The Roles of Bortezomib in the Treatment of Multiple Myeloma

Bortezomib (Velcade) is a new type of drug treatment for multiple myeloma.

Bortezomib is a proteasome inhibitor. Proteasomes are enzyme complexes found within cells, which break down old proteins. They are important in regulating cell growth and function. In cancer cells, proteasomes may be even more important, because they may contribute to the excessive growth and survival of abnormal cells. Bortezomib is a strong, specific and reversible proteasome inhibitor. It seems to work both directly on multiple myeloma cells, as well as acting on the surrounding cells in the bone to inhibit myeloma cell survival. Recent research presented at the 2007 American Society of Clinical Oncology annual meeting examined the roles of bortezomib in the treatment of multiple myeloma.Bortezomib as an induction agentInduction chemotherapy is used before stem cell transplantation for multiple myeloma. This treatment is usually only appropriate in young patients. Mazumder et al studied the use of the drugs thalidomide and bortezomib as induction agents in multiple myeloma. Patients received either thalidomide or bortezomib in combination with dexamethasone (dexamethasone is a standard part of multiple myeloma induction regimens). After treatment with induction agents, patients received G-CSF (a drug which stimulates production of bone marrow stem cells), and the stem cells produced were collected using a process called pheresis.Patients who were treated with bortezomib required fewer cycles of pheresis to collect adequate numbers of stem cells. In addition, the type of cells collected differed slightly between the two treatment groups, with the bortezomib group producing significantly more CD34+ cells/kg than the thalidomide group. This suggests that bortezomib induction results in a higher yield of stem cells when compared to thalidomide. Bortezomib induction also resulted in significantly more CD34+ cells/kg than thalidomide induction.Rositol et al also investigated the use of bortezomib with dexamethasone as an induction regimen for the treatment of younger patients with multiple myeloma. They used bortezomib and dexamethasone on an alternating basis (bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 (cycles 1, 3, 5) and dexamethasone 40 mg p.o. on days 1-4, 9-12 and 17-20 (cycles 2, 4 and 6)). Autologous stem cell transplantation (ASCT) was then performed. This study found that bortezomib alternating with dexamethasone was highly effective, resulting in an overall response rate after stem cell transplantation of 90%. Toxicity was low, with no patients developing grade 4 toxicity. Bortezomib maintenance therapyGoyal et al studied the use of bortezomib prior to, and as maintenance therapy after, autologous stem cell transplant (ASCT) in multiple myeloma. In this trial, bortezomib 1.3 mg/m2 was given before stem cell transplant. Autologous stem cell transplant with melphalan 200mg/m2 was performed, and then maintenance bortezomib 1.3 mg/m2/d was given weekly for 4 of 5 weeks × 6 cycles, starting 90-120 days post-transplant. The results of this trial were impressive. Treatment with bortezomib before the transplant did not adversely affect the number of stem cells collected. After the transplant, the overall response rate at 90-120 days post-transplant was 92%, with a complete response/very good partial response of 53%. Again, toxicity was low, with the major toxicity observed being peripheral neuropathy.Bortezomib in combination with other drugsHarousseau et al, in their study ‘Effect of the combination of pegylated liposomal doxorubicin and bortezomib on time to progression (TTP) and overall survival of patients with relapsed/refractory multiple myeloma compared with bortezomib alone,’ investigated the combination of bortezomib with another chemotherapy drug (pegylated liposomal doxorubicin (PLD)).646 patients were randomised to receive either bortezomib on days 1, 4, 8, and 11 of every 21-day cycle, or the same bortezomib regimen with the addition of a dose of pegylated liposomal doxorubicin on day 4.One of the study’s primary endpoints, the average time to progression of disease, improved from 6.5 months for bortezomib alone to 9.3 months for the PLD plus bortezomib combinationIn addition, the complete plus partial response rate, median duration of response and overall survival were all significantly improved with combination therapy. The combination therapy with bortezomib plus PLD was expected to have higher toxicity than bortezomib alone, and this was shown to be the case. Overall, bortezomib represents a new approach to the treatment of multiple myeloma. It may play a role in both induction and maintenance therapy, and appears to be effective in combination with other chemotherapy agents.