Citations

Abstract Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluation. In Arm B (VSV + rux), 2 patients have been enrolled and data are maturing for dose limiting toxicity (DLT) evaluation. Other grade 1 and 2 toxicities have included fever, hypertension, headache, electrolyte abnormalities, nausea, vomiting, transient elevation of liver function tests and creatinine. All grade 1 and 2 toxicities resolved within 72 hours. Among the 6 patients evaluable for response, there was one partial remission (TCL patient treated at dose level 2), and 5 with progressive disease. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h.Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping and ELIspot assays for shared antigens are ongoing. Conclusion: In the lowest dose levels tested to date, VSV-IFNβ-NIS has not led to any observed dose limiting toxicity. Dose escalation is ongoing and updated results will be reported. Disclosures Lacy: Celgene: Research Funding. Peng:Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; Medscape: Consultancy; celgene: Consultancy; Apellis: Consultancy; Prothena: Honoraria; Amgen: Consultancy; annexon: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Al-Kali:Novartis: Research Funding. Naik:Vyriad: Equity Ownership. Kumar:AbbVie: 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; Janssen: 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; Celgene: 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; Celgene: 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; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background/Objective: The association between paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size at disease onset and outcomes in patients with PNH remains unclear. Most but not all reports examining the relationship have shown a positive correlation between clone size and thrombotic events [TEs] in patients with PNH, but without a clear temporal association showing the prognostic value of clone size on the risk of TEs. The ongoing International PNH Registry (NCT01374360) is the largest prospective, observational study of patients with PNH conducted to date. The objective of this analysis was to examine the relationship between PNH granulocyte clone size at disease onset and risk of thrombosis after disease onset while untreated with a complement inhibitor in patients enrolled in the Registry. Methods: The current analysis included patients enrolled in the Registry as of April 2018 who had known demographics, were untreated with complement inhibitor therapy at enrollment, and had ≥12 months of untreated follow-up after disease onset. Baseline was defined as disease onset (earliest of a reported PNH clone, date of PNH diagnosis, or reported PNH symptom), and patients were stratified into 5 cohorts based on clone size at baseline (using the earliest reported clone prior to enrollment): cohort 1, clone size: 0.01-1%; cohort 2, clone size: >1-5%; cohort 3, clone size: >5-10%; cohort 4, clone size: >10-50%; cohort 5, clone size: >50%. Event rates for TEs and all major adverse vascular events (MAVEs; including TEs) were calculated for the time period from baseline to last follow-up. Other outcomes of interest included LDH ratio (LDH/LDH upper limit of normal [ULN]), hemoglobin levels, platelet counts, absolute neutrophil counts, and absolute reticulocyte counts at last follow-up. Results: A total of 2489 patients were eligible for the analysis. The majority of patients in the overall study population were female (54.0% [1343/2489]) and white (79.2% [1967/2484]). Mean (standard deviation [SD]) age at PNH start ranged from 36.4 (16.53) in cohort 5 to 44.2 (20.70) in cohort 1. Median time from baseline to last follow-up was 3.7 years in cohort 1, 4.3 years in cohort 2, 4.7 years in cohort 3, 5.6 years in cohort 4, and 6.8 years in cohort 5. Results for the outcomes of interest are summarized in the Table. All cohorts showed a risk of MAVE and TE during follow-up. Although estimated rates of MAVE and TE were highest in the >50% clone size cohort, there was no difference in the rate of MAVE or TE during follow-up across the 4 cohorts with clone size <50% at disease onset. Mean LDH ratio (LDH/LDH ULN) at last follow-up showed a statistically significant difference by clone size at baseline among the cohorts, ranging from a mean (SD) of 1.1 (1.34) in the patients with clone size <1% and increasing to 5.1 (3.81) in the patients with clone size >50% (P<0.0001). No difference in hemoglobin level at last follow-up was observed in the smaller clone size cohorts, although mean hemoglobin level was lower in patients with clone size >50% (P<0.0001). Similar trends were seen in mean platelet and absolute neutrophil counts across the smaller clone size cohorts, while patients with clone size >50% showed higher values (P<0.0001). Mean absolute reticulocyte count at last follow-up was lowest in patients with clone size 0.01-1%, and were incrementally higher in each successive clone-size cohort (P<0.0001). Conclusions: In this study, all patients with a PNH clone at disease onset were at risk for TEs and other MAVEs. Patients in the highest baseline PNH clone size strata (clone size >50%) had an approximately 2-times higher risk of TEs than patients with smaller clone sizes; Patients with small clone sizes (0.01-1%) were older and showed a higher prevalence of BMD. There was no difference in the prognostic value of clone size at disease onset on the risk of TEs and other MAVEs in patients with small (0.01-1% and 1-5%) versus medium-sized (5-10% or 10-50%) clones. Table Table. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Gustovic:Alexion Pharma GmbH: Employment, Equity Ownership. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria.

