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Background Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. Methods In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0–2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60–72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61–72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0–8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2–5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64–0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4–22·8) in the melflufen group and 16·3 months (10·1–23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1–25·6) at a median follow-up of 19·8 months (IQR 12·0–25·0) in the melflufen group and 25·0 months (95% CI 18·1–31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8–23·7; HR 1·10 [95% CI 0·85–1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Interpretation Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma., Oncopeptides AB

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

PURPOSE Salvage autologous stem-cell transplantation (sASCT) in patients with multiple myeloma (MM) relapsing after a prior autologous stem-cell transplantation leads to increased remission duration and overall survival. We report a comprehensive study on patient-reported outcomes, including quality of life (QoL) and pain in sASCT. METHODS Patients were randomly assigned to either sASCT or nontransplantation consolidation (NTC). Pain and QoL were assessed as secondary outcomes using validated QoL instruments (European Organisation for Research and Treatment of Cancer QLQ-C30 and myeloma-specific module, QLQ-MY20; the Brief Pain Inventory [Short Form]; and the Leeds Assessment of Neuropathic Symptoms and Signs [Self-Assessment] scale). RESULTS A total of 288 patients (> 96%) consented to the QoL substudy. The median follow-up was 52 months. The European Organisation for Research and Treatment of Cancer QLQ-C30 Global health status scores were higher (better) in the NTC group at 100 days after random assignment (P = .0496), but not at later time points. Pain interference was higher (worse) in the sASCT group than in the NTC group at 6 months after random assignment (P = .0267), with patients with sASCT reporting higher scores for Pain interference with daily living for up to 2 years after random assignment. Patients reporting lower concerns about adverse effects of treatment after sASCT had a time to progression advantage. CONCLUSION Patients with sASCT with relapsed MM demonstrated a comparative reduction in QoL and greater impact of treatment adverse effects lasting for 6 months and up to 2 years for pain, after which patients who had received sASCT reported better outcomes. Patients who experienced lower adverse effects after sASCT had longer time to progression and overall survival, showing the need to improve symptom management peritransplantation. To our knowledge, this study provides the most comprehensive picture of QoL before and after sASCT in patients with relapsed MM.

Introduction: Recent developments in management of patients with myeloma have resulted in longer survival. Availability of newer class of agents for treatment has prolonged survival, improved quality of life and achieved better disease control. Use of SCT, either autologous (AutoSCT) and to a lesser extent allogeneic (AlloSCT) still forms an important aspect of myeloma treatment pathway. Improved survivorship mandates evaluation of long term consequences and risk of SMN is one of the most important long-term consequences affecting overall outcome. Aim: Estimate the risk of SMN post SCT in patients with Myeloma. Methods and Materials: Analysis includes 779 patients who received SCT for myeloma from January 2002 to December 2019. Data was collected using case records, electronic patient records, transplant database and information from referring hospitals. Follow-up was updated to June 2020. Results: Analysis includes 779 patients with myeloma (M: 488, F:291; median age:59yr, range: 26-75) receiving AutoSCT (n=716) or AlloSCT (n=63). Conditioning for AutoSCT was high dose melphalan in majority (n=714, 99.7%). AlloSCT conditioning was RIC (n=40/63, 63.5%) or MAC (n=23/63, 36.5%). TBI was part of conditioning in 51/779 (6.5%). There was no difference in demographics between two groups. Results: Median follow-up was 46 mo (range: 0.2-220). Second malignancy was identified in 48 of 779 cases (6.0%). SMN developed in 6/63 (10%) AlloSCT and 42/716 (6%) AutoSCT patents (p=0.25). SMN types were haematological (n=21), lymphoma (n=6) and solid tumours (n=21). MDS was the only haematological SMN in this series. Secondary MDS developed in 20/21 of AutoSCT as compared to 1/63 in AlloSCT (p=0.01). Non-haematological SMN were breast (n=3), upper GI (n=3), lower GI (n=2), hepato-billiary (n=2), prostate (n=3), skin (n=5), and unknown primary (n=1). SMN incidence was higher with increasing follow-up (2002-2014, 8%; 2015-2017, 2.8%, 2018-2019, 0%, p=0.002). There was no association with development of SMN and gender, age at transplant, type of stem cell source or transplant conditioning. Incidence of SMN was significantly higher for all sites as compared to general population. Cumulative incidence of SMN was 5% at 5 yr, and 15% at 10 yr for AutoSCT patients. Conclusion: Myeloma patients are at increased risk of SMN and need monitoring for long term side effects. Development of MDS post AutoSCT is the commonest SMN post AutoSCT but there is increased incidence of solid tumours as well. Impact of new modalities of treatment needs long term monitoring. Disclosures Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria.

Background The novel daratumumab immunotherapy is a human IgG1 kappa antibody targeted against CD38, which is almost universally expressed on myeloma plasma cells. Daratumumab has efficacy in clinical trials for the treatment of multiple myeloma; however, it complicates laboratory monitoring of the serological response to treatment, as it is detected by serum electrophoresis and/or immunofixation. Methods Laboratory reports of electrophoresis patterns serially performed in a single laboratory of six patients with relapsed multiple myeloma receiving daratumumab therapy as part a clinical trial were reviewed retrospectively. Results Post administration of daratumumab therapy, an additional band was visible by serum electrophoresis, migrating to the mid-gamma region, which was confirmed as IgG kappa by immunofixation. In five out of the six patients, this band was quantified at Conclusions The clinical laboratory must be aware of the interference of daratumumab in serum electrophoresis. Effective communication between clinicians and the laboratory is essential for the production of clinically valuable, non-misleading reports for these patients.

The Myeloma X trial previously reported improved durability of response (time to disease progression) in patients with relapsed multiple myeloma with salvage autologous stem-cell transplantation (ASCT) compared with oral cyclophosphamide in patients with multiple myeloma relapsing after a first ASCT. We report the final overall survival results of the trial.BSBMT/UKMF Myeloma X was a multicentre, randomised, open-label, phase 3 trial done at 51 centres in the UK. Eligible patients with multiple myeloma relapsing after a previous ASCT were re-induced with intravenous bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11), intravenous doxorubicin (9 mg/m(2) per day on days 1-4), and oral dexamethasone (40 mg/day on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during cycles 2-4), with supportive care as per local institutional protocols before randomisation in a 1:1 ratio to either high-dose melphalan (200 mg/m(2)) and salvage ASCT or weekly oral cyclophosphamide (400 mg/m(2) per week for 12 weeks). Randomisation was by permuted blocks stratified by length of first remission and response to re-induction treatment. The primary endpoint was time to disease progression; the study was also powered to detect a difference in the secondary endpoint, overall survival. Further secondary endpoints were the proportion of patients achieving an objective response, progression-free survival, overall survival, toxic effects and safety, pain, and quality of life. Prespecified exploratory endpoints included time to second objective disease progression (PFS2). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24, and is now in long-term follow-up.Between April 16, 2008, and Nov 19, 2012, 297 patients were registered into the study and 174 were randomly assigned to receive either high-dose melphalan and salvage ASCT (n=89) or oral weekly cyclophosphamide (n=85). 173 (58%) of 297 patients relapsed after more than 24 months from first ASCT. 75 (43%) of 174 randomised patients had died at follow-up: salvage ASCT (n=31 [35%]) versus oral weekly cyclophosphamide (n=44 [52%]). Updated time to disease progression shows continued advantage in the salvage ASCT group compared with the weekly cyclophosphamide group (19 months [95% CI 16-26] vs 11 months [9-12]; hazard ratio [HR] 0·45 [95% CI 0·31-0·64] log-rank p0·0001). Median overall survival was superior in the salvage ASCT group compared with weekly cyclophosphamide group (67 months [95% CI 55-not estimable] vs 52 months [42-60]; log-rank p=0·022; HR 0·56 [0·35-0·90], p=0·0169). Time to second objective disease progression was superior in the salvage ASCT group compared with the weekly cyclophosphamide group (67 months [52-not estimable] vs 35 months [31-43]; HR 0·37 [0·24-0·57], log-rank p0·0001). During extended follow-up, no further treatment-related or treatment-unrelated adverse events were reported. 15 second primary malignancies were reported in 12 patients (salvage ASCT [n=7] vs oral weekly cyclophosphamide [n=5]). The cumulative incidence of second primary malignancies at 60 months after trial entry was 5·2% (2·1-8·2).Salvage ASCT increases overall survival during consolidation of re-induction treatment in patients with multiple myeloma at first relapse after a first ASCT. The delay of salvage ASCT to third-line treatment or later might not confer the same degree of advantage as seen with salvage ASCT at first relapse.Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK.

The phase III British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X trial (MMX) demonstrated prospectively, for the first time, superiority of salvage autologous stem cell transplantation over chemotherapy maintenance for multiple myeloma (MM) in first relapse after previous ASCT. However, many patients have stored insufficient stem cells (PBSC) for second ASCT and robust evidence for remobilization after first ASCT is lacking. We report the feasibility, safety, and efficacy of remobilization after bortezomib-doxorubicin-dexamethasone reinduction in MMX and outcomes of second ASCT with these cells. One hundred ten patients underwent ≥1 remobilization with 32 and 4, undergoing second and third attempts, respectively. Toxicities of remobilization were similar to those seen in first-line mobilization. After all attempts, 52% of those with insufficient previously stored PBSC had harvested a sufficient quantity to proceed to second ASCT. Median PBSC doses infused, neutrophil engraftment, and time to discharge after second ASCT were similar regardless of stem cell source, as were the toxicities of second ASCT. No significant differences between PBSC sources were noted in depth of response to ASCT or time to progression. Harvesting after bortezomib-doxorubicin-dexamethasone reinduction for MM at first relapse is safe and feasible and yields a reliable cell product for second ASCT. The study is registered with ClinicalTrials.gov (NCT00747877) and EudraCT (2006-005890-24).

