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BACKGROUND: Elotuzumab plus lenalidomide and dexamethasone has shown improved progression-free and overall survival versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. We aimed to assess these regimens in patients with newly diagnosed multiple myeloma who are ineligible for haematopoietic stem-cell transplantation (HSCT). METHODS: ELOQUENT-1 is an open-label, multicentre, randomised, phase 3 trial conducted at 185 hospitals, oncology practices, and research centres in 19 countries. Eligible patients were aged 18 years or older with newly diagnosed, untreated, symptomatic myeloma and not candidates for high-dose therapy plus HSCT, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Patients were randomly assigned (1:1) to receive elotuzumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone using an interactive voice response system, stratified by the International Staging System (ISS; stage I-II vs III), age (

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.

Background Renal impairment (RI) is a common complication of multiple myeloma (MM) and remains a poor prognostic factor despite improved survival with newer therapies. Patients and Methods We evaluated baseline characteristics, treatment, and outcomes of newly diagnosed MM patients with RI at diagnosis in the Australia and New Zealand Myeloma and Related Diseases Registry over 5 years to April 2018; we compared patients with RI (estimated glomerular filtration rate [eGFR] Results Overall, 36% of patients with newly diagnosed MM had RI; they were older, had more advanced disease and comorbidities, and worse performance status. Bortezomib-based induction therapy was most commonly used, although administered to fewer RI patients, despite similar response rates. Patients with RI were less likely to receive ASCT; however, recipients had longer progression-free survival (PFS) and overall survival (OS). Patients with RI had shorter OS and PFS after adjusting for age. In ASCT recipients with RI versus no RI, there was no difference in PFS and OS. Conclusion Our findings in “real world” MM patients with RI confirm that patient-, disease-, and treatment-related factors (such as suboptimal bortezomib and ASCT use), and delays in commencing therapy, might contribute to poorer outcomes, and support the use of ASCT in patients with RI.

Efficacy and safety of bortezomib-based consolidation following ASCT were investigated in newly diagnosed multiple myeloma patients from Australia, Korea, and China. Patients received three cycles of bortezomib-cyclophosphamide-dexamethasone induction followed by high-dose therapy/ASCT, then were randomized (1:1) to consolidation with TP (thalidomide 100 mg/d for ≤12 months/until disease progression; prednisolone 50 mg on alternate days indefinitely/until disease progression

© The Author(s)., Background: Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM). [Methods]: This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10-5 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk. [Results]: After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21-0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR. [Conclusion]: These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status. Trial registration: ClinicalTrials.gov, NCT02136134. Registered 12 May 2014, This CASTOR study was sponsored by Janssen Research & Development, LLC. Open access funding provided by Projekt DEAL.

Introduction Daratumumab, when added to standard of care regimens in relapsed and untreated myeloma, has consistently demonstrated significant improvements in response rates, induction of MRD negative responses and prolonged progression-free survival (PFS) while proving highly tolerable with minor increases in overall regimen toxicity. In non-transplant eligible patients daratumumab has been added in randomized studies to lenalidomide and dexamethasone (Rd) and bortezomib, melphalan and prednisolone (VMP) backbones, but not to the VCD regimen. Furthermore, the randomized studies excluded a significant proportion of patients with comorbidities so the benefit of daratumumab in a frail, elderly myeloma population remains untested. Methods Inclusion criteria included untreated patients with symptomatic myeloma who were considered ineligible for high-dose chemotherapy with autologous stem cell transplantation due to either age >65years or the presence of comorbidities. Any degree of renal impairment, including dialysis dependence, was allowed as were patients with a prior history of systemic malignancy that had been disease-free for 2 years. The trial was designed using a response adapted randomisation strategy and patients continued to be randomized 1:1 to receive VCD or VCDD throughout trial accrual. VCD consisted of nine 5-week cycles of V 1.3 mg/m 2 SC on Days 1, 8, 15 and 22; C 300mg/m 2 PO on Days 1, 8, 15 and 22 and D 20 mg PO on Days 1, 8, 15 and 22. VCDD consisted of nine 5-week cycles of VCD plus daratumumab 16 mg/kg IV on Days 1, 8, 15 and 22 of cycles 1 and 2, Days 1 and 15 of cycles 3 to 6 and Day 1 of cycles 7 to 9, followed by daratumumab maintenance 16 mg/kg IV every 4 weeks until progression. The primary endpoint was PFS with secondary endpoints being response rates, MRD negativity rates by Euroflow (lower limit of detection 10 -5), overall survival, toxicity and quality of life. Landmark analysis was used to assess the impact of treatment outcomes (response rate, MRD) on EFS. Results A total of 129 patients were randomized, but 8 did not commence trial therapy. The following modified ITT analysis is based on the 121 randomized patients, 57 in the VCD group and 64 in the VCDD group, who received protocol therapy. Baseline characteristics were balanced between the two arms. Median age was 75 years (range, 62-91yrs), with 19% being ≥80 years of age. 30% were female. ECOG performance status was 0 (43%),1 (34%), 2 (18%) and unknown (5%). ISS stage was I (19%), II (46%), III (27%) and unknown (8%). The estimated median potential follow-up is 23.7 months. On an intent-to-treat basis, overall response rate after 4 cycles of induction was significantly better for VCDD compared to VCD (81% vs 60%, p=0.0089). Similarly, there was a trend to improved VGPR after 4 cycles of induction with VCDD (39% vs 23%, p=0.0545). At the end on induction, 17% of patients in the VCDD arm were MRD negative compared to 5% of patients in the VCD group (p=0.049). Median PFS for the entire cohort was 21.8m (95%CI 19.0 - 29.7m), and was 26.0m (95%CI 19.9 - NA) and 18.9m (95%CI 15.6 - 28.2m) in the VCDD and VCD arms respectively (log-rank test p=0.125). There was no significant difference in PFS according to age Conclusions The addition of daratumumab to the VCD regimen improves response rates and achievement of MRD negativity in elderly patients with myeloma. While there is a trend to daratumumab improving EFS, further follow-up is required to fully assess this effect and the impact on OS. VGPR after 4 cycles of induction may be a useful early surrogate marker of EFS in elderly patients treated with daratumumab-based regimens. Disclosures Mollee: Janssen, Pfizer: Research Funding; Amgen, BMS, Janssen, Caelum, EUSA, Pfizer, SkylineDx, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: No personal fees received. Reynolds: Abbvie: Research Funding; Alcon: Current equity holder in publicly-traded company; Novartis AG: Current equity holder in publicly-traded company. Janowski: BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Quach: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Campbell: AstraZeneca: Consultancy; CSL Behring: Consultancy; Roche: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS/Celgene: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gibbs: Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria; AbbVie: Consultancy. D'Rozario: BMS, Abbvie: Membership on an entity's Board of Directors or advisory committees. Weber: Amgen: Membership on an entity's Board of Directors or advisory committees. Spencer: Amgen: Honoraria, Research Funding; BMS: Research Funding; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria; Takeda: Honoraria, Research Funding, Speakers Bureau.

