Towards individualisation of combination chemotherapy in myeloma

Abstract

Multiple myeloma is an incurable haematological malignancy caused by malignant plasma cells that leads to bone lesions, anaemia, immune suppression and renal damage. Recent improvements in survival can be attributed to the availability of stem cell transplant and an ever-growing armoury of drugs deployed in combinations that are determined by a patient’s tolerance and the tumour’s sensitivity. Predicting either of these is beyond the scope of the disease staging or risk stratification systems available to clinicians and will remain so until the range of biomarkers reflects the great complexity of the disease.

The study described here employed multiplex immunoassays and multicolour flow cytometry to measure a broad range of cellular and immunological parameters in 86 patients who have either myeloma or one of its precursor conditions, MGUS and smouldering myeloma. These parameters were compared across different patient groups and over time to identify potential biomarkers capable of predicting disease progression or treatment response.

The proteomic study identified protein signatures of MGUS, smouldering myeloma, untreated and treated myeloma together with six proteins, IL-18, Fas ligand, Granzyme B, Granzyme H, ARG1 and MMP7, that showed potential as a biomarker of progression to myeloma from its precursor conditions. One of these six, Fas ligand, also showed a strong relationship with disease relapse. In addition, differences in levels of the chemokine CCL23 in blood plasma were observed when patients were receiving drug therapy.

Flow cytometric data suggested a role for detection of circulating cells by showing that myeloma cell, normal plasma cells and B lymphocytes in the peripheral blood appear to track the condition of the bone marrow and thus blood sampling might be considered a convenient surrogate for bone marrow aspiration. In addition, numbers of circulating myeloma cells showed an inverse relationship to the number of normal plasma cells in the bone marrow. Some concordance was also observed between circulating tumour cells and sensitive paraprotein measurement using Binding Site’s HevyLite® assay, while a more complicated relationship was suggested between amounts of circulating normal plasma cells and paraprotein. Finally, the data strongly suggested a decrease in circulating CD4+ T cells as the disease progresses, and an association between granzyme and CD8+ T cells, but not NK cells.

The study identified potential protein and cellular biomarkers while providing clues as to the biology underlying disease progression and the concomitant suppression of normal immune function.

Date of Award	Jun 2018
Original language	English
Sponsors	Department of Education and Learning (DEL)
Supervisor	Tony Bjourson (Supervisor) & H. Denis Alexander (Supervisor)