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Infection remains a significant contributor to morbidity and mortality in patients with myeloma. This guideline was developed by a multidisciplinary group of clinicians who specialise in the management of patients with myeloma and infection from the medical and scientific advisory group from Myeloma Australia and the National Centre for Infections in Cancer. In addition to summarising the current epidemiology and risk factors for infection in patients with myeloma, this guideline provides recommendations that address three key areas in the prevention of infection: screening for latent infection, use of antimicrobial prophylaxis and immunoglobulin replacement and vaccination against leading respiratory infections (severe acute respiratory syndrome coronavirus 2, influenza and Streptococcus pneumoniae) and other preventable infections. This guideline provides a practical approach to the prevention of infection in patients with myeloma and harmonises the clinical approach to screening for infection, use of prophylaxis and vaccination to prevent infectious complications., (© 2023 Royal Australasian College of Physicians.)

Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogenous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores, not just as a prognostic instrument, but also as a predictive tool to allow for a frailty-adapted treatment approach. This paper reviews the various frailty assessment frameworks used in the evaluation of patients with MM, including the International Myeloma Working Group Frailty Index (IMWG-FI), the Mayo Frailty Index and the simplified frailty scale. While the IMWG-FI remains the most widely accepted tool, the simplified frailty scale is the most user-friendly in busy day-to-day clinics based on its ease of use. This paper summarises the recommendations from the Myeloma Scientific Advisory Group (MSAG) of Myeloma Australia, on the use of frailty assessment tools in clinical practice and proposes a frailty-stratified treatment algorithm to aid clinicians in tailoring therapy for this highly heterogeneous patient population., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Amyloidosis is a collection of diseases caused by the misfolding of proteins that aggregate into insoluble amyloid fibrils and deposit in tissues. While these fibrils may aggregate to form insignificant localised deposits, they can also accumulate in multiple organs to the extent that amyloidosis can be an immediately life-threatening disease, requiring urgent treatment. Recent advances in diagnostic techniques and therapies are dramatically changing the disease landscape and patient prognosis. Delays in diagnosis and treatment remain the greatest challenge, necessitating physician awareness of the common clinical presentations that suggest amyloidosis. The most common types are transthyretin (ATTR) amyloidosis followed by immunoglobulin light-chain (AL) amyloidosis. While systemic AL amyloidosis was previously considered a death sentence with no effective therapies, significant improvement in patient survival has occurred over the past 2 decades, driven by greater understanding of the disease process, risk-adapted adoption of myeloma therapies such as proteosome inhibitors (bortezomib) and monoclonal antibodies (daratumumab) and improved supportive care. ATTR amyloidosis is an underdiagnosed cause of heart failure. Technetium scintigraphy has made noninvasive diagnosis much easier, and ATTR is now recognised as the most common type of amyloidosis because of the increased identification of age-related ATTR. There are emerging ATTR treatments that slow disease progression, decrease patient hospitalisations and improve patient quality of life and survival. This review aims to update physicians on recent developments in amyloidosis diagnosis and management and to provide a diagnostic and treatment framework to improve the management of patients with all forms of amyloidosis., (© 2022 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

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., (© 2021 Royal Australasian College of Physicians.)

Background: Central venous access devices (CVAD) are commonly employed in the management of cancer patients. While having several benefits they are associated with significant risks., Aim: To review the incidence and risk factors for catheter-related thrombosis (CRT) in cancer patients with a CVAD., Methods: We performed a prospective observational cohort study of adult patients with cancer requiring a CVAD between 1 January 2004 and 29 June 2016. The rate of, and risk factors for the development of, symptomatic CRT were evaluated., Results: A total of 4920 central lines was inserted into 3130 patients. The incidence of CRT was 3.6%. CRT developed a median of 12 days following line insertion. Peripherally inserted central catheters (PICC) were associated with the highest rates of CRT (hazards ratio (HR) 22.2, 95% confidence interval (CI) 2.9-170.6). Older age groups developed CRT at lower rates (HR 0.57; 95% CI 0.39-0.84 for age 50-61 years, and HR 0.63; 95% CI 0.45-0.89 for age >61 years) compared to age <50 years. Increased CRT was seen in patients with prior CRT (HR 1.81; 95% CI 1.19-2.77). There was a trend to more CRT events with a Khorana tumour score of 1 compared to those with a score of 0 (HR 1.37, 95% CI 1.00-1.88). Hodgkin lymphoma, germ cell and oesophagus cancers had the highest CRT rates. Side of insertion was not associated with thrombosis risk (HR 0.77; 95% CI 0.57-1.05; P = 0.10)., Conclusions: Age <50 years, PICC lines and prior CRT were associated with highest CRT rate. Cancer subtype and insertion side were not predictive of thrombosis., (© 2020 Royal Australasian College of Physicians.)

