Name of the project:
Understanding the mechanisms underlying treatment resistance and disease progression in myeloma
– Prof Gareth J Morgan
– Dr Lorenzo Melchor
The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG United Kingdom
– Dr Joaquín Martínez López,
Unidad de Hematología, I+12 Hospital 12 de Octubre
– Dr Jesús San Miguel
– Dr Bruno Paiva
Flow Cytometry Unit, Clinica Universidad de Navarra; Centro de Investigaciones Médicas Aplicadas (CIMA). Universidad de Navarra (Spain)
– Dr Michele Cavo
– Dr Annamaria Brioli
Istituto di Ematologia Seràgnoli, Policlinico S. Orsola-Malpighi, University Hospital of Bolonia (Italy)
Timeline: January 2014 – January 2016
Donations received: €166.000
PURPOSE OF THE STUDY AND CLINICAL IMPACT
Multiple myeloma (MM) is an incurable disease, diagnosed in 4,700 patients a year in the UK. The outcome for patients with MM has improved substantially over the past 20 years due to several therapeutic advances. However, MM patients not only still show a heterogeneous response to treatment, which goes from a complete response to a lack of response; but also, and irrespective of the depth of response, eventually all relapse. This clinical history of relapse and remission with subsequent treatment is likely due to the acquisition of additional genetic mutations in the myeloma cells that confer proliferative advantage leading to relapse and treatment resistance [1-3]. Although there have been major efforts to identify which cells drive relapse, there are conflicting results due to differences in techniques, sample series and cellular contamination.
In the current study, we aim to take advantage of the most recent advances in cell separation [4, 5] and molecular genetics [3, 6] to study a series of samples derived from a large collaborative effort between research institutions in the UK and in Spain. We will use state-of-the-art techniques to identify the myeloma stem cells that are resistant to therapy and that, following cell proliferation, are responsible for driving relapse and disease progression in myeloma. This comprehensive characterisation of the nature of the myeloma propagating/stem cells will help us to understand the impact of treatment in myeloma, where the treatment-resistant cells are located, and how treatment can be targeted at myeloma progenitor cells.
In a collaborative effort between three research groups, which are renowned for their expertise in molecular genetic analysis and flow cytometry in multiple myeloma, we will address an important therapeutic and biologically relevant questions.
Our major aim is the understanding of the molecular and cellular mechanisms underlying treatment resistance and disease progression in myeloma.
To achieve this aim, we have the following objectives:
- a) To elucidate the cellular origins of multiple myeloma by identifying the myeloma propagating/stem cell population and its distribution in the B cell lineage
- b) To understand the clinical impact of different treatment regimens on the cellular composition of multiple myeloma during remission and relapse
- c) To characterise the myeloma propagating/stem cells driving relapse to define better therapies able to eradicate these populations
We will achieve these by addressing the following biological/molecular questions:
- What is the impact of different induction treatment (CRD or CVD) on the genetic architecture of MRD states?
- What is the biology of myeloma propagating/stem cell in MM patients and how does it contribute to patient relapse?
- What is the clonal composition of the CD138 high plasma cells, as opposed to the CD138 low plasma cells? Are there any genetic differences attributed to phenotypic plasticity and to treatment resistance?
- What is the clonal architecture of bone marrow plasma cells and circulating plasma cells? How do circulating plasma cells contribute to disease dissemination and metastasis?
- What are the founder mutations and could they precede VDJ recombination and be the myeloma initiating event?
- What are the acquired mutations which drive MM progression?