Medicine (St Vincent's) - Research Publications
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ItemBisphosphonate guidelines for treatment and prevention of myeloma bone disease(WILEY, 2017-08)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.
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ItemUpfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study(WILEY, 2017-05)The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.
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ItemTreatment of patients with Waldenstrom macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group(WILEY, 2017-01)Waldenström 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.
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ItemConsiderations for pre-transfusion immunohaematology testing in patients receiving the anti-CD38 monoclonal antibody daratumumab for the treatment of multiple myeloma(WILEY, 2018-02)In recent years, the anti-CD38 monoclonal antibody daratumumab (Darzalex; Janssen-Cilag Pty Ltd) has been shown to be highly efficacious in relapsed and refractory multiple myeloma, with the final results of treatment in newly diagnosed patients awaited. Despite awareness of the potential interference of daratumumab in pre-transfusion immunohaematology testing during phase I and II clinical studies, there was a degree of unpreparedness in the community upon the introduction of this drug into the clinics, particularly the impact that it has on the operational processes in hospital transfusion laboratories and timely issue of red blood cells (RBCs). Anti-CD38 interference in pre-transfusion immunohaematology tests is a particular problem in patients being treated with daratumumab for multiple myeloma as many will require RBC transfusions during their disease treatment. Panagglutination caused by anti-CD38 monoclonal antibody during the indirect antiglobulin test may mask the presence of a clinically significant RBC alloantibody in the patient's plasma during the antibody screen and identification process, which may be overlooked, particularly in urgent situations, subsequently resulting in a delayed or acute haemolytic transfusion reaction. Here, we summarise daratumumab's effects on pre-transfusion immunohaematology testing and its impact on clinical practice and make practical recommendations based on a consensus from medical and scientific transfusion experts and myeloma specialists on behalf of the Australian and New Zealand Society of Blood Transfusion and Myeloma Scientific Advisory Group to Myeloma Australia, respectively.
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ItemNilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd(WILEY, 2017-10)The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).
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ItemDesign and development of the Australian and New Zealand (ANZ) myeloma and related diseases registry(BMC, 2016-11-09)BACKGROUND: Plasma cell dyscrasias (PCD) are a spectrum of disorders resulting from the clonal expansion of plasma cells, ranging from the pre-malignant condition monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). MM generates a significant burden of disease on the community and it is predicted that it will increase in both incidence and prevalence owing to an ageing population and longer survival secondary to new therapeutic options. Robust and comprehensive clinical data are currently lacking but are required to define current diagnostic, investigational and management patterns in Australia and New Zealand (ANZ) for comparison to both local and international guidelines for standards of care. A clinical registry can provide this information and subsequently support development of strategies to address any differences, including providing a platform for clinical trials. The Myeloma and Related Diseases Registry (MRDR) was developed to monitor and explore variations in practices, processes and outcomes in ANZ and provide benchmark outcomes nationally and internationally for PCD. This paper describes the MRDR aims, development and implementation and discusses challenges encountered in the process. METHODS: The MRDR was established in 2012 as an online database for a multi-centre collaboration across ANZ, collecting prospective data on patients with a diagnosis of MGUS, MM, solitary plasmacytoma or plasma cell leukaemia. Development of the MRDR required multi-disciplinary team participation, IT and biostatistical support as well as financial resources. RESULTS: More than 1250 patients have been enrolled at 23 sites to date. Here we describe how database development, data entry and securing ethics approval have been major challenges for participating sites and the coordinating centre, and our approaches to resolving them. Now established, the MRDR will provide clinically relevant and credible monitoring, therapy and 'real world' outcome data, to support the conduction of high quality studies. In addition, the Myeloma 1000 sub-study is establishing a repository of paired peripheral blood specimens from registry patients to study mechanisms underlying disease progression. CONCLUSION: Establishment of the MRDR has been challenging, but it is a valuable investment that will provide a platform for coordinated national and international collaboration for clinical research in PCD in ANZ.
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ItemDaratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma(Massachusetts Medical Society, 2016-08-25)Background: Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. Methods: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. Results: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. Conclusions: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone.
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ItemHaemolytic crisis in G6PD-deficiency triggered by recreational use of synthetic cannabis(Sciedu Press, 2016)Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited cause of haemolytic anaemia. Recognition and avoidance of haemolytic triggers is an important part of management, both during haemolytic crises and in the long-term. We report a case of haemolytic crisis in a patient with previously undiagnosed G6PD-deficiency, triggered by the use of synthetic cannabis in the form of “spice”. To our knowledge, this is the first report of G6PD deficiency-related haemolytic crisis triggered by synthetic cannabinoids.
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ItemPharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study(SPRINGER, 2017-06)PURPOSE: The pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m2. This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m2 in normal renal function and ESRD patients. METHODS: Patients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m2 (cycle 1 day 1-2), escalated to 27 mg/m2 on cycle 1 day 8; if tolerated, 56 mg/m2 starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively. RESULTS: 26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients. CONCLUSION: There were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure-response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.
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ItemCytarabine-based induction immunochemotherapy in the front-line treatment of older patients with mantle cell lymphoma(Nature Publishing Group, 2019-09-19)The role of cytarabine-based induction and autologous stem cell transplantation (ASCT) in front-line treatment of younger patients with mantle cell lymphoma (MCL) is well established, however the utility of intensive approaches in older patients remains unclear. This retrospective study compared first line treatment outcomes in patients aged 60 years or more, treated at six tertiary centres between 2000-2015. 70 patients included had a median age of 69 (60-91) and most (94%) demonstrated advanced stage disease. Treatment regimens included: R-CHOP-like (n = 39), alternating R-CHOP/R-DHAC (n = 10), R-HyperCVAD/R-MA (n = 7), R-CHOP/Cytarabine (Nordic Protocol) (n = 10) and other (n = 4). 16 patients underwent an ASCT. The median follow-up for surviving patients was 37 months. Compared to R-CHOP-like therapies, cytarabine-based regimens were associated with an improved overall response rate (ORR) of 70% vs 33% (p < 0.001) and overall survival (OS) (HR 0.541, [0.292-1.001], p = 0.05). No difference in efficacy between different cytarabine-based regimens was detected, but R-HyperCVAD/R-MA was associated with increased hospitalisation and transfusion requirements. Patients undergoing ASCT demonstrated an improved median OS (HR 0.108 [0.015-0.796], p = 0.029) but were significantly younger. These results reaffirm the use of cytarabine in MCL for selected patients aged over 60. Such regimens should be strongly considered for this population in frontline therapy.