Background: The public subsidy in Australia of bortezomib (Velcade) for untreated non-transplant multiple myeloma patients was based on the VISTA trial., Aims: To ascertain the health outcomes of bortezomib in 'real world' transplant-ineligible elderly patients, compared to trial data., Methods: Patient and treatment data were extracted from an oncology information system, laboratory information system and medical chart audits for three Queensland public hospitals., Results: We identified 74 patients; the median age was 75 years. Our cohort comprised 47% patients who were International Staging System stage III, 45% at stage II and 8% at stage I. Patients who had comorbidities, such as cardiac disease (41%), pulmonary disease (14%), diabetes (22%), peripheral neuropathy (14%) and other comorbidities (41%) at baseline were included. The common regimens prescribed were VMP, CVD and VD, and most patients (n = 73) received bortezomib on a once-weekly or twice-a-week basis. The overall response rate was 81%. Half (53%) of the patients did not complete their planned therapy due to toxicity (30%), suboptimal response or disease progression (15%), or death on treatment (8%). Overall survival was 40.7 months and progression free survival was 17.7 months., Conclusions: Our patients were older, had worse disease characteristics and more comorbidities than patients in the VISTA trial. While response rates were similar, survival outcomes appeared worse. Bortezomib-based treatment in the real world setting still carries a high risk of toxicity in the elderly population., (© 2020 Royal Australasian College of Physicians.)

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., (© 2018 Royal Australasian College of Physicians.)

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., (© 2017 Royal Australasian College of Physicians.)

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., (© 2017 Royal Australasian College of Physicians.)

Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) have an inferior prognosis, due in part to advanced age and pre-existing comorbidities, with reduced tolerability and deliverability of standard R-CHOP chemotherapy., Aims: To examine the deliverability, toxicity and efficacy of R-CHOP and the prevalence of the germinal and non-germinal phenotype DLBCL in an elderly Australian cohort., Methods: This retrospective analysis included patients ≥75 years diagnosed with DLBCL. Comprehensive chemotherapy and toxicity data were collected for patients treated with R-CHOP. Baseline demographics and chemotherapy characteristics were compared with progression-free (PFS) and overall survival (OS). Immunohistochemical staining identified the prevalence of the non-germinal centre (non-GCB) phenotype., Results: Of the 111 patients, 92 (83%) commenced R-CHOP with 26/92 (28%) receiving ≤4 cycles. Median average relative dose (ARD) was 0.80 (0.07-1.17). Median average relative dose intensity (ARDI) was 0.89 (0.33-1.18). Serious adverse events occurred in 77% of patients with ≥Gd3 adverse events in 74%. Overall response rate was 85%. Two-year PFS was 63% and OS 74%. ARD and performance status ≥2 were significant prognostic factors for PFS and OS but not ARDI. Non-GCB-phenotype was identified in 44/72 (61%) of patients with immunohistochemical data., Conclusion: Despite high response rates and respectable survival estimates, the absence of standard therapy in 17% of patients, and dose reductions and serious toxicity of R-CHOP in this Australian cohort highlights the need for the development of less toxic yet efficacious treatments for very elderly patients with DLBCL. The high prevalence of the non-GCB phenotype highlights the potential value of targeted biological therapy for this demographic., (© 2015 Royal Australasian College of Physicians.)

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 enrollment 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., (© 2014 Royal Australasian College of Physicians.)

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., (© 2015 Royal Australasian College of Physicians.)

The survival of patients with multiple myeloma (MM) has improved substantially since the introduction in the late 1980s of high-dose chemotherapy (HDT) supported by autologous stem cell transplantation (ASCT). Further improvements have been observed following the availability of immunomodulatory drugs (IMiD) such as thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib. Here, we summarise the recommendations of the Medical Scientific Advisory Group to the Myeloma Foundation of Australia for patients considered suitable for HDT + ASCT as part of initial therapy. These recommendations incorporate the various phases of treatment: induction, HDT conditioning and maintenance therapy., (© 2015 Royal Australasian College of Physicians.)

Amyloidosis is a rare but devastating condition caused by deposition of misfolded proteins as aggregates in the extracellular tissues of the body, leading to impairment of organ function. High clinical suspicion is required to facilitate early diagnosis. Correct identification of the causal amyloid protein is absolutely crucial for clinical management in order to avoid misdiagnosis and inappropriate, potentially harmful treatment, to assess prognosis, and to offer genetic counselling if relevant. This review summarises the current evidence on which the diagnosis and subtyping of amyloidosis is based, outlines the limitations of various diagnostic techniques, particularly in an Australian and New Zealand context, and discusses optimal strategies for the diagnostic approach to these patients. Recommendations are provided for when particularly to suspect amyloidosis, what investigations are required, as well as an approach to accurate subtyping of amyloidosis., (© 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.)

