Medicine (St Vincent's) - Research Publications

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    Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)
    Bahlis, NJ ; Baz, R ; Harrison, SJ ; Quach, H ; Ho, S-J ; Vangsted, AJ ; Plesner, T ; Moreau, P ; Gibbs, SD ; Coppola, S ; Yang, X ; Al Masud, A ; Ross, JA ; Bueno, O ; Kaufman, JL (LIPPINCOTT WILLIAMS & WILKINS, 2021-11-10)
    PURPOSE: Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS: This phase I study (NCT03314181) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS: Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION: VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).
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    Myeloma natural killer cells are exhausted and have impaired regulation of activation
    D'Souza, C ; Keam, SP ; Yeang, HXA ; Neeson, M ; Richardson, K ; Hsu, AK ; Canfield, R ; Bezman, N ; Robbins, M ; Quach, H ; Ritchie, DS ; Harrison, SJ ; Trapani, JA ; Prince, HM ; Beavis, PA ; Darcy, PK ; Neeson, PJ (FERRATA STORTI FOUNDATION, 2021-09-01)
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    Low rates of invasive fungal disease in patients with multiple myeloma managed with new generation therapies: Results from a multi-centre cohort study
    Lim, C ; Sinha, P ; Harrison, SJ ; Quach, H ; Slavin, MA ; Teh, BW (WILEY, 2020-09-17)
    INTRODUCTION: A multi-centre study to determine the outcomes and risks for invasive fungal disease (IFD) in myeloma (MM) patients treated with second-generation immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies was conducted. METHODS: Clinical and microbiology records were reviewed to capture patient demographics, disease characteristics, treatment, IFD episodes and outcomes. Categorical and continuous variables between patients with IFD and without IFD were compared using chi-square test, Fisher's exact test and Mann-Whitney rank sum test, respectively, with P-value < .05 considered statistically significant. RESULTS: Five out of 148 (3.4%) MM patients were diagnosed with five episodes of IFI: 3 were proven, 1 probable and 1 possible. Median time from commencement of new generation therapy to IFD diagnosis was 4.0 months (Interquartile range [IQR]: 3.4-5.7). In patients with IFD, median cumulative steroid dose over 60 days was 1119 mg (IQR: 1066-1333 mg). None of the patients with IFD had prolonged neutropenia (neutrophil count < 0.5 × 109 /L for more than 10 days). Common sites of infection were the respiratory tract (40.0%) and bloodstream (40.0%). Cryptococcus neoformans (n = 2) and Candida krusei (n = 1) were the fungal pathogens isolated in the three proven cases. 30-day mortality rate was 40.0%. Patients with IFD were younger (median 58 versus 68 years, P = .52) and treated with more lines of therapy (median 5 vs 3, P = .04). CONCLUSION: IFD rate is low in heavily treated MM patients treated with second-generation therapy including monoclonal antibodies. Patients do not appear to have traditional risk factors such as prolonged neutropenia.
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    Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic
    Di Ciaccio, P ; McCaughan, G ; Trotman, J ; Ho, PJ ; Cheah, CY ; Gangatharan, S ; Wight, J ; Ku, M ; Quach, H ; Gasiorowski, R ; Polizzotto, MN ; Prince, HM ; Mulligan, S ; Tam, CS ; Gregory, G ; Hapgood, G ; Spencer, A ; Dickinson, M ; Latimer, M ; Johnston, A ; Armytage, T ; Lee, C ; Cochrane, T ; Berkhahn, L ; Weinkove, R ; Doocey, R ; Harrison, SJ ; Webber, N ; Lee, H-P ; Chapman, S ; Campbell, BA ; Gibbs, SDJ ; Hamad, N (WILEY, 2020-05-15)
    The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.
