Chapter 4

Thalidomide, Bortezomib and Lenalidomide – Three Drugs that Changed Multiple Myeloma

Jiri Minarik and Vlastimil Scudla

Abstract

Multiple myeloma (MM) is a hematological malignancy with a very heterogenous presentation, course and prognosis. Despite an immense progress in the understanding of the tumour biology, neoplastic transformation and progression, we still do not know all the processes that contribute to the multistep pathogenesis of this disease.

For quite a long time there have been a lot of efforts at the improvement of therapeutic approaches in order to intensify the treatment to reach a better response rate, and to prolong the overall survival in MM patients. For more than 30 years, combined chemotherapeutic regimens, and later on high-dosed regimens with autologous stem cell transplantation tried to establish the best approach, however, none of the conventional regimens finally turned out to be significantly superior than the regimen MP (melphallan and prednisone) in the elderly, and HD-ASCT (high-dosed chemotherapy with support of autologous stem cell transplantation) in younger patients.

The last 10 years, however, dramatically changed therapeutic outcomes, and the long lasting “golden-standard” treatment schedules were modified substantially. This change was caused by the introduction of the first generation of novel drugs with “biological mechanism of action”. These new drugs are thalidomide, bortezomib and lenalidomide.

Thalidomide, this teratogenic agent whose short sad history started in 1950´s and ended in 1961 was re-discovered for multiple myeloma in 1999. Since then, several randomized studies have confirmed its superiority in the treatment of relapsed and refractory MM as well as in the frontline treatment of the disease. Unlike many other “biological drugs”, the “biological effect” of multiple myeloma is not aimed solely at one pathogenetic pathway, and does not influence the tumor cells only. It relies on the anti-angiogenic and immunomodulatory effects, together with the inhibition of IL-6 (the most prominent MM growth factor), activation of apoptotic pathways and activation of T-cells.

Bortezomib is the first proteasome inhibitor tested on humans. Its unique mechanism of action by the inhibition of proteasome has a specific affinity to the tumor tissue and widely influences all – proliferation, differentiation and apoptosis of myeloma plasmocytes. Laboratory experiments as well as randomized clinical trials brought surprisingly high percentage of response rates with manageable toxicity. Moreover, rapid effect of bortezomib influenced a substantial number of patients with initial renal failure. Very soon, combined regimens with bortezomib became a new “golden standard” in the management of multiple myeloma.

Lenalidomide was first introduced in 2004. This analogue of thalidomide belongs to the group of drugs called IMiDs - immunomodulatory drugs. Similarly as thalidomide, it has a direct antimyeloma effect as well as the effect on immunity system and bone marrow microenvironment. Lenalidomide has many times greater effect on the inhibition of tumor necrosis factor-alpha, and it has less severe toxicity profile than thalidomide. Unlike both, thalidomide and bortezomib, lenalidomide does not cause neuropathy and is well tolerated in most patients, making it one of the most suitable drugs for frontline treatment as well as for the long-term administration.

The aim of the presented chapter is to make an overview of the history, background and therapeutic applications of thalidomide, bortezomib and lenalidomide in multiple myeloma. Advantages as well as drawbacks of individual treatment approaches will be discussed, and supported by the data of recent clinical studies and papers.

Total Pages: 103-178 (76)

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