BACKGROUND Survival rates in multiple myeloma (MM) have significantly improved in recent decades with the advent of high-dose chemotherapy conditioned autologous stem cell transplantation (ASCT) and the availability of novel agents for induction therapy (Kumar SK et al. Blood 2008). Failure to respond to front-line bortezomib-based induction therapy remains a significant clinical challenge in transplant eligible (TE) newly diagnosed multiple myeloma (NDMM), and is associated with poor outcomes with shortened progression free survival (PFS) and overall survival (OS) (Lee SE et al. Ann Hematol. 2014). In combination with immunomodulatory agents (IMiDs), carfilzomib, a second generation proteosome inhibitor, has been shown to be highly effective in the context of MM induction with high rates of negativity for minimal residual disease (MRD) and few dose limiting toxicities (Langren O et al. Leukemia 2019). The ALLG MM17 trial is a multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in TE NDMM patients refractory or with suboptimal response to bortezomib-based induction therapy, designed to evaluate the efficacy of early response adaption with a switch to an intensive salvage strategy. METHOD Eligible patients included those with TE NDMM, aged 18 years and older, demonstrating sub-optimal response to bortezomib-based induction therapy (failure to achieve a minimal response after 2 cycles, partial response [PR] after 4 cycles, or disease progression within 60 days of completing induction). Salvage therapy consisted of 100mg daily oral thalidomide, with 20 mg of oral dexamethasone and 20mg/56mg of IV carfilzomib on days 1, 2, 8, 9, 15, and 16, with of each 28-day cycle. Following 4 cycles, patients in stringent complete response (sCR) proceeded to melphalan conditioned ASCT whereas those in less than sCR received a further 2 cycles of KTd prior to ASCT. Consolidation therapy consisted of a further 2 cycles of KTd, followed by maintenance 100mg daily thalidomide and 40mg weekly dexamethasone (Td) continuing until progressive disease, unacceptable toxicity, or 12 months of therapy. Primary objectives were to determine the overall response rate (ORR) and safety profile of treatment with KTd salvage therapy, with secondary objectives to determine the maximal depth of response, progression free survival (PFS), and overall survival (OS) achieved with sequential treatment with KTd salvage, ASCT, post-ASCT consolidation, and maintenance Td therapy. Efficacy assessments were performed via serum protein electrophoresis, serum free light chain and bone marrow evaluation. Next generation flow (NGF) cytometry MRD evaluation of bone marrow aspirate was undertaken pre-ASCT, at day 100 post-ASCT, after 2 cycles of consolidation KTd, and following completion of Td using standardized 8-colour EuroFlow platform. RESULTS 50 patients were recruited across 6 Australian sites between September 2016 and April 2018. Overall response rate to KTd salvage was 78% (Credible Interval 95%: 64.4-87.1%), with dual proof of concept criteria met (observed ORR ≥ 50% and posterior probability that the true ORR exceeds 30% is ≥ 0.90). Response rates included 12% sCR, 6% CR, 38% VGPR, and 22% PR. Sixteen patients discontinued treatment (32%) including 10 cases (20%) of progressive disease, and 2 patient deaths without progression. NGF MRD negativity was found to be 32%, 36% and 55% at the pre-ASCT, post-ASCT and post-consolidation time-points. At the cut-off date, estimated median follow-up for disease status was 38.6 months and median PFS and OS had not been reached. At 36 months PFS and OS were 63.9% (95%CI: 49.0 - 75.5%) and 79.9% (95%CI: 65.8 - 88.6%) respectively (Figure 1). KTd was found to be well tolerated with 44% of patients experiencing a grade 3 of higher adverse event (AE). Most common AEs included upper respiratory infection (48%), peripheral neuropathy (36%), musculoskeletal pain (32%), dyspnoea (28%), fatigue or lethargy (28%), and constipation (28%). Significant cardiac toxicity was not observed at this higher dose level of carfilzomib. CONCLUSION Results demonstrate that response-adaptive utilisation of KTd salvage, ASCT, and consolidation therapy induces high response rates, improving depth of response with high levels of sequential MRD negativity, and durable responses with an acceptable toxicity profile in TE NDMM patients failing bortezomib-based induction therapy. Figure 1 Figure 1. Disclosures Quach: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kalff: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Roche: Honoraria; CSL: Honoraria; Sandoz: Honoraria. Bergin: Amgen: Other: Travel to workshop; Celgene: Consultancy. Reynolds: Novartis AG: Current equity holder in publicly-traded company; Alcon: Current equity holder in publicly-traded company; Abbvie: Research Funding. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria.

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Introduction: The achievement of minimal residual disease (MRD) negativity is being increasingly recognised as the optimal measure of therapeutic response for both newly diagnosed and relapsed and/or refractory multiple myeloma (MM) patients. Bone marrow (BM) evaluation with either Next Generation Sequencing (NGS) or Next Generation Flow-cytometry (NGF) affords a high level of sensitivity and the attainment of MRD negativity (< 1 in 10-5 MM cells) with either approach is a powerful predictor of superior progression free survival (PFS). Both, however, are limited by the requirement for invasive bone marrow biopsy and the technical limitations imposed by variability in sample quality. Moreover, we and others have demonstrated the presence of significant spatial heterogeneity in MM that increases in the context of disease progression. Against this background we have evaluated a blood-based strategy for disease burden evaluation, Quantitative ImmunoPrecipitation (Mass Spectometry (QIP MS) and Free Light Chain Mass Spectometry (FLC MS) in a uniformly treated cohort of functional high-risk MM patients also undergoing sequential NGF (EuroFlow platform) MRD evaluation. Methods: Newly diagnosed MM patients failing ( Results: Fifty patients were enrolled onto the ALLG MM17 trial. QIP and/or FLC MS identified the serum monoclonal paraprotein (PP) at baseline in all cases (100% sensitivity). Serum samples for MS with matched BM for NGF were available on 33 patients pre-ASCT, 32 post-ASCT and 26 post-KTd consolidation (91 matched samples in total). Sequential MS demonstrated serological complete remission (disappearance of MS baseline detectable monoclonal intact immunoglobulin [PP] and/or FLC) (CRMS) in 11%, 47% and 53% of patients pre-ASCT, post-ASCT and post-KTd, respectively. NGF MRD negativity at the same time points was 39%, 52% and 71% (the latter equivalent to a 50% MRD negativity rate within the original n=50 intention-to-treat population). The Cohen's kappa values for the 3 time-points were 0.21, 0.18 and 0.35 indicating fair to moderate concordance with the best concordance at the post-KTd consolidation time-point and with a Cohen's kappa value for the entire cohort (n=91) of 0.30. The sequential MS demonstrated that 12 patients had discordant disappearance of baseline PP and free light chains (FLC) prior to achieving CRMS. In 11 the FLC disappeared before the PP and in 1 the PP prior to the FLC. The former though to be due to either the FLC falling below the sensitivity of the technique following successful therapy or the presence of 2 sub-clones with differential drug sensitivity, whereas the latter was likely secondary to the persistence of a FLC expressing sub-clone. Post-KTd MS demonstrated good concordance with serological response (Cohen's kappa value = 0.61) but with 18% of patients demonstrating sCR/CR despite persisting MS detectable PP and/or FLC. Conclusion: These preliminary data confirm the utility of QIP MS and FLC MS for the sequential monitoring of tumour burden in HR MM. Concordance with standard monitoring was good with MS detectable disease in some patients with serological sCR/CR consistent with the higher sensitivity of MS. Concordance with NGF was only fair to moderate mandating the future comparison of larger sample sets to better understand the relationship between the 2 methodologies. Disclosures Spencer: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Specialised Therapeutics Australia: Consultancy, Honoraria. Khong:Novartis Oncology: Research Funding. Quach:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Kalff:Amgen: Honoraria; Celgene: Honoraria; pfizer: Honoraria. Reynolds:Novartis Australia: Honoraria; Alfred Health: Employment, Other: Biostatistician for trials funded by the Australian government and Abbvie, Amgen, Celgene, GSK, Janssen-Cilag, Merck, Novartis, Takeda, but sponsored by Alfred Health.; AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP (ALLG): Consultancy; Novartis AG: Equity Ownership.

