Bortezomib Combination Therapy in Multiple Myeloma

Abstract

Bortezomib was approved for the treatment of multiple myeloma in 2003. Since then several bortezomib-based combination therapies have emerged. Although some combinations have been preceded by preclinical investigations, most have followed the inevitable process in which active (or potentially active) drugs are combined with each other to create new treatment regimens. Regimens that have combined bortezomib with corticosteroids, alkylating agents, thalidomide, and/or lenalidomide have resulted in high response rates. Despite the higher and often deeper response rates and prolongation of progression-free survival with bortezomib-based multiagent regimens, an overall survival (OS) advantage has not been demonstrated with most combinations compared to the sequential approach of utilizing anti-myeloma agents, particularly in patients less than 65 with newly diagnosed myeloma. The unique properties of some of these regimens can be taken into account when choosing a particular regimen based on the clinical scenario. For example, bortezomib, thalidomide, dexamethasone (VTD) has particular value in renal failure since none of the drugs need dose modification. Similarly, the combination chemotherapy regimen VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) is of particular value in patients presenting with aggressive disease such as extramedullary plasmacytomas or plasma cell leukemia. Ongoing clinical trials are testing combinations of bortezomib with several other classes of agents, including monoclonal antibodies, and inhibitors of deacetylases, heat shock proteins, phosphatidyl inositol 3-kinase/Akt/mammalian target of rapamycin pathway and farnesyl transferase.

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

“…Researchers have observed promising preclinical activity with mapatumumab in patient with advanced solid cancers (Hotte et al, 2008). Currently, mapatumumab in combination with bortezomib in patients with refractory myeloma (Kapoor et al, 2012) and cisplatin and radiotherapyin patients with cervical cancer is in phase II clinical trials (Vici et al, 2014).…”

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

“…4 Despite such advancements, relapse following prolonged bortezomib treatment is inevitable due to either genetic modifications 5 or emergence of bortezomib-resistant plasma cell sub-clones. 6 Once myeloma cells acquire bortezomib resistance, they can no longer be treated with bortezomib. Clinical data shows that roughly half of initially bortezomib-sensitive MM patients do not respond to bortezomib once the disease is relapsed.…”

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

“…The proteasome inhibitor (PtdIns) bortezomib, approved for the treatment of MM by the FDA in 2003, 3 is one such debulking agent that has greatly contributed to improved outcomes observed in MM 4 Despite this advance, however, relapse following bortezomib therapy remains inevitable due to the emergence of bortezomib-resistant plasma cell sub-clones 5 For example; recent 'whole genome' sequencing studies of MM patients confirmed a high level of genetic heterogeneity; occurring both between separate patients, and within patient samples before and after therapy, 6 indicating the presence of a variety of genetically distinct plasma cell 'sub-clones' 7,8 Different subclones further indicate the presence of numerous minor tumor initiating cell populations with complex and divergent evolutionary histories. 9 The potential quiescence of these MM subclones, coupled with their diversity, can contribute to enhanced tumorigenicity and an intrinsic resistance to therapy.…”