B cell function and risk of progression in smouldering myeloma

Multiple myeloma (MM) is a cancer of the blood and bone marrow which affects 24,000 patients in the UK at any one time. Patients with MM have an abnormal growth of plasma cells in their bone marrow. These cancerous plasma cells grow in an uncontrolled manner and can cause symptoms such as kidney failure, bone pain and fractures, and anaemia caused by low red blood cells. Although many new treatments exist, MM remains incurable. MM starts as a pre-cancerous condition called smouldering myeloma, where abnormal plasma cells are detected in the bone marrow, but patients do not have symptoms. Currently these patients are not treated but are monitored as many will progress to symptomatic disease over time and need chemotherapy, however others will not. Although there is interest in treating these patients to see if we can delay progression to active MM, we do not have a full understanding of why some people progress, and others don't, to predict which patients will need treatment. In addition, if we understand the factors that contribute to disease progression from smouldering myeloma we hope that targeted treatments could be given to stop active myeloma developing.

We now understand that progression of pre-malignant conditions to cancer occurs when cancer cells have escaped from the control of immune cells, and that these immune cells play a part in controlling the smouldering plasma cells in patients who do not progress. But we do not understand the functions of the different types of immune cells here. Most research has focussed on a type of white blood cells called T cells which can kill cancer cells. B cells are another type of immune cell, that fight infection by making antibodies. We know that the B cells in MM patients are often defective, and do not make normal levels of antibodies in response to infection or vaccination. Thus MM patients often get frequent infections. Plasma cells, which are the cancer cell in myeloma, are also related to B cells. We do not understand how B cells in the bone marrow change as myeloma develops, although we have evidence that they are already reduced in number in smouldering myeloma patients. We also do not understand whether marrow B cells play a part in the development of the cancer or if they can be protective. Different subtypes of B cells exist and some of these types have been shown to be protective or harmful in other cancers.

We have started to look at the B cells in patients with smouldering myeloma, and we have found that there are marked changes in distinct sub-families of these cells. We believe that these changes hold clues as to how B cells may play a part in the development of this cancer.

The aims of this project are:
1. Characterise the B cell populations in smouldering myeloma
2. Look at how these B cells function in smouldering myeloma, compared to B cells from healthy people
3. Recreate this dysfunction in a mouse model of myeloma to study how B cells affect the development of myeloma.

This will be carried out at UCL, with other collaborators in the UK. Patient samples are collected from a national clinical trial where patients consent for extra samples to be used for research when they are having blood or bone marrow taken. These patients have chosen to consent to the trial because they want to help further understanding of this disease. A mouse model of myeloma will be studied to follow the changes in B cell behaviour and numbers.

The goal of this work is to try and understand if we can predict more accurately which patients with smouldering myeloma will progress to MM, and to understand what part B cells play in this progression. Our work will discover if changes in certain B cells can signal a greater risk of progression, and how to use this knowledge to design treatments to prevent progression from smouldering myeloma to active MM.

Multiple myeloma (MM) is an incurable haematological malignancy with all cases preceded by an asymptomatic precursor state, either monoclonal gammopathy of unknown significance (MGUS) and/or smouldering myeloma (SMM). Patients with precursor conditions have a risk of progression to active disease, but not all patients will progress. This project focuses on SMM as these patient have a 50% risk of progression over 5 years. Tumour factors such as genetics and disease bulk influence this risk but the immune microenvironment is increasingly understood to play a role. Most work however has focused on T, NK or myeloid cells, and little is known about B cells in SMM. MM patients have increased infections, impaired vaccine responses and have low immunoglobulins, indicating defective B cell function. This work aims to profile B cell populations and their function in SMM, correlating with clinical outcomes and other known factors of risk such as disease bulk and tumour genetics.

Specific Aims:
1. Characterise changes in B cell subsets in SMM and compare with healthy controls (HC) and MM
2. Assess functional activity of BM B cells from SMM to confirm transcriptomic and phenotypic data
3. Track dynamic changes in B cell subsets during disease progression to MM

Patient bone marrow and blood samples from the NCRN observational SMM study, COSMOS, will be studied using single cell and bulk RNA sequencing, flow and mass cytometry, comparing with healthy donors and MM. Functional studies will examine B-cell receptor signalling via calcium flux assays and cytokine production. An in vivo model will be used to study dynamic changes in B cell populations with disease development. This will test our hypothesis that B cell subsets and function dynamically change in SMM development. Results will be integrated with parallel projects on T, NK and myeloid cells to understand how altered immune function contributes to malignant transformation from SMM to MM.