The ALLG MM14 trial evaluated the impact of low dose dexamethasone (LoDEX) withdrawal in lenalidomide (LEN) refractory and relapsed (RR) multiple myeloma (MM) patients achieving initial disease control with pomalidomide (POM) and LoDEX re-induction. As previously reported, patients continuing with POM LoDEX had superior progression free survival (PFS) compared to maintenance with POM alone, however, this early PFS benefit was lost and by 18m was reversed to favour POM only. In patients who received post-progression therapy, more durable responses (second PFS: 12.7m vs 4.6m, p=0.034) and superior survival (OS: 19.4m vs 12.5m, p=0.092) were seen in those previously treated with POM alone. Here we present findings from the preliminary correlative immune studies of this trial. Aims To undertake mass cytometry (CyTOF) based immune profiling in patients with advanced MM receiving treatment with POM LoDEX. Methods MM14 was a multicentre, open-label, randomised phase 2 study of LEN refractory RRMM patients who had received ≥ 2 prior lines of therapy. Patients were treated with POM 4mg d1-21 (28d cycle) and LoDEX (40mg weekly). After 4 cycles (induction), patients with stable disease or better (≥SD) were randomised to receive maintenance with ongoing POM-LoDEX or POM alone. Therapy continued until toxicity/progression. PBMCs were collected at baseline and sequentially while on treatment. Cells were barcoded using the Cell-ID 20-Plex Pd barcoding kit (Fluidigm) followed by staining with sub-set/function defining antibodies (targeting myeloid, B, T and NK cells: CD16, CD24, CD11c, CD45RO, CD314, CD38, CD336, HLA-DR, CD14, CD56, CD158a, CD27, CD28, CD159a, CD8, CD19, CD45RA, CD11b, CD4, IgD, CD335, FOXP3, CD25, CD66b, CD3, CD337, CD20, CD158b, CD127 CD57, CD197, CD194, CD304 and CD279). Samples were acquired on the Helios instrument. Data were clustered in the VORTEX package. Significant differences in cluster frequency were assessed by Mann-Whitney test for statistical significance. Cluster phenotypes were determined and validated via multiple visualisation approaches. CD3-CD19-CD56+ NK cells were pre-gated from patient datasets. We then performed Boolean gating using seven NK cell activation/inhibitory markers - CD158a, CD158b, CD159a, CD314, CD335, CD336 and CD337. Boolean populations that comprised 3% or greater of the total NK cell population (median) were then compared. A Mann-Whitney test was used to determine statistical significance. Results 154 patients from 11 Australian sites were enrolled. The median number of prior treatment lines was 4.5, 82.5% were double refractory. 78 patients who achieved ≥SD were randomised to maintenance: POM n = 40, Pom LoDEX n = 38. CD336+CD20+ cells ("NK-B-cells") were identified in the pre-induction samples of all patients and were significantly more frequent in responders (median 2% of total cells) than in non-responders (0.8% of total cells, p Conclusion Utilising CyToF, we have identified a novel "NK B cell" population in RRMM patients, with a higher baseline frequency of these cells being associated with a greater likelihood of response to POM LoDEX. Importantly, we have also confirmed the presence of these cells in an independent MM cohort. Moreover, subsequent to POM LoDEX exposure we have demonstrated the enrichment of heterogeneous neutrophil populations as well as an increase in activated NK cells and commensurate decrease in inhibited NK cells. These novel observations may provide new insights into the mechanisms of action of pomalidomide in MM. Disclosures Kalff: Amgen: Honoraria; Celgene: Honoraria; pfizer: Honoraria. Khong:Novartis Oncology: Research Funding. Reynolds:Alfred Health: Employment, Other: Biostatistician for trials funded by the Australian government and Abbvie, Amgen, Celgene, GSK, Janssen-Cilag, Merck, Novartis, Takeda, but sponsored by Alfred Health.; AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP (ALLG): Consultancy; Novartis AG: Equity Ownership; Novartis Australia: Honoraria. Quach:GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Ho:Novartis: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs; Janssen: Other: Trial Investigator meeting travel costs. Mollee:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spencer:Takeda: Other: Consulting/advisory role, Research Funding; Janssen Oncology: Other: Consulting/advisory role, Research Funding, Speakers Bureau; Amgen: Other: Consulting/advisory role, Research Funding; AbbVie: Other: Consulting/advisory role, Research Funding; Servier: Other: Consulting/advisory role; Secura Bio: Other: Consulting/advisory role; Haemalogix: Other: Consulting/advisory role; Celgene: Other: Consulting/advisory role, Research Funding, Speakers Bureau; Sanofi: Other: Consulting/advisory role; Specialised Therapeutics Australia: Consultancy, Honoraria.

Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow-up is presented. After 19.4 (range: 0 to 27.7) months of median follow-up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P 12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow-up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse.

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP–cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m2 all on day 1, and prednisolone 100 mg days 1–5; i-CEOP–cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m2 all on day 1, and prednisolone 100 mg days 1–5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity. Am. J. Hematol. 89:536–541, 2014. © 2014 Wiley Periodicals, Inc.

