Thalidomide for the treatment of multiple myeloma

Abstract

Although thalidomide was withdrawn in the 1960s after its teratogenic property was recognized, it was subsequently found that this drug possesses immunomodulatory and anti-inflammatory effects. Recent studies have also demonstrated that thalidomide has antineoplastic activity via an antiangiogenic mechanism. Observations in the late 1990s that the microenvironment in the bone marrow plays a role in tumor progression in multiple myeloma provided an impetus to use thalidomide for the treatment of this disease. It is known that thalidomide monotherapy is effective in one-third of refractory cases, and in combination with glucocorticoids and/or antineoplastic drugs, thalidomide provides a response rate of more than 50%. Thus, thalidomide therapy is considered a standard approach for the treatment of relapsed and refractory myeloma. The exact mechanism of the antimyeloma effect of thalidomide is not yet clearly understood. Anti-angiogenic effects, direct activity in tumor cells such as the induction of apoptosis or G1 arrest of the cell cycle, the inhibition of growth factor production, the regulation of interactions between tumor and stromal cells, and the modulation of tumor immunity have been considered as possible mechanisms. In addition to its teratogenicity, the adverse effects of thalidomide have been general symptoms such as somnolence and headache, peripheral neuropathy, constipation, skin rash, and other symptoms. Although these adverse effects are generally reversible and mild, grade 3 and 4 toxicities such as peripheral neuropathy, deep venous thrombosis, neutropenia, and toxic dermal necrosis have occasionally been reported. The application of thalidomide therapy in patients with multiple myeloma is being broadened to include not only cases of refractory myeloma, but also previously untreated cases, as well as for maintenance therapy after hematopoietic stem cell transplantation and for the treatment of other hematological diseases. The safe use of this drug will depend on the establishment of diagnostic and treatment guidelines. In addition, the establishment of a nation-wide regulation system is urgently needed in Japan.

Arterial thrombosis and thalidomide

“…But then, the therapeutic effect of thalidomide as a single agent in multiple myeloma has been demonstrated and the response rate achieved in patients with relapsed or refractory multiple myeloma. However, venous thrombosis incidence is increased during treatment with thalidomide [3][4][5][6]. Pathogenetic mechanisms of thalidomide-associated thrombosis have not been clearly assessed.…”

Suppression of Urokinase Receptor Expression by Thalidomide Is Associated with Inhibition of Nuclear Factor κB Activation and Subsequently Suppressed Ovarian Cancer Dissemination

“…Antiangiogenic effects, direct activity in tumor cells such as the induction of apoptosis or G 1 arrest of the cell cycle, the inhibition of growth factor production, the regulation of interactions between tumor and stromal cells, and the modulation of tumor immunity have been considered as possible mechanisms of thalidomide (46). The present data allow us to speculate that thalidomide inhibits tumor cell invasion by mechanisms other than antiangiogenesis.…”

Case Study of Intracerebral Recurrence of Plasmablastic Myeloma with Achievement of Complete Response after Treatment with Lenalidomide

“…A recent study by Gozzetti A et al, of action of Lenalidomide is not yet fully understood, one theory is the inflammatory reaction and angiogenesis induced by the drug that leads to increased vascular permeability and allows some of these drugs to pass through the blood brain barrier. 10 …”