Introduction Multiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients. Methods and analysis The Myeloma UK nine OPTIMUM trial (MUK nine ) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUK nine a ), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUK nine b ) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUK nine b primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing. Ethics and dissemination Ethics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal. Trial registration number ISRCTN16847817 , May 2017; Pre-results.
Abstract Background The Myeloma Response Assessment and Diagnosis System (MY-RADS) guidelines establish a standardised acquisition and analysis pipeline for whole-body MRI (WB-MRI) in patients with myeloma. This is the first study to assess image quality in a multi-centre prospective trial using MY-RADS. Methods The cohort consisted of 121 examinations acquired across ten sites with a range of prior WB-MRI experience, three scanner manufacturers and two field strengths. Image quality was evaluated qualitatively by a radiologist and quantitatively using a semi-automated pipeline to quantify common artefacts and image quality issues. The intra- and inter-rater repeatability of qualitative and quantitative scoring was also assessed. Results Qualitative radiological scoring found that the image quality was generally good, with 94% of examinations rated as good or excellent and only one examination rated as non-diagnostic. There was a significant correlation between radiological and quantitative scoring for most measures, and intra- and inter-rater repeatability were generally good. When the quality of an overall examination was low, this was often due to low quality diffusion-weighted imaging (DWI), where signal to noise ratio (SNR), anterior thoracic signal loss and brain geometric distortion were found as significant predictors of examination quality. Conclusions It is possible to successfully deliver a multi-centre WB-MRI study using the MY-RADS protocol involving scanners with a range of manufacturers, models and field strengths. Quantitative measures of image quality were developed and shown to be significantly correlated with radiological assessment. The SNR of DW images was identified as a significant factor affecting overall examination quality. Trial registration ClinicalTrials.gov, NCT03188172 , Registered on 15 June 2017. Critical relevance statement Good overall image quality, assessed both qualitatively and quantitatively, can be achieved in a multi-centre whole-body MRI study using the MY-RADS guidelines. Key points • A prospective multi-centre WB-MRI study using MY-RADS can be successfully delivered. • Quantitative image quality metrics were developed and correlated with radiological assessment. • SNR in DWI was identified as a significant predictor of quality, allowing for rapid quality adjustment. Graphical Abstract
Introduction Multiple myeloma is a malignancy of plasma cells with around 6000 new cases per year in the UK. Cyclophosphamide plus prednisolone is considered a standard of care for disease and symptom control in the advanced relapsed or refractory myeloma setting within the UK NHS. The selective nuclear export inhibitor, selinexor, has been relatively well tolerated in previous clinical trials and offers promise when used in combination with a wide range of other anti-cancer treatments. Here, we investigate if the addition of selinexor can improve responses to cyclophosphamide plus prednisolone without adding prohibitive toxicity. Methods and analysis MUKtwelve is a UK-based, randomised, controlled, open, parallel group, multicentre phase II trial designed to evaluate clinical efficacy of selinexor in combination with cyclophosphamide and prednisolone (SCP) in patients with relapsed or refractory multiple myeloma. A calibration arm will receive cyclophosphamide and prednisolone alone (CP). Participants who experience disease progression on the CP arm may, if eligible, receive SCP. The MUK twelve trial results will be the first to assess clinical efficacy of selinexor with low-dose CP in relapsed/refractory multiple myeloma. It is widely accepted that the relapsing-remitting nature of the disease is accompanied by cellular changes that often result in the requirement for novel agents and drug combinations to regain disease control. Patients also often experience cumulative toxicities throughout their treatments, limiting the treatment intensity that can be given at relapse. Thus, there is a need for novel effective combination therapies with acceptable toxicity profiles. Ethics and dissemination Ethics approval is obtained. Results will be submitted for publication in a peer-reviewed journal. Trial registration number ISRCTN15028850 .
Motivation: Standardisation of imaging protocols in multi-centre studies is challenging, which can hamper clinical translation. Goal(s): This study aimed to develop and demonstrate a software tool that automatically assesses imaging protocol compliance. Approach: The tool was containerised and integrated into an imaging repository. It was applied to a dataset from a whole-body MRI (WB-MRI) myeloma study, which included 174 examinations acquired across 10 sites with scanners from three manufacturers. Results: The software successfully identified some parameters and sites where persistent deviations occurred, although 88% of examinations were conducted according to the relevant clinical guidelines with good overall compliance to site-specific protocols. Impact: Repository-integrated software is presented for automated monitoring of imaging protocol compliance to support standardisation in multi-centre studies and clinical translation. A multi-centre whole-body MRI study demonstrates good compliance that could have been improved further with proactive monitoring using this tool.
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