Search

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

Cardiac amyloidosis has a very poor prognosis, but it is the nature of the involved precursor protein that ultimately dictates treatment and survival.Definitively characterise the amyloid subtype by mass spectrometry (MS) in an Australian cohort of patients with cardiac amyloidosis.We report the clinical characteristics and survival of 47 cardiac amyloid patients across two Australian centres including 39 patients evaluated for definitive amyloid subtype utilising laser microdissection and tandem mass spectrometry.A quarter (n = 12) of patients were classified as wild-type transthyretin amyloidosis (ATTRwt), 33 patients as light or heavy chain amyloidosis (AL or AH) and two as hereditary mutant transthyretin amyloidosis. Greater left ventricular hypertrophy (interventricular septum 22 vs 15 mm; P = 0.005) and history of cardiac arrhythmia (75% vs 31%; P = 0.016) were significantly associated with ATTRwt patients compared with AL/AH patients. AL patients demonstrated significantly shorter median survival compared with ATTRwt patients (3.5 vs 37 months; P = 0.007). New York Heart Association class III-IV symptoms or plasma cells ≥10% at diagnosis, were the only independent predictors of worse survival in AL patients on multivariate analysis.AL amyloidosis accounted for 68% of our cohort of patients with cardiac amyloidosis while ATTR accounted for 26%. In the era of novel therapies for both AL amyloid and ATTR, identification of the correct amyloid subtype is essential in making therapeutic decisions and providing accurate prognostic information to patients. Laser microdissection and tandem mass spectrometry plays an important role in identifying amyloid subtype, particularly in complex cases.

© 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.

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.

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM display evidence of myeloma bone disease (MBD), characterised by the formation of osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly increases the risk of skeletal-related events such as pathologic fracture, spinal cord compression and hypercalcaemia. MBD is the result of MM plasma cells-mediated activation of osteoclast activity and suppression of osteoblast activity. Bisphosphonates (BP), pyrophosphate analogues with high bone affinity, are the only pharmacological agents currently recommended for the treatment and prevention of MBD and remain the standard of care. Pamidronate and zoledronic acid are the most commonly used BP to treat MBD. Although generally safe, frequent high doses of BP are associated with adverse events such as renal toxicity and osteonecrosis of the jaw. As such, optimal duration and dosing of BP therapy is required in order to minimise BP-associated adverse events. The following guidelines provide currently available evidence for the adoption of a tailored approach when using BP for the management of MBD.

Waldenstrom macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab-induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib- and bortezomib-based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work-up and therapy of WM to assist Australian clinicians in the management of this disease.

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.

BACKGROUND Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m2 intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS. Cancer 2016;122:2050–6. © 2016 American Cancer Society.

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.

Systemic AL amyloidosis is a plasma cell dyscrasia with a characteristic clinical phenotype caused by multi-organ deposition of an amyloidogenic monoclonal protein. This condition poses a unique management challenge due to the complexity of the clinical presentation and the narrow therapeutic window of available therapies. Improved appreciation of the need for risk stratification, standardised use of sensitive laboratory testing for monitoring disease response, vigilant supportive care and the availability of newer agents with more favourable toxicity profiles have contributed to the improvement in treatment-related mortality and overall survival seen over the past decade. Nonetheless, with respect to the optimal management approach, there is a paucity of high-level clinical evidence due to the rarity of the disease, and enrolment in clinical trials is still the preferred approach where available. This review will summarise the Clinical Practice Guidelines on the Management of Systemic Light Chain (AL) Amyloidosis recently prepared by the Medical Scientific Advisory Group of the Myeloma Foundation of Australia. It is hoped that these guidelines will assist clinicians in better understanding and optimising the management of this difficult disease.

Options for treatment of elderly patients with multiple myeloma have expanded substantially following the development of immunomodulatory drugs (IMiD), proteasome inhibitors and with enhancement in safety of high-dose therapy and autologous stem cell transplant (HDT + ASCT). The recognition of biological heterogeneity among elderly patients has made delivery of therapy more challenging. An individualised approach to treatment selection is recommended in an era in which highly efficacious treatment options are available for transplant-ineligible patients. Here, we summarise recommendations for patients who are considered unsuitable for HDT + ASCT, including pretreatment considerations, and induction, maintenance and supportive care therapies.

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.

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.

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

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. .

Multiple myeloma is a plasma cell neoplasm that is currently incurable. Older patients are managed with melphalan and prednisolone.