Whilst the addition of dexamethasone to upfront therapy with immunomodulatory (IMiD®) agents in myeloma (MM) is important to mediate rapid reduction in disease burden, preliminary findings suggest that the NK stimulatory effects of IMiD® compounds are best harnessed without the co-administration of dexamethasone. This may be especially effective in the setting of minimal disease burden (i.e. maintenance) when some inherent immune recovery has occurred, however this has yet to be confirmed in a prospective clinical trial. Aims: To evaluate the effect of maintenance with pomalidomide (POM) alone versus POM-low dose dexamethasone (LoDEX) following treatment with POM-LoDEX induction on progression free survival (PFS), overall survival (OS) and kinetics of response (overall response rate (ORR), clinical benefit rate (CBR)) in relapsed/refractory MM patients who were refractory to lenalidomide (R-LEN). Methods: MM14 was a multicentre, open-label, randomised phase 2 study of relapsed R-LEN MM patients who had received at least 2 prior lines of therapy. Patients commenced POM 4mg d1-21 (28d cycle) and LoDEX (40mg weekly). After 4 cycles (induction), patients with stable disease (SD) or better were randomised to receive POM alone (P) or combined with LoDEX (Pd) as maintenance. Therapy continued until toxicity/progression. All statistical analyses were performed using SAS software v9.4. The log-rank test was used to compare the survival distributions in the maintenance arms and pre-specified pointwise comparisons, with adjustment for multiplicity, were used to explore the possibility of non-proportional hazards. Results: 154 patients from 11 Australian sites were enrolled (M:F 80:74), median age: 67yrs (range 35-88). Median number of prior treatment lines: 4.5 (2-14). All were R-LEN, 127 (82.5%) were bortezomib refractory (double refractory). Median follow-up for all registered patients was 27.8m. Median PFS for all patients was 4.5m (IQR 2.3-8.3m) and median OS was 14.5m (IQR 6.7-30.7m). ORR was 40.9% (63/154); median time to achieve ORR was 4.6 months. CBR was 53.3% (82/154); median time to achieve CBR was 2.6m. Eighty-one patients were randomised; however 3 were randomised in error. Therefore, a modified intention-to-treat (mITT) analysis included 78 (51%) patients who achieved ≥SD with induction and commenced maintenance: P = 40, Pd = 38. Median PFS (from time of randomisation) for P was 2.58m versus 5.73m for Pd (p=0.051) [Figure A]. Comparison of PFS at six 3-monthly intervals favoured Pd (from 3m to 12m) (p There was no difference in response (ORR, CBR) between P and Pd in the mITT population: ORR P (8/21) versus Pd (8/18), CBR P (12/21) versus Pd (11/18). In a landmark analysis for response achieved (ORR/CBR) at 4 months post registration, there was no difference in PFS or OS for patients within either arm according to whether they achieved ORR/CBR. Of the mITT population (n=78), 39 had post-progression therapy data available (P = 21, Pd = 18). Of the remainder, 18 were palliated and 21 did not have available data. There was no difference in response (ORR, CBR) to salvage therapy between the two arms. However, responses were more durable for P compared to Pd: median second PFS (from start of post-progression therapy) was 12.7m versus 4.6m respectively (p=0.034) [Figure C]. P tended towards superior OS (from start of post-progression therapy): median 19.4m versus 12.5m (p=0.0922) [Figure D]. There was no difference in PFS/OS between individual treatment groups (bortezomib, carfilzomib, chemotherapy, thalidomide, LEN, other). Conclusion: After initial disease control with POM-LoDEX, MM patients continuing with POM-LoDEX had superior PFS compared to maintenance with POM alone. However, this early PFS benefit is lost and in fact reversed by 18m; and in those randomised patients who went on to receive post-progression therapy, more durable responses and superior survival were seen in those previously treated with POM alone. Correlative studies are underway to investigate the immunological mechanisms behind these observations. Disclosures Kalff: Janssen: Honoraria; Amgen: Other: travel to preceptorship; Celgene: Honoraria; Takeda: Honoraria. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. . Quach:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy; Sanofi Genzyme: Research Funding. Ho:Amgen: Honoraria; Celgene: Other: Travel to meeting; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: travel to meeting. Mollee:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Estell:Janssen: Membership on an entity's Board of Directors or advisory committees.

BACKGROUND & METHODS Cfz/Dex is a standard of care in relapsed MM, and renal impairment is a poor prognostic factor. The ALLG MM16 trial was initiated to assess the feasibility of treating patients (pts) who have significant RI (eGFR 15 - 40 ml/min) with Cfz/Dex, and to determine whether an early reduction in serum free light chains (SFLC), with a short half-life, could predict renal outcome. A pre-planned interim analysis was conducted after Cycle 1 of the 32nd registered pt, to assess disease and renal response, predictive value of early SFLC measurements and tolerability. Of concern was whether acute kidney injury (AKI) in the early stages of Cfz treatment may be more common in pts with RI. eGFR was calculated using the MDRD formula. SFLC was measured by the FreeLite assay. RESULTS Patient characteristics Mean age was 56.7 ±1 yr; Stage II/III: 4/28. Median eGFR at enrolment was 27 (IQR 21-32) ml/min. The first 11 pts received Cfz 20/27 mg/m2. After a safety analysis, the next 21 pts were treated at 20/56 mg/m2. Twelve pts were treatment naïve (TN) (all receiving 20/56) and 20 pts had relapsed MM (median 3 prior lines; range 1 - 8). One to 29 cycles were administered, median 4.5 in 20/27 and 4 in 20/56 group. Median follow up was 5.1 (0.1 - 26.5) months. Disease Response Of pts who received ≥4 cycles, 83% achieved ≥PR. In TN pts, best response rates were sCR 33%, CR 17%, VGPR 33%, PR 17%; in relapsed pts, CR 17%, VGPR 25%, PR 33%, PD 25%. Renal response After the first 2 cycles, 24% of pts had a complete renal response (IMWG criteria). To determine if Cfz acutely worsened eGFR, change in eGFR from baseline to day 7 (D7) and D28 was calculated. D7 eGFR showed substantial improvement in TN compared to relapsed pts (+5.6 vs -1.2 ml/min). At D28, the improvement in TN vs relapsed pts (+21.4 vs +3.5 ml/min), and in the 20/56 vs 20/27 group (+14.2 vs +3.5 ml/min) was more pronounced. Comparable results were seen in serum creatinine. Early free light chain kinetics Mean change in involved SFLC after 1 & 2 cycles were -54.5% and -67.0% respectively, with mean increase in eGFR of 9.3 and 11.4 ml/min. Involved LC reduction was significantly greater in 20/56 vs 20/27 doses (at C2D1, 81 vs 13%; p Tolerability A total of 25 pts have ceased treatment: disease progression (10), CR after 10 cycles per protocol (2), autologous transplant (3), AE (8), investigator or pt decision (1 each). Total AEs (CTCAE V.4.0) were more frequent in more severe RI (78% in 30-60 ml/min; 89% 15-30 ml/min). AEs ≥Grade (Gd) 3 occurred in 50%. The most common ≥Gd 3 AEs were thrombocytopenia (12.5%), cardiac dysfunction (12.5%) and anemia (9%). AEs of particular interest were hypertension (Gd 2 - 3, 19%) and tumour lysis syndrome (6%). There was only 1 case (3%) of AKI (Gd 2). More respiratory AEs occurred in the 20/56 compared to 20/27 cohort (5 vs 1) and all 3 cases of cardiac dysfunction occurred in 20/56 group, but there were no differences in other AEs. To date 8/32 pts have died, all in relapsed MM group - primary causes were myeloma (5), infection (1), respiratory failure (1) and chronic kidney injury (1). CONCLUSIONS In MM pts with RI, Cfz/dex showed disease response rates comparable to pts with normal renal function in ENDEAVOR. There was no increased AKI due to Cfz; instead, creatinine and eGFR improved with time, with a greater improvement in the 20/56 dose group and in TN pts. Our results also demonstrate the value of early SFLC kinetics measured at C1D3 and C1D10 in predicting renal response. A suboptimal early ∆LC may be an appropriate indicator to use a higher dose density to achieve a better renal outcome. Disclosures Ho: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to meeting; Celgene: Other: Travel to meeting ; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bryant:Celgene: Consultancy, Honoraria. Trotman:PCYC: Research Funding; Beigene: Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board. Gibbs:Amgen: Honoraria. Joshua:Amgen: Honoraria.

