Response adaptive salvage treatment with daratumumab-lenalidomide-dexamethasone for newly diagnosed transplant-eligible multiple myeloma patients failing front-line bortezomib-based induction therapy-ALLG MM21.

In Australia, bortezomib-based induction (V-IND) is used in >90% of newly diagnosed transplant-eligible multiple myeloma (MM) patients. Four cycles of V-IND with bortezomib-cyclophosphamide-dexamethasone or bortezomib-lenalidomide-dexamethasone are available via the Pharmaceutical Benefits Scheme prior to autologous stem cell transplantation (ASCT). Patients who demonstrate suboptimal response or who are refractory to V-IND demonstrate inferior survival, representing a subgroup of MM where an unmet need persists. We evaluated an early, response-adapted approach in these patients by switching to an intensive sequential therapeutic strategy incorporating daratumumab-lenalidomide-dexamethasone-based (DRd) salvage, high-dose melphalan ASCT followed by DRd consolidation and R maintenance. The overall response rate following four cycles of DRd salvage was 72% (95% credible interval: 57.9-82.4); prespecified, dual, Bayesian proof-of-concept criteria were met. Euro-flow minimal residual disease (MRD) negativity was 46% in the intention-to-treat population and 79% in the evaluable population following 12 cycles of DRd consolidation. At the 24-month follow-up, median progression-free survival and overall survival were not reached. DRd salvage was well tolerated with grade 3 and 4 events reported in 24% and 8% respectively. Response-adapted DRd combined with ASCT achieves high rates of MRD negativity and durable disease control in this functional high-risk group.

The Fragility of Scientific Rigour and Integrity in "Sped up Science": Research Misconduct, Bias, and Hype and in the COVID-19 Pandemic.

During the early years of the COVID-19 pandemic, preclinical and clinical research were sped up and scaled up in both the public and private sectors and in partnerships between them. This resulted in some extraordinary advances, but it also raised a range of issues regarding the ethics, rigour, and integrity of scientific research, academic publication, and public communication. Many of the failures of scientific rigour and integrity that occurred during the pandemic were exacerbated by the rush to generate, disseminate, and implement research findings, which not only created opportunities for unscrupulous actors but also compromised the methodological, peer review, and advisory processes that would usually identify sub-standard research and prevent compromised clinical or policy-level decisions. While it would be tempting to attribute these failures of science and its translation solely to the "unprecedented" circumstances of the COVID-19 pandemic, the reality is that they preceded the pandemic and will continue to arise once it is over. Existing strategies for promoting scientific rigour and integrity need to be made more rigorous, better integrated into research training and institutional cultures, and made more sophisticated. They might also need to be modified or supplemented with other strategies that are fit for purpose not only in public health emergencies but in any research that is sped-up and scaled up to address urgent unmet medical needs.

Response adaptive salvage with KTd and ASCT for functional high-risk multiple myeloma-The Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial.

We evaluated re-induction incorporating carfilzomib-thalidomide-dexamethasone (KTd) and autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (NDMM) refractory, or demonstrating a suboptimal response, to non-IMID bortezomib-based induction. KTd salvage consisted of thalidomide 100 mg daily and dexamethasone 20 mg orally combined with carfilzomib 56 mg/m2 days 1, 2, 8, 9, 15 and 16, of each 28-day cycle. Following four cycles, patients achieving a stringent complete response proceeded to ASCT whereas those who did not received a further two cycles then ASCT. Consolidation consisted of two cycles of KTd then Td to a total of 12 months post-ASCT therapy. Primary end-point was the overall response rate (ORR) with KTd prior to ASCT. Fifty patients were recruited. The ORR was 78% with EuroFlow MRD negativity of 34% in the intention-to-treat population and 65% in the evaluable population at 12 months post-ASCT. With follow-up >38 months median PFS and OS have not been reached with PFS and OS at 36 months of 64% and 80%, respectively. KTd was well tolerated with grade 3 and grade ≥4 adverse events rates of 32% and 10%, respectively. Response adaptive utilisation of KTd with ASCT is associated with both high-quality responses and durable disease control in functional high-risk NDMM.

Oral health and dental morbidity in long-term allogeneic blood and marrow transplant survivors in Australia.

