Citations

Abstract Intensification of therapy for adults with ALL using pediatric regimens with intensive asparagine depletion is feasible. Targeted therapies are improving outcomes. We hypothesized that the UCSF 8707 regimen (Linker et al.JCO 2002;20:2462) could be safely intensified with the addition of pegylated asparaginase (peg asp), cyclophosphamide, rituximab, dasatinib, and intrathecal liposomal cytarabine. Methods: Patients (pts) enrolled at 4 centers. The primary objective was 3-year (yr) EFS (goal >55%). Eligible pts were age 18-60 yrs with untreated ALL or LBL. Treatment consisted of induction Course 1A (C1A): daunorubicin 60 mg/m2 IV d1-3, vincristine (VCR) 1.4 mg/m2 (2 mg if age >50 yrs) IV day 1,8,15,22, prednisone 60 mg/m2 orally (PO) d1-28, peg-asp 2,000 IU/m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d15, cyclophosphamide 750 mg/m2 IV d1,15 (or 500 mg/m2 IV q12h d15,16 if d14 marrow M2 or M3). ALL pts in CR/CRi and LBL pts in CR or PR proceeded to post-remission Course 1B (C1B): methotrexate (MTX) 220 mg/m2 IV bolus then 60 mg/m2/hr CIV for 36 hrs d1,15 with leucovorin rescue, 6-mercaptopurine (6-MP) 60 mg/m2 PO d1-7, 15-21, peg-asp 2,000 IU/ m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d16. Course 1C (C1C) consisted of cytarabine 2,000 mg/m2 IV d1-4 and etoposide 500 mg/m2 IV d1-4. Courses A-C repeated once then a third course B given. Maintenance POMP (6-MP 60 mg/m2 PO daily, VCR 1.4 mg/m2 (2 mg age >50 yrs) IV monthly, MTX 20 mg/m2 PO weekly, prednisone 60 mg/m2 PO d1-5) repeated monthly for 12 months then POMP with every other month VCR and prednisone for 12 months. Peg asp was given d16 of maintenance month 1. If B-ALL (+/- CD20 expression), rituximab 375 mg/m2 IV was given every 2 weeks for 8 doses starting day 1 of C1A. If Ph+ ALL, dasatinib 140 mg PO daily was given but held during high-dose MTX then restarted when serum [MTX] was </= 0.1 μM. CNS prophylaxis was liposomal cytarabine 25 mg intrathecal C1A d1,15, C2A d1,15 then 50 mg monthly for 4 doses in maintenance. Bone marrow biopsies were performed C1A d14 and after C1A, C1B, C3B, and maintenance. Measurable residual disease (MRD) was evaluated centrally by multi-parameter flow cytometry. BCR-ABL1 QPCR was performed locally. EFS is the time from start of therapy to failure of response by induction day 28, relapse, or death censored for HCT. RFS is the time from response to relapse or death censored for HCT. OS is the time from start of therapy until death. Survival was estimated by the method of Kaplan and Meier. Toxicity was graded with NCI CTCAE version 4.0. Results: Between 4/2014 and 2/2017, 31 pts enrolled and 29 were eligible. Median age was 28 yrs (20-54), 62% were male, 52% were Hispanic, and 86% had ALL. The end induction ORR (CR + PR) was 90% (2 ALL with PR, 1 early death). ORR for LBL was 100% (n= 4). The CR rate for ALL was 88%. For Ph- B-ALL (n=16), the CR rate was 86% with MRD <0.1% and <0.01% in 90% and 80% of CR pts, respectively. For Ph+ B-cell ALL (n=7), the CR rate was 88% (1 early death) with MRD <0.1% and <0.01% in 100% and a CMR rate of 67% at CR. The 2 T-ALL pts achieved CR with MRD >0.1%. Five pts underwent allogeneic HCT in first CR to study therapy. With a median follow up of 32 months (16-44), the 2- and 3-yr EFS were 59%. EFS was similar for B-ALL, T- ALL, LBL, Ph- B-ALL, and Ph+ B-ALL. Five pts relapsed. The 2- and 3-yr RFS were 66%. Concomitant marrow and CNS relapse occurred in 1 pt. No isolated CNS relapses occurred. Transplant-censored 2- and 3-yr OS were 80% and 72%. Uncensored 2- and 3-yr OS were 75% and 70%. Among eligible pts, 8 died: 4 after relapse, 1 in induction from infection, 2 in CR from infection, and 1 from allogeneic HCT complications. Three reversible grade 3-4 events were attributed to liposomal cytarabine, all grade 3: syncope, pseudotumor cerebri, and headache. Grade 3-5 possible peg asp toxicities were transaminitis (58%), hyperbilirubinemia (42%), hyperglycemia (29%), hypertriglyceridemia (26%), elevated GGT/alkaline phosphatase (19%), thrombosis (19%, 1 