Guidelines provide recommendations on the management of multiple myeloma (MM), but there are no standard algorithms for the choice and sequencing of treatments. As a result, there is widespread variation in the interpretation and implementation of these guidelines. Areas covered: This review will cover: the real-world data on MM treatment patterns; the approved agents available for the treatment of MM; a comparative summary of the national and international clinical guidelines; a discussion on the impact reimbursement decisions have on treatment availability. Expert commentary: In the future, treatment choices may become even more complex as clonal heterogeneity is better understood in the context of response to treatment, and next-generation agents become available. Although information on real-world practice patterns can provide further guidance, to date, few studies have generated data on patients treated with the newer agents in real-world settings. Furthermore, the translation of guideline recommendations into clinical practice across Europe is inconsistent. Additional real-world data are therefore vital to understanding current clinical practice patterns, so that new agents can be effectively incorporated into existing treatment strategies. Such information may aid the development of better guidance, which will ultimately help to ensure that patients receive the best possible care.

Summary Background Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT. Methods This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m 2 plus salvage ASCT or oral cyclophosphamide (400mg/m 2 per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24. Findings Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19–42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16–25] vs 11 months [9–12]; hazard ratio 0·36 [95% CI 0·25–0·53]; p 10% of patients) grade 3–4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). Interpretation This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients. Funding Cancer Research UK.

Introduction: Chimeric antigen receptor (CAR) T cell therapies directed against B cell maturation antigen (BCMA) have shown significant activity in patients with RRMM, however single antigen targeting with CAR-T cells can result in antigen negative relapse. Dual antigen targeting increases targetable tumor antigens and may reduce the risk of antigen negative disease escape. 'A proliferation-inducing ligand' (APRIL) is a natural high affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI). Like BCMA, TACI is also a tumor necrosis factor receptor and is involved in maturation of B-cells, including their maturation to plasma cells. Importantly, TACI is expressed on MM cells. In this study, we are evaluating the safety and efficacy of AUTO2, a CAR-T cell therapy designed to target BCMA and TACI. Methods: We designed a novel CAR construct using a truncated form of APRIL as the tumor-targeting domain which recognizes both BCMA and TACI on MM cells. AUTO2 is retrovirally transduced to express APRIL CAR and the RQR8 safety switch. The APRIL CAR construct is in a third-generation format with composite endodomains of CD28, OX40 and CD3 zeta. The cell product was manufactured on a semi-automated and closed process. Patients (≥ 18 years) with RRMM; Eastern Cooperative Oncology Group Performance Status Results: As of the data cut-off date (July 03, 2019), 12 patients have been enrolled. Eleven patients have been dosed on study, 1 at 15 x10e6, 3 at 75x10e6, 3 at 225x10e6, 3 at 600x10e6 and 1 at 900x10e6 CAR-T cells. Two patients have been retreated. All patients were successfully manufactured and received target dose. Median age was 61 years (range 45-69 years), median 5 prior lines of treatment (range 3-6) ,73% had prior autologous transplant, 100% were refractory to a PI or IMiD, 80% were refractory to both and 45% were refractory to daratumumab. Eleven patients had a minimum of 4 week follow up and were evaluable for safety analysis. No AUTO2 related deaths were observed and no DLTs were observed. The most frequent ≥ Grade 3 adverse events (>30%) were anemia (82%), neutrophil count decreased (73%). Five patients (45%) experienced CRS, all were grade 1, no ≥ G2 CRS was noted. Tocilizumab was given to 3 patients (27%). No cases of neurotoxicity occurred. Seven patients were dosed, in the ≥ 225x10e6 dose cohorts, the ORR was 43% (28% PRs and 14% VGPRs). Interestingly the patient dosed at 15x10e6 CAR-T cells maintained stable disease (SD) for a year and was retreated at higher dose of 225x10e6 CAR-T cells and continues with SD without further treatment. This patient had the highest baseline levels of TACI and was previously primary refractory to treatment. Another patient initially treated at 75 x10e6 CAR -T cells was retreated with 225x 10e6 CAR-T cells and achieved a partial response. Updated data as well as cellular kinetics, product characteristics and additional biomarker analysis including BCMA and TACI will be presented. Conclusions: AUTO2 is a novel CAR-T therapy, with a manageable safety profile at doses up to 900x10e6 CAR-T cells. Disclosures Popat: Janssen: Honoraria, Other: travel support to meetings; GSK: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Other: travel, accommodations, expenses. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: 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. Cavet:Amgen: Other: congress support , Research Funding, Speakers Bureau; Oncopeptide: Other: congress support , Research Funding, Speakers Bureau; EUSA: Other: congress support , Research Funding, Speakers Bureau; GSK: Other: congress support, Research Funding, Speakers Bureau; Celgene: Other: congress support , Research Funding, Speakers Bureau; Janssen: Other: Congress support , Research Funding, Speakers Bureau; Takeda: Other: congress support , Research Funding, Speakers Bureau. Yong:Autolus: Consultancy; Sanofi: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Lee:Autolus Therapeutics: Equity Ownership, Research Funding. Faulkner:Autolus Therapeutics: Employment, Equity Ownership. Kotsopoulou:Autolus Therapeutics: Employment, Equity Ownership. Al-Hajj:Autolus Therapeutics: Employment, Equity Ownership. Thomas:Autolus: Employment, Equity Ownership. Cordoba:Autolus: Employment, Equity Ownership. Pule:Autolus: Employment, Equity Ownership, Patents & Royalties. Cerec:Autolus Therapeutics: Employment, Equity Ownership. Peddareddigari:Autolus Therapeutics: Employment, Equity Ownership. Khokhar:Autolus Therapeutics: Employment, Equity Ownership. Menne:Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant.

To the editor: Adult Burkitt lymphoma/leukemia (BLL) is a rare, aggressive B-cell neoplasm with typical morphologic appearances. It is characterized by rapid proliferation of mature B cells (Ki67/MIB-1 staining ≥ 99%) and overexpression of c -Myc, which most commonly results from the

High-dose therapy and autologous stem cell transplantation (ASCT) have proven efficacy in patients with multiple myeloma responding well to induction therapy. For those who fail to achieve a stable partial response (PR), the effect of ASCT is unclear. We report on 126 patients identified from a national database, who underwent ASCT having achieved

