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The Oxford Centre for Translational Myeloma Research

Research

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The mission of the newly launched Oxford Centre for Translational Myeloma Research is to undertake internationally competitive research into the processes underlying multiple myeloma and related plasma cell diseases. The investigators of the Centre are committed to translate this research into improved patient health by combining outstanding clinical research with excellent basic science in Oxford, thereby generating testable novel therapeutic options and advances. We are working together with the National Institute of Health Research, the NHS, patient organisations as well as national and international public academic institutions and private companies with the aim of further and constantly improving the diagnosis, treatment and standard of care of myeloma.

Research Themes

IDENTIFICATION AND VALIDATION OF NOVEL DRUG TARGETS FOR TREATMENT OF MULTIPLE MYELOMA

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Currently, Multiple Myeloma (MM) is a treatable but incurable disease. The introduction of proteasome inhibitors and immunomodulatory drugs (IMIDs) constitutes a major advancement in expanding life expectancy, where remissions may be induced with combinations of steroids, chemotherapy, proteasome inhibitors (eg bortezomib) and IMIDs such as thalidomide derivatives, as well as stem cell transplantation. Radiation therapy can be used to reduce pain from bone lesions. However, MM remains incurable because most patients eventually relapse or become refractory to current treatments. Due to heterogeneity within the cancer cell microenvironment, cancer cell populations employ a dynamic survival strategy to chemotherapeutic treatments, which frequently results in a rapid resistance to therapy. In addition to resistance conferring genetic alterations within new tumor cell populations arising from selection during drug treatment, there is also evidence for non-mutational mechanisms of drug resistance, involving epigenetic changes, and the generation of populations of “cancer stem cells”, which are intrinsically more refractory to the effects of a variety of anticancer drugs. The aims of this research theme are to identify and validate novel drug targets and treatment concepts that address the current problems in MM therapy.

PROJECTS:
Disrupting ER homeostasis to induce apoptosis in multiple myeloma

PI: John Christianson, Ludwig Institute of Cancer Research, Oxford

The haematological malignancy multiple myeloma (MM) is typified by excessive proliferation of clones producing excessive amounts of non-functional immunoglobulin, which interfere with normal haematopoietic functions in bone marrow. The plasma cells from which MM arises are highly optimised protein factories, assembling antibodies in the endoplasmic reticulum (ER) at rates nearing ~ 1 x 103/cell/sec. These extraordinary rates of biosynthesis can only be maintained because of robust, adaptive quality control (QC) machinery that safeguards the integrity of secretory cargo by concomitantly promoting maturation while eliminating any aberrant forms that arise. Together, these tandem activities enable the ER to maintain homeostasis while accommodating elevated rates of protein flux. With a hypersecretory phenotype, MM is a disease tacitly relying on the QC machinery maintaining ER homeostasis in order to remain malignant. It is for this reason that strategies to disrupt ER homeostasis have proved therapeutically beneficial for the treatment of MM. The proteasome inhibitor class of small molecules (e.g. bortezomib, carfilzomib) exemplifies this strategy; blocking protein degradation which elevates ER stress to levels sufficient enough to activate cell death pathways and abate proliferation. After prolonged exposure however, patients become refractory to treatment with these compounds, likely due to cellular adaptation through enhancement of alternative protein degradation pathways. Thus, identifying cellular targets and processes in MM linked with ER homeostasis, which are non-redundant and thus more difficult to bypass and/or adapt to for viability (i.e. an Achilles heel), remains an important endeavour to find new therapeutic opportunities. Our laboratory has sought to define the extensive network of ER-resident ubiquitination machinery, their functions and relationship to organelle homeostasis. Of particular interest will be ubiquitin-related candidates sensitising proteasome inhibitor-resistant model cell lines, as they may reflect alternative entry points for apoptotic induction. The mechanisms responsible for maintaining homeostasis in the ER represent potentially valuable targets for therapeutic strategies to induce stress and cause cell death in MM. From our insight into the ubiquitination mechanisms at the ER, we anticipate that essential components will emerge from MM model cell lines, whose disruption will lead to ER stress and cell death.