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: Outcomes in multiple myeloma have significantly improved in recent times owing to the availability of newer more effective therapies. Autologous stem cell transplantation (ASCT) has been used for over three decades to treat multiple myeloma. We aimed to evaluate the outcome of patients receiving ASCT at our institution between 1990 and 2015. Patients and Methods: A total of 2025 patients received ASCT at Mayo Clinic Rochester between 1st January 1990 and 31st December 2015. The patients were divided in to three cohorts of approximately equal time period, Cohort 1 (1990-1999, n=144), Cohort 2 (2000-2009, n=909) and Cohort 3 (2010-2015, n=972). Outcomes of interest were early mortality, progression free survival (PFS) and overall survival (OS). Disease characteristics were documented from time of diagnosis and PFS and OS were calculated from date of ASCT unless otherwise stated. Results: Median age for the whole cohort was 60 years (range 24-77) and increased over time (55 Cohort 1 vs 59 Cohort 2 vs 61 Cohort 3, p<0.0001). The proportion of males (60% for whole cohort) was not significantly different between the 3 time periods. Almost all patients (99%, n=2018) received chemotherapy prior to transplantation (median lines of therapy 1, range 0-6). The number of patients receiving >1 line of therapy prior to transplantation decreased over time (67% Cohort 1 vs 27% Cohort 2 vs 34% Cohort 3, p<0.0001). The use of novel agents was congruous with their availability and increased over time (0% Cohort 1 vs 59% Cohort 2 vs 100% Cohort 3, p<0.000). After a median follow up of 84 months (95% CI, 78-91 months), median PFS and OS for the whole cohort were 24 and 66 months respectively. Both PFS and OS improved significantly over time (median PFS: 12 months Cohort 1vs 18 months Cohort 2 vs 33 months Cohort 3, p<0.0001; median OS: 26 months Cohort 1vs 63 months Cohort 2 vs 83 months Cohort 3, p<0.0001), Figure 1. The improvement in PFS and OS over the 3 time periods was seen in patients receiving early (≤ 12 months from diagnosis) and delayed (>12 months) ASCT, Table 2. OS from diagnosis was no different for early versus delayed transplant in Cohort 1 and Cohort 2 (Cohort 1: median OS 57 months for early vs 56 months for delayed, p=0.24 and Cohort 2: median OS 81 months for early vs 82 months for delayed, p=0.70) and showed a trend towards a marginal benefit for delayed transplant in Cohort 3 (median OS 105 months for early vs 109 months for delayed, p=0.046).Treatment related mortality (100 days post transplant) improved over time (7.6% Cohort 1 vs 1.8% Cohort 2 vs 0.7% Cohort 3, p<0.0001), Figure 2A. Mortality within 12 months of ASCT also improved over time (24% Cohort 1vs 8% Cohort 2 vs 6% Cohort 3, p<0.0001). A landmark analysis of OS from 12 months post ASCT continued to reveal improved survival over time(median OS 26 months Cohort 1vs 63 months Cohort 2 vs 83 month Cohort 3, p<0.0001), Figure 2B. Conclusion: ASCT remains an important therapeutic option for eligible patients with multiple myeloma. There has been a marked improvement over time in PFS and OS and reduction in treatment related mortality and early mortality in myeloma patients receiving ASCT. This is likely to reflect the addition of novel agents to induction regimens and improved post transplant therapies. Despite these improvements myeloma remains incurable with patients continuing to relapse and die many years after ASCT. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. 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. Kumar:Janssen: 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; Celgene: 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. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; spectrum: Consultancy, Honoraria; celgene: Consultancy; annexon: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; Ionis: Honoraria; Teva: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Prothena: Honoraria.