Introduction: As the number of long-term survivors following HSCT is increasing, the long-term risks and associated morbidity has become important component of survivorship program. The known risk factors for developing cancer include use of chemotherapy agents, radiation exposure, immune dysfunction, previous malignancy in addition to other factors and as HSCT process involves all these factors, this single centre retrospective analysis was undertaken to evaluate the risk of developing SSC in the patients receiving transplant. Methods: From February 1982 to February 2016, 2231 patients received 2495 transplants (median age: 46yr., range: 14-76 yr.; M: 1586, F: 909) for haematological malignancies (Leuk: 744, lymphoma:767, myeloma:848, solid tumours/other:136). Donor was allogeneic (n=744) or autologous (n=1751) and conditioning was with (n=614) or without TBI (n=1881). Donor was sibling (n=375), matched unrelated (n=355), haploidentical relative (n=3) or umbilical cord blood (n=11). Source of stem cell was marrow (n=367), PBSC (n=2086), both (n=31) or cord blood (n=11). GVH prophylaxis included Campath or ATG in 369 cases. Of all the patients 1985 received single transplant, 231 had two, 13 had 3 and 2 had 4 HSCT procedures. Data was analysed as of 15/04/2016 using competing risk model with death as the competing event. Comparison of incidence to general population was performed by computing standardized incidence rates (SIR). Patients with second haematological malignancy were not included in this analysis. Results: Median follow-up was 5.3 years (range: 0-32 years). Patient follow-up was more than 10 years in 467 cases (19%), between 5 to 10 years in 430 (17%), 2 to 5 years in 607 (24%) and less than 1 year in 997 cases (40%). 36% patients were followed-up for more than 5 years. Second solid cancers developed in 116 patients with the incidence of 1% at 5yr (95% CI: 0.5-2.6), 3% at 10 yr (95% CI: 1.6-5.3), 6% at 15yr (95%CI: 3.6-8.8) and 10% (95% CI: 5.9-15.5) at 20 years. Median time to develop SSC from date of HSCT was 11 yr (range: 0.4-28.1 yr). Primary site for SSC included skin (n=37), breast (n=22), GI (n=15), GU (n=16), H&N (n=10), lung (n=6), CNS (n=4), Endocrine (n=4) & HPB (n=2). There was no difference with type of transplant i.e. auto or allograft. Autograft and allograft groups were analysed separately. In univariate analysis, allograft group showed higher cumulative incidence of SSC with use of PBSC (p Conclusion: This single centre analysis confirms that the risk of developing SSC increases with advancing age, use of RIC allograft, longer follow-up and leads to inferior survival. Since the year 2000, SSC are developing early after transplant and it needs to be evaluated if this is a trend seen at other centers and if so, is it related to increasing use of RIC, increasing number of elderly patients, severity of immune-suppression or higher incidence of GVHD. Disclosures Somervaille: Novartis: Consultancy, Honoraria; Imago Biosciences: Consultancy. Bloor:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Introduction: Community acquired SRVI increase hospital referrals, hospitalization and ICU admissions resulting in high morbidity and mortality during winter season. As there are no defined preventative or treatment measures for most of the SRVI, there is increasing burden on health service resources during SRVI season. This analysis was carried out to evaluate the SRVI incidence, risk factors, impact on mortality and changes in incidence trends over 9 year period in immunocompromised cancer patients. Methods: 2906 cancer patients (haematology: n=1098, 37.8%, lymphoma: n=643, 22.1%, other cancers: n= 1156, 40.1%) treated from January 2006 to January 2015 who had respiratory virus PCR were evaluated. Patients with haematological cancers included ALL (n=137), AML (n=338), Myeloma (n=396), CLL (n=131) or other cancers (n=96) [median age: 50 yr., 5-87, Male: 692, Female: 406). Common solid tumour diagnosis included cancer of Breast (n=280, 24.0%), GI tract (n=207, 17.8%), Lung (n=190, 16.3%), Genitourinary (n=180, 15.5%) or other sites (n=299, 25.7%), [Males: 461, Females: 695; median age: 55 yr., range: 6-89]. Patients with haematological malignancies were younger than patients with other cancers (median age: 50 yr. vs. 55 yr., p Results: In patients with malignancy, the season for ParaFlu, Rhinovirus, Metapneumovirus and FluA lasted longer than in general population (average: 2 months, started early and ended later). Incidence of RSV (6.2%, 4.9%, 1.6%, p=0.001), Adenovirus (1.3%, 1.7%, 0.33%, p=0.004), Rhinovirus (16.6%, 19.9%, 8.5%, p=0.001) and ParaFlu (7.4%, 6.3%, 2.6%, p=0.057) was higher in hematology and lymphoma patients. Incidence of PCP was higher in oncology patients (15.1%, 7.2%, 9.6%, p=0.001). Incidence of PCP was higher with increasing age (5.8% age< 50, 12.2% age>50 yr., p=0.001). Rhinovirus (18.7% age75 yr., p=0.001) and ParaFlu (8.1% age 25 yr., p=0.02) was higher in younger patients. Stem cell transplant increased risk of RSV (6.8% vs. 3.5%, p=0.001), Adenovirus (1.7% vs. 0.6%, p=0.001) and ParaFlu (8.1% vs. 0.23%, p=0.001) but risk of PCP (7.7% vs. 11.8%, p=0.0001) was lower. Risk of positive PCR for any respiratory virus was higher with increasing age, hematological cancers, and use of stem cell transplant. Surprisingly, diagnosis of CLL and Myeloma did not increase SIRV risk. Thirty-day mortality was higher in patients who had SRVI (p=0.041). Mortality was higher in patients with solid tumours (p Conclusion: This is one of the first reports that compares incidence of SRVI in patients with cancer to that in general population. The analysis of SRVI using PCR based diagnosis demonstrates that incidence of SRVI in cancer patients show different trends than in general population. SRVI season lasts longer and RSV, FluA and PCP contribute to 30-day mortality. Increasing PCP incidence in patients with solid tumours raises the questions about need to use of PCP prophylaxis in all these cases. Disclosures Somervaille: Novartis: Consultancy, Honoraria; Imago Biosciences: Consultancy. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Introduction: Histone deacetylase inhibitors (HDACis) have demonstrated clinical efficacy in multiple myeloma, particularly in combination with proteasome inhibitors. CHR-3996 is a class 1 selective HDACi with potent anti-myeloma activity in vitro. Aminopeptidase inhibitors act downstream of the proteasome and prevent breakdown of proteasome generated peptides into amino acids. Synergistic cytotoxicity was observed in vitro when CHR-3996 was combined with the aminopeptidase inhibitor, tosedostat through rapid activation of NFkB followed by increased expression of the repressors IκBα, A20, CYLD, BIRC3. The MUK-three study was designed to translate these pre-clinical findings into a phase 1 clinical trial. This dose escalation study aimed to determine the maximum tolerated dose, safety and preliminary activity of CHR-3996 administered in combination with Tosedostat for patients with relapsed, refractory MM. Here we present the final study results. Methods: MUK-three was an open label multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had failed conventional treatments. Patients were permitted to meet the haematological entry criteria using growth factor and/or blood product support. During dose escalation subjects received CHR-3996 (20-40mg days1-28) and Tosedostat (0-60mg days 1-28) (Table 1) every 28 day cycle until disease progression or withdrawal. Dose limiting toxicities (DLTs) were evaluated during cycle 1 and dose escalation followed the 3+3 design. Responses were assessed using modified IMWG uniform response criteria, with the primary endpoint for the expansion phase of stable disease (SD) rate after 4 cycles of therapy. Toxicity was graded by CTCAE V4.0. Results: The trial was open to recruitment from July 2012 to December 2015. 20 patients were treated during dose escalation, including 8 at the recommended dose (RD) and 12 at dose levels (DL) 1-3. Only 1 DLT was observed at DL3 (grade 4 thrombocytopenia); however, this DL was deemed not tolerable due to the high incidence of low grade gastrointestinal toxicities. Hence the RD was determined as DL3b, CHR-3996 20mg and Tosedostat 60mg. A further 2 patients were treated at RD during dose expansion to make the required 10 patients for the protocol defined initial analysis at which point the trial closed. At the RD (n=10) median age was 63 years (range 47-73). 80% of patients had received at least 4 prior lines of therapy (median 4, range 2-9); 50% were ISS II, 30% ISS III; 4/6 patients with evaluable FISH data had 1q gain. The median time from diagnosis to treatment for the overall population was 85.3 months (27.5-198.8). The median number of cycles received was 2.5 (range 2-8) and 2 patients remain on treatment with 8 stopped due to disease progression. The 2 patients ongoing (received 5 & 9 prior lines) had their schedule adjusted to a 5 day a week dosing to further improve tolerability. Both had a clinical response (1MR, 1PR) and remained progression free at 6 months. 3/10 patients had SD after 4 cycles, the overall response rate (≥PR) was 1/10(10%) and the clinical benefit rate (≥MR) 2/10 (20%). Overall outcomes were: PR 10%, MR 10%, and SD 30%. Median time to maximum response was 1.84 months (95% CI [1.09, 8.65]). Toxicities at the RD were manageable, 30% of patients required a dose reduction. 22 serious adverse events were reported in 16 patients across all doses, mainly infections (10/22, 45.5%). The commonest grade 3-4 toxicities reported for all 22 patients were: platelet count decrease (12, 54.5%), white blood cell decreased (6, 27.2%), diarrhoea (5, 22.7%). The most frequent grade 1-2 toxicities were fatigue (15, 68.2%), nausea (14, 63.3 %), anorexia (14, 63.6%), anaemia (13, 59.1%). 1 patient withdrew due to toxicity, and there were no treatment related deaths. Conclusions: This study demonstrated that the novel combination of CHR-3996 and tosedostat was safe and tolerable in multiply relapsed, refractory myeloma patients many of which had poor bone marrow function. The recommended dose of the combination was 20mg and 60mg, respectively. Following further adjustment to an intermittent 5 day/ week dosing schedule, treatment was well tolerated and clinical benefit observed. This suggests that further evaluation of this novel combination is warranted. Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 24989786. Disclosures Williams: Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Cook:Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Introduction: Prevention of Graft versus host disease (GVHD) forms the mainstay of obstacle in the successful outcome of alloHSCT. Various strategies are employed but combination of calcineurin inhibitors with methotrexate or mycophenolate is the commonest preventative measure used. Cyclosporine is dosed according to trough (C0) levels and the optimum level is defined as between 200 and 300 ng/ml. Daily doses are adjusted to achieve the therapeutic levels. As there can be fluctuations in the daily levels, it was postulated that area under the curve (AUC) extrapolated from daily levels may be more useful to define the optimum cyclosporine exposure for prevention of GVHD. Hence this retrospective analysis was carried out to evaluate if cyclosporine AUC for first 14 days has correlation with the incidence of GVHD. Methods: 549 patients who received allograft and had cyclosporine C0 levels available for first 14 days were included in the analysis. The patient population included 353 males (64.3%) and 196 females (35.7%) with a median age of 44 yr. (range: 16-71). Underlying diagnosis included Ac. Leukaemia (n=319, 58.1%), Chr. Leukaemia (n=42, 7.7%), lymphoma (n=119, 21.7%), myeloma (n=57, 10.4%) or other (n=12, 2.2%).Donor was matched unrelated (n=330, 60.1%), sibling (n=204, 37.2%) or cord (n=15, 2.7%). Stem cell source was PBSC (n=454, 82.7%), BM (n=78, 14.2%), both (n=2, 0.4%) or cord blood (n=15, 2.7%). 415 patients had RIC (75.6%) and 134 had full intensity SCT (24.4%). Alemtuzumab or ATG was used in conditioning in 311 cases (56.6%). The target Cyclosporine AUC with a daily level of 200 was predicted as 2600, 2470 for cyclosporine level of 190 and 2730 for levels of 210. Results: The median AUC for the entire cohort was 3338 (range: 370-6390). Only 56 cases (10.2%) had AUC below 2600. Incidence of AGVHD was significantly higher with use of PBSC (53.7% vs. 21.7%, p Conclusion: This retrospective analysis had high proportion of cases receiving Alemtuzumab/ATG based GVHD prophylaxis and shows that even though there is no effect of cyclosporine AUC on the incidence of either AGVHD or CGVHD, patients receiving Alemtuzumab/ATG with sub-therapeutic cyclosporine AUC have poor OS. This raises the possibility that in this group of patients it is imperative to have target cyclosporine levels in first 14 days. The duration of target cyclosporine levels before tapering the doses needs to be established to improve OS without increasing the toxicity. Disclosures Somervaille: Imago Biosciences: Consultancy; Novartis: Consultancy, Honoraria. Bloor:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria; GSK: Consultancy, Speakers Bureau.