Modulating the ubiquitin-proteasome system as a therapeutic strategy in multiple myeloma

PI: Benedikt Kessler, Target Discovery Institute, NDM, Oxford

Supported by EPSRC, CRUK/Forma Therapeutics

Inhibitors of the proteasome such as Bortezomib, Carfilzomib and Izazomib have been approved by the FDA and are used in the clinic to treat patients with multiple myeloma. Under current development are small molecule inhibitors against ubiquitin/SUME E1, E3 enzymes as well as deubiquitylating enzymes (DUBs), all of which have the potential to be effective against multiple myeloma, especially in relapsed patients. Multiple myeloma cells seem to be particularly vulnerable to interferences within protein turnover pathways. This is because a considerable proportion of secreted proteins are misfolded and need to be eliminated via the unfolded protein response and the ubiquitin system. In our laboratory, we are specifically exploring the role of DUBs in controlling protein turnover and metabolism in cancer cells. In particular, we have available a panel of small molecule inhibitors (through a collaboration with CRUK/Forma Therapeutics) with selectivity against DUBs. We intend to study their potency against a panel of cancer cell types, in particular multiple myeloma cells. We shall test cell type-specific sensitivity for these small molecules, and then subsequently study the role of the targeted DUBs in multiple myeloma cell viability. For instance, small molecule inhibitors against USP7 have already been shown to effectively kill multiple myeloma cells, including subtypes that have adapted to grow in otherwise toxic concentrations of proteasome inhibitors. We plan to study the roles of USP7 and other DUBs and their cellular ubiquitome in multiple myeloma cells using quantitative mass spectrometry, small molecules and genetic knockdown approaches.


Catalysing new drug targets for Myeloma through open science, and deep partnerships with industry, patient groups and academics across the globe.

PIs: Chas Bountra and all PIs at the SGC

Supported by SGC and IMI

Our primary objective in the SGC is to help our academic and industry colleagues discover and develop new drugs for patients. We have chosen to do this in four ways: (1) Pool expertise, infrastructures and resources: we are now working closely with nine large pharmaceutical companies, six patient organisations (including Myeloma UK), several SMEs and >200 academic labs dispersed across the globe. (2) Catalyse innovation by generating high quality novel reagents for novel drug targets, or targets considered to be undruggable. (3) Make all these reagents freely available to the global biomedical community, to enable ‘crowd sourcing’ of science and thereby de-risking of such targets. (4) Release all data, knowledge and reagents immediately, in order to minimise wastage of resources in other labs. As part of the Oxford Centre for Translational Myeloma Research we will: (1) Produce ‘Target Enabling Packages’ (TEPs: purified human proteins, biophysical and biochemical assays, three dimensional structures, chemical starting points for drug discovery, CRISPr reagents, antibodies) for novel genes or targets linked with Myeloma. We are already working with academic and industry scientists to prioritise such novel genes in cancer, inflammatory and metabolic diseases. We will help evaluate the potential of all cancer TEPs, and likely some of those linked with inflammatory and metabolic diseases in Myeloma. Cryo EM capabilities will allow us to explore integral membrane protein drug targets, more quickly than previously possible. (2) Generate novel, potent, selective, and cell penetrant inhibitors for high priority drug targets. We are routinely producing chemically similar but inactive molecules as controls for ex vivo work, and multiple chemotypes of inhibitors, for each drug target. Such target focussed toolkits are enabling superior ‘drug target discovery’. To date we have produced >60 novel inhibitors for novel epigenetic proteins, and >10 novel kinase inhibitors. In future we will produce several more of these, but also inhibitors for yeats, nudix, deaminase and ubiquitin proteins. Several of these are likely to have potential in Myeloma. Furthermore, from our pharma network we have acquired >20 inhibitors, some of which have previously been evaluated in patients. We are studying the effects of these in patient derived immune and cancer cells. We will assess all such novel inhibitors, in appropriate cellular Myeloma assays in order to identify new drug targets.


