The clinical role of novel biological agents and the in vivo immunological effects of immunomodulatory drugs (IMiDs) in the management of multiple myeloma

Abstract

© 2010 Dr. Hang Ai QuachOver the last decade, the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortezomib has revolutionised the treatment and outlook of multiple myeloma (MM), an incurable plasma cell malignancy with significant morbidity. Our experience with these novel agents has yet to improve however, with regards to the optimal scheduling and combination therapy that would maximise response duration and survival. Furthermore, the exact anti-myeloma mechanisms of these agents are poorly understood, and many of the proposed mechanisms in vitro have yet to be corroborated in vivo. The work presented in this thesis aims to improve our current understanding of the in vivo immune modulation by lenalidomide in patients with MM, and to fine tune current treatment regimens based on our matured experience with these novel therapeutic agents, so as to minimise toxicity and maximise response and survival outcome. The first chapter (1A) reviews the current treatment paradigm of MM, and the current accepted role of thalidomide, lenalidomide, bortezomib and histone-deacetylase inhibitors. The current understanding of MM pathophysiology and the mechanism of actions of novel agents is reviewed in chapter 1B, providing a background for the correlative immunological studies in chapter 3B. The work from chapters 1A and 1B have culminated in 2 published review manuscript in Drugs and Aging 2007 and Leukemia 2009, respectively (see preface). The second chapter explores the long-term outcome to thalidomide-based treatment to show that depth of response to thalidomide correlates to survival outcome. This chapter highlights the importance complete remissions in the quest for durable responses in the era of novel therapeutic agents. The work from this chapter has been published as a manuscript in Leukemia & Lymphoma 2009. The following chapters (3,5,6) are a series of investigator-driven phase II trials exploring optimal scheduling of lenalidomide or bortezomib with dexamethasone in the treatment of relapsed or refractory MM, as well as the safety and preliminary efficacy of a novel bortezomib-romidepsin combination therapy. To enable the ongoing optimisation of treatment schedules or combinations of novel-agent, an understanding of their individual in vivo effects is important. Correlative immunological studies were therefore performed, as outlined in chapter 3B, to investigate the in vivo immunological changes in patients treated with immunomodulators, and how immune stimulation can be optimised to further improve clinical outcome. Indeed it was found that the concurrent use of dexamethasone abrogates lenalidomide-induced NK cell stimulation, and may subvert the full immune stimulatory capacity of lenalidomide. These findings have been submitted as a manuscript to Blood at the time of this thesis submission, and have been presented at several international scientific meetings. The insight that was gained from this correlative immunological study also resulted in a review manuscript on drug-mediated and cellular immunotherapy in MM, was published in Immunotherapy 2010. Overall, the work from this thesis aims to contribute to the shaping of optimal treatment strategies for MM, as well as an improved understanding of the in vivo effects of lenalidomide. We remain in an era of exploration of the role of novel therapeutic agents in the treatment of MM, and how to best manipulate sequential or combination therapy with the ultimate aim of cure, if not durable disease control