cerebral venous), hypoalbuminemia (10%), hypersensitivity (6.5%), elevated lipase (6.5%), pancreatitis (3.2%), encephalopathy (3.2%), and avascular necrosis (3.2%). One pt died from encephalopathy. Conclusions: Intensification of UCSF 8707 is feasible and effective. Post-induction remissions were deep with high MRD-negativity rates. EFS, RFS, and OS are favorable with follow up and accrual ongoing (NCT02043587). Strategies to limit peg asp toxicity are needed. Disclosures Wieduwilt: Amgen: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership; Leadiant: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Mannis:AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity's Board of Directors or advisory committees. Curtin:Amgen: Research Funding; Onconova: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Andreadis:Genentech: Consultancy, Employment; Bayer: Consultancy; Astellas: Consultancy; Gilead: Consultancy; Juno: Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Damon:Actelion: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Novartis: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company.

Abstract Introduction: Prognosis of AL amyloidosis has improved in recent years; however for many patients prognosis remains poor. We aimed to define patient-, disease- and treatment characteristics which are associated with long-term survival. Method: A retrospective chart review of all patients with biopsy-proven systemic AL amyloidosis, who were seen within 90 days of the confirmed diagnosis. Long-term survival was defined as 5-year and 10-year survival from the time of diagnosis. For 5-year survival we selected patients seen between January 1, 2000 and December 31, 2012 (allowing a minimum of 5-year follow-up, n=1331) and for 10-year survival we screened patients seen between January 1, 2000 and December 31, 2007 (allowing a minimum of 10-year follow-up; n=779). Treatment allocation was defined as the first regimen given, irrespective of subsequent treatment modifications. Results: Of the screening population, 498 patients survived ≥5 years from diagnosis (37% of the 5-year screening cohort) and 168 patients survived 10 years or more (22% of the 10-year screening cohort). Five-year survivors and 10-year survivors as compared to their counterparts were (Table): younger, higher proportion of women, more likely to have single organ involvement, less heart/liver/nerve involvement and more kidney involvement. Long-term survivors also had lower bone marrow plasma cell percentage at the time of diagnosis and lower tumor burden measured by the difference between involved to uninvolved light chain (dFLC). Similarly, long-term survivors had lower Mayo stages and higher systolic blood pressure. No difference in light chain isotype was observed between long-term survivors to long term non-survivors. Long-term survivors were less likely to be seen within 30 days of diagnosis compared to their counterparts (52% among 5-year survivors vs 67% among 5-year non-survivor; P<0.001). FISH abnormalities (data available for 555/1331 patients, 42%) were comparable between groups with regard to t(11;14) (50% among 5-year survival compared to 50% among 5-year non-survivors; P=0.93) and 13q abnormalities (34% vs 36%, respectively; P=0.53). However, trisomies were less frequently encountered in the 5-year survivor group (20% vs 29%, respectively; P=0.01), and far less common among 10-year survivors (11% vs 26%, respectively; P=0.04). Autologous stem cell transplantation (ASCT) was more likely to be associated with long-term survival. Of all patients who underwent ASCT, 74% survived more than 5 years and 49% survived more than 10 years. In comparison, among the standard-intensity therapies, 5-year survival rates for melphalan-dexamethasone, bortezomib-based regimens, immunomodulatory drug-based regimens and single agent dexamethasone/ melphalan-prednisone were 29%, 28%, 30% and 10%, respectively. The corresponding 10-year survival rates were 15%, 20%, 20% and 5%, respectively. Conclusions: Long-term AL survivors have distinct