Purpose Thalidomide is effective in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). However, the role of thalidomide in the post-autologous stem cell transplantation (ASCT) context remains unclear. This study assessed whether the addition of thalidomide consolidation following ASCT would improve the durability of responses achieved and overall survival. Patients and Methods Between January 2002 and March 2005, 269 patients with newly diagnosed MM who achieved disease stabilization or better with conventional induction chemotherapy received a single high-dose melphalan conditioned ASCT. Post-ASCT, 129 patients were randomly assigned to receive indefinite prednisolone maintenance therapy (control group) and 114 to receive the same in addition to 12 months of thalidomide consolidation (thalidomide group). The primary study end points were progression-free survival (PFS) and overall survival (OS). The secondary end point was tolerability. Results After a median follow-up of 3 years, the postrandomization 3-year PFS rates were 42% and 23% (P < .001; hazard ratio [HR], 0.5; 95% CI, 0.35 to 0.71) and the OS rates were 86% and 75% (P = .004; HR, 0.41; 95% CI, 0.22 to 0.76) in the thalidomide and control groups, respectively. There was no difference in survival between groups 12 months after disease progression (79% v 77%; P = .237). Neurological toxicities were more common in the thalidomide arm but there were no differences between arms for thromboembolic events. Conclusion Consolidation therapy with 12 months of thalidomide combined with prednisolone prolongs survival when used after a single high-dose therapy supported ASCT in patients with newly diagnosed MM. Furthermore, thalidomide consolidation therapy did not adversely impact on survival in the subsequent salvage setting.

Purpose This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. Patients and Methods Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m2 on day 4. Results Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome. Conclusion PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.

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.

Angiogenesis, or the formation of new blood vessels from pre-existing vasculature through sprouting or invagination, is a complex process involving many factors. The role of angiogenesis in the progression of cancer has been extensively explored, and it is now well established that elevated levels of angiogenesis in many solid tumors correlates with poor prognosis. Similarly, recent evidence suggests that blood vessel formation plays a pivotal role in the progression of hematological malignancies, including the plasma cell malignancy, multiple myeloma. Several studies have shown that bone marrow angiogenesis is significantly increased in patients with active multiple myeloma and is indicative of poor prognosis. Malignant myeloma cells are known to secrete several angiogenic factors which may play a role in the increased angiogenesis in the bone marrow of myeloma patients. Anti-angiogenic therapy with thalidomide is now considered to be a standard therapy for advanced myeloma patients and a number of new anti-angiogenic therapies are currently undergoing clinical trials for use in this disease.

Background: Even after high dose chemotherapy (HDT) and autologous haemopoietic stem cell transplantation, the majority of patients with multiple myeloma eventually relapse. Aim: The aim of the present study was to study the ­feasibility and outcome of delivering a regimen including in vivo and in vitro purging and double HDT in patients with multiple myeloma. Methods: Thirty-four patients with advanced multiple myeloma were enrolled in a program of vincristine, doxo­rubicin and dexamethasone chemotherapy, high dose cyclophosphamide/granulocyte macrophage colony stimulating factor (GM-CSF) stem cell mobilisation, CD34 selection of harvested stem cells (in vitro purging), double HDT (cyclophosphamide/epirubicin in the first, busulphan/melphalan in the second) rescued by CD34+-selected cells, the second rescue using cells harvested following the first HDT (in vivo purging) and interferon maintenance. Results: Forty-four per cent of patients completed the program. Fifty-three per cent of withdrawals were as a result of insufficient stem cells. This correlated to previous chemotherapy. Therapy-related mortality was 6%. CD34+ selection achieved more than a 2-log reduction of CD38++ cells; in vivo purging achieved 80%. Although similar numbers of CD34+ cells were reinfused at both HDT, platelet recovery was slower after the second HDT. Additional complete remissions were achieved after each phase of therapy, 3% at the end of vincristine, doxorubicin and dexamethasone and 33% after completing planned HDT. Factors associated with longer overall survival included age less than 60 years (P = 0.044), serum β-2-microglobulin below 3 µγ/L at entry (P = 0.042) and less than 2 months between the two HDT (P = 0.024). The only factor associated with a longer event-free survival was less than 2 months between HDT on study (P = 0.038). Conclusions: (i) dose intensification with two HDT delivered within 2 months might be associated with a better patient outcome, (ii) early mobilisation should be incorporated in multiple myeloma HDT programs and (iii) higher CD34+ doses may be required for tandem transplants. (Intern Med J 2004; 34: 167−175)

A 33-year-old male presented with acute lymphoblastic leukemia (ALL) characterized by translocation (11;19)(q23;p13.3). He received an allogeneic bone marrow transplant from a matched unrelated donor. Two years later his disease relapsed with an isolated intracardiac mass, presenting as right heart failure. He had no evidence of concomitant relapse in the bone marrow. Tumor cytogenetics revealed clonal evolution with the karyotype 46,XY,t(3;16)(q23;p13),t(11;19)(q23;p13.3), the chromosome 16 breakpoint involving the band where the genes for multidrug resistance-associated protein and CREB binding protein are known to reside. To our knowledge, this is the first report of an isolated extramedullary relapse of ALL in the heart.