Autologous stem cell transplant as primary (first ASCT) therapy in multiple myeloma (MM) is standard practice. The role of a second ASCT as management of relapsed disease remains uncertain. We conducted a retrospective case-matched control analysis on patients (n = 106) who underwent a second ASCT compared with conventional chemotherapy (CCT) as for relapsed MM. The median age was 53 years (range: 26-75) and median follow-up 48 months (range: 8, 136). The cumulative incidence of 1 and 5 years nonrelapse mortality (NRM) was 7% (95% confidence interval [CI] 3%-13%) and 12% (95% CI 7%-19%), with a second ASCT inducing a greater partial remission (PR) rate of 63%. The 4-year overall survival (OS) rate was 33% (95% CI 24%-45%). Factors associated with improved OS and progression-free survival (PFS) included younger age (9 months from first ASCT, and a greater PR in response to their first ASCT. In a matched-cohort analysis with patients receiving conventional chemotherapy (CCT), the same factors were associated with improved OS, with the exception of a longer remission duration (>18 months) from first ASCT. Second ASCT in relapsed MM is associated with superior OS and PFS compared with CCT, offering a potential consolidative option for selected patients.

Introduction: Autologous transplantation (ASCT) in myeloma (MM) is standard consolidative therapy in first line therapy in eligible patients. We have shown definitely that a salvage ASCT in relapse setting can induce superior durability of responses (time-to-progression; TTP) over non-transplant consolidation with oral cyclophosphamide after a proteasome inhibitor-based re-induction schedule (ISRCTN601231201). The secondary end point of this multi-centre phase III randomised controlled trial was to evaluate the impact of salvage ASCT on the overall survival (OS_ of patients relapsing after a prior ASCT and delineate patient subgroups that may benefit the most. Patients and Methods: Eligible patients with MM relapsing after a prior ASCT were enrolled. All patients were re-induced with Bortezomib, Doxorubicin and Dexamethasone (PAD) therapy delivered in 2-4 21-day cycles before 1:1 randomization to either a second ASCT (melphalan 200mg/m2 iv; ASCT2 supported by either stored or remobilized stem cells) or low dose consolidation with weekly cyclophosphamide 400mg/m2 PO for 12 weeks (Non-Transplant Consolidation; NTC). Response was assessed (by IMWG criteria) after re-induction and 100 days post-randomization with TTP being determined as the primary end-point. Patients were stratified by β2microglobulin (β2M) at trial entry, ASCT1 TTP and response to re-induction, analyzed according to cytogenetic abnormalities by iFISH (unfavorable: t(4;14), t(14;16) and del17p) with OS was a key secondary endpoint. Results: 297 patients were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n=89, NTC n=85. Median age was 61 (range 38-75) with 73.6% of patients relapsing more than 24 months from first ASCT. ORR to re-induction therapy was 79.4% with a 16.0% sCR/CR rate. Post-randomization, sCR/CR was significantly higher after ASCT2 (39.3% [95% CI 29.1,50.3] vs 22.4% [95% CI 14.0,32.7]; p=0á012). The median follow-up is 52 months (IQR range 41, 62) and the up-dated TTP demonstrates continued advantage in ASCT2 cohort compared to NTC (19 months [95% CI 16,26] vs 11 months [95% CI 9,12]; Log Rank p 24m (HR0.60, p=0.089), β2M level Conclusion: This long-term follow-up analysis demonstrates a clear advantage in terms of OS when salvage ASCT consolidates bortezomib-based re-induction therapy in patients with MM at first relapse. The delay of salvage ASCT to third line, though being suggestive of benefit over no salvage ASCT, does not confer the same degree of OS advantage as shown with a salvage transplant in second line. This data is key for patient-centered clinical decision-making. 1. G Cook, et al.. The Lancet Oncology, Vol. 15, No. 8, p874-885 Figure 1. Forest plots showing (a) heterogeneity of effect of randomised treatment on OS and (b) effect on OS of randomised treatment followed by ASCT at second relapse (NTC/ASCT2) Figure 1. Forest plots showing (a) heterogeneity of effect of randomised treatment on OS and (b) effect on OS of randomised treatment followed by ASCT at second relapse (NTC/ASCT2) Figure 1B. Figure 1B. Disclosures Cook: Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Sanofi: Consultancy, Speakers Bureau; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Williams:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Snowden:MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau; Sanofi: Consultancy. Parrish:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Yong:Takeda: Honoraria; Autolous: Consultancy; Janssen: Honoraria; Novartis: Consultancy; BMS: Honoraria; Amgen: Honoraria. Cavet:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Bird:Janssen: Other: Educational support; Celgene: Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Heartin:Celgene: Speakers Bureau; Janssen: Consultancy. O'Connor:Celgene: Research Funding. Ashcroft:Janssen: Consultancy, Other: Educational support. Brown:Janssen: Research Funding; Roche: Research Funding; Celgene: Research Funding; Bayer: Research Funding. Morris:Janssen: Other: Meeting support; Celgene: Other: Meeting support.