Background: Carfilzomib lenalidomide and dexamethasone (KRd) is FDA-approved for the treatment relapsed/refractory multiple myeloma (RRMM) based on data from the ASPIRE study (Stewart K et al. NEJM 2015). Thalidomide, a first generation immunomodulatory drug (IMiD) is less costly than lenalidomide and is synergistic in combination with proteasome inhibitors in the treatment of MM. ALLG MM018/ AMN003 is an open label phase II study of carfilzomib thalidomide and dexamethasone (KTd) for patients with RRMM. The primary end point is progression free survival (PFS). Secondary endpoints include overall response rate (ORR), duration of response (DOR), safety and health related quality of life. Method: Eligible patients were those with RRMM who have had 1-3 prior lines of treatment. The KTd regimen consisted of carfilzomib [20mg/m2 IV C1D1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from C1D8 onwards], thalidomide (100mg po nocte) and dexamethasone [40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, thalidomide was omitted and Kd [carfilzomib 56mg/m2 (36/m2 for patients age ≥75 years) on days 1,2,15,16 and dexamethasone 40mg (20mg for patients age ≥75 years) on days 1,15 every 28 days]was continued for a further 6 cycles. Peripheral blood and bone marrow aspirate and trephine for correlative studies were collected from the first 30 patients, at baseline, after cycle 6 and at confirmed disease progression. The aim of the correlative study was to assess for immunological correlates to clinical outcome. Immunological parameters that will be assessed include NK and T cells subsets on peripheral blood via mass cytometry (CyTOF). On the bone marrow trephine, NK cells, T cells, GRP78 expression within CD38 positive plasma cells, PD1 and PDL1 expression will be assessed at the myeloma site and the surrounding microenvironment using OPAL multiplex immunohistochemistry technology. Results: Between March 2017 to June 2018, 56 patients (median age 66 years, range 56-79; 77% Caucasian and 23% Asian) out of the planned 100 were enrolled, with a median follow up of 4.9 (range, 1.0-13.7) months. Response rates in 39 evaluable patients were ≥MR (97%), ≥PR (89%) and ≥VGPR (66%). Median PFS is not reached, and no patients with ≥MR have relapsed. Grade ≥3/4 AEs occurred in 56% of patients, the most common of which were peripheral sensory neuropathy (13%), dyspnoea (13%) and infections (7%). All grade cardiovascular AEs included dyspnoea (27%), cardiac complications (5%), systemic-hypertension (9%) and pulmonary-hypertension (1.9%), however very few were grade ≥3. Three patients have died on study from disease complications, haemorrhage, and primary cardiac ischaemic event. Thus far, we have not found a significant difference in rates or profile of adverse events between the Caucasian versus Asian subgroups of patients. Conclusion: This preliminary analysis demonstrates that the KTd combination is a tolerable regimen for patients with RRMM with a safety profile in line with previous reports for each of carfilzomib and thalidomide. Initial response rates appear very promising and durable with responses up to 13.7 months thus far in some patients. Patient accrual is ongoing. Disclosures Quach: Janssen Cilag: Consultancy; Sanofi Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Harrison:Janssen-Cilag: Other: Scientific advisory board. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Durie:Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Chng:ASLAN Pharmaceuticals: Research Funding.

Background Data from the Australian and New Zealand (ANZ) Myeloma and Related Diseases Registry (MRDR) shows that 85% of newly diagnosed multiple myeloma (NDMM) patients (pts) in ANZ are induced with bortezomib(V)-containing therapies, predominantly triplets of V-cyclophosphamide-dexamethasone (VCD). Of these, 15% demonstrate treatment failure - either a sub-optimal response ( Methods MM17 was a multi-centre single arm study sponsored by the ALLG. Eligible pts were TE NDMM undergoing pre-autologous stem cell transplant (ASCT) induction with V-based therapy and demonstrating either SOR (defined as Results Fifty pts were recruited from 6 Australian sites between September 2016 and April 2018. EMC92 stratification was successful in 21 pts with 10 (48%) being high-risk and with cfDNA successfully obtained from 49 pts and currently undergoing baseline TAS. Data cut-off date was July 18 2018 with 39 pts evaluable for the primary end-point with the reverse-Kaplan-Meier estimate of the median potential follow-up for survival being 10.9 months (95% CI: 6.0 - 13.1 months). Median age was 50 years (36-71) with 72% males. Disease status at study entry was SOR in 26 (66%) (< MR n = 13, < PR n = 13) and 1REF in 13 (33%). The median number of pre-ASCT KTd cycles was 6 (6 cycles, n = 27 [69%]; 5 cycles, n = 1 [3%], 4 cycles, n = 5 [13%]; ≤ 3 cycles, n = 6 [15%]). Two pts were withdrawn due to treatment related toxicity - pulmonary arterial hypertension (n=1) and acute renal failure (n=1). One pt died of sepsis on treatment and one was withdrawn and subsequently died due to a second primary malignancy. ORR was 72% (95% CI: 56-83%)* - sCR 13%, CR 5%, VGPR 36% and PR 18%. Euroflow confirmed MRD negativity in 36% (14 of 39) of pts pre-ASCT and in 43% (12 of 28) at day 100 post-ASCT. Eight pts have progressed, 7 with highly aggressive extra-medullary disease. Neither median PFS (left panel) nor OS (right panel) have been reached. Conclusions This preliminary analysis of the ALLG MM17 trial demonstrates that early response adaptive escalation to KTd results in high response rates, including MRD negativity, in patients failing V-based induction therapy. *95% Credible interval from the posterior distribution. Bayesian updating based on observed data and a minimally informative prior for ORR with a median of 35%. Figure. Figure. Disclosures Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Quach:Sanofi Genzyme: Research Funding; Janssen Cilag: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kalff:Janssen: Honoraria; Amgen: Other: travel to preceptorship; Celgene: Honoraria; Takeda: Honoraria. Bergin:AMGEN: Other: Travel to education meeting; Celgene: Consultancy. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. .

