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Part of an occasional series of articles where University of Oxford researchers from our department look at recently published research in their field.
High Success Rates Utilizing Local Standard of Care Cytogenetic Testing for Risk Stratified Frontline Therapy for Newly Diagnosed Multiple Myeloma: Experience from the Ukmra RADAR Study
Background. Recent studies in genetically high risk (HR) multiple myeloma (MM) such as the UKMRA OPTIMUM study have reported high response rates with intensive induction and post-ASCT consolidation and maintenance strategies, providing the rationale for stratified therapy based on genetic risk. Whilst centralised testing in clinical trials offers ready uniformity and quality control, the use of local laboratories for testing within a clinical trial paves the way for genetic testing to be available for all patients, facilitating risk stratified therapy in routine care. We designed the UKMRA RADAR study to use local laboratories for cytogenetic (CGN) testing to assign treatment according to genetic risk. Methods. RADAR is an ongoing national, multi-center, risk-adapted, response-guided multi-arm, multi-stage (MAMS) phase II/III trial for patients with newly diagnosed MM eligible for ASCT. Patients receive induction with RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. Post ASCT, HR patients are randomised to receive isatuximab or not, alongside RBorD consolidation and R maintenance whilst standard risk (SR) patients receive MRD response guided regimens. A protocol amendment (2022) included isatuximab throughout the HR pathway, removing the post-ASCT randomisation. Risk assessment, failure rates and turnaround time are overseen by a genomics working group (GWG) including clinical and specialist cytogenetic representation. Genetic risk testing is undertaken in local genetic labs on CD138 selected bone marrow (BM) plasma cells. HR is assigned based on the presence of at least two of: t(4;14), t(14;16), t(14:20), del(17p), del(1p) and gain(1q). Clone size cut-offs are 10% for IgH translocations and 20% for copy number changes. CGN results from local laboratories are centrally reviewed to assign risk in real-time. Indeterminate cases are discussed by the GWG. Repeat testing is mandated if the initial sample fails to yield a definitive risk result for risk. Subjects with no definitive result despite 2 samples are treated as SR. Results. As of 19 th June 2023, the trial has recruited 472 patients from 72 sites across the UK. Median age is 61 years, 59.3% male, 79.9% white, 11.7% other ethnicity and 8.5% missing ethnicity data. 25 local laboratories were used for CGN testing. Of those with CGN results 354/453 patients (78.1%) were assigned standard risk, 84 (18.5%) high risk and 15 (3.3%) risk category undefined. Risk stratification is ongoing for 19 patients. Of the high risk lesions gain(1q) was most prevalent (35%), followed by t(4;14)(10.6%), del(17p)(8.7%), del(1p32)(8.7%), t(14;16)(3.8%) and t(14;20)(0.8%). In 376/453 patients (83.0%), risk was assigned from a first BM sample. 77 (17.0%) patients required a second sample; the success rate of repeat samples is 71.4%, 22 (4.9%) patients were unable to be risk-stratified despite 2 samples. Figure 1 shows the success rate of first and repeat tests. The overall median turnaround time (from D1 cycle 1 until site notified of result) was 11 days (IQR 0 to 21). Sites were sent risk status prior to cycle 1 in 99 (21.9%) patients , 285 (62.9%) prior to cycle 2 and 341 (75.3%) cycle 3. Note this is calculated where treatment data is available. Conclusion. The RADAR study demonstrates that risk-stratified treatment approaches are feasible in the context of a national phase II/III clinical trial with the use of local laboratories for risk assignment. The vast majority of patients have been successfully allocated to a risk-adapted treatment pathway following a first FISH test (83.0%). Protocol v4 requires time-critical risk-stratification for addition of isatuximab to induction treatment from cycle 2 in high-risk patients, and this has proven to be achievable in almost 2/3 of patients with over ¾ by the end of cycle 2. The RADAR study also enables hospitals across the UK to access CGN testing via a network model of laboratories with standardization of testing and clinically relevant turnaround times. This model is applicable internationally in both public and privately funded healthcare systems and supports the infrastructure for accessible genetic risk stratification for all newly diagnosed MM patients. Ongoing studies within the RADAR trial are evaluating novel and clinically deliverable risk stratification protocols to inform risk stratified approaches in newly diagnosed MM.
