Abstract
The treatment of multiple myeloma (MM) is rapidly evolving. In the United States, four drugs (panobinostat, ixazomib, daratumumab and elotuzumab) were approved for the treatment of MM in 2015. As a result of improved diagnosis and therapy, there has been a dramatic improvement in the outcome of MM in the last decade, probably more than any other malignancy. Numerous agents continue to be studied in preclinical models and in clinical trials, with many demonstrating clinical efficacy that appears promising enough to have a trajectory for regulatory approval. The purpose of this article is to summarize the current data and provide perspective on new investigational agents with promising single-agent activity in MM. The agents reviewed include Isatuximab, an anti-CD38 monoclonal antibody; marizomib, a new proteasome inhibitor; oprozomib, an oral proteasome inhibitor; filanesib (ARRY-520), a kinesin spindle protein inhibitor; dinaciclib, a cyclin-dependent kinase inhibitor; venetoclax (ABT-199), a selective BCL-2 inhibitor; and LGH-447, pan PIM kinase inhibitor.
Highlights
Randomized phase 3 trial of the phase 3 studies that can inform the best sequence of therapy, the deacetylase inhibitor panobinostat plus bortezomib and dexamethasone versus most effective combinations and the optimal strategy by which we can maximize efficacy with the lowest amount of side effects and cost
Monoclonal antibodies in the treatment of multiple myeloma: current status and future perspectives
Clin Lymphoma Myeloma Leuk 2015; 15: e43
Summary
Multiple myeloma (MM) is a clonal plasma cell malignancy that accounts for ~ 10% of hematologic malignancies.[1,2] It is a complex disease with several distinct cytogenetic subtypes, and is generally considered incurable in the majority of patients.[3,4] From the 1950s until the end of the 1990s, the mainstay of therapy of MM was alkylators (melphalan and cyclophosphamide), anthracyclines, corticosteroids (prednisone and dexamethasone)[5] and in selected patients high-dose chemotherapy with autologous stem cell transplantation.[6,7] Subsequently, thalidomide,[8] bortezomib[9] and lenalidomide[10] emerged as effective agents and greatly improved clinical outcome.[11,12] Thalidomide and lenalidomide are considered immunomodulatory drugs (IMiDs), recent studies show that these drugs work by binding to and activating cereblon E3 ligase activity, resulting in the rapid ubiquitination and degradation of two specific B-cell transcription factors, Ikaros family zinc-finger proteins Ikaros (IKZF 1) and Aiolos (IKZF3). Bortezomib is a first-in-class proteasome inhibitor that acts by inhibiting the ubiquitin–proteasome catalytic pathway in cells by binding directly with the 20S proteasome complex These three drugs have changed the treatment and outcome of MM dramatically, with many studies indicating at least a doubling of overall survival over the last decade. Many new drugs are already showing significant single-agent activity in MM in phase 1 and 2 clinical trials, and there is a high likelihood that they will be eventually approved for the treatment of the disease in the near future. The development of these agents for regulatory approval is proceeding in parallel with efforts to develop new active combinations for clinical use. CD38 is a type 2 transmembrane protein expressed on both hematopoietic and
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