Drug Target Identification and Biomarker Profiling in Multiple Myeloma Using Chemoproteomics

PI: Kilian Huber, Target Discovery Institute, SGC, NDM, Oxford

Supported by Myeloma UK

Understanding the molecular targets of drugs and compounds discovered in phenotypic screens is a key parameter for drug discovery and personalized medicine. Many effective cancer therapeutics act by interfering with multiple protein targets some of which are referred to as “on-targets” required for cancer cell killing whereas “off-targets” can cause side effects by perturbing homeostasis in normal tissue. Uncovering the tumour-specific targets can thus enable the development of novel, more potent and selective treatments and prevent toxic side effects. As every cell expresses thousands of proteins, drug target identification represents a formidable challenge and requires systems-level approaches capable of surveying entire cellular proteomes. Our laboratory uses a suite of chemoproteomic approaches including drug affinity chromatography as well as thermal stability profiling to reveal the direct physical interactions between small molecules and proteins in cells and patient samples.


Identification of epigenetic mechanisms as target to treat drug resistance in multiple myeloma

PI: Udo Oppermann, Botnar Research Centre, NDORMS, Oxford

Supported by Oxford NIHR BRC

Epigenetic mechanisms comprise posttranslational chromatin modifications controlling gene expression programs, chromatin organisation and ultimately cellular phenotypes. The discovery that epigenetic and chromatin effector proteins are frequently dysregulated in cancer has led to the introduction of epigenetic therapies into the clinic, including e.g. inhibitors against histone methyl transferases (“writers”), demethylases or deeacetylases (“erasers”) and acetyl-lysine recognition (“reader”) domains. Our research aims to evaluate the therapeutic potential of epigenetic inhibitors using unique chemical and antisense toolkits that target epigenetic effector proteins.

We suggest that targeting the epigenetic and chromatin environment is not only a viable therapeutic concept in MM, but also has the potential to overcome acquired drug resistance which is observed in the vast majority of myeloma patients. Furthermore, we aim to understand the complex regulatory mechanisms within the network of MM cancer cells and the immune and stromal environment in the bone marrow with a view to modulate the pro-inflammatory tumor environment towards a milieu that allows selective tumor cell eradication.


Targeted delivery of drugs to bone-tissue to increase efficacy and reduce adverse effects in Multiple Myeloma

PIs: Oppermann, Russell, Ramasamy, Ebetino, Boeckmann

Supported by the Rosetrees Trust, Oxford NIHR BRC

The development of a bone-targeted drug for use in MM would represent a potential medical breakthrough for the treatment and management of MM and perhaps also for other haematopoietic or primary bone tumours. First, the future drug would augment existing drug treatments by addressing simultaneously the detrimental hallmarks of these tumour types, namely infiltration of bone tissue by cancer cells and induction of excessive bone resorption, which in turn leads to increased skeletal complications, including bone destruction, fractures and pain. Second, a tissue- targeted strategy will lower systemic drug levels, resulting in significantly fewer occurrences of adverse side effects, an important factor that in clinical practice often limits efficient treatments. Third, the ability to selectively and directly modulate and reshape the tumour microenvironment (including bone tissue, osteoclasts, osteoblasts and immune cells), addresses the challenges in MM therapy, where relapse and development of therapy resistance are thought to be critically dependent on the complex changes occurring in the cancer microenvironment.

In this project we are developing bone-tissue specific molecules for treatment of MM by combining highly active anti-cancer molecules with inert bisphonate molecules via a cleavable linker moiety. The well-studied bone tissue specificity of bisphosphonates provides an excellent vehicle to enrich anti-cancer molecules at their intended target sites.


