**Part 1**

**Multiple Myeloma: Disease Biology and It's Therapeutic Applications** 

**1** 

**Proteasome Inhibitors in the Treatment** 

*Centre for Cancer Research and Cell Biology, Queen's University Belfast* 

The ubiquitin proteasome system is responsible for the degradation of proteins involved in a wide range of cellular processes such as the cell cycle, apoptosis, transcription, cell signalling, immune response and antigen presentation. Protein homeostasis is essential for normal cell growth and inhibition of proteasome function has emerged as a viable strategy for anti-cancer treatment. The first proteasome inhibitor to enter clinical practice, bortezomib, was approved by the Food and Drug Administration as a single agent to treat relapsed/refractory Multiple Myeloma in 2003 and expanded to first-line treatment in combination with melphalan and prednisone in 2008. It is now a routine component of Multiple Myeloma therapy and has had a major impact on expanding treatment options in the last few years. Bortezomib exhibits novel action against Multiple Myeloma by targeting both intracellular mechanisms and interactions within the bone marrow environment. Although it demonstrates significant anti-Myeloma activity when used alone, it has been shown to have even greater benefits when used in combination with conventional and novel chemotherapeutic agents. There are currently over 200 clinical trials ongoing or recently completed examining bortezomib alone and in combination in various stages of disease and treatment. The clinical success of bortezomib has prompted the development of a number of second generation proteasome inhibitors with improved pharmacological properties. In this chapter, we review the development of bortezomib as a novel therapeutic agent in Multiple Myeloma and summarize the key observations from recently completed and ongoing studies on the effect of bortezomib both as a single agent and in combination therapies in the setting of newly diagnosed Multiple Myeloma and for relapsed disease. We also discuss

The ubiquitin proteasome pathway represents the major pathway for intracellular protein degradation. It is responsible for the degradation of approximately 80% of cellular proteins, including misfolded and mutated proteins as well as those involved in the regulation of development, differentiation, cell proliferation, signal transduction, apoptosis and antigen presentation. Proteins are degraded by the ubiquitin proteasome pathway via two distinct and successive steps: the covalent attachment of multiple monomers of ubiquitin molecules to a protein substrate and degradation of the tagged protein by the 26S proteasome. Tagging

the progress of next generation proteasome inhibitors in the clinic.

**2. The ubiquitin proteasome system** 

**1. Introduction** 

**of Multiple Myeloma** 

 *Northern Ireland* 

Lisa J. Crawford and Alexandra E. Irvine
