Variation in immunoglobulin use and impact on survival in myeloma.

Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real-world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia-Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow-up time of 29.5 months (interquartile range 13.3-54.3 months) were included in the analysis - 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in-situ hybridisation status, receive first-line myeloma treatment with immunomodulatory drugs or anti-CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow-up (adjusted hazard ratio 0.72, 95% CI 0.46-1.14, p = 0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources.

Developing and validating a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways using a national clinical registry.

Multiple myeloma is a haematological malignancy typically characterised by neoplastic plasma cell infiltration of the bone marrow. Treatment for multiple myeloma consists of multi-line chemotherapy with or without autologous stem cell transplantation and has been rapidly evolving in recent years. However, clinical trials are unable to provide patients and clinicians with long-term prognostic information nor policymakers with the full body of evidence needed to perform economic evaluation of new therapies or make reimbursement decisions. To address these limitations of the available evidence, this study aimed to develop and validate the EpiMAP Myeloma model, a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways. Risk equations were estimated using the Australian and New Zealand Myeloma & Related Diseases Registry after multiple imputation of missing data. Risk equation coefficients were combined with multiple myeloma patients at diagnosis from the Registry to perform the simulation. The model was validated with 100 bootstraps of an out-of-sample prediction analysis using a 70/30 split of the 4,121 registry patients diagnosed between 2009 and 2023, resulting in 2,884 and 1,237 patients in the training and validation cohorts, respectively. For 90% of the 120 months in the 10-year post-diagnosis period, there was no significant difference in overall survival between the validation and simulated cohorts. These results highlight that the EpiMAP Myeloma model is robust at predicting multiple myeloma disease outcomes and treatment pathways in Australia & New Zealand. In the future, clinicians will be able to use the EpiMAP Myeloma model to provide personalised estimates of life expectancy to patients based on their specific characteristics, disease stage, and response to treatment. Policymakers will also be able to use the model to perform economic evaluation, to forecast the number of patients receiving treatment at different stages, and to determine the downstream impact of listing new, effective therapies.

Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis.

Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18-70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.

A minority of women of childbearing potential are tested for pregnancy before chemoimmunotherapy: an Australian cancer centre experience.

BACKGROUND: Chemotherapy is potentially harmful to a developing foetus, and there are limited data on the foetal impact of chemoimmunotherapy (CIT). Therefore, determining pregnancy status prior to initiation of CIT should be standard of care. AIMS: To determine how many women of childbearing age are tested for pregnancy prior to immunochemotherapy administration. METHODS: A retrospective chart review at a large Australian metropolitan cancer referral centre, including 304 women aged 18-51 years with a diagnosis of cancer receiving outpatient-based CIT between 1 May 2015 and 12 June 2020. We assessed the uptake of pregnancy screening and contraception counselling prior to and during first-line CIT. RESULTS: Only 17.3% of CIT cycles (n = 416) screened patients for pregnancy no more than 90 days prior to administration, and the median time between pregnancy screening and treatment was approximately 3 weeks. One patient with early breast cancer had a spontaneous miscarriage estimated at 3-4 weeks' gestation, and neither the patient nor the treating oncologist was aware of this event. This was also the only patient who had a pregnancy test beyond the first cycle of CIT during their treatment. CONCLUSIONS: Our results highlight a concerningly low rate of pregnancy screening in women of childbearing age receiving CIT. The implication of missing a positive pregnancy test in this group of women could result in foetal complications, accidental miscarriage, potential bleeding risks and avoidable psychosocial stress. This highlights the urgent need for guidelines to mandate pregnancy testing in women of childbearing age receiving CIT and evidence-based implementation tools.

Rates of Menstrual History-Taking and Counseling With Anticancer Treatments Are Low: People Who Menstruate Deserve Gender-Specific Cancer Care.

BACKGROUND: Chemotherapy predisposes people who menstruate to abnormal uterine bleeding that can be life-threatening and may also damage ovaries, resulting in premature menopause. The purpose of this study was to explore the incidence of menstrual history documentation and counseling before, during, and after cancer treatment. PATIENTS AND METHODS: The medical charts of 137 consecutive females (self-reported) aged 18 to 49 years receiving anticancer treatment at a major tertiary metropolitan hospital in Australia between 2017 and 2020 were reviewed. Data collected included primary diagnosis, stage of cancer, treatment(s) received, rates of remission or progression, documentation of involvement of a specialist gynecologist, reproductive history, menstrual disturbances, menstruation counseling or intervention offered, and diagnosis of early ovarian failure. RESULTS: Only 16.1% of patients had their menstrual history documented at the initial consult, and 49.6% had their menstrual history documented at a subsequent consult with their treating oncologist or hematologist. Most (82.4%) patients with a menstrual history documented experienced menstrual disturbance posttreatment, most commonly amenorrhea (48.0%), followed by menopause or menopause symptoms (20.6%), irregular menstrual bleeding (16.7%), menorrhagia (13.7%), dysmenorrhea (3.9%), and iron deficiency from bleeding (2.9%). Menopause/Menopausal symptoms and iron deficiency were more likely to be treated than other disturbances. CONCLUSIONS: Menstruation disturbance is a common side effect of cancer treatment. Menstrual care should be integral to cancer care for people who menstruate, and higher engagement could be achieved through education of medical and allied health staff, information technology systems automating prompts and referral pathways, regular audits to ensure compliance, better alliances between cancer and fertility specialists, and the creation of accessible patient information to promote awareness and facilitate discussion.