UNDERSTANDING THE BONE AND IMMUNE MICROENVIRONMENT

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The importance of cellular interactions within the bone marrow microenvironment in multiple myeloma has long been recognised, with interactions between myeloma cells, osteoclasts and osteoblasts driving both the development of the destructive osteolytic bone disease and the growth and survival of the tumour. Over recent years, it has become clear that many, if not all, components of the bone marrow microenvironment have important roles to play in disease pathogenesis, including the immune system, endothelial cells, bone marrow stromal cells and adipocytes. Evidence is increasing to demonstrate the remarkable ability of myeloma cells to co-opt their environment to support their changing requirements for growth and survival. The importance of the microenvironment is not limited to late-stage disease. The significance of subtle changes within the bone marrow microenvironment in patients with pre-cancerous MGUS is increasingly becoming evident and constitutes a factor that may drive subsequent progression to myeloma. The aims of this research theme are to elucidate the key cellular and molecular interactions between myeloma cells and the bone marrow microenvironment that drive disease development, from MGUS through to multiple myeloma, with the ultimate goal of identifying new therapeutic approaches and mechanisms to identify those patients at greatest risk.

PROJECTS:
Targeting adiposity and osteoblasts in the development of MGUS and MM

PI: Claire Edwards, Botnar Research Centre

Co-Investigators: Hal Drakesmith, WIMM, University of Oxford; Karthik Ramasamy, OUH, Nikki Horwood, University of Oxford, Alison Banham, NDCLS, University of Oxford, Matthew Drake, Mayo Clinic

Supported by Bloodwise, Chinese Scholarship Council

Multiple myeloma is a fatal blood cancer. It is nearly always preceded by the non-cancerous blood cell disorder termed monoclonal gammopathy of undetermined significance (MGUS). Not all patients with MGUS will develop myeloma, and the reasons why only some patients with MGUS progress to myeloma are poorly understood. We have identified a number of changes within the bone microenvironment that may contribute to disease progression, including an increase in adiposity, a decrease in adiponectin and changes in BMP signalling.

Our goals are to elucidate how these changes occur, and whether blocking these changes may prevent or delay disease progression. We use a comprehensive combination of measurements in patient blood and bone marrow samples, cellular and molecular studies and preclinical models of myeloma to investigate this. Our studies will discover potential approaches to delay progression from MGUS to myeloma, help identify those patients at greatest risk for progression from MGUS to multiple myeloma and discover whether new approaches are effective for the treatment of multiple myeloma, and the associated anaemia and bone disease.

Effects of glycosphingolipid inhibition on immune responses and adipocyte function in multiple myeloma

PI: Nicole Horwood, Kennedy Institute of Research

Co-Investigators: Claire Edwards, Botnar Research Centre; Tim Cox, University of Cambridge; Anastasios Karadimitris, Imperial College London

Supported by Chinese Scholarship Council, Genzyme

The myeloma bone microenvironment is central to the propensity to develop multiple myeloma. Glycosphingolipids (GSL) are integral components of the plasma membrane that vary between different tissues and during cell differentiation. We recently demonstrated that alterations in GSL are observed in myeloma cells from patients, and that GSL blockade can reduce tumour burden and bone disease. Our goal is to determine whether GSL blockade is effective to block the changes in myeloma progression that occur in response to increased adiposity in the bone marrow with age. Using a combination of myeloma models, cellular assays and lipidomics, we are investigating the effect of GSL inhibition on adipocyte function and consequent effects on cells of the immune system during the progression of multiple myeloma.


Role of blood vessels in Multiple Myeloma progression

PIs: Anjali Kusumbe, Nikki Horwood, Karthik Ramasamy

Supported by KIR trust

Bone-marrow vascular niches have been proposed to support the propagation of multiple myeloma (MM) progression. However, the crosstalk between endothelial cells and MM cells remains vague. Furthermore, the effects of anti-angiogenic therapies on the fate of MM cells remain unstudied. Blood vessels in bone are heterogeneous and distinct blood vessel subtypes differentially regulate osteogenesis and hematopoiesis. These distinct blood vessel subtypes in bone may distinctly regulate the fate of MM cells and disease progression. Therefore, we will interrogate in this project the role of distinct blood vessel subtypes during MM progression. A powerful combination of advanced imaging, mouse genetics and transcriptional profiling will be applied to investigate the interactions between blood vessels and MM cells and to decipher the role of angiogenesis at different stages of disease. This interdisciplinary work at the frontiers of cancer and vascular biology will identify novel strategies for targeting endothelial cells and blood vessel growth to treat or even prevent MM.