BACKGROUND: Oral and dental disease is a major cause of long-term morbidity following allogeneic blood and marrow transplantation (Allo-BMT). This study aimed to describe the extent and range of oral and dental complications in BMT recipients and to identify gaps in service provision provided to this high-risk group. METHODS: Participants were Allo-BMT recipients, aged >18 years, and received transplants between 2000 and 2012 in NSW. They completed seven surveys, the purpose-designed Sydney Post-BMT Study survey and six other validated instruments. RESULTS: Of 441 respondents, many reported dry mouth (45.1%), dental caries (36.7%), mouth ulcers (35.3%), oral GVHD (35.1%), gingivitis (16.2%), tooth abscess (6.1%) and oral cancer (1.5%). Regular dental visits were reported by 66.2% of survivors. Middle-high income, older age and geographic location showed a positive association with regular dental visits. Of those who did not visit the dentist regularly, 37% stated they did not feel it necessary, 36% reported cost and 20% stated it was not advised by the treating team. CONCLUSION: Despite oral complications commonly occurring after Allo-BMT, many survivors receive inadequate dental care. These results emphasize the need for improved oral health education, the importance of regular dental checks and improvement in the delivery of dental health services for BMT survivors.

Gene editing advance re-ignites debate on the merits and risks of animal to human transplantation.

In Australia, and internationally, the shortage of organ and tissue donors significantly limits the number of patients with critical organ or tissue failure who are able to receive a transplant each year. The rationale for xenotransplantation - the transplantation of living cells, tissues or organs from one species to another - is to meet this shortfall in human donor material. While early clinical trials showed promise, particularly in patients with type I diabetes whose insulin dependence could be temporarily reversed by the transplantation of porcine islet cells, these benefits have been balanced with scientific, clinical and ethical concerns revolving around the risks of immune rejection and the potential transmission of porcine endogenous retroviruses or other infectious agents from porcine grafts to human recipients. However, the advent of CRISPR/Cas9, a revolutionary gene editing technology, has reignited interest in the field with the possibility of genetically engineering porcine organs and tissues that are less immunogenic and have virtually no risk of transmission of porcine endogenous retroviruses. At the same time, CRISPR/Cas9 may also open up a myriad of possibilities for tissue engineering and stem cell research, which may complement xenotransplantation research by providing an additional source of donor cells, tissues and organs for transplantation into patients. The recent international symposium on gene editing, organised by the US National Academy of Sciences, highlights both the enormous therapeutic potential of CRISPR/Cas9 and the raft of ethical and regulatory challenges that may follow its utilisation in transplantation and in medicine more generally.

The experience of survival following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) entails long-term morbidities that impair survivors' quality of life through broad physical and psychosocial sequelae. Current data and survival measurements may be inadequate for contemporary Australian allo-HSCT recipients. This study sought to comprehensively describe survivorship in an up-to-date, local setting through validated measurements and a novel questionnaire designed to complement and address limitations of current instruments. All adults who received an allo-HSCT between 2000 and 2012 in New South Wales were eligible and included, if alive, those literate and consenting to the study, which encompassed seven survey instruments. Four hundred and forty-three survivors participated, which is 76% of contactable (n=583) and 66% of eligible survivors (n= 669). Chronic GVHD (cGVHD) and co-morbidity rates were similar to published data. Noteworthy results include prevalent sexual dysfunction (66% females, 52% males), loss of income (low income increased from 21 to 36%, P<0.001) and employment (full-time employment fell from 64 to 33%, P<0.001), suboptimal vaccination (31% complete), and health screening (≈50%). Risk factors for poor vaccination and health screening were cGVHD, younger age, less education, rural/regional residence and transplantation <2 years. This study suggests that improvement in survivorship may necessitate structural changes in the current delivery of health services.

Correlates of unmet needs and psychological distress in adolescent and young adults who have a parent diagnosed with cancer.

