Spencer Group - Myeloma
Division of Blood Cancers
Absent - Dr Krystal Bergin, Ms Ashley George, Dr Jay Hocking, Dr Anna Kalff, Dr Patricia Walker
To identify better therapeutic strategies and methodologies to improve the survival of multiple myeloma (MM) patients.
The Myeloma Research Group (MRG) within the Division of Blood Cancers, ACBD, focuses on the pre-clinical identification and development of novel and emerging anti-MM therapeutic agents and improve methodologies for genomic characterisation and therapeutic monitoring through the utilisation of liquid biopsy, including cell-free DNA, RNA, extracellular vesicles and proteins. The group utilizes a wide range of commercially available and unique in-house generated human myeloma cell lines, an expansive bank of clinically annotated samples obtained from MM patients, the 5T33 syngeneic murine model of systemic myelomatosis and human-murine xenograft in NSG mice for biological studies and drug testing. The MRG works in close collaboration with the Haematology Clinical Research Unit (CRU, Alfred Hospital) and undertakes focused correlative studies with a particular emphasis on biomarker recognition and development. The MRG also facilitates the collection and storing of samples from the national biobank, M1000 that aims to procure liquid biopsy samples from n=1000 each of pre-malignant and newly diagnosed MM.
Multiple myeloma (MM), a cancer of plasma cells, is the second most common form of blood cancer, and despite the significant advances made in cancer treatment over the past decade is one of the few cancers that still remains incurable with a relative 5-year survival of 48.5% among newly diagnosed (ND) patients. Notably, the overall survival of patients deemed as poor-risk (high risk chromosomal signature and/or early relapse) is <2 years. Data from the 2019 Australian Institute of Health and Welfare ‘Cancer in Australia’ report demonstrates that the MM in Australia continues to rise, and while representing only 1-2% of cancers, MM is in the top ten cancer diagnoses in terms of frequency of requirement for hospitalisation.This is attributed to the fact that MM is a highly complex and genetically heterogenous disease that involves multiple organs and can cause pathological bone fractures, kidney failure and severe immunosuppression necessitating access to complex supportive care. Currently, the therapeutic approach for MM in Australia is based on the use of 2 classes of anti-MM drugs – immunomodulators (IMIDs) and proteasome inhibitors (PIs) – either individually or in combination, and in younger patients, the use of high-dose chemotherapy conditioned autologous stem cell transplantation (ASCT). No new class of anti-MM therapeutic agent had been listed on the PBS in Australia for 13 years, in contrast to many first-world nations, where in the last 5 years, one or all of, a range of new and highly active anti-MM therapeutics with alternative mechanisms of action have been made available to MM patients. The MRG focuses on identifying novel and emerging anti-MM therapeutics to improve treatment options for MM patients.
Genomic characterisation is an important facet of identifying novel therapeutic targets and relies on single-site BM biopsy that is inadequate for capturing the spatial genetic heterogeneity of this multi-focal disease. Consequently, identifying genomic markers of disease progression is challenging, uncomprehensive and underexplored. We have identified an innovative alternative approach - liquid biopsy. Cancer cells shed small amounts of nucleic acids and proteins into the blood stream that provides a more holistic picture of the genetic landscape of MM. Our research focus utilises this novel concept of liquid biopsy, instead of a BM biopsy to improve the methodologies for tumour genome characterisation and therapeutic monitoring in MM.
Projects and Opportunities
- Determining the mechanisms of action of novel inhibitors (immunomodulatory drugs, proteasome inhibitors, epigenetic modifiers, beta-catenin inhibitors, RAS-MAPK) in MM
- Evaluation of circulating cell-free DNA and extracellular RNA in tumour genome characterisation and therapeutic monitoring in MM
- Utilisation of proteomics and metabolomics to identify biomarkers of disease progression/drug resistance in MM
- Extracellular vesicles (EVs) as liquid biomarkers and potential drivers of disease progression and drug resistance.