Background Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all- trans -retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. Design and Methods In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all- trans -retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all- trans -retinoic acid, methotrexate and 6-mercaptopurine. Results Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P =0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P

In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m(2) prior to melphalan 200 mg/m(2). Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

Aim/Background: The outcomes of high risk multiple myeloma (HR-MM) remain poor. As per the revised international staging system (R-ISS), high risk patients, defined by International Staging System (ISS) stage 3 plus high risk chromosomal abnormality and/or high Lactate Dehydrogenase (LDH), have particularly poor outcomes with 5 year progression free survival (PFS) and overall survival (OS) of 24% and 40% respectively.1 Tandem autologous - non-myeloablative allogeneic stem cell transplantation (ASCT-NMA AlloSCT), when used as upfront consolidation may improve the outcome via a graft versus myeloma effect. We performed a retrospective analysis comparing patients who had upfront tandem ASCT-NMA allo SCT for HR-MM with a HR-MM control group who were conventionally treated with upfront ASCT alone. Method: From May 2008 to June 2015, 29 HR-MM patients were treated at the Alfred Hospital Melbourne, with upfront tandem ASCT-NMA alloSCT. HR-MM was defined by the presence of at least 2 of 5 high risk features including International Staging System (ISS) score III, adverse cytogenetics [t(4;14 and/or 17p- identified on FISH and/or complex karyotype on metaphase analysis], elevated lactate dehydrogenase (LDH), plasma cell leukemia (all at diagnosis) or induction failure (less than partial remission (PR)) with proteosome inhibitor (PI) or immunomodulator (IMID) based combination chemotherapy. Outcomes for these patients were compared with 12 HR-MM patients contemporaneously treated at the Royal Adelaide hospital, Adelaide with upfront ASCT alone. All ASCT were conditioned with melphalan 200mg/m2; NMA were conditioned with oral fludarabine 48mg/m2 on days -4 to -2 and 2Gy TBI on day 0. All tandem ASCT-NMA allo SCT patients received cyclosporine and mycophenylate mofetil for graft versus host disease prophylaxis. Results: Median age of the tandem cohort was 52 years (range: 22-66 years) whereas the ASCT cohort was older with a median age of 59 years (range: 51-72 years; p=0.01). 44.8% of the tandem group and 50% of the ASCT group were male (p=0.77). 18 patients (62.1%) of the tandem cohort were transplanted from unrelated donors. Within the tandem cohort 24.1% developed grade II-IV acute graft versus host disease (GVHD) and 44.8% had extensive chronic GVHD. After a median follow up of 48.9 months, progression free survival (PFS) was significantly superior for tandem group compared to ASCT group (median PFS=1166 days versus 399 days; p=0.001) (Fig:1). The 3-year cumulative incidence of relapse was 31.9% for tandem group against 79.8% for ASCT group (p=0.005). The 5-year overall survival of tandem and ASCT groups were 59.84% and 44.56%, respectively (p=0.38). Transplant related mortality was not significantly different between the groups (20.7% for tandem group and 8.3% for ASCT group; p=0.32). To avoid any age bias, we then compared the ASCT cohort with an older subgroup of the tandem cohort (17 patients with a median age of 58 years, range: 51-66 years, p=0.61 when compared with ASCT cohort) and demonstrated that the PFS was still significantly superior for the tandem approach (median PFS=1179 days for tandem cohort versus 399 days for ASCT cohort; p=0.009). Minimal residual disease (MRD) analysis by 8-colour Euroflow (sensitivity at 10-5) was negative in 12 of 17 tandem patients tested. Conclusion: Upfront tandem ASCT-NMA AlloSCT for HR-MM results in superior PFS and an emerging OS benefit with acceptable toxicity when compared to conventional ASCT. High-resolution MRD negativity in a significant proportion of tandem patients predicts for extended disease free survival. Ref: 1. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-69. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Daratumumab is a human CD38 IgGκ monoclonal antibody that demonstrated significant activity and a manageable safety profile in combination with bortezomib and dexamethasone. In a randomized phase 3 study, daratumumab in combination with bortezomib and dexamethasone (DVd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone alone (Vd) in a pre-specified interim analysis of patients (pts) with relapsed or refractory multiple myeloma (RRMM; Palumbo A. N Engl J Med 2016; in press). Herein, we examine subgroups from this study to compare the efficacy of DVd vs Vd in bortezomib-naive and bortezomib-experienced pt populations. In addition, the efficacy of DVd vs Vd in pts who were refractory to lenalidomide at last prior line of therapy was also evaluated. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of Vd (bortezomib: 1.3 mg/m2 SC on Days 1, 4, 8, 11; dexamethasone: 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, 12) with or without daratumumab (16 mg/kg IV qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Pts who were refractory to bortezomib were not eligible. The primary endpoint was PFS. Bone marrow aspirate samples that had been prepared with Ficoll were evaluated for minimal residual disease (MRD) using three different thresholds (10-4, 10-5, and 10-6) based on the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA). Results: Median follow-up was 7.4 months. Among bortezomib-naive pts (DVd, n=89; Vd, n=83), PFS was significantly improved with DVd vs Vd (median: not reached [NR] vs 7.5 months; HR, 0.25; 95% CI, 0.13-0.47; P For pts who previously received a bortezomib-containing regimen (DVd, n=162; Vd, n=164), PFS was also significantly longer with DVd vs Vd (median: 12.3 vs 6.7 months; HR, 0.46; 95% CI, 0.32-0.66; P Among pts who were refractory to lenalidomide at the last prior line of therapy (DVd, n=45; Vd, n=60), PFS was significantly longer in DVd vs Vd (median: 10.3 vs 4.4 mo; HR, 0.37; 95% CI, 0.21-0.65; P=0.0004; Figure). Within this subgroup, ORR was significantly higher for DVd vs Vd (81% vs 50%; P=0.0021), and the same trends were observed for rates of ≥VGPR (54% vs 12%; P Updated efficacy and safety data, including MRD analyses across different sensitivity thresholds (10-4, 10-5, and 10-6), will be presented at the meeting. Conclusions: These analyses confirm that addition of daratumumab to Vd significantly improves outcomes for RRMM pts regardless of prior treatment with bortezomib. Importantly, this treatment benefit of DVd vs Vd was maintained in pts who were refractory to lenalidomide at the last prior line of therapy. These data lend further support to adding daratumumab to a standard-of-care regimen in RRMM. Figure Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Figure. Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Disclosures Lentzsch: BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. Quach:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Ovilla:Janssen: Consultancy. Qi:Janssen: Employment. Deraedt:Janssen: Employment, Equity Ownership. Schecter:Janssen: Employment, Equity Ownership. Amin:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Background Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to bortezomib, or what causes primary or acquired resistance. The ‘unfolded protein response’ is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib.Design and Methods Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested.Results Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself.Conclusions The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662)

RANKL is a key mediator of osteoclast differentiation, activation, and survival. Preclinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma (MM) cells in the bone marrow. Reports have also shown that inhibiting RANKL may have a direct effect on RANK-expressing myeloma cells and a therapeutic role in treating the disease. In mouse myeloma models, inhibition of RANKL led to reduced serum paraprotein levels and tumor burden. Based on this hypothesis, this proof-of-concept, single-arm study investigated whether RANKL inhibition with denosumab could reduce serum M-protein levels in relapsed or plateau-phase myeloma subjects. All subjects received denosumab monthly, with loading doses on days 8 and 15 of month one, until disease progression or subject discontinuation. Results of this ongoing study demonstrated that no subjects in either cohort met the protocol-defined objective response criteria of complete response (CR) or partial response (PR), but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates, as evidenced by suppressed levels of the bone turnover marker, serum C-terminal telopeptide of type 1 collagen (sCTx). Eleven (21%) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months. Nineteen (46%) subjects with plateau-phase myeloma maintained stable disease for up to 18.3 months. The adverse event (AE) profile for denosumab and its dosing schedule in these populations was consistent with that for advanced cancer patients receiving systemic therapy. Additional controlled clinical studies of denosumab in subjects with both relapsed and plateau-phase MM are warranted.