Ageing Mechanisms in Multiple Myeloma Development

PI: James Edwards, Co-PIs: Sam Olechnowicz, Claire Edwards, Botnar Research Centre

Supported by Oxford NIHR BRC

There is an inexplicable link between increasing age and the development of MGUS and myeloma. This suggests that common factors might exist controlling both longevity and the development of myeloma. However, the role of lifespan-regulating factors in the pathogenesis of multiple myeloma remains poorly understood. Multiple Myeloma is a late-onset malignancy, with a mean presentation age of 60yrs. However, the pre-malignant MGUS stage might exist many years earlier. This project aims to identify and characterise how ageing-related factors might underlie MGUS development and investigate cellular, molecular and environmental triggers related to increased ageing and lifespan. Furthermore, the work of the Musculoskeletal Ageing group aims to better understand the causes of declining skeletal integrity and to better treat the consequences of an ageing skeleton. This includes why aged (and normal) bone is a preferential site for cancer development and metastases.


Development of patient-derived tissue assays and reagents for target identification and validation in Multiple Myeloma

PIs: Udo Oppermann (Oxford), Susanne Graslund, Michael Sundstrom (SGC, Karolinska Institute, Stockholm)

Meaningful phenotypic assays that reflect multiple key features of myeloma cells and their interactions with the microenvironment are required to identify and validate novel pharmacological therapeutic approaches in multiple myeloma. In this project we are developing novel reagents for single cell technologies such as mass cytometry (Cytof) and next-generation sequencing and incorporate these into assay systems using patient-derived tissue such as bone marrow. Building on a successfully established pipeline for identification and validation of renewable affinity reagents or biological probes, necessary to characterise pathways of immune, stromal and cancer cell populations, we will generate and validate novel reagents freely available to the scientific community. These tools will be used as readouts for screening of anti-proliferative and immune modulatory effects against libraries of small molecule inhibitors.


EXPERIMENTAL MEDICINE

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Experimental medicine provides invaluable understanding in the drug development process for myeloma. Cell lines and animal model work largely drive myeloma research outside of clinical trials. Pre malignancy models in myeloma are also significantly lacking. But several drugs selected through this process fail in clinical trials. Demonstrating proof-of-mechanism early provides greater certainty before committing to the large, lengthy and expensive clinical trials necessary to take a drug candidate through development. It is imperative that we design experimental medicine studies to understand drug response and resistance in carefully designed studies. Established myeloma drugs often have adverse effects, which remain unexplained. Experimental studies help us tease out the mechanisms underpinning these side effects and enable us to use these medicines effectively for patients

PROJECTS:
Interception of pre-malignant haematopoietic precursor conditions for early intervention

PIs: Prof Anna Schuh, Dr Karthik Ramasamy Cancer and Haematology Centre, Oxford

Funded by Janssen Oncology

This project aims to outline a programme of activity to identify individuals with pre-malignant haematological precursor conditions MGUS, Smouldering Myeloma and Monoclonal B lymphocytosis who are at the greatest risk of progressing to malignant disease. Pre-malignant probands will be longitudinally monitored using an extensive array of molecular analyses, which will generate phenotypic signatures of progression. These signatures would then be used to monitor pre-malignant populations to identify at-risk patients for whom early curative intervention would be most effective and suggest novel therapeutic strategies for these patients. Specifically, we will monitor individuals with pre-malignant, early asymptomatic haematological disorders (which do not normally require treatment) for a period of 5 years using a combination of genomic, single-cell and immunological approaches. We will derive novel surrogate molecular markers of progression to malignant diseas, identify novel surrogate markers of cure, design an early intervention trial to clinically validate these markers, and gather feasibility data in this high-risk subgroup of probands with a pre-malignant condition.