Introduction. The impact of therapy in the management of disease relapse in patients with myeloma (MM) needs to be balanced with the impact on quality of life (QoL). The benefit of a salvage autologous stem cell transplant (ASCT2) has been demonstrated in terms of durability of response over non-transplant consolidation (NTC) (G Cook, et al., Lancet Oncology, 2013 Vol. 15, No. 8, p874-885). However, the impact of ASCT2 on patient reported outcomes (PRO) has not been reported to date. Therefore, patients' experience of pain and global measures of QoL, as part of a systematic assessment of PRO were measured at key points before, during and after randomisation in this multi-centre national phase III trial. Methods. 174 patients were randomised and data are presented on 171 who completed self-rated QoL assessments using EORTC QLQ-C30 and the EORTC myeloma module (MY-20). Pain assessments using BPI-SF were also incorporated. Genomic DNA was prepared from PBMNC using standardised GLP methods. Results. Completion rates for EORTC QoL and BPI-SF assessments were 83.3% and 77.1% at registration, and 59.6% and 53.8% at randomisation, respectively. Over half of patients reaching 1 year post-randomisation completed both assessments. EORTC QoL and BPI-SF forms had average 6% and 10% missing data, respectively. These completion rates are commensurate with previous longitudinal studies. EORTC QLQ-C30 Global health status/QoL subscale scores were significantly higher (better) in the NTC arm at 100 days and 6 month post-randomisation (P=0.0496), but not at later time points. BPI-SF pain scores showed significantly higher pain severity in the NTC (4.3/10) than the ASCT2 (2.9/10) patients only at 2 years post-randomisation. However, for pain interference with aspects of daily living, NTC patients reported significantly lower scores at 6 months (P=0.0155), 1 year post-randomisation (P=0.0466) and 2 years post-randomisation (P=0.0348). The MY-20 assessment showed that at 100 days and 6 months post-randomisation, the subscale scores for Side-effects of treatment were significantly higher in the ASCT2 arm than in the NTC arm, but not at later time points up to 2 years. Kaplan-Meier estimate of time-to-progression (TTP) by randomised allocation suggested that patients with an EORTC global QoL score greater than median (ie better QoL) at randomisation and who received ASCT2 had a significant TTP advantage over those receiving NTC (HR 0.3 (95% CI 0.15-0.61), p=0.006). However, with multivariate Cox regression analysis accounting for stratification factors this difference was not significant. Patients who reported a lower (ie better) than median level of concern on the Side-effects of treatment subscale and who received ASCT2 had a significant TTP advantage over those receiving NTC (Kaplan-Meier HR 0.24 (95% CI (0.10-0.55), p=0.003). This survival difference was still observed after multivariate Cox regression analysis (HR 5.02 (95% CI 1.00-25.20), p= 0.0499). We tested for genomic associations of SNPs from key genes reported to be involved in pain perception and analgesic responsiveness, and subjective outcomes. There were no significant associations for the opioid mu-receptor (OPRM1) and pain or QoL. However, the rs2236861 SNP in the opioid delta-receptor (OPRD1) showed nominally significant associations with worst pain (p=0.022), average pain (p=0.03) and pain interference (p=0.02) at baseline. The rs1045642 SNP in the ABCB1 drug transporter gene was nominally associated with worst pain (p=0.047) and average pain (p=0.019) after bortezomib-based induction therapy. A SNP rs13361160 in the chaperonin CCT5 gene was associated with worst pain (p=0.033), least pain (p=0.006) and pain interference (p=0.03). It was also associated with self-reported global QoL (P=0.014). Conclusions. We report the first PROs using self-reported QoL and pain assessments in myeloma patients having salvage ASCT or NTC. Global QoL was worse and side-effects of treatment higher after ASCT2 for up to 6 months post-randomisation but then equalised. Pain caused less interference with daily living after NTC but became more severe at 2 years, possibly associated with relapse. Patients who reported lower concerns about side-effects of treatment after ASCT2 had a significant TTP advantage. The genomic analyses suggest a potential inherited predisposition that influences both pain and quality of life and warrants further exploration. Disclosures Ahmedzai: Mundipharma: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Grunenthal: Consultancy, Research Funding, Speakers Bureau. Snowden:Sanofi: Consultancy; MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau. Williams:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Cavenagh:Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Parrish:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Yong:Amgen: Honoraria; Novartis: Consultancy; Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Autolous: Consultancy. Cavet:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Bird:Celgene: Speakers Bureau; Janssen: Other: Educational support; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Ashcroft:Janssen: Consultancy, Other: Educational support. Brown:Bayer: Research Funding; Roche: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Morris:Celgene: Other: Meeting support; Janssen: Other: Meeting support. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Introduction: Peg-Asparginase is routinely used in the chemotherapy regimens used for treatment of ALL. Incidence of thrombotic complications is well established in children but there is limited data in adult and young adolescent patients. This is retrospective analysis to assess the risk of thrombotic complications with use of Peg-Asparginase. Methods and Results: 100 patients with Acute Lymphoblastic Leukaemia treated between 2007-2015 who received Peg-Asparginase containing chemotherapy regimen were evaluated for development of thrombotic complications and pancreatitis. There were 69 male patients and 31 female patients. Median age was 29 yr. (range: 16-68 yr). Route of administration for Peg-Asparginase was intravenous in 51 cases and intramuscular in 49 cases. Peg-Aspraginase was administered during induction phase and consolidation cycles according to the relevant chemotherapy protocols. The adverse events included deep vein thrombosis (DVT) in 15 (15%), cerebral venous thrombosis in 7 (7%), Pancreatitis in 2 (2%), DVT and pancreatitis in 1 (1%) and 1 patient had clinically suspected DVT (1%). Complication rate was similar with IV or IM route of administration. 10 patients in IM group (20.4%) and 17 patients in IV group (33.3%) had at least one complication with Peg-Asparginase (P=0.31). Risk of individual complications was similar in both groups (DVT: 14.3% vs. 21.6%, p=0.34; Pancreatitis 2% vs. 3.9%, p=0.57; Cerebral venous thrombosis 4%% vs. 9.8%, p=0.25). There was no difference in the incidence of thrombotic complications with gender, age at diagnosis and use of central venous lines. Conclusions: There is a significant risk of thrombotic events including PE (18% risk of thrombotic events excluding CNS). Risk of CNS events is 7% in this population. Risk appears to be higher with IV administration but this is not statistically significant due to small sample size. Incidence of CNS events is similar to that reported in adolescents participating in UKALL2003 study. The analysis will be extended to evaluate other toxicities especially hepatic toxicity and identify if there are any high risk patients for CNS or thrombotic events including blood counts, clotting, and cytogenetics. Use of LMWH prophylaxis seems reasonable in view of high incidence of thrombotic events even if CNS events are excluded. Disclosures Cavet: Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: Conventionally patients receiving allogeneic HSCT (AlloHSCT) have received CMV negative blood products to obviate the risk of transfusion related CMV transmission. In the era of leucodepletion with more than log 4 reduction in blood product WBC content, the utility of this practice has been questioned and, in line with SABTO (Safety of Blood, Tissues and Organs) guidance, most UK transplant centers have adopted the policy of using unselected blood products for this patient cohort. At this center, our policy was changed to conform to recommended national practice in April 2013. This analysis was carried out to evaluate if this change has resulted in an increased incidence of CMV reactivation. Methods: 868 (M: 561; median age: F: 307; median age:) patients who received HSCT from January 1998 to November 2014 were included in analysis. Transplant types included AutoHSCT (n=384), AlloHSCT-Sibling (n=217) and AlloHSCT-MUD (n=267). Diagnosis was Ac Leukaemia (n=313), Chr Leukaemia (n=36), Myeloma (n=216), Lymphoma (n=261) or other malignancies (n=42). Commonest indication for AutoHSCT was myeloma or lymphoma. TBI based condition was used in 225 AlloHSCT and 50 AutoHSCT cases. RIC was used in 268 cases and full intensity in 215 cases (unknown in 1). Alemtuzumab or ATG was used in conditioning for 274 cases. Source of stem cell was PBSC (AutoHSCT: 363, AlloHSCT: 382), BM (AutoHSCT: 7, AlloHSCT: 97), both (AutoHSCT: 2, AlloHSCT: 9) and 8 AlloHSCT were UCB grafts. Results: 26, 345 blood PCR results were evaluated. 3100 tests were requested in AutoHSCT patients and 109 (3.6%) were positive. There were no differences in the incidence of positive CMV PCR results before and after use of CMV unselected blood products. Further analysis was limited to AlloHSCT patients. AlloHSCT patients were divided in two groups, GrpA: 1998 to 2013 and GrpB: 2013 to 2014 to evaluate the effect of using CMV unselected blood products. In AlloHSCT group, 9.1% of 23278 samples tested for CMV PCR were positive (Median log: 2.7, range: 0.3-7.3). Incidence of CMV reactivation was not different in GrpB as compared to GrpA (47.7% vs. 48.1%, p=0.93). There was no difference with gender (M: 45.8% vs. F: 53.1%, p=0.13), type of donor (Sibling: 48.6% vs. MUD: 47.9%, p=0.98), use of Alemtuzumab/ATG (50.6% vs. 45.4%, p=0.51), source of stem cells (BM: 36.4% vs. PBSC: 51.3%, p=0.07), use of TBI (43.8% vs. 52.3%, p=0.06). Higher incidence was observed with use of RIC transplant (53.2% vs. 42.3%, p=0.02) and donor-recipient CMV mismatch (NP: 24.5%, PN: 80%, PP: 90.8%, p Conclusion: This analysis suggests that the risk of CMV reactivation is related to the donor-recipient CMV mis-match and the transplant intensity. Use of CMV unselected blood products does not increase the risk of CMV reactivation and careful selection of donors using CMV sero-status is the key factor to reduce the risk of CMV reactivation post AlloHSCT. Disclosures Cavet: Janssen: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Ph chromosome is the hallmark of CML. However there are few reports of additional chromosomal abnormalities at the time of diagnosis and the impact this has on overall survival (OS). [NT1] The Cytogenetic laboratory at this hospital provides a regional service as a single facility. The data from this laboratory was combined with survival information to evaluate the impact of additional chromosomal changes on outcomes in patients with CML. Methods: This is a retrospective population based study, it was not possible to obtain consent from individual patients and details about haematological parameters or treatments delivered were not available. The aim was to evaluate if cytogenetic changes should be considered in addition to established risk scoring systems. Patients were classified as complex-Philadelphia (Ph) if they had t(9;22)(q31;q34) with additional chromosomal abnormalities. Impact of individual additional abnormalities was analysed and then the effect was stratified according to presence of chromosomal gains, deletions or translocations. Few cases who had normal cytogenetics on their first sample as they were initially treated elsewhere. Results: 1129 patients were diagnosed with CML between 1985 and 2013, with 4760 samples analysed. The median age of the patient was 52.4 years (4.3-103, 602 male; 511 female; 16 unknown). Median follow up was 6.4 years [0-26.8 years, 725/1129 (64.2%) had follow-up more than 10 years]. End point for analysis was probability of survival at 10yr. 194/1129 (17.2%) had complex-Ph at diagnosis, 759/1129 (67.2%) had standard Ph, 77/1129 (6.8%) had negative cytogenetics and in 34/1129 (3%) cytogenetic analysis failed at diagnosis. Patients with standard Ph translocation had significantly better chance of achieving cytogenetic CR than those with complex-Ph (23.4% vs. 13.4%, p This analysis suggests that incorporating nature of karyotype at diagnosis can refine established scoring systems. However this data needs to be analysed with larger patient population to include all established risk factors and the effect of therapeutic measures. Disclosures Cavet: Novartis: Research Funding; BMS: Research Funding.

Introduction: It is increasingly important to understand the long term risk associated with transplantation because the number of long term survivors is steadily growing. In comparison to other long term risks following transplantation like infertility, cataracts, endocrine dysfunction, etc. the risk of second malignancy is likely to be associated with increased risk of mortality and hence significant impact on survival outcomes. This retrospective, single centre analysis was undertaken to evaluate the risk of second solid malignancy in patients undergoing HSCT. Methods: From February 1973 to November 2013, 1983 patients (median age: 45yr., range: 14-76 yr.; M: 1259, F: 724) received stem cell transplants for haematological malignancies (Ac. Leuk: 507, Chr. Leuk: 97, lymphoma:645, myeloma:621, solid tumours:113). Donor was allogeneic (n=528) or autologous (n=1455) and conditioning was with (n=556) or without TBI (n=1427). Donor was sibling (n=302), matched unrelated (n=220) or cord blood (n=6). Source of stem cell was marrow (n=322), PBSC (n=1627), both (n=28) or cord blood (n=6). GVH prophylaxis included Campath in 203 cases. Of all the patients 1774 received single transplant but 209 received more than one transplant. Data was analysed as of 01/12/2013 using competing risk models with death as the competing event. Patients who developed second haematological malignacy were not included in this analysis. Results: Patient follow-up was more than 10 years in 382 cases (19%), between 5 to 10 years in 328 (17%), 1 to 5 years in 667 (34%) and less than 1 year in 606 cases (31%). Second solid malignancy developed in 70 patients with the incidence of 1% at 5yr (95% CI: 0.5-1.6), 2.2% at 10 yr (95% CI: 1.6-3.3), 4.8% at 15yr (95% CI: 3.6-6.8) and 8% (95% CI: 5.9-10.5) at 20 years. Site of second malignancy was brain (n=2), breast (n=15), cervix (n=3), GIT (n=11), genitourinary (n=9), lung (n=3), skin (n=17), head & neck (n=7), thyroid (n=3) and non EBV related lymphoma (n=3). In univariate analysis 10 yr. probability of developing SSM was not influenced by gender, stage of disease, primary diagnosis, type of HSCT, use of TBI, cranial top-up radiation, type of donor or year of transplant. It was significantly higher with use of PBSC (1.4% vs. 2.6%, p=0.02) and age above 65yr. (1.5% vs. 11%, p=0.001). In multi-variate analysis age above 65yr. (RR: 1.8, 95% CI: 1.1-2.9, p=0.02) and PBSC (RR: 9.4, 95% CI: 1-99, p=0.05) were independently associated with increased risk of SMN. 19 patients have died due to SSM (27%) and survival was significantly shorter with gastrointestinal, genitourinary and lung cancers. Conclusion: This single centre analysis shows that the risk of developing SSM increases with advancing age, longer follow-up and the survival is poor. Long term survivors of stem cell transplants need follow-up probably for life in speciality clinics. Continued vigilance, avoidance of known carcinogens and life style changes are strongly recommended. Disclosures Bloor: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavet:Novartis: Research Funding; BMS: Research Funding.