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 Background: It is well known that the staging stratification at diagnosis predicts survival in immunoglobulin light chain (AL) amyloidosis, but there is a paucity of literature delineating the prognostic value of these systems at the time of 2nd-line therapy. Methods: We conducted a retrospective study to evaluate the prognostic value of AL staging among 563 patients with staging data, who initiated a 2nd-line therapy between 2000 and 2015. Both the Revised Mayo 2012 staging system and the European revision of the Mayo 2004 staging system were used. Results: The median time from initial treatment to 2nd-line therapy was 11.6 months. Median follow-up from institution of 2nd-line therapy was 54.1 months. The 1st-line therapy for patients was autologous stem cell transplant (ASCT) in 216 (38%) patients; and 2) non-ASCT therapies in 347 patients. Both staging systems were prognostic with a risk ratio of 9.4 (95%CI: 6.0, 15.1; p<0.0001) between stage IIIb and I, and of 12.2(8.1, 18.5; p<0.0001) between IV and I. At the time of 2nd-line therapy the staging systems' predictive values were independent of what the patients' 1st-line therapies had been despite the fact that the median time from initial treatment to 2nd-line therapy was 19.4 months in ASCT group and 8.0 months in non-ASCT group. Among the patients receiving 2nd-line therapy after ASCT, the 5-year overall survival (OS) from 2nd-line therapy for those with ≤ stage II versus >stage II was 65% and 31% (Mayo 2004) and 70% and 23% (Mayo 2012). The respective numbers for patients relapsing from a non-ASCT therapy were 57% and 26% (Mayo 2004) and 60% and 23% (Mayo 2012). Conclusions: This study indicates that the Mayo staging systems work well at the time of instituting 2nd-line therapy and is independent of whether 1st-line therapy was ASCT based. Figure. Figure. Disclosures Gertz: annexon: Consultancy; Medscape: Consultancy; Apellis: Consultancy; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; Research to Practice: Consultancy; Teva: Consultancy; janssen: Consultancy; Alnylam: Honoraria. Kumar:KITE: 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; 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. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Background The mutational landscape in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is becoming increasingly apparent. Although some mutations and translocations occur in a substantial fraction of patients, in many, the etiologic mutations are unknown and current cytogenetic testing uninformative. Recent whole genome studies show that the mutational landscape can be very diverse. Genomic studies in families at high risk of developing MDS and AML can be highly informative in identifying potentially oncogenic mutations. We have identified a family with a high incidence of MDS/AML and here report on their unique mutational profile. Patients and Methods An index patient presented to our institution with AML with myelodysplasia related changes (AML-MRC) who required allogeneic stem cell transplantation (SCT). Subsequently, 3 other family members developed MDS. DNA from the index case before and after SCT, 3 affected family members, along with 3 healthy family members (controls) was isolated. Whole exome sequencing was performed using the Agilent V4+UTR capture kit. Sequencing of the index case post SCT served as an additional control (100% donor chimerism). Potentially damaging and novel variations in the index case and additional affected patients were detected by comparing their variant files with those of their unaffected relatives. We further excluded variants with an observed MAF greater than 0.01 using annotated populations in HAPMAP, 1k Genomes, Danish-BGI and ESP5400_EU. All variants with a high or moderate effect based on SNPeff were considered. Results We sequenced an average of 1 billion base pairs per case, with an at least 30 fold exome coverage. The average number of INDELs was 206/patient (range, 187-214), while the average number of SNV was 142/patient (range, 139 – 153). Sixteen mutations were identified in the patients that were not present in controls and in the post SCT sample. This frequency is similar to that recently reported by the Cancer Genome Atlas Research Network. However, none of the mutations we identified have been reported previously in AML/MDS. We identified a heterozygous mutation in the NAPRT1 gene that led to a premature stop codon (R405*). A mutation in the splice site donor of PODNL1 was also identified, together with non-synonymous mutations in IL36RN, ABCA12, GOLGB1, PLXNA1, ABLIM3 