Third-party CMV- and EBV-specific T-cells for first viral reactivation after allogeneic stem cell transplant.

Virus-specific T-cells (VSTs) from third-party donors mediate short- and long-term antiviral effects in allogeneic hematopoietic stem cell transplant (HSCT) recipients with relapsed or refractory viral infections. We investigated early administration of third-party VSTs, together with antiviral therapy in patients requiring treatment for first cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection. Thirty HSCT patients were treated with 1 to 4 VST infusions (2 × 107 cells/m2; CMV n=27, EBV n=3) at a median of 4 days after initiation of antiviral treatment. The overall viral response rate was 100%, with a complete response (CR) rate of 94%. Of the 28 patients who achieved a CR, 23 remained virus PCR negative (n=9) or below quantitation limit (n=14) for the duration of follow-up. Four patients had brief episodes of quantifiable reactivation not requiring additional therapy, and one required a second infusion after initial CR, remaining PCR negative thereafter. All 3 patients treated for EBV post-transplant lymphoproliferative disorder achieved sustained CR. Rates of aGVHD and cGVHD after infusion were 13% and 23%, respectively. There were no serious infusion-related adverse events. VST infusion was associated with rapid recovery of CD8+CD45RA-CD62L- and a slower recovery of CD4+CD45RA-CD62L- effector memory T-cells; CMV-specific T-cells comprised up to 13% of CD8+ cells. At 1 year post-transplant, non-relapse mortality was 10%, cumulative incidence of relapse was 7%, overall survival was 88% and 25 of 27 patients had ECOG status of 0 or 1. Early administration of third-party VSTs in conjunction with antiviral treatment appears safe and leads to excellent viral control and clinical outcomes. Registered on Australian New Zealand Clinical Trials Registry as #ACTRN12618000343202.

Lenalidomide, bortezomib and dexamethasone induction therapy for the treatment of newly diagnosed multiple myeloma: a practical review.

For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United States; fortunately, there is now increasing access worldwide. This review discusses the rationale for use of RVD as induction therapy and aims to provide guidance in prescribing this regimen in order to optimise efficacy while minimising the toxicities of treatment. We also highlight the increasing evidence for the utility of addition of a monoclonal antibody to the RVD backbone to deepen responses and potentially provide longer disease control.

Clinical characteristics and prognosis of cardiac amyloidosis defined by mass spectrometry-based proteomics in an Australian cohort.

BACKGROUND: Cardiac amyloidosis has a very poor prognosis, but it is the nature of the involved precursor protein that ultimately dictates treatment and survival. AIM: Definitively characterise the amyloid subtype by mass spectrometry (MS) in an Australian cohort of patients with cardiac amyloidosis. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Chromosome microarray characterisation of chromosome arm 12p loss associated with complex molecular karyotype and recurrent adverse cytogenetic markers in multiple myeloma.

Copy number loss within chromosome 12 short arm (12p) has gained attention as an adverse cytogenetic marker in multiple myeloma. The prognostic significance and characterisation of the common minimal deleted region remains controversial between various studies with loss of CD27 proposed as the putative critical gene. We aimed to determine the frequency of 12p loss, its correlation with adverse cytogenetic markers further to define and characterise 12p deletions. Our study included a prospective cohort of 574 multiple myeloma patients referred for cytogenetic testing, including interphase fluorescence in situ hybridisation for IGH (14q32.33) translocations and chromosome microarray. Loss of 12p was detected in 54/574 (9.4%) patients and when compared with the non-12p loss group [520/574 (90.6%)], 12p loss patients demonstrated a statistically significant association with specific recurrent cytogenetic markers: complex molecular karyotypes (98.1% vs 45.2%), 1p loss (50.0% vs 20.2%), t(4;14) (20.4% vs 7.7%), 8p loss (37.0% vs 15.0%), 13/13q loss (70.4% vs 41.7%), and 17p loss (33.3% vs 6.5%). The size and location of 12p losses were heterogeneous with a common 0.88 Mb minimally deleted region that included ~9 genes from ETV6 to CDKN1B in 52/54 (~96.3%) patients but did not include CD27. Our findings support 12p loss being a secondary chromosome abnormality frequently co-occurring with adverse cytogenetic markers and complex molecular karyotypes indicative of chromosome instability.