Introduction E.coli are one of the commonest organisms causing blood stream infections (BSI) in oncology and hematology patients. With the growing incidence of extended spectrum beta lactam resistance (ESBL) this single centre retrospective analysis was undertaken to identify the predictors of outcome of E.coli septicaemia in hemato-oncology patients. From 2002 to 2012, 1089 patients with haematological malignancies had 3528 episodes of BSI and of them 257 in 177 patients (7.3%) were with E.coli. Methods 177 (M: 114, F: 63; median age: 52yr., range: 16-89) patients with haematological malignancies treated from April 2002 to April 2012 were included in analysis. Underlying diagnosis was AML (n=47), ALL (n=23), Lymphoma (n=73), MDS (n=6), myeloma (n=19) or other conditions (n=9). There were 257 episodes of E.coli septicaemia in 177 patients and each episode was analysed as an individual event. Of the 257 episodes, 34 (13%) developed following stem cell transplant (Allo=18, Auto=16), 85 (33%) following intensive chemotherapy, 55 (21%) after non-intensive therapy, 47 (18%) after various other forms of chemotherapy and 36 (14%) did not have any therapy prior to BSI. E.coli were isolated from peripheral blood (PB, n=112, 44%), central venous access (Line, n=130, 51%) or unspecified source (NK, n=15, 6%). At the time of developing E.coli BSI, ANC was below 0.5 in 136 cases (53%), 167 (65%) had platelet count below 100, 78 (30%) had BUN above 10, 69(27%) had creatinine above 120, 74(29%) had serum bilirubin above 34 and 129 (50%) had trans-aminitis. E.coli BSI increased significantly from year 2007 onwards (110/2073, 5% vs. 137/1455, 9%; p=0.0001). Mortality within 30 days of BSI with E.coli was used as a marker to estimate the impact of the event. 28 of 257 episodes (10.9%) resulted in death within 30 days. In univariate analysis, mortality was significantly higher with age above 45yr. (26/185 vs. 2/72, p=0.01), GGT more than 50 (25/180 vs. 3/77, p=0.02), BUN above 10 (17/78 vs. 11/179, p=0.0002), creatinine above 120 (12/22 vs. 16/188, p=0.035) and PB as source of BSI (18/112 vs. 10/145, p=0.02). In Cox multivariate analysis, PB as source (HR: 2.2, 95% CI: 1.0-4.9, p=0.048), GGT above 50 (HR: 4.4, 95% CI: 1.2-15.5, p=0.022), age above 45 yr. (HR: 4.5, 95% CI: 1.1-19.6, p=0.04) and creatinine above 120 (HR: 3.1, 95% CI: 1.1-8.7, p=0.03) were independently associated with mortality within 30 days of E.coli BSI. Mortality increased significantly with the number of risk factors [0-1: 2/68 (3%), 2-3: 22/140 (16%), 4: 8/25 (32%), HR: 3.9, 95% CI: 2.0-7.4, p=0.0001]. 16% of E.coli were resistant to beta lactam antibiotics but the number was too small to assess the impact on mortality. HSCT was not associated with increased mortality. Conclusion E.coli BSI are associated with significant mortality that is not associated with underlying diagnosis but with the age and associated organ dysfunction. Continued surveillance is needed to assess the impact of ESBL incidence, status and its clinical significance. Disclosures: Cavet: Celgene: Consultancy, Honoraria; Eli Lilly: Honoraria.

Introduction Although ASCT in MM is standard consolidative therapy in first line treatment definitive evidence for its use in salvage therapy is lacking. The principal aim of this multi-centre phase III randomised controlled trial was to evaluate the durability of response (DuR) of a second ASCT compared with a less intensive alkylating agent consolidation, after a bortezomib-containing re-induction strategy. Patients and Methods Eligible patients with MM relapsing after a prior ASCT were enrolled. All patients were re-induced with PAD therapy (Bortezomib 1.3mg/m2 iv D1, 4, 8 & 11; Doxorubicin 9mg/m2/day iv D1-4; Dexamethasone 40mg/day PO D1-4: additionally D8-11 & D15-18 on cycle 1 only) delivered in 4-6 21-day cycles before 1:1 randomization to either a second ASCT (Melphalan 200mg/m2 iv; ASCT2 supported by either stored stem cells or remobilized stem cells) or low dose consolidation with weekly cyclophosphamide 400mg/m2 PO for 12 weeks (C-weekly). Response assessment (by IMWG criteria) was analyzed after re-induction and 100 days post-randomization and time-to-disease progression (TTP) determined. Patients were stratified by β2microglobulin (β2M) at trial entry and response to re-induction and analyzed according to cytogenetic abnormalities by iFISH (unfavorable: t(4,14), t(14,16) and del17p). The primary endpoint was Time-to-progression (TTP) with secondary endpoints of OS, overall response rate (to PAD and randomized intervention), feasibility of stem cell mobilization in salvage therapy, safety & quality of life. Results The Data and Safety Monitoring Board (DSMB) recommended randomization closure and early result release owing to the primary end-point having been met. 297 patients were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n = 89, C-weekly n = 85. Median age was 61 (range 38 -75) with 73.6% of patients relapsing more than 24 months from first ASCT. ORR to re-induction therapy was 79.4%% with 16.0% sCR/CR rate. Post-randomization, sCR/CR was significantly higher in ASCT2 (39.3%, 95% CI 29.1, 50.3) than C-weekly (22.4%, 95% CI 14.0, 32.7) cohorts with more patients upgrading response to sCR/CR in the ASCT2 (n = 22) than C-weekly (n = 7) cohorts. At the time of analysis, 125 of 174 patients have progressed, 57 in the ASCT2 (64%) and 68 in the C-weekly (80%) cohorts. Median TTP was 19 months (95% CI 16, 25) for ASCT2 compared with 11 months (95% CI 9, 12) for C-weekly (HR 0.36 95% CI 0.25, 0.53; Cox regression analysis p Conclusion The final analysis demonstrates a clear advantage in terms of durability of response when a second high dose Melphalan-conditioned ASCT consolidates re-induction therapy with a bortezomib-containing regimen in myeloma patients at first relapse. The impact on overall survival and quality of life remains to be clarified. Disclosures: Cook: Janssen: Honoraria, Research Funding, Speakers Bureau. Williams:Janssen: Honoraria, Speakers Bureau. Snowden:Janssen: Honoraria, Research Funding, Speakers Bureau. Cavet:Janssen: Research Funding.

Background Bendamustine has efficacy as first-line treatment in multiple myeloma (MM) (in combination with prednisone), and in refractory patients who have been heavily pre-treated. Dose finding studies have not been performed for bendamustine in heavily pre-treated relapsed/refractory patients. MUK one is a randomised phase II selection trial assessing the activity & tolerability of two doses of bendamustine (B), 60mg/m2 vs 100mg/m2, in combination with thalidomide (T) & dexamethasone (D) in patients with relapsed/refractory MM. Methods Patients were randomised to receive B(60)TD or B(100)TD (B days 1 & 8 ; T 100mg od; D 20mg d1, 8, 15 & 22; 28 day cycle). Eligibility was based on confirmed MM with measurable disease, ECOG 0-3, platelets >75x109/L & neutrophils >1.5x109/L at 1st or later relapse. In the initial protocol, patients with lower platelets/neutrophils attributable to myeloma were eligible. Activity and tolerability were joint primary endpoints. The primary activity endpoint was ≥PR within 6 cycles. Tolerability was defined as the ability to receive at least 2 cycles of treatment at full dose with no delays of >2 weeks, without primary growth-factor support. Response rates Results 95 patients were randomised: B60TD n=66, B100TD n=29. In the primary analysis population, 56% (25/45, 80% CI [45-66]) of B60TD patients achieved ≥PR, the median progression free survival (PFS) was 8.2 months (95% CI [7.2-10.6]). In the B100TD primary population, 36% (5/14, 80% CI [19-56]) achieved ≥PR, median PFS was 5.1 months (95% CI [2.3-9.0]). Following an interim analysis the B100TD arm was discontinued due to tolerability. Thereafter, patients were recruited to B60TD arm only, and included only with unsupported neutrophil >1.5x109/L and platelets >75x109/L, regardless of marrow infiltration. Consequently, two analysis populations are defined. (i) Primary analysis population: patients fulfilling amended eligibility criteria without PD after 1 cycle, having ≥1 dose of study drug, (B60TD evaluable n=45; B100TD evaluable n=14). (ii) Combined population: as for (i) but including patients with PD after cycle 1, (B60TD combined n=54; B100TD combined n=20). This group represents an intention to treat population with the amended criteria. 46% (80% CI [37-56]) of patients in the B60TD combined population achieved ≥PR, with a median PFS of 7.5 months (95% CI [5.3-8.7]). In the B100TD combined population 25% (80% CI [13-42]) of patients achieved ≥PR, with a median PFS of 2.6 months (95% CI [1.7-5.6]). In the assessment of tolerability, 70% (80% CI [59-79]) of B60TD primary patients assessable for tolerability received ≥2 cycles of full-dose treatment with no delay >2 weeks. Median number of B60TD cycles was 6 (range 1-9), with 64% patients receiving ≥6 cycles. 32% patients experienced ≥ grade 3 neutropenia, 25% ≥ grade 3 thrombocytopenia, & 14% ≥ grade 3 anaemia. There was 1 grade 3 neurotoxicity, & no grade 3 nausea or GI disturbance. Of the B100TD primary patients 71% (80% CI [51-87]) met tolerability criteria. Median number of cycles was 4 (range 1-9), 29% patients receiving ≥6 cycles. 64% patients experienced ≥ grade 3 neutropenia, 21% ≥ grade 3 thrombocytopenia, & 21% ≥ grade 3 anaemia. There were 3 grade 3 neurotoxicities, no grade 3 nausea & 1 grade 3 diarrhoea. Thromboembolism rates with prophylactic anticoagulation was 4% overall. 84% of patients had ≥3 prior therapies, PS 0/1 (85%) & relapsed MM (78%); 37% were ISS 3 at entry, mean b2M=5.6. Most had prior T (90%), Lenalidomide (74%) & Bortezomib (84%); 74% had ≥1 prior autograft. Discussion The combination of BTD shows promising response rates at the 60mg/m2 dose, despite only 70% of evaluable patients receiving at least 2 full cycles of bendamustine with ≤2 week delay, in this challenging multi-treated group of patients. The B100TD arm closed to recruitment at interim analysis due to lack of tolerability on the basis of pre-defined stopping rules. Responses were also lower in this arm compared to B60TD arm, which may reflect the ability of patients to receive more cycles of treatment to schedule at 60mg/m2 than at 100mg/m2. Although not passing the strict pre-specified tolerability boundaries, B60TD appears deliverable beyond 2 cycles in multiply-pretreated MM, with PR in excess of 45%, comparing favourably other novel agent combinations in this heavily pre-treated population. Disclosures: Schey: Napp: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cook:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Cavet:Celgene: Consultancy, Research Funding.