favorable baseline characteristics (including those introduced by referral bias) and ASCT as their initial therapy. Identification of these patients, especially the Mayo 2004 stage III and the Mayo 2012 stage III-IV patients who unexpectedly survived 10 years, will allow for further study and insights. Disclosures Gertz: Teva: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; janssen: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Introduction Lenalidomide is an immunomodulatory drug that is active in newly diagnosed as well as relapsed multiple myeloma (MM). The goal of this study is to describe patients with newly diagnosed MM remaining on lenalidomide for more than 3 years (long term responders) as well as patients that after discontinuing lenalidomide were able to maintain disease control while only on observation (LenO group). Methods We retrospectively reviewed 283 patients with newly diagnosed MM that were treated with lenalidomide between January 2003 and January 2011. We excluded patients that underwent early autologous stem cell transplant (n=102) or had less than 3 years of follow-up (n=6), leaving 175 patients for the current analysis. Results Long term responders Thirty-three patients (19%) received lenalidomide for more than 3 years. When compared to patients receiving lenalidomide for less than 3 years, at baseline, long term responders were more likely to have standard risk disease (64% versus 44%, p=0.03) and less likely to have high risk disease (18% versus 4%, p=0.04). They were more likely to have achieved a deeper response (VGPR versus PR, p<0.001) and had a longer median time to best response (6 versus 4 months, p<0.001). When considering the 12 patients who received lenalidomide for more than 5 years, this group was more likely to have achieved a deeper response (CR versus PR, p<0.0001) and had a longer median time to achieving best response (9 versus 4 months, p<0.0001) than those 163 patients who remained on lenalidomide for fewer than 5 years. Observation group Thirty-three patients (19%) discontinued lenalidomide for reasons other than progression and were observed without receiving further treatment (LenO group). Prior to moving to observation, five patients had received lenalidomide for more than three years. Indications for stopping in the LenO group included: prolonged disease stability (n= 20); and toxicity (n=13). The only differences in baseline characteristics between the LenO group and patients that were not observed off any treatment was depth of response, with 61% (n=20) of LenO in VGPR or better versus 23% (n=23) in the remainder, p=0.0003. Median PFS from the time of discontinuing lenalidomide was significantly longer in those patients who took lenalidomide for more than 1 year (n=24) when compared to patients taking it for less than one year (n=9) (median PFS off therapy was 38.5 months versus, 14.9 months log rank 0.08; Wilcoxon p<0.05), figure 1a; PFS for those treated for 1-2 years (n=11) as compared to 2 years or greater (n= 13) were comparable to each other (data not shown). Among those taking lenalidomide for at least a year, PFS from time of discontinuing lenalidomide was superior in patients who had achieved a VGPR/CR (n=20) as compared to those who achieved only a PR (n=13) (Median 48.4 months versus 14.8 months, log-rank p<0.05; Wilcoxon p=0.01), figure 1b. Conclusion Approximately one out of five patients with newly diagnosed MM can achieve responses lasting more than three years while on treatment with lenalidomide. Patients with standard risk FISH and those achieving at least VGPR are more likely be long-term responders. Furthermore, long-term responders were more likely to be slow responders. We also demonstrate that suspension of lenalidomide therapy after 1 year among those patients achieving a VGPR or better can result in long-term disease control and can be considered as a therapeutic strategy. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Gertz:Celgene: Honoraria. Lacy:Celgene: Honoraria. Dispenzieri:Celgene: Research dollars Other.