OBJECTIVE: Young people who have a parent with cancer experience elevated levels of psychological distress and unmet needs. In this study, we examined the associations between demographics, cancer variables and family functioning and levels of distress and unmet needs amongst young people who have a parent diagnosed with cancer. METHODS: Young people aged 12-24 years with a parent with cancer (n = 255) completed the Offspring Cancer Needs Instrument (unmet needs), the Kessler-10 (distress) and the Family Relationship Index (family functioning), along with measures of demographics and cancer variables (such as age, sex and time since cancer diagnosis). Variables associated with distress and unmet needs (including unmet need domains) were assessed using multiple linear regression. RESULTS: Being female and older, having more unmet cancer needs and poorer family functioning were associated with increased distress. Having a father with cancer, a shorter time since diagnosis and poor family functioning were associated with increased unmet needs. Family conflict and expressiveness were particularly important components of family functioning. Having a parent relapse with cancer was also associated with unmet needs in the domains of practical assistance, 'time out' and support from other young people who have been through something similar. CONCLUSIONS: Delineating factors associated with increased distress and unmet needs assist in identifying at-risk young people allowing improved assessment and tailoring of support to improve the psychosocial outcomes of young people impacted by parental cancer.

Attitudes of the general public towards the disclosure of individual research results and incidental findings from biobank genomic research in Australia.

BACKGROUND: Over the past decade, managing the disclosure of findings of genomic research has been the subject of extensive scientific, ethical and legal commentary and is a major challenge for biobanks. AIMS: To examine views of the general Australian public about the disclosure of individual research results (IRR) and incidental findings (IF) from biobank genomic research. METHODS: A national computer assisted telephone interview was conducted amongst a representative sample of (n = 800) adult residents across each Australian State and Territory. RESULTS: The majority of the Australian general public would be interested in receiving IRR and IF if they allowed their blood/tissue to be used in research; 94.4% (n = 800) reported that they would like to receive 'specific information obtained from your sample that may be important to your health or treatment', and 83.4% their 'potential genetic risk of an inherited disease'. Although fewer desired to receive 'any IF that were not directly related to your (potential) diagnosed condition' (70.0%), most would still like to receive IF. A latent class analysis on the desire to receive (or not) all types of results revealed differences in preferences in the information they wished to receive. CONCLUSION: The majority of Australians desire to receive most information arising from research involving their tissue, including IRR and IF. Differences in the extent and type of information they desire to receive are noted. Biobanks must establish strategies to identify information needs of donors, assess research data and communicate with donors and donor families. Processes need to take account of differences in donor preferences and in the clinical or research context(s).

Oral chronic graft-versus-host disease in Australia: clinical features and challenges in management.

Data from the Australasian Bone Marrow Transplant Recipient Registry show a steady increase in the number of allogeneic haemopoietic stem cell transplantations (HSCT) performed annually in Australia and New Zealand. In 2012, 629 allogeneic HSCT were performed. Allogeneic HSCT is associated with numerous potential complications, including chronic graft-versus-host disease (cGVHD). The oral cavity is one of the most frequent sites affected by cGvHD, often leading to significant disability and reduced quality of life. Management strategies are often complex, of variable efficacy and influenced by the availability of various therapeutic agents, access to compounding pharmacies and associated costs. This paper summarises the current status of allogeneic HSCT in Australia and New Zealand with a focus on oral cGvHD and the associated challenges in its management.

Dilemmas in the compassionate supply of investigational cancer drugs.

In Australia, patients who want to access medicines that are not yet approved have only two options: to enroll in a clinical trial if they are eligible, or obtain their medicine through 'compassionate supply', which is provided at the discretion of the manufacturer. In this article, we explore ethical issues associated with the provision of oncology medicines that are still in development, either prior to regulatory approval or government reimbursement.

Medicine's inconvenient truth: the placebo and nocebo effect.

Placebo and nocebo effects are often regarded by clinicians as either a quaint reminiscence from the pre-therapeutic era, or simply as a technique for establishing the efficacy of therapeutic interventions within the locus of evidence-based practice. However, neither of these explanations sufficiently account for their complexity or their persistence and impact in clinical medicine. Placebo and nocebo effects are embedded in the very fabric of therapeutic relationships and are both a manifestation and outcome of the rituals that characterise clinical practice. They are also a stark reminder of the many personal and environmental factors, including the attitudes, beliefs and expectations of both doctor and patient, that shape the outcomes of health professional-patient interactions. We describe how recent biological and neuropsychiatric data have clarified the operation of placebo and nocebo effects in clinical practice - demonstrating the ability of the therapeutic context to modulate endogenous biological processes in a targeted manner. This, in turn, illustrates the potent philosophical and sociocultural aspects of medical praxis.

Australians' knowledge and perceptions of direct-to-consumer personal genome testing.

