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Nicholas Burwick *
Irene M Ghobrial**
(*)Department of Internal Medicine
Beth Israel Deaconess
Harvard Medical School
(**)Jerome Lipper Multiple Myeloma Center
Division of Hematologic Neoplasia
Department of Medical Oncology
Dana Farber Cancer Institute
Harvard Medical School
Multiple myeloma (MM) is a plasma cell malignancy that accounts for 10% of all haematological malignancy and is the most common cause of mortality in blood cancer.(1) The first effective treatment for MM was described in 1962 with the use of melphalan.(2) Subsequently, melphalan and prednisone became the standard of care for MM, resulting in a median survival of three years.(3) Over the last five years the elucidation of molecular pathways involved in the pathogenesis of MM has led to the development of novel therapeutics. Chief among these agents are thalidomide, lenalidomide and bortezomib. These medications specifically showcase the success of bench-to-bedside research in MM. In this review, we will discuss the mechanisms of action of thalidomide, lenalidomide and bortezomib and we will briefly outline the clinical utility of each in the treatment of MM.
Three recently approved novel agents for the treatment of MM include thalidomide, lenalidomide and bortezomib.
Thalidomide, a glutamic acid derivative, was first used in the 1950s as a sedative hypnotic and antiemetic in pregnant women.(4) However, it was subsequently withdrawn from the market due to its teratogenic side-effects.(5) Subsequently, thalidomide was studied as an anticancer agent, given its known inhibitory effect on growing fetal tissue.(6,7) Initial studies were disappointing, but following the discovery of thalidomide’s antiangiogenic properties in the 1990s, studies were rejuvenated.(8) MM was initially targeted because of its proposed dependence on bone marrow angiogenesis. Later it was also found that thalidomide had immunomodulatory and specific antimyeloma properties.
Thalidomide and its analogues have been shown to induce apoptosis or growth arrest in myeloma cell lines in vitro.(9) These agents trigger activation of caspase-8, enhance MM cell sensitivity to Fas-induced apoptosis and downregulate nuclear factor (NF)-ÎºB activity.(10) In addition, thalidomide and its analogues modulate the bone marrow microenvironment, inhibiting the upregulation of interleukin (IL)-6 and vascular endothelial growth factor (VEGF) and disrupting bone marrow angiogenesis.(11)
Thalidomide is given orally and is typically administered at up to 200mg/day, although lower doses (50ï¿½100mg) are being increasingly utilised. Doses greater than 200mg per day are associated with higher toxicity, both cumulatively and with higher dose.(12) The most common side-effects include peripheral neuropathy, constipation, somnolence and fatigue.(12) Peripheral neuropathy affects 50-80% of patients treated with thalidomide and may limit long-term use.(13,14) In addition, deep vein thrombosis occurs in 1-3% of patients receiving thalidomide alone, and up to 25% of patients when combined with dexamethasone or another cytotoxic agent.(12,15) The risk of thromboembolic disease can be reduced by therapeutic anticoagulation.(16,17)
Studies have examined the efficacy of thalidomide in both relapsed/refractory and newly diagnosed MM. In a phase II study by Singhal and colleagues, single-agent thalidomide for relapsed/refractory MM resulted in a response rate of 41% at three months.(18) The combination of thalidomide and dexamethasone increases response rates to about 50%, and the addition of an alkylating agent (ï¿½cyclophosphamide, melphalan) to this regimen increases response rates to over 65%.(18-20) In newly diagnosed MM, dexamethasone plus thalidomide has a response rate between 58% and 72%, compared with 41% with dexamethasone alone.(21,22) Given the consistent efficacy seen, these studies have led to the recent FDA approval of thalidomide as first-line therapy in patients with MM in May 2006.
Lenalidomide is an analogue of thalidomide, modified with an additional amino group at the number four position of the phthaloyl ring. It is also classified among the new class of oral immunomodulatory drugs (IMiDs), inducing growth arrest or apoptosis in drug-resistant myeloma cell lines.(10) Lenalidomide inhibits binding of MM cells to the bone marrow extracellular matrix, modulates cytokine secretion and inhibits bone marrow angiogenesis.(23) Compared with their parent compound thalidomide, IMiDs have been found to be more potent in inhibiting TNF-alpha and in costimulating CD(4)+ and CD(8)+T-cells.(24)
Lenalidomide, like thalidomide, can be taken orally. It is generally dosed at 25mg per day. Clinical trials have studied doses between 5mg and 50mg per day. Lenalidomide can cause reversible myelosuppression, but unlike thalidomide does not ï¿½generally lead to constipation, somnolence or peripheral neuropathy.(25) In addition, lenalidomide appears to lack the teratogenic properties of thalidomide.(26) Similar to thalidomide, deep vein thrombosis has emerged as an important toxicity. The rate of thrombosis is 10-15% when lenalidomide is used in combination with dexamethasone, as compared with 2-3% with lenalidomide monotherapy.(27)
Clinical trials have studied the efficacy of ï¿½lenalidomide in both relapsed/refractory and newly diagnosed MM. Two phase III studies (the US-based MM-009 and Euopean MM-010) evaluated the combination of lenalidomide and dexamethasone in relapsed/refractory MM. Preliminary results were similar, with response rates around 50%, compared with 18-30% for dexamethasone alone.(28) Based on these studies, lenalidomide was FDA approved in June 2006 for the treatment of MM relapsing after one line of prior therapy.