and others. We found no correlation between total SNV and total reads mapped (r=0.48). Given the potential role of NAPRT1in genome repair, we evaluated the frequency of SNV in individuals with and without this mutation. There was no difference in SNV frequency in heterozygotes compared to controls (p=0.45) and the frequency of SNV in patients with the R405* mutation did not increase with age. These observations argue against this mutation as a cause of genomic instability. We found a bimodal distribution of SNV (0.14% versus 0.08%, p=0.00024) that did not correlate with the presence/absence of disease. The mechanism behind this distribution is being evaluated. Conclusions The mutational landscape of MDS/AML continues to expand. The functional significance of mutations identified still has to be understood at the molecular level. Although some mutations in AML may be recurrent, it is likely that a substantial number of patients with leukemia have ‘private’ mutations that are oncogenic. Disclosures: No relevant conflicts of interest to declare.

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.

Abstract Background Multiple myeloma (MM) is a heterogeneous disease with variable responses to different therapeutic regimens and wide spectrum of survival. Much of the heterogeneity in the outcomes appear to be related to the underlying primary genetic abnormality, which in the majority of patients consist of either translocations involving the heavy chain region on chromosome 14 (IgH translocation) or trisomies of odd numbered chromosomes. We hypothesized that the response to lenalidomide (Len) therapy would vary significantly based on the underlying molecular subtype of myeloma. Methods We examined a cohort of 518 patients with available FISH results, who had been exposed to Len-based regimens. Medical records were reviewed and data regarding the best response and time to next therapy following treatment with Len-based regimen was obtained. Data from the first use of Len was collected. Len was given in combination with dexamethasone (Dex) with or without alkylators in combination. Patients who received a combination of IMiD and bortezomib as their first exposure to Len were excluded. Patients were grouped according to whether FISH showed a trisomy or an IgH translocation. Results The median age was 62 (28-91), and the median estimated follow up from diagnosis was 52 months (95% CI; 50, 54) with 359 (69%) alive at the time of analysis. An IgH translocation was seen in 129 (30%) of patients and a trisomy in 268 (62%) of patients. IgH translocations included t(11;14) in 92 (18%), t(4;14) in 45 (9%), t(14;16) in 21 (4%); 34 (8%) had both translocations and trisomies. For the current analysis, we included only patients with either a translocation or trisomy (n=397) excluding those with neither or both of the abnormalities. The median time to start of Len from diagnosis was 0 months (range, 0-64). A PR or better was seen in 80% of patients with trisomy compared with 63% of the patients with translocation (p<0.001); and the response rate was similar among the different translocation types. The median TTNT was 28 months among trisomy pts compared with 17 months for translocated patients (p<0.001, figure). The median TTNT was similar across the different types of translocations (Figure). Among this group, 134 patients proceeded to an autologous SCT after Len induction. Among these patients, no difference was seen in terms of TTNT (29 months for patients with translocation vs. 28 months for those with trisomy (p=0.8). Finally, the TTNT was no different if Len was used with Dex or as part of an alkylator combination. Conclusion The current data supports the hypothesis that the underlying primary genetic abnormality can affect the response to a particular therapy. In this study response to Len was significantly higher in myeloma with trisomy compared with IgH translocated myeloma. Although the routine use of combinations of a proteasome inhibitor plus Len in frontline therapy in all patients with myeloma may overcome the lower response rate in IgH translocated patients, in most countries such a regimen is not approved or economically feasible. Based on our study, newly diagnosed patients with evidence of trisomy on FISH could be considered for a Len-based regimen such as lenalidomide-low dose dexamethasone. Additional studies should examine if use of bortezomib in patients with IgH translocation will lead to better outcomes compared with Len based therapies. Disclosures: Lacy: Celgene Corporation: Research Funding. Gertz:Celgene: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding.

