Targeted Therapy in Multiple Myeloma

Abstract

Background: Multiple myeloma (MM) is an incurable malignancy. Recent insights into its biology has allowed the use of novel therapies targeting not only the deregulated intracellular signaling in MM cells but also its interaction with the bone marrow microenvironment that confers drug resistance, growth, and survival advantage to the malignant cells. Methods: We review and summarize the recent advances in our knowledge of myeloma biology as well as the mechanism of action and clinical efficacy for novel therapeutic agents in clinical trials. Results: Several novel therapeutic agents are currently in clinical trials. Thalidomide is already established for both initial and salvage treatment. Bortezomib is being tested alone and in combination with conventional chemotherapy in various settings. Other agents are less effective in producing response but have been able to stabilize disease in patients with relapsed and/or refractory disease, such as arsenic trioxide, farnesyltransferase inhibitors, 2-methoxyestradiol, and vascular endothelial growth factor receptor inhibitors. Insights into drug resistance mechanism have also led to the development of novel agents that sensitize myeloma cells to chemotherapy (Bcl-2 antisense). Gene expression studies have in many instances identified pathways other than the intended target of the drug and have provided insights into the therapeutic mechanisms. Conclusions: In the future, patients with MM will have more therapeutic options available than ever before. The challenge will be to identify patient subgroups that will benefit most from the different therapies and then determine how these biologically based therapies could be combined and incorporated into the overall management of patients.

Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival

“…14,[37][38][39] In this context, it has been suggested to use statins together with thalidomide or lenalidomide for the treatment of multiple myeloma. 22,23 We propose that statins may also potentiate the effect of corticosteroids on tumor cells of the B lineage and at the same time relieve T cells from suppressive effects, thus favoring T cell-mediated effector functions.…”

“…20 Recently, BMSC have been considered a target for the therapy of hematologic malignancies as it is becoming evident that these cells can help neoplastic stem cells to proliferate and evade the immune-mediated control. 15,16,[20][21][22] Indeed, the use of thalidomide or lenalidomide, hitting the mesenchymal stromal component besides myeloma cells, has been introduced in the treatment of multiple myeloma, with a striking improvement in prognosis of this disease. [20][21][22] More recently, it has been proposed to use lenalidomide together with statins: [22][23][24] these drugs are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-CoenzymeA (HMG-CoA) reductase involved in cholesterol biosynthesis and are commonly used for the treatment of hypercholesterolemia.…”

“…15,16,[20][21][22] Indeed, the use of thalidomide or lenalidomide, hitting the mesenchymal stromal component besides myeloma cells, has been introduced in the treatment of multiple myeloma, with a striking improvement in prognosis of this disease. [20][21][22] More recently, it has been proposed to use lenalidomide together with statins: [22][23][24] these drugs are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-CoenzymeA (HMG-CoA) reductase involved in cholesterol biosynthesis and are commonly used for the treatment of hypercholesterolemia. [25][26][27] Statins are also able to affect proliferation of smooth muscle cells and inhibit lymphocyte function both in vitro and in vivo.…”

Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

“…27 Despite substantial advances in the understanding of contextual molecular mechanisms, MM still remains highly incurable. Our study essentially addresses a novel role for miR-152 and its inverse relationship with DKK1 in the pathogenesis of MM.…”

Maintenance and Consolidation Strategies in Non-Hodgkin’s Lymphoma: A Review of the Data

“…The drug is classified as an immunomodulatory agent, and has significant effects on the "normal" cells in the tumor microenvironment, besides having some effects on tumor cells themselves [53,54]. Some of these effects include inhibition of binding of tumor cells to the tumor bed, inhibition of release and activity of cytokines associated with tumor cell proliferation, suppression of tumor-induced angiogenesis, and activation of natural killer cells and macrophages, although its major mechanisms of action in patients with lymphoproliferative diseases are still uncertain.…”