e190 acquired factors, including race,age,general conditions, prior history of VTE, time from diagnosis, and treatments. As VTE is supposed to influence the prognosis,IMW proposed the first guideline of thromboprophylaxis in 2008, followed by BSH, ASCO, and GFTC. However, these guidelines are based on a limited number of studies with low evidence level and extrapolation of data from studies with other disorders and varies. Thus, controversy exists about the validity of thromoprophylaxis,agents,and duration. Methods: We searched relevant studies with 200 or more patients by the PubMed on-line system since 2008. Results: 8 articles have been identified. 1 metaanalysis from Canada, 2 prospective randomized studies(PRS) without control from Italy, 1 PS without control from France, and 3 retrospective studies(RS) with control from USA, Korea, and Japan(our report), and 1 RS without control from Greece. Patient no.;200-1035 (median;524), age(y);24-93(61), follow-up period(mo); 4-29 (20), IMiDS given; thalidomide;4, lenalidomide;2, both;2, thromboprophylaxis; aspirin (ASA) 1, LMWH;1, ASA,vitamin K agonists(VKA);1, ASA or LMWH;1, ASA, VKA or LMWH;4, total VTE(%); 1.4-6.0(4.6), VTE(%) with or without thromboprophylaxis in 3 RS; 18 and 15(p1⁄40.16) (LMWH, all high risk patients, USA), 3.5 and 4.0(p1⁄40.77) (ASA, every risk patients, Korea), 1.7 and 1.2(p1⁄40.55)(ASA and VKA, every risk patients, Japan), 2 Italian studies with standard/ low risk patients without control revealed similar benefits of ASA, LMWH, and/or VKA, 3 other studies no benefits. Risk factors were inconsistent. Because of low VTE rate, PRS with thousands of patients would be necessary for each arm of control and thromboprophylaxis to obtain statistically significant results, however, it is not feasible. Conclusion: None of the thromboprophylactic agents has demonstrated a clear benefit and risk factors were inconsistent. Thus, we propose a reasonable and feasible guideline; high risk (age 65y, prior VTE history,immobility,and/or administration of erythropoietin); attending Dr’s discretion, low risk(all others); ASA or VKA(INR1⁄42-3) for Western patients. Dr’s discretion for Asian patients of any risk. Thromboprophylaxis duration; newly diagnosed patients; 1 y. Refractory/relapsed patients;Dr’s discretion depending on tumor burden.

This study investigated whether pegfilgrastim support would enable on-schedule delivery of dose-dense cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP-14) to elderly patients with non-Hodgkin's lymphoma (NHL). Thirty patients 60 years of age and older with aggressive NHL were evaluated after receiving up to six cycles of CHOP-14 supported with pegfilgrastim. The median age was 68 years (range 61 – 74). Forty-seven per cent of patients received full dose chemotherapy on schedule for all cycles (range 65 – 93). Chemotherapy was delayed in 10 patients and dose reduced in 15 patients. Hematological toxicity was the most common reason for delays and dose reduction. Six of nine patients (67%) achieved a peripheral blood CD34+ count of at least 20 cells×106 L−1 on day 12 of cycle one. The delivery on schedule of dose-dense CHOP-14 to elderly patients with previously untreated aggressive NHL is safe and efficacious with once per cycle pegfilgrastim support.

Introduction Previous results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here. Methods Subjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, >2.5 and ≤5.5, or >5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]). Results A total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups. Conclusion Despite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. Disclosures Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

For 10 consecutive patients in our unit who did not show a significant rise in blood progenitor cells within 14 days following chemotherapy and G-CSF, we increased the G-CSF dose from 5 to 10 microg/kg/day (n = 9) or from 10 to 15 microg/kg/day (n = 1). As a result, there were significant increases in total yield as well as yield per apheresis of mononuclear cells, CD34+ cells and CFU-GM (P < 0.025

Daclizumab has poor efficacy in steroid-refractory severe acute graft-versus-host disease: a single centre experience with 12 allograft patients

Abstract 4065 Background: Amplification of chromosome 1q occurs in 40% of myeloma and predicts lower response to induction regimens. We assessed if a PAD regimen overcomes effects of 1q amplification on overall response rate (ORR), event-free (EFS) and overall survival (OS) in newly-diagnosed, transplant-eligible myeloma. Methods: This phase II trial enrolled 107 patients, stratified by 1q amplification. All could receive 4× 21-day cycles of PAD induction: bortezomib 1.3mg/m2 D 1,4,8,11; doxorubicin 20mg/m2 D1,4; dexamethasone 20mg D1,2,4,5,8,9,11,12. Responders proceeded to melphalan 200mg/m2 and ASCT. ORR after PAD was primary endpoint. Secondary endpoints included ORR 3 monthspost-ASCT, and 2-year EFS and OS. Results: 22% (20/93 evaluable cases) had amplified 1q. Median PAD cycles was4. ORRs were similar in amplified and non-amplified cases (100% vs. 87% post-PAD; 100% vs. 93% post-ASCT). After median 2 years, 2-year EFS was similar in amplified and non-amplified cases (70% vs. 75%; log-rank p=0.86), but with a trend to lower 2-year OS in amplified cases (86% vs. 94%; log-rank p=0.28). Common grade 3 or 4 adverse events included constipation (0% vs. 8% of patients), neutropenia (12% vs. 4% of patients), anaemia (4% vs. 6% of patients), back pain (4% vs. 6% of patients), neuralgia (0% vs. 6% of patients) and neuropathy (8% vs. 4%). Conclusions: Four cycles of PAD induced high response rates in both 1q amplified and non-amplified myeloma with acceptable toxicity. After 2 years, EFS was also similar, but with a non-significant trend to lower OS in patients with 1q amplification. Funding: This study is sponsored by Janssen-Cilag Pty Ltd, Australia. Trial Registration: ACTRN12609000296235. Disclosures: Joshua: Janssen-Cilag Pty Ltd: Research Funding. Hertzberg:Janssen-Cilag Pty Ltd: Research Funding. Auguston:Janssen-Cilag Pty Ltd: Research Funding. Spencer:Novartis: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria. Horvath:Janssen-Cilag Pty Ltd: Research Funding. Bashford:Janssen-Cilag Pty Ltd: Research Funding. Campbell:Janssen-Cilag Pty Ltd: Research Funding. Ashurst:Janssen-Cilag Pty Ltd: Employment. Wade:Janssen-Cilag Pty Ltd: Employment. Copeman:Janssen-Cilag Pty Ltd: Employment. Butcher:Janssen-Cilag Pty Ltd: Consultancy. Prince:Janssen-Cilag Pty Ltd: Research Funding.

