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By Dixie-Lee Esseltine, M.D., FRCPC, Vice President, Oncology Clinical Research, Takeda

My 16 plus years at Takeda Oncology have given me the opportunity to participate in and contribute to the evolution of treatment for multiple myeloma, a rare cancer that affects nearly 230,000 people around the world, according to five-year prevalence estimates.1 While the disease remains incurable, we have made important advances in research and development in recent years.

The average survival of a patient diagnosed with multiple myeloma between 2001 and 2005 was just over four and a half years. For those diagnosed during 2006 to 2010, median overall survival increased to more than six years.2 That change is likely due in part to the availability of novel medicines such as proteasome inhibitors.

Demonstrating the Clinical Utility of a New Mechanism of Action
Proteasome inhibition is now considered a standard of care in the treatment of multiple myeloma, but when I joined Takeda Oncology in 2000, the utility of this class of medicines was far from proven. It was a very different time in myeloma research and treatment, without the consensus statements or guidelines we have today, and with very few randomized clinical trials. As one of my colleagues remarked recently, “we knew a lot about very little.”

What we did know was that the proteasome, part of the human cell structure, serves an important function: it is responsible for breaking down unneeded or damaged proteins at a cellular level. Blocking the proteasome’s activity causes proteins to accumulate in the cell, which can lead to apoptosis, or cell death.3 Initially, some researchers assumed that inhibiting this pathway would have widespread deleterious effects by destroying healthy cells in addition to cancerous cells.4-5

This view was overturned by the discovery that proteasome inhibition preferentially induced apoptosis in vitro in abnormal, transformed cells, such those that cause myeloma.6-7 After discovering methods for inhibiting the proteasome, our next step was to investigate the use of this approach in treating patients.

In the beginning, we did not have a huge staff or a complex infrastructure. We were a small group of passionate people — working around the clock — with countless great collaborators towards the collective goal of learning more about how this class of medicines might work for patients. Following initial study results, our team focused intensely on advancing proteasome inhibitors through early — and then late-stage clinical trials. And with each encouraging data readout, I knew that we were on the cusp of a new paradigm in multiple myeloma treatment.

The Next Frontier for Proteasome Inhibition
It was a long road from “bench to bedside,” but ultimately our efforts and those of many others paid off for patients. The widespread adoption of proteasome inhibitors and immunomodulatory drugs8-9 as a treatment strategy in multiple myeloma has led to a substantial improvement in outcomes compared to first-generation treatments introduced more than forty years ago.10

Scientists across the world have continued to study proteasome inhibition, identifying drug candidates that may offer improved efficacy, reduce side effects and address unmet needs for patients. We have extended our research beyond multiple myeloma into related diseases affecting the plasma cells, such as amyloidosis, and subtypes of non-Hodgkin lymphoma.11-12 Our understanding of the complex signaling pathways affected by proteasome inhibition continues to grow, which in turn opens up new areas of potential exploration for its use and aids in the development of rational approaches to combination therapy.

During my time in hematology clinical practice, there were many days when there was nothing more that could be done for the patients we treated. Those moments fueled my desire to investigate novel treatment pathways and challenge assumptions about the feasibility of therapeutic approaches. I have no doubt that there is more to come for proteasome inhibition and other pathways — and I look forward to seeing more options be developed for patients. It has been an honor and a privilege to be part of this research.

1International Agency for Research on Cancer. Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence in 2012. Accessible on: Accessed November 8, 2016.
2Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 2014;28(5):1122–8.
3Moreau P, Richardson PG, Cavo M, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood 2012;120:947–59.
4Rolfe M, Chiu MI, Pagano M. The ubiquitin-mediated proteolytic pathway as a therapeutic area. J Mol Med (Berl). 1997;75:5–17. 37.
5Orlowski RZ, Kuhn DJ. Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res. 2008; 14:1649-57.
6Delic, J., Masdehors, P., Omura, S. et al, The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer. 1998;77:1103–1107.
7Orlowski, R.Z., Eswara, J.R., Lafond-Walker, A. et al, Tumor growth inhibition induced in a murine model of human Burkitt’s lymphoma by a proteasome inhibitor. Cancer Res. 1998;58:4342–4348.
8Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117:6063–73.
9Ludwig H, Beksac M, Blade J, et al. Multiple myeloma treatment strategies with novel agents in 2011: a European perspective. Oncologist. 2011;16:388–403.
10Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–20.
11Gertz MA. Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2011;86:180–6.
12Goy A, Kahl B. Mantle cell lymphoma: the promise of new treatment options. Crit Rev Oncol Hematol. 2010; 80:69–86.