For patients with newly diagnosed MM, a phase II trial using lenalidomide plus dexamethasone was recently reported in 34 patients. Thirty-one of 34 patients achieved an objective response, including two complete responses. Two phase III trials of lenalidomide with dexamethasone in newly diagnosed MM patients are currently underway.
Bortezomib is a first-in-class 26S proteasome inhibitor.
The proteasome is normally responsible for the enzymatic degradation of ubiquitinated proteins. Bortezomib disrupts this process by selectively, but reversibly, binding to the 20S catalytic domain of the proteasome, inhibiting its activity.(29) Inhibition of this protease affects many different signalling pathways, including those for transcriptional regulation, response to stress and receptor function.(30,31) Among the proteins affected, I-ÎºB (inhibitor of nuclear factor-kappa B) and p53 levels accumulate, which may promote cellular apoptosis.(32-34)
Bortezomib is delivered intravenously, typically at a dose of 1.3mg/m(2), twice weekly for two weeks on days 1, 4, 8 and 11. In phase I trials bortezomib caused dose-limiting diarrhoea and sensory neurotoxicity.(35) Peripheral neuropathy is often painful in nature and develops in 30% of patients. Thrombocytopenia (platelet count <50,000) also develops in almost one-third of patients treated. Dose reductions to 1.0mg/m(2) or 0.7mg/m(2) may be required.(36)
A phase II study evaluated bortezomib in 193 patients with relapsed/refractory MM. The overall response rate was 35% with a median overall survival of 17 months. Responses were durable (median of 12.7 months), and median time to progression was seven months versus a median of three months with the last prior therapy.(37) In another phase II trial patients were randomised to 1.3mg/m(2) or 1.0mg/m(2) of bortezomib, with dexamethasone added for progressive disease. Overall response rate was greater in the high-dose arm (50% vs 33%).(38) Based on the success of these trials, bortezomib was FDA approved for the treatment of relapsed and refractory myeloma in 2003. This was followed by a phase III trial of bortezomib versus high-dose dexamethasone in patients with relapsed/refractory MM, showing a similar response rate of 38% for bortezomib versus 18% with high-dose dexamethasone, with a median overall survival of 29.8 months.(39) This study led to the FDA approval of bortezomib in patients with first relapse in 2005.
Bortezomib has also been studied in newly diagnosed patients with MM. A study reported by our group in 32 newly diagnosed patients who received one to eight cycles of bortezomib monotherapy until disease progression or unacceptable toxicity,demonstrated an overall response rate of 45% with one complete response and 11 partial responses.(40) An updated analysis in 66 patients revealed an overall response rate (CR and PR) of 40% with 10% CR.(41) Toxicity proved modest, and the benefit of a steroid-sparing approach was apparent. Neuropathy was a challenge with a higher than anticipated baseline rate of underlying peripheral neuropathy in newly diagnosed and previously untreated patients observed. Treatment-emergent neuropathy was almost entirely mild to moderate, proving manageable and reversible with dose reduction, the use of supportive medications and completion of therapy. Combination approaches with steroids, IMiDs and cytotoxic chemotherapy have been especially promising, with high CR rates observed (between 20% and 35%) that have proven durable and a tolerable side-effect profile.(42-45)
The recent understanding of molecular pathways and of the key role of the microenvironmental interactions involved in the pathogenesis of MM has led to the development of novel therapeutics with specific antimyeloma activity.
Rapid translation of laboratory data to clinical trials has led to the FDA approval of thalidomide, lenalidomide and bortezomib for relapsed and refractory and newly diagnosed MM. Ongoing trials will study the efficacy of modulating other unique targets in MM, including heat shock protein inhibitors, histone deacetylase inhibitors and Akt-inhibitors as part of a new paradigm of therapies that target both MM and its microenvironment, with the goal of developing less toxic and more active treatments to further improve patient outcome.