Investigation of platelet function and cell signalling in multiple myeloma and its treatment

PIs: Prof Jon Gibbins (University of Reading), Dr Karthik Ramasamy Cancer and Haematology Centre, Oxford

Research fellows: Dr Dalia Khan, Dr Rekha Rana

Funded by Celgene Corporation

The incidence of arterial and venous thrombosis in myeloma is substantially higher than that in the normal population and varies between 5 and 10%. In this study we will establish the impact of MM and its treatment on the function of platelets to explore the potential of these cells in mediating associated thrombosis. The goal of this study is to characterise platelet function in MM patients compared to healthy individuals, and understand the impact of MM on thrombus formation during disease progression and exposure to treatment. We will study the effects of IMiDs on platelet function using platelets from healthy volunteers and from MM patients (in vitro ) and in patients undergoing therapy. The molecular basis of altered platelet function will be determined through analysis of platelet cell signalling by the platelet activatory pathways that trigger platelet function in health and disease. This will enable us to understand the basis of the observation that patients with MM who are at a higher risk of arterial/venous thrombosis in comparison to that of the normal population. An additional goal of this pilot study is to define optimal preclinical platelet function assays that could be used to correlate the pharmacological properties of the generation molecules ‘CELMoDs™’ to limit unwanted properties that result in platelet dysfunction that would lead to thrombotic events. This pilot study will help to facilitate improvement in current and future therapeutic strategies, and hence support myeloma patients on treatment with or without IMiDs and/or CELMoDs, who are at greatest risk of thrombosis.


Systems approaches to understand MM clonal development in relation to immune marrow environment enabling tumour persistence and relapse in myeloma

PIs: Paresh Vyas, Udo Oppermann, Karthik Ramasamy

Research fellows: Dr Sarah Gooding, Dr Manman Guo, Dr Reshma Nibhani, Dr Adam Cribbs

Supported by Celgene and Oxford-NIHR BRC

Myeloma is a clonally heterogeneous disease and therapeutic outcomes depend upon underlying mutational composition as well as subsequent evolution in the clonal landscape following exposure to sequential therapy combinations. The combination of therapy-driven clonal evolution and the tumour’s ability to adopt a reversible, microenvironment-dependant dormancy, are proposed as fundamental reasons why even deep remissions inevitably relapse. The existence of “myeloma stem cells” or myeloma propagating clonal cells, and whether they reside in a preplasmablast or B cell stage of maturation remains an area of contention.

Despite new and highly effective therapies in recent years, multiple myeloma remains incurable. It is known that the lower the measurable residual disease (MRD) fraction that can be obtained from induction and consolidation therapy, the longer the progression free and overall survival. Achievement of MRD negativity depends upon therapy efficacy and sensitivity of the assessment technique. ‘Next Generation Flow’ MRD enumeration has recently been demonstrated to rival the 10-6 sensitivity of next-generation sequencing (NGS). Both NGS and immunophenotyping methods have been shown to have prognostic significance. Single cell sequencing is beginning to be employed in myeloma. These approaches permit a timely analysis of the effect of specific treatment combinations on clonal structures and immune responses using longitudinal samples. In this project we investigate the MM clonal developments and bone marrow immune and stromal interactions in response to therapy using systems approaches combining NGS, mass cytometry, proteomic and metabolomic approaches.


CLINICAL STUDIES

Myeloma patient PET

Observational and interventional clinical studies have been designed in areas of unmet need in myeloma; renal impairment and myeloma bone disease. Working in partnership with researchers at the Nuffield orthopaedic centre, Oxford centre for magnetic resonance and imaging observational studies have been designed to understand the burden of myeloma bone disease and to develop new imaging technique sin myeloma. Myeloma patients presenting with renal impairment have been excluded from drug interventional clinical trials due to safety concerns. We have designed a prospective trial which enrolls patients with renal impairment and will help collect required information to developing new studies in this area.

PROJECTS:
Myeloma RUDY project

PIs: Kassim Javaid, Karthik Ramasamy

Supported by AMGEN and Oxford NIHR BRC

To date, most research in myeloma has focused on improving patient survival through novel therapies. However, a comprehensive patient survey performed by Myeloma UK in 2011 showed bone pain was a significant concern to patients with 68% experiencing pain each day. This emphasises the importance of optimising bone health to reduce bone complications and improve bone health outcomes and quality of life (QoL) in addition to improving survival. Novel therapeutic strategies have significantly improved survival in myeloma. Understanding the contemporary frequency, predictors and outcomes of myeloma bone disease from the patient and health economic perspective will inform future personalised research strategies as well as commissioning of clinical services in the NHS.