Treatment of cancer cells with Hsp90 inhibitors/antagonists results in cell cycle arrest, destabilisation and apoptosis. This ability of Hsp90 antagonists to modulate tumour microenvironments and initiate the selective degradation of various factors needed for cell proliferation and survival make them potential candidates for the treatment of B-cell malignancies such as multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin’s lymphoma (NHL). KW-2478 is a novel non-ansamycin, non-purine analogue antagonist for Hsp90. This study investigated KW-2478 in patients (aged ≥18 y) with relapsed/refractory MM, CLL or NHL. Fifteen patients (5 cohorts of 3) received escalating doses of KW-2478 at 14, 28, 47, 71, 99 mg/m2, IV over 60 min, once daily on Days 1 to 5 of a 14-day cycle. Patients could receive further cycles for up to one year, with a dose escalation option. Study objectives were to determine safety, tolerability, pharmacokinetic and pharmacodynamic profiles of KW-2478. Safety was assessed throughout the study (AEs, dose-limiting toxicities [DLTs], vital signs, ECG, physical examination, safety laboratory tests and visual ophthalmological examination with electroretinogram [ERG]). DLT was defined as an event during the first cycle which was considered related to KW-2478 and either led to treatment delay, persisted beyond Day 14, was a clinically significant ERG change, was a grade 4 or clinically significant grade 3 non-hematological event, or was a grade 4 hematological toxicity not related to primary disease that had not recovered to ≤ grade 3 by Day 14. On Days 1 and 5 (first cycle), blood samples were collected at pre-dose, 50 min post start of infusion and 10 and 30 min, and 1, 2, 4 and 8 h post infusion for KW-2478 pharmacokinetic analysis. Blood was sampled for pharmacodynamic analysis at pre-dose and 8 h on Days 1 and 5. Hsp70 expression in PBMCs was analyzed by Western blot. Results showed good tolerability with no DLTs between KW-2478 doses of 14 and 99 mg/m2. Patients received a median of three treatment cycles though one MM patient underwent 19 treatment cycles and had two dose escalations with no toxicity. Overall, six patients (40%) had KW-2478 related toxicities (seven grade 1, seven grade 2 and two grade 3) and there were three grade 4 toxicities, not related to KW-2478. There were no trends noted for any specific toxicities associated with KW-2478, though one grade 1 and one grade 2 KW-2478 related episodes of hypertension were observed in a single patient, leading to hospitalization overnight. Two grade 3 related episodes of QTc interval prolongation were reported in one patient. Overall, KW-2478 related toxicities led to dose interruption (6%) or withdrawal from the study (13%). Two patients died from disease progression and no patients died from treatment related causes. Peak plasma concentrations were observed at the end of the infusion, after which KW-2478 plasma concentrations decayed in a biphasic manner with a dose-independent half-life of approximately 6 h. For Day 1, maximum plasma concentration (Cmax) and area under the KW-2478 concentration-time curve from time zero to infinity (AUC0–∞) values increased in a dose-dependent manner at all doses. Repeated 5-day administration had no effect on plasma concentration at all doses. Mean [range] Day 5 KW-2478 Cmax varied from 656 [482–1050] ng/mL at the 14 mg/m2 dose to 2977 [2440–3640] ng/mL at 99 mg/m2. Mean [range] Day 5 KW-2478 AUC to last measurable concentration (AUC0-t) varied from 836 [532–1336] ng/mL at the 14 mg/m2 dose to 3465 [2997–4318] ng/mL at 99 mg/m2. Pharmacodynamic data were variable but there was a trend toward increased Hsp70 expression with increasing doses of KW-2478. This trend was most evident at 71 and 99 mg/m2, at 8 h post dose on Day 5. Once-daily infusions at doses of up to 99 mg/m2 achieved exposure levels similar to those that showed anti-tumor activity in pre-clinical models including models of human MM. Hsp70 induction data suggested that these exposure levels may be sufficient to affect function of Hsp90 in B-cell malignancies. Overall, KW-2478 was well tolerated with no DLTs at doses up to 99 mg/m2 and demonstrated a predictable pharmacokinetic profile in its target population. The study is proceeding with a KW-2478 dose of 132 mg/m2; further dose escalation is planned.

Background: CHIR-258 is an orally active small molecule receptor tyrosine kinase (RTK) inhibitor which exhibits potent single digit nanomolar inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis (IC50 Methods: CHIR-258 was administered orally to adult patients with relapsed/refractory AML on a 7 on/7 off schedule followed by continuous daily dosing for 28 days (1 cycle). Subsequent 28-day cycles of continuous dosing were permitted. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were serially performed and drug tolerability assessed. Results: As of May 2005 8 patients have been treated in 2 (50mg and 100 mg) cohorts of 3–6 patients [median age: 62 years (range: 46–72), sex: 4M/4F, median prior relapses = 1 (range: 1–3), FAB subtypes: M1–1, M2–2, M5–1, M6–2, unclassifiable-1, no information-1] Five patients remain on study with a median number of treatment cycles=3 (range=1–11). There have been no DLTs to date. Dose escalation to 200 mg has been tolerated and accrual continues. Drug related adverse events include fatigue, anorexia, nausea/vomiting, and headache and were generally mild (CTC G1-2). Of the 8 patients treated, 1 had FLT-3 ITD mutation and 7 were wt for ITD and D835. A patient with AML-M6 with wt FLT-3 continues with stable disease after 11 cycles of therapy and was dose escalated from 50mg to 100mg after 8 cycles. The patient with FLT-3 ITD mutation treated at the 100mg dose had near complete clearing of blasts from marrow and peripheral blood. This patient later died due to a presumed fungal infection, not attributed to CHIR-258. Plasma exposure and Cmax increase proportionally across the dose range, and Cmax at the 100mg dose level is in the range where antitumor activity was seen in a preclinical oncogene addicted tumor models for FLT-3 ITD AML (MV4;11). Conclusions: CHIR-258 has demonstrated activity in relapsed refractory patients with AML, both with a FLT-3 mutation and wt FLT-3. Accrual continues at the 200mg dose cohort and updated data will be presented at the meeting.

Allogeneic transplantation with reduced intensity conditioning is increasingly being used in patients with non-Hodgkin’s Lymphoma (NHL) who fail standard therapy. We report extended follow-up on 121 patients with NHL, who underwent allogeneic transplantation with reduced intensity conditioning at 8 UK centres. Conditioning was with fludarabine 150mg/m2, melphalan 140mg/m2 and alemtuzumab (60–120mg). Cyclosporin A was administered at 3mg/kg from day-1, and stem cell source was bone marrow or PBSC. Diagnoses were in 3 categories: low grade follicular NHL (n=50), mantle cell lymphoma (n=21), and high-grade NHL (n=50, including transformed low grade disease n=15). Donors were HLA-matched siblings in 75 (62%), and unrelated in 46 (38%), of whom 18 were HLA-mismatched at up to 3/10 loci. 48% of patients had failed previous autologous transplantation. Median follow-up was 35 months (1–78). For the group with low grade follicular NHL (n=50), estimated overall survival (OS) was 76% at 1yr and 67% at 4yrs, and non-relapse mortality (NRM) was 16% at 4yrs. Disease relapse or progression occurred in 12 patients, of whom 8 received donor lymphocyte infusions (DLI), with responses in 6. Current progression-free survival (cPFS) is 68% at 4yrs. For the group with mantle cell lymphoma (n=21), estimated OS was 83% at 4yrs, NRM was 11% at 4yrs and relapse or progression occurred in 6 patients. Three patients received DLI, with non-sustained responses in 2. Current PFS is 43% at 4yrs. For high-grade NHL (n=50), estimated OS was 52% at 1yr and 45% at 4yrs. Prior autologous transplantation was common in this group (72%), and NRM was higher at 34% at 1yr and 40% at 4yrs. Progression/relapse occurred in 15 patients, of whom 10 received donor lymphocytes, with responses in 5. Current PFS is 48% at 1yr and 43% at 4yrs. These results, from patients who were often heavily pre-treated, including having failed autologous transplantation, provide encouraging evidence to support the application of reduced intensity allogeneic transplants in NHL. NRM in low grade follicular or mantle cell lymphoma is low, consistent with the use of T cell depletion, and graft-versus-lymphoma effects can be induced with DLI in a subset of cases. The data in follicular lymphoma, in particular, supports consideration of this therapy earlier in the disease. In high-grade disease, NRM appears to be higher, but durable remissions are attainable in a proportion of patients.