- Genetic mutations and cellular pathways that drive disease progression in extramedullary MM, including the exploration of possible diagnostic and therapeutic implications
- Exploration of MYC oncogene as a driver of disease progression in MM
- Application of bioinformatic computational techniques to identify key genetical modifications in MM patients and utilise that information to improve patient care
For current project opportunity descriptions please visit our honours page.
- The Myeloma Landscape in Australia and New Zealand: The First 8 Years of the Myeloma and Related Diseases Registry (MRDR).
- Human myeloma cell- and plasma-derived extracellular vesicles contribute to functional regulation of stromal cells.
- Evaluation of EuroFlow minimal residual disease measurement and donor chimerism monitoring following tandem auto-allogeneic transplantation for multiple myeloma.
- Phase II trial of single-agent panobinostat consolidation improves responses after sub-optimal transplant outcomes in multiple myeloma.
- A preliminary study of the anti-κ myeloma antigen monoclonal antibody KappaMab (MDX-1097) in pretreated patients with κ-restricted multiple myeloma.
- Monitoring tumour burden and therapeutic response through analysis of circulating tumour DNA and extracellular RNA in multiple myeloma patients.
- β-Catenin Inhibitor BC2059 Is Efficacious as Monotherapy or in Combination with Proteasome Inhibitor Bortezomib in Multiple Myeloma.
- Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma.
- MDX-1097 induces antibody-dependent cellular cytotoxicity against kappa multiple myeloma cells and its activity is augmented by lenalidomide.
- A rare case of IGH/MYC and IGH/BCL2 double hit primary plasma cell leukemia.
Bergin K, Wellard C, Moore E, McQuilten Z, Blacklock H, Harrison SJ, Ho PJ, King T, Quach H, Mollee P, Walker P, Wood E, Spencer A; Clin Lymphoma Myeloma Leuk. 2021 Jan 30: S2152-2650(21)00034-3.
Reale A, Carmichael I, Xu R, Mithraprabhu S, Khong T, Chen M, Fang H, Savvidou I, Ramachandran M, Bingham N, Simpson RJ, Greening DW, Spencer A. Proteomics. 2021 (In Press).
Tan JLC, Das T, Kliman D, Muirhead J, Gorniak M, Kalff A, Walker P, Spencer A. Bone Marrow Transplant. 2021 May;56(5):1116-1125.
Mithraprabhu S, Kalff A, Gartlan KH, Savvidou I, Khong T, Ramachandran M, Cooke RE, Bowen K, Hill GR, Reynolds J, Spencer A. Br J Haematol. 2021 Apr;193(1):160-170.
Spencer A, Walker P, Asvadi P, Campbell DH, Reed K, Herbert BR, Breen EJ, Copeman MC, Dunn RD. Blood Cancer J. 2019 Jul 31;9(8):58.
Mithraprabhu S, Morley R, Khong T, Kalff A, Bergin K, Hocking J, Savvidou I, Bowen KM, Ramachandran M, Choi K, Wong BKL, Reynolds J, Spencer A. Leukemia. 2019 Aug;33(8):2022-2033.
Savvidou I, Khong T, Cuddihy A, McLean C, Horrigan S, Spencer A. Mol Cancer Ther. 2017 Sep;16(9):1765-1778.
Mithraprabhu S, Khong T, Ramachandran M, Chow A, Klarica D, Mai L, Walsh S, Broemeling D, Marziali A, Wiggin M, Hocking J, Kalff A, Durie B, Spencer A. Leukemia. 2017 Aug;31(8):1695-1705.
Asvadi P, Cuddihy A, Dunn RD, Jiang V, Wong MX, Jones DR, Khong T, Spencer A. Br J Haematol. 2015 May;169(3):333-43.
Kalff A, Khong T, Wall M, Gorniak M, Mithraprabhu S, Campbell LJ, Spencer A. Haematologica. 2015 Feb;100(2): e60-2.