Title: Improving the monitoring and treatment of multiple myeloma patients by comparing cellular and serological markers of minimal residual disease
Funder: Health Education England

Abstract: Background to Research Multiple myeloma (MM) is a haematological malignancy formed by malignant plasma cells in the bone marrow. The annual incidence of new MM cases in the UK is 5500, with a median age at diagnosis of 66 years. The median survival time from diagnosis is 6 years. The optimal treatment for MM is chemotherapy followed by an autologous stem cell transplant (ASCT). However some patients may not be eligible for transplant due to advanced age or other co-morbidities. MM is currently incurable and the majority of patients will relapse and require further treatment. A prognostic factor for the length of time till relapse is the presence or absence of minimal residual disease (MRD) in the bone marrow after treatment. The current gold standard method for detecting this MRD is performing multi-parameter flow cytometry (MFC) of a bone marrow sample to sensitively detect malignant plasma cells. In order to use this test to monitor patients for relapse, frequent bone marrow samples would need to be taken which is invasive and distressing for the patient. Two new sensitive serological assays, Freelite and Hevylite (The Binding Site), may lead to new ways of detecting MRD outside of the bone marrow. The Freelite assay detects free light chains (FLC) produced by malignant plasma cells. The Hevylite assay detects the specific heavy chain joined to the light chain (HLC) produced by the malignant plasma cells. At diagnosis the results of these two tests are often abnormal in MM patients. I aim to determine whether blood assays are a useful tool for sensitively monitoring patients without the trauma of repeated bone marrow aspirations. Aims of Research The primary aim of this research is to determine if the normalisation of the serological markers FLC and HLC is a valuable surrogate marker for a lack of MRD in the bone marrow of MM patients. The intention is to show that FLC and HLC assays can act as safe, sensitive and effective markers of MRD. Further to this FLC and HLC will be used to monitor patients for early signs of relapse with the hope of detecting relapse earlier than currently used serological assays such as serum protein electrophoresis and as sensitively as bone marrow MFC. The use of FLC and HLC will also be assessed in the relapse setting of those patients who are ineligible for transplant. Plan of Investigation Recruitment of newly diagnosed MM patients who are on course to receive ASCT will occur over 18 months. Bone marrow analysis using MFC and serum analysis using FLC and HLC will be performed both pre- and post-ASCT. Comparison of the prognostic utility of these tests will be assessed through up to 28 months of follow up, assessing for signs of relapse using FLC and HLC assays alongside conventional methods of response assessment to determine if FLC/HLC can detect relapse at an earlier time point. FLC and HLC will be used to monitor transplant ineligible patients during and after chemotherapy to assess for signs of relapse and evaluate the efficacy of treatments. Benefits to the Patient and the NHS This project aims to improve the patient experience by lowering the number of distressing bone marrow samples needed for effective prognosis and monitoring. It will also improve patient treatment by detecting the return of the cancer quickly through regular blood tests, so that treatment can be given before irreversible organ damage occurs. Detecting relapse earlier will help to guide therapeutic decisions, reduce both morbidity and mortality in MM patients, enhance patients' quality of life and lead to the provision of a more efficient healthcare service.

Lay abstract: Research Aim: To improve the care and treatment of multiple myeloma patients by replacement of a bone marrow test with a blood test.Background Multiple myeloma is a cancer in the bone marrow. In the UK 5,500 new patients are identified with multiple myeloma each year. This cancer tends to affect patients over the age of 60 years. The cancerous cells in the bone marrow produce a large amount of protein which is not produced by healthy cells. These cancer cells, and the protein they produce, cause organ damage around the body as the protein travels in the bloodstream. Multiple myeloma patients can have bone pain, bone fractures, kidney problems, weight loss, vomiting and weakness. It is very important to treat multiple myeloma patients quickly to try to avoid this organ damage and stop the cancer cells spreading throughout the body. Despite the many treatment options available multiple myeloma is currently incurable, as the disease will often return after treatment. The average survival time after diagnosis is 6 years. Patients who are identified as having multiple myeloma are given treatment such as chemotherapy. Most patients will also be given a stem cell transplant to get rid of the cancer cells from the bone marrow and replace them with healthy cells. After treatment many patients have either no or very few cancer cells left. The number of cancer cells in the bone marrow may start to increase again after treatment. It is important to detect even a small number of cancer cells as these patients will need to be treated again quickly to avoid more organ damage or death. Very sensitive tests are needed to detect these low numbers of cancer cells in the bone marrow of treated patients. One current test involves counting the number of abnormal cancer cells and normal healthy cells in a bone marrow sample. However, having bone marrow samples taken is painful and unpleasant for the patient. As the returning cancer cells need to be detected as soon as possible, regular bone marrow samples need to be taken from each patient. An alternative way to identify the cancer cells may be to use a blood test to detect the protein produced by the cancer cells. Two new, sensitive blood tests may help us see if these bone marrow tests can be performed less often, or not at all. These blood tests can detect very small amounts of the protein produced by the small number of cancer cells in the bone marrow. In this way we can detect these cancer cells before their numbers begin to grow, potentially without the need for regular bone marrow sampling. What will we do? We aim to work out whether these new blood tests are a useful tool for regularly checking multiple myeloma patients without the trauma of repeated bone marrow samples being taken. We will compare the results of the bone marrow sample, taken after treatment, to blood tests performed at the same time. We will then follow these patients with regular blood tests to help us detect a return of the disease as quickly as possible. Feedback from current multiple myeloma patients has been very positive about this project as many find having a bone marrow sample taken to be a traumatic experience.Summary This research will: - Determine if these new blood tests can be used to predict if the cancer will return in treated multiple myeloma patients without the use of a bone marrow sample. - Improve the patient experience by lowering the number of distressing bone marrow samples taken from a patient. - Improve patient treatment by detecting the return of the cancer quickly through regular blood tests, so that treatment can be given before more organ damage occurs. - Publicise the use of this test to doctors and patients throughout the NHS to help improve patient care nationally. Results will be distributed via several routes including publications, presentations at national and international conferences, reports to patient groups, reports at GP meetings and via the NIHR dissemination centre.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS