CLL/SLL was excluded due to poor single-agent TEM activity. TEM was administered at 25 mg IV weekly, and LEN at 20 mg PO daily (D1-21, q28D). Pts received therapy for up to 1 year, or until disease progression or development of toxicities requiring treatment cessation. All pts received ASA prophylaxis. Response assessments were performed after cycle 2, and every 3 months thereafter. Results: 93 pts (31 female, 62 male), mean age 57 years (range, 23-78 years) were enrolled onto cohort A (n=39 DLBCL), cohort B (n=15 FL), or cohort C (n=39; 20 HL, 9 T-NHL, 5 MCL, 4 MZL, 1 WM). The median number of prior treatments was 4 (range, 1-14). 28 pts had relapsed following autologous stem cell transplantation (ASCT). The median number of cycles delivered was 4 (range, 1-12). Grade 3 or higher non-hematologic adverse events (AE) were uncommon with only fatigue and hypokalemia occurring in 〉10% of pts; ≥ grade 3 hematologic toxicity included anemia (n=27), lymphopenia (n=40), neutropenia (n=44) and thrombocytopenia (n=42). Three grade 5 AEs were observed (colonic perforation, myocardial infarction and sepsis). The overall response rates (ORR) were 25.6% (5 CR; 5 PR), 46.6% (5 CR; 2 PR), and 64.1% (7 CR; 18 PR) for pts in cohorts A, B, and C, respectively. Of note, cohort B (FL) was closed prematurely due to poor accrual. Median progression-free survival (PFS) for pts in cohorts A and C was 6.0 months (95% CI 3.1 - 8.0 months), and 7.3 months (4.2 - 10.8 months), and median duration of response (DOR) was 11.3 months (2.6 months - not reached) and 5.5 months (2.3 months - not reached), respectively. Median overall survival (OS) for pts in cohorts A and C was 10.2 months (5.9 - 20.6 months), 25.5 months (10.1 - not reached), respectively. Among 20 heavily-treated HL pts in cohort C (median prior treatments 6, range 3-14), all of whom progressed on brentuximab vedotin (BV), and 13 of whom had received a prior ASCT, the ORR was 80% (7 CR; 9 PR), and the median PFS, DOR and OS was 9.2 months, 8.1 months, and 25.5 months, respectively. Conclusions: The combination of TEM/LEN therapy was well-tolerated and showed encouraging activity in pts with rel/ref lymphomas. The most significant activity was observed in rel/ref HL, with an 80% response rate, including in pts with prior BV exposure and in those relapsed after ASCT. For DLBCL, the addition of LEN did not improve ORR compared to historical experience with single-agent TEM, but we note a provocative prolongation of both PFS and DOR for this otherwise aggressive disease. Further evaluation of mTOR pathway inhibition and immunomodulatory agents in relapsed HL patients is warranted based on these results. This study was conducted through the University of Chicago Phase II Consortium, supported by NCI contract N01-CM-2011-00071C Disclosures Kline: Vasculox: Research Funding; Merck: Honoraria, Research Funding. Petrich:AbbVie: Employment. Rao:Novocure: Consultancy. Smith:TGTX: Consultancy; Juno: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Genentech: Consultancy, Other: on a DSMB for two trials ; Pharmacyclics: Consultancy; Celgene: Consultancy; Gilead: Consultancy; AbbVie: Consultancy.