Abstract The use of soluble cardiac biomarkers such as NT-proBNP and troponin has revolutionized prognostication for patients with AL amyloidosis and led to their use in the Mayo 2004 and 2012 staging systems. Novel soluble markers with different phenotypic targets may further improve this approach. Soluble ST2 (sST2), which is the circulating form of the IL-33 receptor, has been shown to be a marker of cardiac remodelling and fibrosis, is predictive of mortality in patients with congestive heart failure, and is predictive of risk of GVHD and GVHD mortality. Samples of blood of patients with AL amyloidosis collected and frozen at -20C under a biobank IRB protocol were retrieved and sST2 measured. Patients were eligible for present study if they had a research sample collected within 90 days of their AL amyloidosis diagnosis. We have validated that values do not change significantly with storage at -20C over a 90 day period. Concentrations of sST2 were determined using a novel high-sensitivity sandwich immunoassay (Presagew ST2; Critical Diagnostics, San Diego, CA, USA). The sST2 assay had within-run and total coefficients of variation of <7.5% and 13.0% across its measurement range. Samples from 273 consecutive patients meeting diagnostic criteria for AL amyloidosis seen at our institution from 1/9/2010 to 12/22/2011 were evaluated. Median age was 63. 58% were male. One hundred and thirty have died over 33.9 months. Correlation between sST2 and the other biomarkers was modest with correlation coefficients of 0.48 and 0.20 for NT-proBNP and Troponin T, respectively. Patients with sST2 above and below the median of 27.2 ng/mL (6.3-596) had significant differences in 2 year overall survival: 71.2% to 39% (figure). In multivariate modeling sST2’s prognostic value was independent of the Mayo 2004 and the Mayo 2012 cardiac biomarker staging systems, the latter of which also includes prognostic information relating to plasma cell burden. In these multivariate models, sST2 median had a RR of 2.4, (95%CI 1.6, 3.6 p<0.001) with the Mayo 2004 Staging system (RR of 2.9, 95%CI 2.1, 4.1p<0.001); and sST2 median had a RR of 2.2 (95%CI 1.5, 3.4, p<0.001) with the Mayo 2012 staging system (RR 1.9, 95%CI 1.6, 2.3, p<0.001). A larger cohort including patients with longer follow up will be presented at the meeting as will gender specific cut off values and a comparison of our values with those previously used to prognosticate in patients with heart failure. sST2 appears to be a novel powerful prognostic factor for patients with AL amyloidosis. Because sST2 functions as a decoy receptor, which neutralizes the benefits of IL-33, it may play a role in the deleterious phenotype seen in patients with AL, i.e. myocardial hypertrophy and reduction of contractility. Disclosures: Saenger: Critical Diagnostics : Research Funding; Roche: Research Funding. Jaffe:Critical Diagnostics: Consultancy, Research Funding; Roche: Consultancy.

Introduction With the introduction of novel agents, survival in multiple myeloma has successively increased in the past decade. This improved survival increases the risk for late complications. Patients continue to receive melphalan therapy as a standard induction for those over the age of 65. Lenalidomide is considered a standard component of induction therapy in the United States for patients who are transplant candidates. Stem cell transplantation remains the standard of care for patients eligible to receive it. As a consequence of exposure to lenalidomide, stem cell transplant, and melphalan, the risk of late myelodysplasia and acute leukemia remains significant. We reviewed the Mayo Clinic experience with therapy-induced myelodysplasia beginning with the advent of novel agents. Patients and Methods All patients that carry the diagnosis of multiple myeloma between January 1, 2000, and September 1, 2011, were included. Patients with a synchronous diagnosis of a myeloproliferative or a myelodysplastic disorder or those who developed the myelodysplastic disorder within 15 months of first chemotherapy exposure were excluded. The date of diagnosis for the purpose of this abstract was based on first exposure to chemotherapy and not first detection of a monoclonal protein or smoldering multiple myeloma. All patients had to have morphologic verification in the bone marrow of dysplastic change consistent with therapy-related myelodysplasia. Results Of 3111 patients who had a myeloma diagnosis and first treatment after January 1, 2000, through September 1, 2011, 22 patients were identified to fulfill the criteria of myelodysplasia. There were 13 men and 9 women with a median age of 67 (46 to 82). At the time of this report, 17 have died. Prior to the development of myelodysplasia, exposure to an alkylating agent, lenalidomide, or an