Abstract Aim: The autonomic nervous system plays an essential role in homeostasis and the response to stress. The peri-transplant period can be a challenging time for homeostatic responses due to the fluid shifts, sepsis and cardiac dysrhythmias that can occur. Patients with AL amyloidosis may have significant autonomic neuropathy (AN) that renders the peri-transplant care problematic. The purpose of this study was to compare a cohort of patients with AL amyloidosis complicated by AN with a matched cohort without AN to determine the outcome of patients with AN during and after stem cell transplantation (PBSCT). Methods: We performed a nested case-control study by searching the Mayo Clinic dysproteinemia transplant database for all patients with AL amyloidosis who underwent autologous PBSCT. Patients with proven AN were identified and compared to a large cohort of matched controls. We have complete follow-up on all the patients. The main outcome variables were overall survival (OS), the duration of hospitalization, incidence of sepsis, peri-transplant atrial fibrillation (AF) and engraftment kinetics. Comparisons between groups were performed with the Mann Whitney U test for continuous variables and the chi squared test for nominal variables. Overall survival was determined by the Kaplan-Meier method. A stepwise Cox proportional hazards model was used to evaluate the impact of various parameters on OS. Results: We identified 13 patients with AN who underwent PBSCT and compared them to a control group of 94 patients. The two cohorts were well matched for many of the relevant clinical and laboratory characteristics prior to PBSCT. Notable differences included (i) patients with AN tended to have more organs involved (2.5 versus 1, p<0.001) and as a result (ii) the conditioning dose of melphalan was often reduced (p=0.0015). There was no difference in the number of apheresis sessions required for CD34+ cell collection (2.5 versus 2.0, p=0.99), or the number of CD34+ cell collected (6.75 versus 8.15 x106/kg, p=0.99) between the two cohorts. The median hospital duration was 10 (1 – 78) and 8 (0 – 78) days (p=0.99) respectively. Engraftment kinetics, as measured by the time to reach a neutrophil count > 500/ml (p=0.85), a platelet count > 20,000/ml (p=0.99) and a platelet count > 50,000/ml (p=0.99) were similar in the two cohorts. Culture positive sepsis was more common in patients with AN (75% versus 47%, p=0.014). Atrial fibrillation occurred in all patients with AN but in only 1 patient from the control group (p<0.0001). The median OS from PBSCT was 45.2 months for all the combined groups. However, the median OS for patients with AN was 29 months but not yet reached for the controls (p<0.0001). On univariate analysis, cardiac involvement (p=0.0132), AN (p=0.0011), GFR (p=0.038), number of organs involved (p=0.0064) and NT-pro-BNP (p=0.039) all had an impact on OS. On multivariate analysis, AN remained an independent adverse determinant of OS. Conclusion: Patients with autonomic neuropathy secondary to AL amyloidosis can undergo PBSCT safely with similar engraftment kinetics. They are at a higher risk of peri-transplant atrial fibrillation and sepsis although their hospitalizations are not longer compared to controls. Patients with AN generally have more organ involvement by AL amyloidosis. However, AN is an independent, adverse determinant of OS in AL amyloidosis.