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.

Vincristine, doxorubicin and dexamethasone (VAD) are commonly used as the initial chemotherapy in myeloma patients prior to high-dose therapy and autologous stem cell transplantation. We reviewed monoclonal protein responses and survival of 62 patients treated in this way. Among patients with IgG paraprotein, achievement of at least 50% reduction in paraprotein after the first cycle of VAD correlated with significantly better event-free survival at 3 years, compared with those having less than 50% response. We postulate that early paraprotein response may be used to identify high risk patients.

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.

Background: Bortezomib has been shown to be a safe and efficacious for the treatment of relapsed and refractory multiple myeloma (MM). Here we report a subset analysis of Australian and New Zealand data from the International Extended Access Programme for bortezomib. Methods: Patients with more than or equal to two prior lines of therapy were given bortezomib 1.3 mg/m2 (i.v. bolus days 1, 4, 8, 11) for up to eight 21-day cycles (C). Dexamethasone, 20 mg/day p. o. on the day of, and day after, bortezomib was added after C2 for progressive disease or after C4 for stable disease. Efficacy was assessed using modified Southwest Oncology Group criteria in the intent-to-treat group. Results were compared between the Australian and New Zealand and international cohort. Results: One hundred and eleven patients from 16 centres (55% men, median age 61.9 years) had a median of 5.2 ± 2.8 treatment cycles of bortezomib. Among them, 82% had ≥3 prior therapies. Grade 3–4 treatment-related adverse events were reported in 57 patients (52%); the most common were thrombocytopenia (25.7%), anaemia (8.3%), peripheral neuropathy (7.3%) and diarrhoea (7.3%). Responses were evaluable in 106 patients: 22% achieved a best response of complete response/response and 20% partial response (overall response rate of 42%). Median times to first and best responses were 42 days and 69 days, respectively. Compared with the international cohort, the cohorts from Australian and New Zealand showed inferior overall response rates (54 vs 42%, P = 0.001), possibly due to heavier pretreatment (82% greater than or equal to three prior therapies vs 68%, P

Purpose: Multiple myeloma is an incurable disease with heterogeneous clinical behavior. Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains a paucity of data in patients treated with bortezomib that accurately delineates and identifies such patients. This information is crucial to guide management. Experimental Design: In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy. Results: Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16INK4A, cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1 at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients. Conclusions: Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.

Aims: To study disease characteristics of adult patients with myelodysplastic syndromes (MDS) in South Australia and to analyse their outcome and survival. Methods: One hundred and eight adult patients with confirmed MDS from marrow biopsies in the 76-month period before April 2006 were retrospectively included in an MDS database. Results: The median age at diagnosis of this cohort was 70 years, with skewing of refractory anaemia with excess blasts and refractory cytopenia with multilineage dysplasia in the younger patients. Clonal cytogenetic abnormalities were present in 42% of patients. Median survival was 48 months, and secondary transformation to acute myeloid leukaemia was seen in 27%. Survival, according to the World Health Organization subtypes in ascending order, was refractory anaemia with excess blasts, refractory anaemia, refractory anaemia with ringed sideroblast, refractory cytopenia with multilineage dysplasia and del(5q). The International Prognostic Scoring System score stratified MDS patients into different risk groups and effectively discriminated significantly different survivals, ranging from a median 4 months for high-risk patients to 72 months for low-risk patients. Conclusion: An MDS database provides useful information regarding the disease characteristics and survival of MDS patients in South Australia and confirms the prognostic usefulness of the International Prognostic Scoring System. The future prospective collection of results will be invaluable in evaluating the effect of novel therapies on patient prognosis.

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.