auto stem cell transplant was seen in 13, 15, and 10, respectively. Only one patient had been exposed to lenalidomide alone. Eighteen patients were classified as myelodysplasia. Four had acute non-lymphocytic leukemia. Metaphase cytogenetics was available in 19 and only one was normal. Twelve were hypodiploid. Trisomy 8 or abnormalities of chromosome 5 and 7 were present in 13. Seven patients received a hypomethylating agent with no clear evidence of response in any. Four patients had an allotransplant to manage the MDS/AML and only one survives 487 days after a matched-related donor allogeneic transplant. The median time from initial therapy of multiple myeloma to recognition of MDS or AML was 50.9 months (range: 15.2-146.5 months) fig 1. The median overall survival of the 22 patients is 6.5 months. Fig 2 Six of the 22 had active myeloma at the diagnosis of MDS/AML. Conclusion Myelodysplasia during the era of novel agents is a devastating complication of therapy with a very short survival and low response rate. As a time-dependent complication, the overall risk cannot be accurately estimated but has occurred in <1% of our patient population to date. Hypomethylating agents were ineffective in the seven that received it. One of four allotransplant patients remains alive. Ongoing surveillance for MDS/AML in this population is warranted and more effective therapies are needed. Disclosures: Kumar: Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract Abstract 332 Background: The high response rates seen with the bortezomib, lenalidomide, and dexamethasone (VRD/RVD) regimen (Kumar S, et al. Blood 2012; Richardson PG, et al. Blood 2010) highlight the feasibility of combining a proteasome inhibitor with an immunomodulatory agent and a steroid in patients with previously untreated multiple myeloma (MM). MLN9708 is an investigational, oral, reversible proteasome inhibitor with promising anti-MM effects and favorable toxicity profile with low rates of peripheral neuropathy (PN). Here we report phase (Ph) 1 and preliminary Ph 2 results of the first study of MLN9708 in combination with lenalidomide and dexamethasone in patients with previously untreated MM (NCT01217957). Methods: Patients aged ≥18 yrs with measurable disease, ECOG performance status 0–2, and no grade ≥2 PN, received oral MLN9708 (days 1, 8, and 15) plus lenalidomide 25 mg (days 1–21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to twelve 28-day cycles, then maintenance therapy with MLN9708 (same schedule) every 28 days until progression. Patients could undergo stem cell collection after 3 cycles and discontinue for autologous stem cell transplant (ASCT) after 6 cycles. In Ph 1, dose escalation (1.68–3.95 mg/m2) proceeded using a standard 3+3 design, based on cycle 1 dose-limiting toxicities (DLTs). Ph 1 primary objectives were determination of safety, maximum tolerated dose (MTD), and recommended Ph 2 dose (RP2D); the Ph 2 primary objective was CR+VGPR rate. Secondary and exploratory objectives included characterization of MLN9708 pharmacokinetics (PK) and measurement of minimal residual disease using multiparameter flow cytometry. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: From 22 November 2010 (Ph 1) and 14 October 2011 (Ph 2) to data cut-off (June 27, 2012), 65 patients (36 male) have been enrolled, 15 in Ph 1 and 50 in Ph 2. Median age was 66 yrs (range 34–86); 43% and 13% had ISS stage II and III. Patients have received a median of 5 cycles (range 1–15) – 6 cycles (range 1–15) in Ph 1 and 5 cycles (range 1–8) in Ph 2. 42 (65%) patients remain on treatment, 4 (27%) in Ph 1 and 38 (76%) in Ph 2. At 10 August 2012, 22 patients have discontinued: 16 to receive ASCT, 4 due to AEs (3 drug-related, 1 not drug-related GI bleed), 2 for other reasons (1 disease progression, 1 due to investigator decision). Of those who have undergone stem cell mobilization, a median yield of 9.1 × 106 CD34+ cells/L was reported. MLN9708 MTD was established as 2.97 mg/m2 and RP2D was selected as 2.23 mg/m2; RP2D converts to a 4.0 mg fixed dose based on population PK results. At 27 June, all-grade AEs related to any regimen drug and seen in ≥25% of patients were fatigue (32%), nausea (31%), and vomiting (25%). Grade 3 any-drug-related AEs were reported in 26 (40%) patients, including erythematous rash, nausea and vomiting (5% each). Grade 4 any-drug-related AEs were end-stage renal disease (related to progressing MM) and deep vein thrombosis in 1 patient each. One patient experienced grade 3 PN at the RP2D. At 10 August, 3 patients discontinued due to drug-related AEs – 1 in Ph 2 who stopped due to grade 1 resting tremor, grade 2 occasional memory loss (neurologic work-up was negative), and grade 2 peripheral sensory neuropathy, 1 patient in Ph 2 due to drug-related RSV pneumonia