Thalidomide in Multiple Myeloma: current status and future prospects
Introduction
Thalidomide was introduced in Europe during the 1950s as a sedative agent and was found to be particularly effective at alleviating the symptoms of morning sickness. As is widely known, it was subsequently withdrawn in 1961 after its teratogenic properties were recognised, in particular, its ability to cause phocomelia.
Damage to the fetus occurs early in pregnancy (from days 28-42 post conception) and the limb bud abnormalities are thought to be due to inhibition of normal vessel formation. Since that time, thalidomide's immunomodulatory effects have been recognised and it has been used, in a cautious and restricted manner, in the treatment of such disparate disorders as Behcet's disease, erythema nodosum leprosum, HIV associated oral ulceration and chronic graft versus host disease.
More recently, the drug has been tested in a variety of solid and haematological malignancies and has shown remarkable efficacy in patients with advanced multiple myeloma. Indeed, the use of thalidomide is arguably the most significant advance in the treatment of myeloma since the introduction of high dose melphalan and autologous stem cell transplantation nearly twenty years ago.
Mechanisms of action: anti-angiogenesis
Many tumours require new vessel formation in order to support their continued growth (Folkman, 1974; Holmgren et al, 1995) and various lines of evidence suggest that neoangiogenesis is also important in the pathogenesis of myeloma. Myeloma bone marrow shows increased microvascularity and its density correlates with the clinical aggressiveness of plasma cell neoplasms (Vacca et al, 1994). Furthermore, the density of bone marrow vascularity has important prognostic implications such that patients with extensive vascularity have reduced overall survival (24 months) compared with patients with less extensive vascularity (53 months) (Rajkumar et al, 2000a).
In addition, myeloma cells secrete a variety of angiogenic factors and their level of secretion is again correlated with activity of disease (Vacca et al, 1999; Bellamy et al, 1999). Thalidomide has proven anti-angiogenic activity since it can inhibit angiogenesis induced by bFGF and VEGF (D'Amato et al, 1994) although there is no significant reduction in microvascular density or in the plasma levels of VEGF or bFGF following treatment with thalidomide (Singhal et al, 1999; Neben et al, 2001).
The exact mechanism whereby this effect is achieved remains uncertain although it is known that thalidomide analogues impair VEGF-induced MAPK signalling pathways (Lentzsch et al, 2000). Indeed, thalidomide was first tested in myeloma because of its known anti-angiogenic activity.
Other potential mechanisms of action
Although thalidomide is known to interfere with angiogenesis, it possesses other potential mechanisms of action. Furthermore, a number of thalidomide analogues have been developed that possess distinct spectra of biological activities. The two major classes of analogue are known as 'selected cytokine inhibitory drugs' or SelCIDs and 'immunomodulatory drugs' or IMiDs. The former are phosphodiesterase type 4 inhibitors and result primarily in reduced TNFα production whereas the latter do not inhibit phosphodiesterase type 4 but stimulate T-cell proliferation and the production of IL-2 and Ifn-γ (Corral et al, 1999).
Thalidomide can directly inhibit the growth and survival of myeloma cells, perhaps by oxidative damage to DNA mediated by free radicals (Parman et al, 1999). The drug can certainly directly induce apoptosis even in drug-resistant myeloma cells (Hideshima et al, 2000). IMiD 1 induces apoptosis in myeloma cells in a similar fashion to dexamethasone by activating related adhesion focal tyrosine kinase (RAFTK) (Hideshima et al, 2000). Both dexamethasone and IMiD 1-induced apoptosis are abrogated by exogeneous IL-6 (Hideshima et al, 2000).
In addition, thalidomide modulates cell adhesion molecule expression so it may well interfere with the mutually stimulatory interactions between myeloma cells and the bone marrow microenvironment (Geitz et al, 1996). Importantly, the drug and its analogues also interfere with TNFα production (Corral et al, 1999; Moreira et al, 1993; Turk et al, 1996) and with DNA binding of NF-κB, so abrogating normal inflammatory cytokine production (Payvandi et al, 2000). Finally, thalidomide has direct stimulatory effects on both T and NK-cells (Haslett et al 1998; Davies et al, 2001).
It seems probable that some or all of these mechanisms of action are relevant to the efficacy of thalidomide and its analogues in myeloma. Further clarification of the precise effects of thalidomide and similar agents is likely to be provided by analysis of the differential effects of thalidomide and its analogues.