Whole genome sequence analysis and in-vitro probiotic characterization of Bacillus velezensis FCW2 MCC4686 from spontaneously fermented coconut water.
In this study, the probiotic potential of B. velezensis FCW2, isolated from naturally fermented coconut water, was investigated by in vitro and genomic characterization. Our findings highlight key features of the bacterium which includes, antibacterial activity, high adhesive potential, aggregation capacity, production of nutrient secondary metabolites. In vivo safety assessment revealed no adverse effects on zebrafish. WGS data of B. velezensis FCW2 revealed a complete circular genome of 4,147,426 nucleotides and a GC content of 45.87%. We have identified 4059 coding sequence (CDS) genes that encode proteins involved in stress resistance, adhesion and micronutrient production. The genes responsible for producing secondary metabolites, exopolysaccharides, and other beneficial nutrients were identified. The KEGG and COG databases revealed that genes mainly involved amino acid metabolism, carbohydrate utilization, vitamin and cofactor metabolism, and biological adhesion. These findings suggest that B. velezensis FCW2 could be a putative probiotic in the development of fermented foods.
Genomic and metabolic properties of Staphylococcus gallinarum FCW1 MCC4687 isolated from naturally fermented coconut water towards GRAS assessment.
Staphylococcus gallinarum FCW1 was isolated from naturally fermented coconut-water and identified by biochemical and molecular methods. Probiotic characterization and safety assessment were conducted through a series of in vitro tests. A high survival rate was observed when the strain was tested for resistance to bile, lysozyme, simulated gastric and intestinal fluid, phenol, and different temperature and salt concentrations. The strain showed antagonism against some pathogens, was susceptible to all antibiotics tested except penicillin, and showed no hemolytic and DNase activity. Hydrophobicity, autoaggregation, biofilm formation, and antioxidation tests indicated that the strain possessed a high adhesive and antioxidant ability. Enzymatic activity was used to evaluate the metabolic capacities of the strain. In-vivo experiment on zebrafish was performed to check its safety status. The whole-genome sequencing indicated that the genome contained 2,880,305 bp with a GC content of 33.23%. The genome annotation confirmed the presence of probiotic-associated genes and genes for oxalate degradation, sulfate reduction, acetate metabolism, and ammonium transport in the FCW1 strain, adding to the theory that this strain may be helpful in treating kidney stones. This study revealed that the strain FCW1 might be an excellent potential probiotic in developing fermented coconut beverages and treating and preventing kidney stone disease.
Belantamab Mafodotin Monotherapy for Multiply-Relapsed Myeloma: A Retrospective Study From the United Kingdom and the Republic of Ireland.
INTRODUCTION: Belantamab mafodotin (belamaf) was the first BCMA-targeting immunotherapy licensed in myeloma and was available as monotherapy for a fifth or greater line of treatment. Outcomes for patients in the United Kingdom and the Republic of Ireland potentially differ from those of other regions and may illuminate factors predicting response to therapy. METHODS AND RESULTS: We performed a retrospective study of patients treated with belamaf monotherapy in the United Kingdom and the Republic of Ireland. In our cohort of 88 patients, we saw an overall response rate (ORR) of 60%, a median progression-free survival (PFS) of 8.7 months and a median duration of response (DoR) of 15.8 months. The spectrum of adverse events was as expected, with 84% (71/85) of patients experiencing toxicity. Eye-related adverse events were the most common, affecting 66% (56/85), leading to dose reduction or delay in 41% (35/85) and discontinuation in 6% (5/85). We specifically assessed physician decision-making in the context of ocular side effects and found a relatively high frequency of the drug being administered despite moderate levels of toxicity. CONCLUSION: Our cohort's ORR is significantly different from those of the DREAMM-2 and -3 trials and other real-world studies, though a long-duration response has been reported in other cohorts. Comparative analysis with other real-world studies did not reveal any significant factors predictive of ORR. The frequent administration of belamaf to patients with eye disease may well reflect a more pragmatic approach than was originally prescribed in the landmark trials. TRIAL REGISTRATION: The authors have confirmed clinical trial registration is not needed for this submission.