who subsequently died on study due to this AE, and 1 patient in Ph 1 with syncope (a DLT). Among all 65 patients (at 10 August), median patient follow-up was 3.88 months (Ph 1: 9.03 months, Ph 2: 3.68 months). The overall response rate (ORR; ≥PR, confirmed/unconfirmed) was 88% (100% in Ph 1 and 84% in Ph 2); this includes 40% ≥VGPR (53% in Ph 1 and 36% in Ph 2) and 18% CR (33% in Ph 1 and 14% in Ph 2). Median cycle number is limited, but 50 patients have received ≥4 cycles: ORR was 96%, with 44% ≥VGPR and 26% CR. Analyses by cytogenetic status will be presented at the meeting. At data cut-off, 50 of 52 responders remained in response, with responses durable for up to 13.2+ months. Median time to first response was 0.92 months (range 0.89–6.44). Conclusions: The combination of weekly oral MLN9708 plus lenalidomide and dexamethasone appears generally well tolerated, with one grade 3 PN at the RP2D. Preliminary data show antitumor activity at the RP2D in patients with previously untreated MM, and at data cut-off, 96% of patients had achieved ≥PR, including a ≥VGPR rate of 44% and a CR rate of 26%, with responses consistent with those reported with VRD/RVD. Disclosures: Kumar: Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding; Genzyme: Research Funding; Cephalon: Research Funding; Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Off Label Use: A study of the investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the treatment of patients with previously untreated multiple myeloma. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Hari:Celgene: Consultancy. Vescio:Millennium Pharmaceuticals, Inc.: Speakers Bureau. Berg:Millennium Pharmaceuticals, Inc.: Employment. Lin:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Richardson:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals and Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 636 Cellular vaccine may offer additional benefit as consolidative therapy after autologous stem cell transplant (ASCT) for multiple myeloma (MM). We have reported previously from two phase II studies the survival of MM patients who received APC8020 (autologous antigen presenting cell vaccine) after ASCT (Lacy, AJH '09, (84): 799; Lin, ASH annual meeting 2010, abstract 1958). To determine if there was an outcome advantage for additional consolidative vaccine therapy after ASCT, we performed this matched case control analysis comparing the survival of patients who received ASCT only (control) at Mayo Clinic to those who received APC8020 after ASCT in the same time period. Forty-three study patients accrued between July 1998 and March 2002 were eligible for matching. To reduce bias from disease risks and transplant-related mortality, control patients were required to be alive and progression free six months after transplant and have a M-spike value of < 2g/dL at 4 mos (1st study) or 9 mos (2nd study) after transplant, similar to post-ASCT patients who were enrolled in the two APC8020 studies. A total of 111 control patients were eligible for matching. Control patients were matched to study patients by age (+/− 5 yrs), ISS (International Staging System) stage, and plasma cell labeling index (PLCI, either >= 3 or < 3). A matched control was not identified for one study patient. Of the remaining 42 study patients, all had at least one matched control patient. Thirty-two patients had 2 matched controls. Cox proportional hazards analysis showed that there was no statistically significant difference in time to progression between the study and control patients (HR 1.54, 95% CI 0.92 – 2.58, p = 0.1). However the overall survival is significantly improved among the study patients (HR 0.54, 95% CI 0.30 – 0.99, p = 0.05). This analysis is the only known report of long-term follow-up of the largest group of MM patients treated with APC8020 vaccine. While many current prognostic tests were not available at the time of the initial vaccine studies, the control patients in this analysis were matched by known disease risks that are still in use today. The survival advantage in study patients remained statistically significant compared to matched controls. Interestingly, the time to progression is unchanged between study and control patients. This is similar to other reports of vaccine therapy such as in sipuleucel-T (Provenge™) in prostate cancer where an overall survival benefit is seen without change in progression-free survival. A larger, randomized phase III study is needed to confirm the encouraging survival benefit of this treatment modality in MM. Further insight into the mechanisms of action of APC8020 is needed to improve our understanding of the role of this therapy in the context of current practice of MM maintenance therapies. Disclosures: Sims: Dendreon Corporation: Employment.

