Camilleri, Marquita; (2024) The Role of Autologous Stem Cell Transplantation in High-Risk Multiple Myeloma in the Novel Agent Era. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Novel-agent chemotherapy with high-dose melphalan and autologous stem cell transplantation (HDM-ASCT) is standard of care in young, fit newly diagnosed multiple myeloma (NDMM), giving improved progression free survival (PFS) and disease responses, including MRD negativity. However, outcomes remain considerably heterogenous, with improvement mainly seen in standard-risk NDMM while remaining poor for the 15–20% with high-risk disease. This dissertation initially explores the role of carfilzomib (K)-based induction in high-risk NDMM, comparing HDM-ASCT with K-based chemo-consolidation within the phase II, randomised clinical trial CARDAMON. K-based induction in high-risk vs standard-risk NDMM gave less deep serological responses and shorter PFS; K-induction was also associated with a higher early attrition rate within ISS-III patients. None of the high-risk subgroups had an overt PFS benefit with HDM-ASCT, though K-based consolidation compared with transplantation was associated with a decreased MRD negativity rate and increased early relapse. Real-world data from a large, single transplant centre was used to compare single vs tandem HDM-ASCT in high-risk NDMM in the 3rd chapter. Drawing definitive conclusions from this study is difficult given its non-randomised nature, inconsistent treatment pre- and post-ASCT, and small patient numbers in the subgroup analyses. However, early disease relapse during brief, treatment-free periods remains problematic, even with novel chemotherapeutic agents. Tandem HDM-ASCT may be beneficial in ultra-high-risk NDMM provided it is supported with post-ASCT maintenance treatment. The 4th chapter presents findings from a qualitative study carried out while the transplant service was disrupted during the COVID-19 pandemic. This period of unprecedented change provided a unique opportunity to explore patients’ attitudes, perceptions, and expectations around HDM-ASCT, focusing mainly on the new ways ASCT risk was perceived and balanced within the pandemic setting. Concluding remarks summarise the future directions of ASCT’s role in high-risk NDMM, including likely challenges and possible solutions with a suggested, practical way forward.

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