BACKGROUND: As direct-to-consumer personal genome testing (DTC-PGT) is increasingly available in Australia, knowledge of Australians' perceptions and attitudes towards this technology is needed in order to assess the (potential) impact it might have on the Australian public and healthcare system. AIMS: To explore the knowledge and perceptions of DTC-PGT in an Australian sample. METHODS: An online survey asking about knowledge and perceptions of DTC-PGT, undertaken between October 2011 and April 2012, of 270 Australian residents. Results were analysed using SAS. RESULTS: Our study found limited consumer knowledge of, and interest in, pursuing DTC-PGT in Australia. Ninety-three per cent of respondents correctly identified DTC-PGT as available to consumers directly, but only 40% correctly identified its availability in Australia. When asked about the content and value of the information DTC-PGT provides, the majority of respondents indentified that DTC-PGT could provide information about one's health and/or ancestry (82% and 74%). Additionally, respondents indicated they believed this information to be equally important as non-genetic information about one's ancestry and health. CONCLUSION: While a minority of respondents expressed an intention to pursue DTC-PGT (27%), the majority of respondents, irrespective of whether they wished to pursue it or not, believed that genetic information was as important as non-genetic information in regards to their health and their ancestry. The value ascribed to genetic information suggests that genetics plays a role in people's lives, and that further qualitative research could explore the ways in which people might use and understand the genetic information provided by DTC-PGT.

Health of adults living with a clinically significant haemoglobinopathy in New South Wales, Australia.

AIM: To comprehensively review the health needs of patients living with clinically significant haemoglobinopathies (thalassaemia and sickle-cell disease (SCD)) in New South Wales, Australia. METHODS: A survey-based health needs assessment was undertaken in outpatients cared for at five tertiary institutions in metropolitan and regional centres. Sixty-three of 121 adults (approximately 80-90% of adult patients with transfusion-requiring haemoglobinopathies in New South Wales) completed an in-house and commercial health-related quality assessment survey (SF-36v2). RESULTS: Subjects came from more than eight world regions, with those with SCD being more likely to be born outside of Australia than subjects with thalassaemia (P < 0.001, likelihood ratio 20.64) as well as more likely to have been refugees (26% vs 2%). The population contained socially disadvantaged subjects with 13 subjects (20.6%) having incomes below the Australian poverty line. Complications of thalassaemia were comparable to previous international reports although our subjects had a high rate of secondary amenorrhea (>12 months = 27%) and surgical splenectomy (55.6%). Use of hydroxyurea in SCD was less than expected with only 46.6% of subjects having prior use. Lack of universal access to magnetic resonance imaging-guided chelation (international best practice) was evident, although 65.5% had been able to access magnetic resonance imaging through clinical trial, or self-funding. CONCLUSIONS: Patients with SCD and thalassaemia experience considerable morbidity and mortality and require complex, multidisciplinary care. This study revealed both variance from international best practice and between specialist units. The results of this research may provide the impetus for the development of clinical and research networks to enable the uniform delivery of health services benchmarked against international standards.

Survey of practices and policies relating to the use of complementary and alternative medicines and therapies in New South Wales cancer services.

AIMS: To examine policies and practices relating to the provision, prescription and monitoring of complementary and alternative medicine and therapies (CAM) in conventional cancer services in NSW. METHODS: Self-administered questionnaire sent to directors of all 65 eligible cancer services in NSW in 2009. RESULTS: Forty-three services responded to the survey (response rate 66%). Only six (14%) services reported having formal policies about CAM. Most (n = 33, 77%) expected that patients would be asked about CAM use during their initial assessment. Eight services (19%) provided and/or prescribed CAM for patients, and most of these (n = 7) recorded details of CAM use in patients' records. Only four (9%) services permitted CAM practitioners from the community to attend inpatients, whereas 24 (56%) permitted inpatients to bring in their own CAM. Most of these services (n = 17) required medical approval for the use of CAM. Of the latter, most (n = 13) recorded the use of approved CAM, but only seven recorded use of unapproved CAM and only three refused permission to continue use of unapproved CAM. CONCLUSION: Most cancer services in NSW recognise potential CAM use by patients and expect medical staff to ask patients about their use of CAM. While few cancer services provided or prescribed CAM, over half permitted inpatients to bring their own CAM into hospital. There was little control over the use of CAM, however, and monitoring was lax. Given the wide usage of CAM by patients with cancer, this lack of control may compromise clinical outcomes, with potentially dangerous consequences.