Abstract Background Acquired factor X (FX) deficiency is associated with immunoglobulin light chain (AL) amyloidosis and may be accompanied by hemorrhage. There are limited data on the effects of autologous stem cell transplant (ASCT) on FX deficiency. We reviewed hemorrhagic complications and the effect of high dose melphalan (HDM) and ASCT on FX levels in AL amyloidosis patients with FX deficiency. Methods We conducted a retrospective chart review of patients with AL amyloid with FX levels below 60%, not on chronic anti-coagulation who underwent HDM/ASCT at the Mayo Clinic, Rochester, MN between 1995 and 2011. Results Forty-one of 358 patients (11%) met our study criteria. Median pre-ASCT FX was 45% (range: 2%, 59%). The most common bleeding complication was central line associated n=15 (37%) followed by gastrointestinal n=10 (24%) and genitourinary n=9 (22%). The most frequent and severe bleeding complications occurred in patients with FX levels less than 10%. Four patients required emergent splenectomy owing to splenic rupture; one of these patients died from hemorrhagic shock. Periprocedural prophylaxis included activated recombinant Factor VII (rFVIIa) infusions, fresh frozen plasma (FFP) infusions and platelet transfusions. rFVIIa was efficacious in controlling bleeding during splenectomy (n=5) and, in conjunction with arterial embolization, for retroperitoneal bleed (n=1). Elective splenectomy for FX deficiency (n=1) resulted in only transient improvement in FX level. No relationship between the degree of pre-ASCT FX deficiency and other laboratory values (alkaline phosphatase, AST, total bilirubin, serum albumin, total serum protein, serum creatinine, total urine protein, beta2 microglobulin, troponin T) was found. Post-ASCT FX levels were determined in seventeen patients. In four of these patients, post-ASCT FX levels were determined in the acute/subacute phase of ASCT before steady state FX levels could be achieved; the median change in FX for these patients was -6.5% (range: -19%, 3%). In the remaining thirteen patients, who were between 99 and 1920 days from ASCT, FX improved by median 26% (range: -15%, 92%). Overall post-ASCT FX increased in twelve of thirteen (92%) patients. The improvement in FX correlated with improvement in the degree of proteinuria (p = 0.04) and showed a trend towards significant correlation with improvement in serum alkaline phosphatase (p = 0.06). Conclusions Hemorrhagic complications are most frequent and severe for FX levels below 10%. rFVIIa infusions, FFP and platelets were effective prophylactic agents. In the single patient who underwent elective splenectomy, a transient improvement in FX level was seen. Splenectomy was otherwise reserved for patients with splenic rupture/hematoma. Post-ASCT FX levels increased in twelve (92.3%) of the remaining thirteen patients; five of the patients (38.5%) were no longer FX deficient after ASCT. The degree of improvement in FX levels was correlated with improvement in markers of renal or hepatic involvement by amyloid. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Abstract Background Pomalidomide (POM) is the newest Immunomodulatory agent (IMiDs) that has shown clinical efficacy in relapsed multiple myeloma (MM) refractory to lenalidomide (LEN) and thalidomide (THAL). Studies of MM cell microenvironment suggest that tumor subclones compete for dominance during changes in drug therapy. It was previously observed that a minor clonal population increased in prominence of MM cells after 1 year of treatment with LEN. We examined whether the patients having THAL or LEN as the most recent prior-line therapy affects response to POM. Methods We studied 208 patients enrolled in a phase II trial of POM / dexamethasone between November 2007 and March 2012 at Mayo Clinic, Rochester. We reviewed the immediate prior-line therapy before enrollment in our trial. Comparison of treatment duration of POM and response rates were conducted between patients who had either THAL or LEN as latest prior-line therapy, and patients who were treated with non-IMiDs immediate before enrollment in POM trial. Treatment duration of POM was estimated using Kaplan Meier method and the survival curves were compared using log-rank test. We used univariate Cox proportional hazard models to estimate the prognostic impact of different variables. Results The median age of patients was 63 (range from 32 to 88). 