COVID-19 vaccination in haematology patients: an Australian and New Zealand consensus position statement.

Australia and New Zealand have achieved excellent community control of COVID-19 infection. In light of the imminent COVID-19 vaccination roll out in both countries, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 vaccination in patients with haematological disorders. It is our recommendation that patients with haematological malignancies, and some benign haematological disorders, should have expedited access to high-efficacy COVID-19 vaccines, given that these patients are at high risk of morbidity and mortality from COVID-19 infection. Vaccination should not replace other public health measures in these patients, given that the effectiveness of COVID-19 vaccination, specifically in patients with haematological malignancies, is not known. Given the limited available data, prospective collection of safety and efficacy data of COVID-19 vaccination in this patient group is a priority.

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.

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.

Anticoagulation at the extremes of body weight: choices and dosing.

INTRODUCTION: The landscape of therapeutic anticoagulation has changed dramatically over the past decade, with availability of direct oral anticoagulants (DOACs), which inhibit factor Xa or thrombin. However, the optimal anticoagulant agent and dosing strategy for patients at both extremes of body weight has not been established for any anticoagulant, including DOACs, vitamin K antagonists (VKA), and the various heparin options. Areas covered: This paper reviews available evidence to assist clinicians in prescribing of anticoagulation therapy at the extremes of body weight. Expert commentary: There are limited data to guide prescribing of all available anticoagulants at the extremes of weight and further research regarding efficacy and safety outcomes in these groups is required. Laboratory monitoring to guide dosing of traditional anticoagulants provides reassurance of 'predictable' efficacy. In contrast agents that are not routinely monitored by laboratory testing provide greater challenges. For example, underweight patients are at risk of receiving higher drug exposures of DOACs, whereas the use of fixed dose DOACs in obese patients may be associated with lower drug exposures.

HIT or miss? A comprehensive contemporary investigation of laboratory tests for heparin induced thrombocytopenia.

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy, which in a proportion of patients causes platelet activation and thrombosis. Initial clinical assessment of the likelihood of HIT is facilitated by laboratory testing to confirm or exclude HIT. This prospective investigation was performed over an 18-month period, and has involved testing of over 300 test samples from over 100 consecutive patients. Clinical assessment by 4T score was supplemented by laboratory tests that comprised both immunological [lateral flow ('STiC'), chemiluminescence (AcuStar; HIT-IgG(PF4-H)), ELISA (Asserachrom HPIA IgG)] and functional assays [SRA, platelet aggregation using whole blood ('Multiplate') and platelet rich plasma ('LTA')]. We observed both false positive and false negative test findings with most assays. Overall, the whole blood aggregation method provided a reasonable alternative to SRA for identifying functional HIT. STiC, AcuStar and ELISA procedures were fairly comparable in terms of screening for HIT, although STiC and AcuStar both yielded false negatives, albeit also resulting in fewer false positives than ELISA. The 4T score had less utility in our patient cohort than we were expecting, although there was an association with the likelihood of HIT. Nevertheless, we accept that our observations are based on limited test numbers. In conclusion, no single approach (clinical or laboratory) was associated with optimal sensitivity or specificity of HIT exclusion or identification, and thus, a combination of clinical evaluation and laboratory testing will best ensure the accuracy of diagnosis.

Acquired haemophilia A complicating alemtuzumab therapy for multiple sclerosis.

Alemtuzumab is a highly efficacious therapy used in the treatment of multiple sclerosis (MS), but uncoupling of T and B cell repopulation during immune reconstitution associates with an increasing range of secondary B cell-mediated autoimmune complications. A 34-year-old woman developed Graves' disease 11 months following an initial course of alemtuzumab treatment for MS. Nine months following the second treatment with alemtuzumab, the patient presented with spontaneous intramuscular and subcutaneous haemorrhage due to development of an inhibitory autoantibody to coagulation factor VIII. Acquired haemophilia A (AHA) is an extremely rare complication in patients treated with alemtuzumab. Treatment with rituximab may induce a rapid remission of AHA; however, the patient's high John Cunningham virus (JCV) antibody index and alemtuzumab-induced T cell lymphopenia may lead to an increased risk of progressive multifocal leucoencephalopathy, a potential complication which was unacceptable to the patient.