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    Successful identification of predictive profiles for infection utilising systems-level immune analysis: a pilot study in patients with relapsed and refractory multiple myeloma
    Doerflinger, M ; Garnham, AL ; Freytag, S ; Harrison, SJ ; Prince, HM ; Quach, H ; Slavin, MA ; Pellegrini, M ; Teh, BW (WILEY, 2021-01-01)
    OBJECTIVES: Patients with multiple myeloma (MM) are at increased risk for infection. Clinical assessment of infection risk is increasingly challenging in the era of immune-based therapy. A pilot systems-level immune analysis study to identify predictive markers for infection was conducted. METHODS: Patients with relapsed and/or refractory MM (RRMM) who participated in a treatment trial of lenalidomide and dexamethasone were evaluated. Data on patient demographics, disease and episodes of infection were extracted from clinical records. Peripheral blood mononuclear cells (PBMCs) collected at defined intervals were analysed, with or without mitogen re-stimulation, using RNA sequencing and mass cytometry (CyTOF). CyTOF-derived cell subsets and RNAseq gene expression profiles were compared between patients that did and did not develop infection to identify immune signatures that predict infection over a 3-month period. RESULTS: Twenty-three patients participated in the original treatment trial, and we were able to access samples from 17 RRMM patients for further evaluation in our study. Nearly half the patients developed an infection (8/17) within 3 months of sample collection. Infections were mostly clinically diagnosed (62.5%), and the majority involved the respiratory tract (87.5%). We did not detect phenotypic or numerical differences in immune cell populations between patients that did and did not develop infections. Transcriptional profiling of stimulated PBMCs revealed distinct Th2 immune pathway signatures in patients that developed infection. CONCLUSION: Immune cell counts were not useful predictors of infection risk. Functional assessment of stimulated PBMCs has identified potential immune profiles that may predict future infection risk in patients with RRMM.
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    Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells
    Cooke, RE ; Quinn, KM ; Quach, H ; Harrison, S ; Prince, HM ; Koldej, R ; Ritchie, D (FRONTIERS MEDIA SA, 2020-09-03)
    New diagnoses of multiple myeloma (MM) tend to occur after the age of 60, by which time thymic output is severely reduced. As a consequence, lymphocyte recovery after lymphopenia-inducing anti-MM therapies relies on homeostatic proliferation of peripheral T cells rather than replenishment by new thymic emigrants. To assess lymphocyte recovery and phenotype in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), we tracked CD4+ and CD8+ T cell populations at serial time points throughout treatment and compared them to age-matched healthy donors (HD). Anti-MM therapies and autologous stem cell transplant (ASCT) caused a permanent reduction in the CD4:8 ratio, a decrease in naïve CD4+ T cells, and an increase in effector memory T cells and PD1-expressing CD4+ T cells. Transcriptional profiling highlighted that genes associated with fatty acid β-oxidation were upregulated in T cells in RRMM, suggesting increased reliance on mitochondrial respiration. High mitochondrial mass was seen in all T cell subsets in RRMM but with relatively suppressed reactive oxygen species and mitochondrial membrane potential, indicating mitochondrial dysfunction. These findings highlight that anti-MM and ASCT therapies perturb the composition of the T cell compartment and drive substantial metabolic remodeling, which may affect the fitness of T cells for immunotherapies. This is particularly pertinent to chimeric antigen receptor (CAR)-T therapy, which might be more efficacious if T cells were stored prior to ASCT rather than at relapse.
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    Imaging of patients with multiple myeloma and associated plasma cell disorders: consensus practice statement by the Medical Scientific Advisory Group to Myeloma Australia
    Creeper, K ; Augustson, B ; Kusel, K ; Fulham, MJ ; Ho, J ; Quach, H ; Mollee, P ; Weber, N ; Talaulikar, D ; Johnston, A ; Murphy, N ; Joshua, D ; Ward, C ; Ling, S ; Gibson, J ; Szer, J ; Harrison, S ; Zannettino, A ; Jaksic, W ; Lee, C ; Spencer, A ; Kalff, A ; Szabo, F ; Romeril, K ; Chan, H ; Gibbs, S ; Horvath, N ; Prince, HM (WILEY, 2021-10-01)
    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.
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    Receiving four or fewer cycles of therapy predicts poor survival in newly diagnosed transplant-ineligible patients with myeloma who are treated with bortezomib-based induction
    Boyle, S ; Wellard, C ; Moore, EM ; Blacklock, H ; Harrison, SJ ; Ho, PJ ; Hocking, J ; McQuilten, ZK ; Quach, H ; Spearing, R ; Wood, EM ; Spencer, A ; Mollee, P (WILEY, 2021-06-26)