68 % were males. 80 patients (38.5%) had THAL or LEN immediate prior to POM. Median prior-line therapies were 3. Patients who received THAL or LEN immediately prior to POM had a lower response rate than those who had non-IMiDs as latest therapy (29% vs 44%, p 0.04) and shorter median duration of POM treatment (5.7 months vs 7.3 months, p 0.02). In 190 (91%) patients who were previously treated with LEN and THAL at any time, median time between the end of LEN or THAL treatment and the initiation of POM was higher for POM responders than non-responders (10 months vs 3 months, p 0.0008). Patients responded to POM had a shorter duration of prior LEN or THAL treatment compared to non-responders (9 months vs 15 months, p 0.001). Conclusion THAL or LEN as an immediate prior-line therapy to POM is associated with a lower response rate and shorter effective treatment duration. Longer interval between prior immunomodulatory compounds and POM, and shorter exposure to previous immunomodulatory compounds are associated with better POM treatment response. Disclosures: Gertz: Celgene: Honoraria. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Lacy:Celgene Corporation: Research Funding.

Abstract The nucleoside analogue pentostatin has clinical activity in B-Cell Chronic Lymphocytic Leukemia (CLL) and has shown significant activity and minimal toxicity when combined with cyclophosphamide for previously treated CLL. Building on this, we initiated a trial in 2002 of combined pentostatin (2mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375mg/m2). Of the 33 enrolled eligible patients included in these analyses, seventeen patients were in the high Rai risk group, 25 were male, and median age for this cohort was 62 yrs (range: 40–79); 17 were non-mutated for the immunoglobulin heavy chain variable region gene, and the majority (67%) were CD38 negative. Only 5 patients had no detectable chromosomal abnormalities by FISH at baseline, 20 had a single FISH anomaly, and 8 had 2 or more FISH anomalies. Of all 28 pts with any anomaly, the following specific abnormalities were detected: 13q- (n=17), +12 (n=8), 11q- (n=7), 17p- (n=2), t(14;18) (n=1), 6q- (n=1), and MDM2 (n=1). Of the 33 patients, 22 had grade 3+ toxicity; 16 patients had non-hematologic toxicity wtih the most common symptoms being nausea (6) and vomiting (4). One patient died on study of grade 5 hypoxia as well as hypotension and this was deemed possibly related to treatment. Almost all patients (32/33; 97%) had a best response of PR or better. Including review of bone marrows done 2 months post-treatment, there were 11 CRs (complete response), 7 nPRs (nodal partial response) and 13 PRs. No differences were observed between type of response and mutation status or CD38+ status. Post-treatment FISH analyses were available on 27 patients; results for 25 patients became normal after treatment. Of the remaining 2, one patient was 13q- x1 and went from 94% to 27.5% abnormal nuclei after treatment; the other is the patient who died on study. To establish minimal residual disease (MRD) post-response, we used three color flow cytometry to detect CD5+/CD19+/CD79b− B cells. This approach found all patients had a reduction in CLL B cells with a median reduction of 91% (range: 5 – 100%). Of interest, all 3 response groups (CR vs. nPR vs. PR) had patients with significant reductions in CLL B cells (i.e., >90%). The nPR group was most variable in terms of MRD (median 47%; range: 5–93%) compared to the CR (median: 91%; range: 42–99.9%) and PR (median: 97%; range: 46–100%) groups. In conclusion this novel regimen of pentostatin, cyclophosphamide and rituximab has demonstrated significant clinical activity irrespective of risk stratification parameters with rapid induction of responses, achievement of minimal residual disease in some, and modest toxicity. Patients continue to be accrued to further explore correlative measures of response to treatment.