Background: Recent reports suggest genetic polymorphisms influence susceptibility to rituximab-induced late-onset neutropenia (LON), which in turn may be a predictor of good outcome in B-cell lymphoma., Aims: We report the largest study to date assessing FCGR3A-V158F polymorphisms in diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide/hydroxydaunorubicin/Oncovin (vincristine)/prednisone/rituximab (CHOP-R). The influence of C1qA-A276G polymorphisms in DLBCL, and the impact of both polymorphisms on susceptibility to LON and outcome were also examined., Methods: 115 DLBCL patients treated with CHOP-R were compared with 105 healthy White people controls with regards to FCGR3A-V158F and C1qA-A276G polymorphisms. LON incidence and event-free and overall survival (EFS and OS) were analysed for linkage to either polymorphism., Results: The FCGR3A-V158F but not the C1qA-A276G polymorphism influenced the risk of developing LON. 50% of FCGR3A-158V/V patients experienced LON. In contrast, only 7% V/F and 2% F/F experienced LON. The FCGR3A-158V/V genotype was associated with LON compared with V/F (P = 0.028) and F/F genotypes (P = 0.005). Although no patients with either LON or FCGR3A-158V homozygosity relapsed compared with 33% FCGR3A-158F/F and 21% non-LON, this did not translate into improved EFS or OS., Conclusions: Polymorphic analysis may be a predictive tool to identify those at high risk of LON. Prospective studies are required to establish definitively if LON or FCGR3A-158V/V genotype influences outcome., (© 2011 The Authors; Internal Medicine Journal © 2011 Royal Australasian College of Physicians.)

Background: Thrombotic events in essential thrombocythaemia (ET) are difficult to predict with current risk stratification based on age and prior history of thrombosis., Aims: We aimed to assess the predictive value of the JAK2 V617F mutation (JAK2) and spontaneous erythroid colony (SEC) growth for the development of thrombotic events post diagnosis in patients with ET., Methods: Consecutive patients with ET were retrospectively identified, and clinical and laboratory correlates were evaluated. Thrombotic events were categorized according to their occurrence at or prior to diagnosis (prior thrombosis), and any time post diagnosis of ET (subsequent thrombosis). JAK2 analysis was performed by allele-specific PCR on whole blood or bone marrow., Results: A total of 62 patients was identified, median age 63 years; 67% (41/61) JAK2-positive and 47% (25/53) SEC-positive. Median follow-up was 33 months (range, 1 to 137). JAK2-positive patients showed a trend to increased prior thrombosis (27% vs 5%, P= 0.08), and a significant increase in the development of subsequent thrombosis (5-year event rate 31% vs 6%, P= 0.04), which persisted when stratified for a history of prior thrombosis (P= 0.04). Survival was not affected by JAK2 status. The SEC assay predicted an increased rate of baseline thrombosis (16% vs 0%, P= 0.04), but was not found to be predictive of any subsequent thrombotic events., Conclusions: Patients with ET who are JAK2-positive by whole blood allele-specific PCR appear to be at increased risk of thrombotic complications, which is independent of a prior history of thrombosis., (© 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.)

Background: Organ dysfunction in AL amyloidosis is related to the production and deposition of amyloidogenic monoclonal light chains. These pathological light chains can now be quantified using the recently developed serum free light chain assay., Methods: We retrospectively reviewed 31 patients with AL amyloidosis to determine the frequency of abnormal free light chain assay results at diagnosis and whether changes in the serum free light chain assay predict outcome after therapy., Results: An abnormal free light chain assay was found in 30 of 31 patients (97%) at the time of diagnosis. In the subset of our patients who received treatment for AL amyloidosis, a >50% reduction of the pathological free light chain following treatment was shown to predict improved overall survival. In our series of analyses, achievement of greater magnitudes of reduction of the free light chain result did not appear to provide additional prognostic information, nor did the baseline free light chain result predict outcome., Conclusion: Our findings support the use of the free light chain assay in the diagnostic work-up of patients with suspected AL amyloidosis, and also as a sensitive biomarker of response to therapy.

Background: In severe aplastic anaemia, the treatment of choice for young patients with a human leucocyte antigen-matched sibling is now established as allogeneic bone marrow transplantation (BMT). In older patients and in those without a matched sibling donor, immunosuppressive therapy is the usual first option. 'Alternative' marrow donors are emerging as an option for those without a matched sibling donor., Aims: To review 10 years of local experience in treating severe aplastic anaemia with BMT and immunosuppressive therapy with emphasis on long-term outcomes., Methods: A retrospective analysis was performed of all patients with severe aplastic anaemia presenting to the Royal Brisbane and Royal Children's Hospitals between 1989 and 1999. Data were abstracted regarding patient demographics, pretreatment characteristics and outcome measures, including response rates, overall survival and long-term complications., Results: Twenty-seven consecutive patients were identified, 12 treated with immunosuppression alone and 15 with BMT. In these two groups, transfusion independence was attained in 25% and 100%, respectively, with overall survival being 36% and 100%, respectively. Those treated with immunosuppression were significantly older (median 41.5 versus 22 years, P = 0.008). Long-term survivors of either treatment had extremely low morbidity. Three patients carried pregnancies to term post-transplant. Three patients received alternative donor BMT with correspondingly excellent survival., Conclusions: Patients treated with allogeneic BMT for severe aplastic anaemia enjoyed extremely good long-term survival and minimal morbidity. Patients treated with immunosuppressive therapy had a poorer outcome reflecting their older age and different usage of therapies over the past decade. Optimal treatment strategies for severe aplastic anaemia remain to be determined.