Monoclonal intact immunoglobulin is detectable in the serum of approximately 80% of myeloma patients while SFLC are found to be abnormal in the serum of greater than 90% of patients. One advantage of monitoring SFLC is that they have a half-life of clearance from the serum of 2–6 hours, compared with 20 days for IgG, and can therefore reveal the response to treatment more rapidly. The aim of this study is to determine whether SFLC measurements allow earlier assessment of response to treatment with bortezomib with possible implications to the design and cost of treatment strategy.Patients & Methods Serial serum samples were collected for simultaneous measurement of SFLC and serum paraprotein. Data from 8 patients receiving 2–6 cycles of bortezomib, on compassionate basis, to treat multiply treated myeloma at various stages of relapse are presented. Bortezomib was administered at a dose of 1.3mg/m2 on days 1,4,8 and11. Samples were kept frozen until thawed for SFLC measurement (using Freelite kits; Binding Site, UK on an Olympus Chemistry analyser). Results & Discussion Six of 8 patients showed a response to treatment by EBMT/Blade criteria (>25% fall in paraprotein). In 3 of these patients the tumour SFLC showed a fall and rapid recovery within 10–20 days of a treatment cycle. These patients were monitored over multiple treatment cycles and showed repeated falls in SFLC co-incident with treatment and recovery in between. This appears to correspond with the mechanism of action and biological half life of proteosome inhibition. Recovery of SFLC when seen is rapid (doubling in Conclusion: We conclude that monitoring SFLC provides a unique opportunity to follow the kinetics of tumour kill, which is obscured by the slow clearance of intact immunoglobulin monoclonal proteins. The pattern of fluctuation in the SFLC levels could suggest a temporary inhibition of tumour protein synthesis rather than tumour kill and re-growth. While extension of this study is ongoing, it does indicate that SFLC can be used as a biomarker to assess response to treatment significantly earlier allowing relevant changes of treatment strategy. This also may have major bearing on cost of treatment and utilisation of resources.

Hodgkin’s Lymphoma is curable with primary therapy in the majority of patients. For those with relapsed or refractory disease, salvage with high dose chemotherapy plus autologous stem cell rescue is effective for a significant proportion. Patients relapsing following autologous stem cell transplantation, however, have an extremely poor prognosis. Allogeneic transplantation with conventional conditioning has proved excessively toxic in this setting, and reduced intensity conditioning has therefore been introduced, with encouraging preliminary results. This is a study of 72 patients relapsing following autologous transplantation, analysed in 2 groups. One group (A: n=38) then underwent allogeneic transplantation with reduced intensity conditioning at 6 UK centres (1998–2004), with alemtuzumab 100mg, fludarabine 150mg/m2 and melphalan 140mg/m2. Donors were HLA-matched related in 63% of cases, and unrelated in the remaining 37%. The second group (B: n=34) is a control cohort, who relapsed before the advent of reduced intensity conditioning, and were treated with chemotherapy +/− radiotherapy alone. The groups were equivalent in age (median- A 31yrs [20–51]; B 29yrs [13–47]), disease subtype (>85% nodular sclerosing both groups), time from diagnosis to autograft (median-A 18mo [7–139]; B 20mo [4–185]), and lines of prior therapy pre-autograft (median 3 both groups). Median time from autograft to relapse for group A was 13mo (2–56) and for group B 10mo (3–40), and patients were only selected for inclusion in group B if they responded to further salvage therapy, attained at least a stable response to treatment, and lived for >12 months following relapse (median time from relapse to allogeneic transplant for group A is

The most important consideration in modern SCT practices is the fine balance that is required to achieve adequate immunosuppression and stable engraftment thus allowing the platform to mount an effective GVL response. Though CsA facilitates this objective, it is associated with several adverse clinical manifestations due to its narrow therapeutic index (TI) and wide variability in the absorption kinetics. Weekly monitoring of trough CsA levels are used to adjust the dose. The aim of this study is to determine whether daily monitoring of CsA levels enables better achievement of these goals and yet reduce the serious toxicities. Patients & methods: Twenty three patients (M=15, F=8, median age 46yrs range 19–63) received an allogeneic transplant (sibling-15, MUD-7 mismatched unrelated-1) since March 2004 when we started to monitor daily CsA levels (Biostat TDX analyser using fluorescent immunoassay) from the day of first administration until the time of discharge. The transplants included full intensity (FI=11), reduced intensity (RI=11) or customised (1) for various haematolymphoid malignancies. Patients received uniform GVHD prophylaxis with IV CsA (RI+FI) and methotrexate (FI) as per standard loading doses. The CsA target level was adjusted to 200–220 ng/ml from Day-1 onwards and was later modified according to the treatment strategy. Oral CsA administration was started when patients were able to switch over. Results Nine of 23 (40%) patients developed acute GVH (n=7 grade1–2, n=2 grade 3–4) at a median of 23.5 days (10–28). Two of 9 patients required addition of steroids by Day+30. The median CsA level at the first occurrence of GVH was 247ng/ml (113–333) and the median CsA level during hospitalisation was 207 ng/ml (136–291). Only one patient who received T cell addback required increased dose of IV CsA to manage Grade 4 GVH. Twenty two/22 patients engrafted with a median day to neutrophil recovery being 13 days (8–35). One patient lost his graft due to a low initial cell dose and the inability of the MUD donor to donate any further cells. There was no significant difference in the baseline and Day30 creatinine levels (median highest creatinine 108μmol/l range 58–267) or bilirubin levels (median highest bilirubin 27μmol/l, range15–251). Five/22 patients developed CMV reactivation/infection and 1 developed RSV infection. No patients developed seizures and in one patient pre-existent neuropathy was exacerbated which was directly attributable to CsA. Twenty one/22 patients (95.5%) switched to oral CsA by Day+25. In 8/22 (36.36%) patients, the target CsA levels was around 100–150 ng/ml at the time of discharge. The median duration of hospital stay was 35days (24–130). Conclusions: These observations suggests that daily monitoring of CsA is safe and successful. This allowed successful engraftment and a more liberal management of Grade 1–2 GVH thus allowing us to maximise the GVL effect. Despite concomitant use of other toxic drugs, side effects were minimal and reversible. Close observation of early clinical manifestations enabled us to modify the immunosuppressive strategy at later time periods. This approach also allowed us to better manage patients suffering from CMV and EBV/PTLD (patient number 10 on day+88) by reducing the dose during active infections.

Despite impressive primary response rates relatively few patients with multiply relapsed or refractory Hodgkin lymphoma (HL) are ultimately cured with conventional chemotherapy. The application of allogeneic stem cell transplantation has historically been limited in this group by high transplant related mortality (TRM) rates, and evidence for a clinically relevant graft-versus-lymphoma (GvL) effect has been limited. Reduced intensity transplantation (RIT) approaches enable durable engraftment of allogeneic stem cells with a low spectrum of toxicity, but graft-versus-host disease (GvHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion (TCD), using alemtuzumab, has been shown to reduce the incidence of GvHD. However, this approach potentially adversely impacts on disease response by abrogating GvL activity. To explore the impact of TCD in HL we have compared the results in 89 recipients of a RIT enrolled in 2 prospective studies based on conditioning with the same combination of fludarabine (30mg/m2 x 5) and melphalan (140 mg/m2). The studies differed in GvHD prophylaxis. The United Kingdom regimen (MF-A, n=49) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (MF, n=40) used cyclosporin A plus methotrexate. There were no significant differences in age (median 32 versus 35 years), sex or histological subtype (nodular sclerosis in 86% versus 88%). Median follow-up in surviving patients is 826 (MF-A) versus 376 (MF) days. In those with matched sibling donors use of alemtuzumab resulted in a trend towards a lower incidence of acute GvHD (29% versus 46% at day 180, P=0.09) and significantly less chronic GvHD (10% versus 57%, P=0.0003). This was associated with a trend towards lower TRM in the MF-A group (actuarial 2 year TRM 17% versus 33% for MF, P=0.06), but no apparent excess of relapse/progression (actuarial 2 year relapse risk 49% for MF-A versus 68% for MF, P=0.16). In this sibling transplant cohort both overall and event-free survival were superior in the MF-A group (actuarial 2 year OS 72% versus 48%, P=0.04; EFS 47% versus 19%, P=0.009). Sixteen patients in the MF-A group and 10 in the MF group received donor lymphocyte infusions (DLIs) to achieve disease control. Nine (8CR, 1PR) of the former, and 6 (3CR, 3PR) of the latter achieved a response. On univariate analysis of the entire cohort chemo-sensitivity significantly influenced relapse risk (p=0.01), OS (P=0.01) and EFS (P=0.003). TCD significantly improved EFS (P=0.01) despite an excess of unrelated/mismatched donors (18 versus 3, P=0.001) and patients who had failed a prior autograft in the MF-A cohort (44 versus 29, P=0.03). Prior autograft or donor source had no significant influence on TRM, relapse, OS or EFS. More patients were chemo-sensitive prior to RIT in the MF-A group (36 versus 20, P=0.03) but TCD retained independent positive prognostic significance for EFS in multivariate analysis (P=0.02; Hazard ratio 0.69(0.51–0.93)), as did chemo-sensitivity (P=0.01). In conclusion, alemtuzumab significantly reduced GvHD without resulting in an apparent impact on disease relapse. Both groups often required DLIs to achieve tumor control and the response rates support a significant GvL activity.