The primary objective is to describe the incidence and predictors of bone complications including pain, bone fractures and use of bone-specific treatments in patients with a diagnosis of myeloma.

We will adapt the ongoing web-based prospective cohort RUDYstudy to include all myeloma patients. The RUDY study will consist of features relevant to myeloma such as pertinent history questions, chemotherapy, radiotherapy, bone treatments and surgeries. We will also develop a new module to capture healthcare usage in a diary format. The RUDY cohort is offered dynamic consent to be invited in future studies and so will form a valuable research resource for the myeloma research community.

To describe the frequency of bone complication/s and their impact on healthcare usage in patients with myeloma in a real-world setting, we will use routinely-collected primary care data within the Clinical Practice Research Database (CPRD).


The development and pilot testing of a new Magnetic Resonance (MR) imaging protocol to quantify both myeloma disease burden and associated bone loss (LOOMIS)

PIs: Karthik Ramasamy, Sarah Gooding

Research fellow: Guido Nador

Supported by Amgen, Oxford BRC

A number of tests are used for disease quantification to guide therapy; however these tests each have limiting factors. Bone marrow histology using a bone marrow biopsy is painful and invasive; it also cannot predict global myeloma infiltration, which is not uniform and varies through the skeleton, and no bone loss information can be obtained. Serum paraprotein, light or heavy chain quantification must be used for regular monitoring; however this fails in non-paraprotein secreting myelomas, and although it tracks the secretory capacity of a plasma cell clone, that feature can change over the course of the disease. The extent of lytic bone disease, the major cause of morbidity in myeloma affecting over 90% of patients, still cannot be quantified. Lytic lesions as seen on X-rays take many years to heal. In MGUS (Monoclonal gammopathy of uncertain significance), a precursor of multiple myeloma without any signs of the malignant disease (Bauerle et al, 2009), it is suspected that early bone destruction is associated with transformation to malignancy, but no appropriate imaging modality exists to assess or monitor this, meaning this patient cohort may be missing out on disease modifying therapies. We wish to address this important unmet clinical need by piloting a novel MR imaging assessment of disease burden and bone loss in myeloma.


Optimising Renal outcome in Myeloma renal failure (OPTIMAL) -- A study of Thalidomide, Bendamustine and Dexamethasone (BTD) vs Bortezomib, Bendamustine and Dexamethasone (BBD) in patients with renal failure defined as a GFR below 30 mls/min.

PI: Karthik Ramasamy

Funders: Bloodwise, Janssen Oncology

Renal impairment is a life threatening complication of myeloma. Up to 20-25% of patients will present at myeloma diagnosis with renal dysfunction. Outcome is poor as a result of a high early mortality, with 28% of newly diagnosed myeloma patients in myeloma trials with renal failure not surviving beyond 100 days compared with 10% overall. The MERIT trial and results of studies in the Mayo Clinic and Birmingham show that within weeks of diagnosing myeloma with renal failure, treatment with dexamethasone alone or combined with bortezomib lowers serum free light chain (sFLC) levels by more than 50% in half of patients. Importantly, achieving lower sFLC levels in this early period is associated with a greater chance of being alive and dialysis free at 100 days. In this study we aim to (i) establish whether proteasomal inhibition (bortezomib) or immunomodulatory (thalidomide) based therapy achieves threshold reduction of sFLCs in a significant majority of patients; (ii) establish whether sFLC response to the first two cycles (early responder) predict haematological and renal response to next two cycles of therapy and lastly (iii) establish an early time point for assessment of sFLC reduction as a biomarker for response.

The results of this trial will be used to show if bortezomib based induction is superior to thalidomide based induction for threshold sFLC reduction, which is important in light of NICE approval for bortezomib use upfront only in thalidomide contraindicated or intolerant patients. Early identification of poor responders based on sFLC response who may benefit from alternative therapy will be derived from this study to build a Phase III question.