Purpose: Multiple myeloma is an incurable hematologic malignancy characterized by increased bone marrow angiogenesis and extensive lytic bone disease. We have previously shown that elevated levels of stromal-derived factor-1α (SDF-1α) in peripheral blood plasma are associated with osteolysis in multiple myeloma patients. We have now examined whether SDF-1α levels also correlate with angiogenesis. Experimental Design: We examined the contribution of multiple myeloma plasma cell–derived SDF-1α in the stimulation of in vitro angiogenesis using a tube formation assay. We also collected trephine and peripheral blood plasma samples from patients with multiple myeloma to analyze microvessel density and SDF-1α levels, respectively. Results: We show that multiple myeloma plasma cell line–derived conditioned medium containing SDF-1α stimulates in vitro angiogenesis. In addition, in a large cohort of patients with multiple myeloma and its precursor condition monoclonal gammopathy of undetermined significance, we confirm previous findings that plasma cell burden correlates with both angiogenesis and plasma levels of SDF-1α. We now extend these observations and show the novel finding that peripheral blood plasma levels of SDF-1α positively correlate with the degree of bone marrow angiogenesis in multiple myeloma and monoclonal gammopathy of undetermined significance patients. Conclusions: High levels of SDF-1α produced by multiple myeloma plasma cells promote osteolysis and bone marrow angiogenesis. Therefore, we propose that inhibition of SDF-1α may be an effective mechanism by which angiogenesis and osteolysis can be reduced in multiple myeloma patients.

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.

the aim of this paper was to review the initial use of Palifermin(rHu-KGF1) in a single institution, for the prevention of oral mucositis in high-dose chemotherapy and stem cell transplantation.the case records of the first five patients treated with Palifermin at the Royal Adelaide Hospital Cancer Centre were reviewed, and incidence,severity and duration of the oral mucositis were recorded, as well as demographics and toxicities.two of the five patients developed grade 4 mucositis, and the remaining three patients developed grade 2 mucositis. Palifemin was well tolerated with only one patient developing a rash.the severity of oral mucositis was less than would be expected in these patients without anti-mucositis therapy. Palifermin was well tolerated. Obviously this single institution report is from a very small cohort of patients, but it is encouraging for the ease of use of this drug in the future.

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.

Early transplant mortality is related to acute GvHD, which this study in older patients (40 to 60 years) decreased by reducing the graft T-cell number while maintaining a high CD34 cell number--by positive CD34 cell selection. Potential increased risk of relapse is addressed by giving donor leucocyte infusion (DLI) post-transplant.CD34 cells selected by Isolex devices from leukophereses obtained from Filgrastim-treated matched sibling donors were transplanted and DLI given later if there was no GvHD.Selection of CD34 cells achieved a median of 5.2 million cells/kg, with minimum target for transplantation achieved in 17 of 21 donors. Median CD3 cell number was 0.24 million/kg. Engraftment was rapid and graft failure rare. Transplant-related mortality was low (6% at 3 months). Acute GvHD ofor=Grade 2 occurred in only two patients (12.5%). DLI were given to only six patients who had resolved Grade 1 or no GvHD. Eight of the 17 patients relapsed, including three of the six who had DLI. Extensive chronic GvHD developed in six of 12 evaluable patients, two of these had received DLI. Seven of the 17 patients (41%) are alive at median follow-up of 56 months.CD34 selection allows transplantation of high numbers of CD34 cells with low CD3 cell count, reducing early mortality in patients 40-60 years old because of rapid hemopoietic reconstitution and low acute GvHD incidence. Administration of DLI was often precluded by low-grade acute GvHD.

Purpose: To evaluate the incidence of renal dysfunction after total body irradiation (TBI). Methods and Materials: Between 1990 and 1997, 64 patients (median age 50 years) received TBI as part of the conditioning regimen before bone marrow transplantation (BMT). Five patients with abnormal renal function at the beginning of treatment or with incomplete data were excluded. All patients received a total of 12 Gy (6 fractions twice daily for 3 consecutive days) prescribed to the peak lung dose (corrected for lung transmission) at a dose rate of 7.5 cGy/min. Renal shielding was not used. Renal dysfunction was assessed on the basis of the serum creatinine levels measured at the start and end of TBI and at 6, 12, 18, and 24 months after completion of BMT. Cox proportional hazard analysis was used to evaluate the various factors known to affect renal function. Results: Only 4 patients had elevated serum creatinine levels at 12 months and subsequently only 2 of the 33 surviving patients had persistent elevated renal serum creatinine levels 24 months after BMT. A fifth patient developed proteinuria and mildly elevated serum creatinine levels at 2.5 years. In 2 patients, the elevation coincided with disease relapse and normalized once remission was achieved. In the third patient, the elevation in serum creatinine levels coincided with relapse of multiple myeloma and the presence of Bence-Jones proteinuria. The fourth patient was the only patient who developed chronic renal failure secondary to radiation nephritis at 2 years. The etiology of the fifth patient's rise in creatinine was unknown, but may have been secondary to radiation nephritis. On univariate analysis, but not on multivariate analysis, a significant correlation was found between TBI-related renal dysfunction and hypertension before and after BMT. Conclusion: A dose of 12 Gy at 2 Gy/fraction resulted in only 1 case of radiation nephritis in the 59 patients studied 24 months after the completion of TBI and BMT.

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

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