Abstract 3059 Aim Despite novel agents, multiple myeloma (MM) remains incurable. The majority of patients with MM will relapse at some stage after induction therapy and high dose chemotherapy with autologous stem cell transplant (ASCT). Published studies have recommended salvage ASCT as an effective option in patients with relapsed MM. However, the patient cohort who will derive maximum benefit from salvage ASCT is still undefined and is likely to evolve with increasing therapeutic options. We aimed to evaluate the role of salvage ASCT in relapsed MM patients. Methods We performed a retrospective analysis of patients who underwent salvage ASCT for relapsed MM in South Australia between 1992 and 2011. Results During this period, autologous stem cell transplants were performed for 457 patients with newly diagnosed MM. Thirty-nine patients subsequently underwent salvage ASCT for relapsed MM. The median age of patients at salvage ASCT was 59 (34–73) years, and 85% were ISS I and II at diagnosis. The majority of patients (90%, n=35) had a progression free interval (PFI) of at least 12 months after initial ASCT, consistent with recommendations by current literature. Salvage ASCT was performed for four patients with PFI shorter than 12 months, due either to suboptimal response to novel agents (thalidomide, lenalidomide, bortezomib), or the lack of novel agent availability in the earlier years. The median progression-free survival (PFS) and median overall survival (OS) following salvage ASCT were 22 months (95% CI: 11–32) and 52 months (95% CI: 30–74) respectively. Non-relapsed mortality at 2 years was 7%. Following salvage ASCT, the median PFS (28 vs. 12 months, p = 0.006) and OS (83 vs. 26 months, p = 0.02) were significantly longer in patients whose progression free interval after the initial ASCT was > 24 months (Figures 1 and 2). Use of novel agents in salvage induction and maintenance therapy post salvage ASCT did not appear to influence outcome. Conclusion Our results suggest that there remains a role for salvage ASCT, even in the era of novel therapies. Salvage ASCT may result in durable responses, particularly in patients with longer progression free interval (> 24 months) following initial ASCT. This interval could be included as a selection criterion for patients with relapsed myeloma who remain transplant eligible. Disclosures: No relevant conflicts of interest to declare.

Denosumab is a fully human monoclonal antibody that inhibits RANKL, an essential mediator of osteoclast (OC) formation, function, and survival. Denosumab is being investigated in a phase 3 study to delay skeletal-related events in patients (pts) with MM. Preclinical data suggest that OCs may interact either directly with MM cells or indirectly through a “vicious cycle” of bone destruction that releases factors promoting myeloma cell growth. In a mouse MM model, RANKL inhibition reduced OC number, osteolysis, serum paraprotein levels, and prolonged survival. In this single-arm, proof-of-concept study of denosumab in pts with R (≥ 2 prior therapies and relapse after a response to most recent therapy) or PP (response to the most recent therapy and stable, detectable serum M-protein for ≥3 mos) MM, we report efficacy data on pts who could have completed 6 mos of treatment; for the R cohort, this represented a complete analysis and for the PP cohort, this was an interim analysis. Eligible MM pts (age ≥18 yrs; measurable M-protein; ECOG of 0 or 1; life expectancy >3mos) were given subcutaneous injections of denosumab 120mg monthly with additional loading doses on days 8 and 15 of mo 1. Pts were instructed to take calcium 500mg and Vit D 400 IU daily. The primary endpoint was the % of pts with complete response (CR) or partial response (PR), which included serum M-protein reductions ≥50%. Pt incidence of adverse events (AEs) was measured. 52 pts in R (13 women, 39 men) and 33 pts in PP (20 women, 13 men) received 1 to 12 mos of denosumab. The median ages of the R and PP cohorts were 63 and 62 yrs. 79% of the R cohort, and 58% in PP had ≥3 prior therapies. In R, the median on-study follow up time was 3.1 mos; 85% of pts who discontinued denosumab was due to disease progression. In PP, the median on-study follow up time was 8.1 mos; 81% of pts who discontinued treatment was due to disease progression. No objective CR or PR was observed in either cohort. In R, 13 pts (25%) had stable disease for >6 mos; maximum reductions of ≥25% in serum M-protein levels were seen in 3 pts (6%) and 6 mos; maximum reductions of ≥25% in serum M-protein levels were seen in 4 pts (13%) and

Aim: To explore the role of thalidomide in pre-transplant induction treatment in multiple myeloma. Patients and methods: Between Sept 2002 and March 2005, 37 patients with advanced, de-novo multiple myeloma (mean age 56 years, mean Serum. albumin 33g/L, and median b -2-microglobulin 4.0mg/L) were entered into a multicentre, phase 2 study of pre transplant induction treatment. The regimen included TDx3 (thalidomide 400mg/d, pulse dexamethasone 32mg TDS x 5d every 3 weeks PO), followed by DT-PACEx2 (thalidomide 400mg/d, dexamethasone 40mg/d x 4 PO and cisplatin 10mg/m2/d, doxorubicin 10mg/m2/d, cyclophosphamide 400mg/m2/day, etoposide 40mg/m2/d as 4 day infusion administered 4 weeks apart, supported with G-CSF 10m g/Kg/d). Thromboprophylaxis was warfarin (target INR 1.5–2.0) during TD and enoxaparin 40mg/day (adjusted according to platelet count) during DT-PACE. Stem cells were harvested at recovery from the second cycle of DT-PACE in the first 27 patients, but after review of the harvest results the remaining patients were harvested after first cycle of DT-PACE with an option to re-harvest after the second if the initial harvest was insufficient. Paraprotein and BJP responses and stem cell collections were compared to a historical cohort of 58 patients treated with VAD and mobilised with cyclophosphamide 5G/m2 and G-CSF 5m g/Kg. Results: 23/37 patients completed study treatment, 21 had successful stem cell harvests. There were 2 deaths (1 sepsis, 1 haemorrhage) and 2 failed stem cell harvests. After TD x 3 and VAD x3 the mean levels of paraprotein (or BJP) were 21% and 34% of pre-treatment levels, respectively (p=0.02). After DT-PACE x 2 and HD cyclophosphamide the mean levels of paraprotein (or BJP) were 14% and 31 % respectively (p=0.014). At the completion of TDx3 42% of patients had achieved VGPR and 50% PR, whereas after VAD x 3 there was 12% CR, 17% VGPR and 45% PR (p=0.231). Following DT-PACEx2 there was 22% CR, 39% VGPR and 26% PR and after HD cyclophosphamide there was 9% CR, 19% VGPR and 45% PR (p=0.039). The median number of CD34+ cells/kgBW harvested was 4.7 x 106 after DT-PACE and 11.6 x 106 after HD cyclophosphamide (p=0.001). The median number of aphereses procedures required was 2 for both study patients and historical controls. 58 serious adverse events included 20 episodes of infection (9 during TD and 11 during DT-PACE), 3 episodes of haemorrhage, 1 pulmonary embolus and 2 deaths. Conclusion: Thalidomide dexamethasone combination appears to be as efficacious as VAD in reducing tumour burden in de-novo multiple myeloma. The addition of DT-PACE improves the pre-transplant CR and VGPR rate. In most patients adequate stem cell harvest can be obtained, but yields appear to be less than after VAD/HD cyclophosphamide. Thalidomide dexamethasone followed by DT-PACE is associated with tolerable but not insignificant toxicity.

Autologous transplantation has been used increasingly over the last 10 years for the treatment of multiple myeloma. As is the case in other cancers treated by high-dose therapy and stem cell rescue, the contribution of occult tumor cells in the graft to relapse posttransplant remains to be resolved. In this report, we review the biology and differentiation of plasma cells in the context of their significance as an origin of relapse in multiple myeloma.