The Roles of Bortezomib in the Treatment of Multiple Myeloma

Bortezomib is a novel treatment for multiple myeloma. It is a potent, specific, and reversible proteasome inhibitor, which appears to act both directly on myeloma cells and on the bone microenvironment to inhibit myeloma cell survival.4

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 agentMazumder et al performed a retrospective analysis of the effect of induction therapy with novel agents (thalidomide or bortezomib) on stem cell mobilisation in multiple myeloma.³ Patients received either thalidomide or bortezomib in combination with dexamethasone. After induction, patients received G-CSF 10mcg/kg and underwent large volume pheresis. The researchers found that significantly fewer patients in the bortezomib group required more than three phereses to reach the goal of at least 6×10(6) CD34+ cells/kg for tandem transplant (4/18 in the bortezomib group, compared to 17/22 in 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. Rosinol et al also investigated the use of bortezomib with dexamethasone as an induction regimen for the treatment of younger patients with multiple myeloma.⁵ 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 with melphalan-200. They found that bortezomib alternating with dexamethasone was highly effective, resulting in an overall response rate after ASCT of 90% (40% complete response, 20% very good partial response). 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.¹ In this trial, bortezomib 1.3 mg/m2 was administered pre-transplant on d 1, 4, 8, and 11 q21d × 2 cycles. ASCT with melphalan 200mg/m2 was performed, and then maintenance bortezomib 1.3 mg/m2/d was administered weekly for 4 of 5 weeks × 6 cycles, starting 90-120 days post-transplant. The results of this trial were impressive. The overall response rate at 90-120 days post-transplant was 92%, with a complete response/very good partial response of 53%. Pre-transplant treatment with bortezomib did not adversely affect stem cell yield or engraftment. Again, toxicity was low, with the major toxicity observed being peripheral neuropathy.Bortezomib in combination with other agentsHarousseau 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 pegylated liposomal doxorubicin (PLD).²646 patients were randomised to receive either intravenous bortezomib 1.3 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, or the same bortezomib regimen with pegylated liposomal doxorubicin 30 mg/m2 on day 4.One of the study’s primary endpoints, median time to progression, improved from 6.5 months for bortezomib alone to 9.3 months for the PLD plus bortezomib combination. In addition, the complete and partial response rate, median duration of response and overall survival were all significantly improved with combination therapy. Toxicity of the combination therapy was as expected; grade 3/4 adverse events were more common in the combination group due to increased myelosuppression and gastrointestinal toxicity. 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.References

1. Goyal SD et al. ‘Bortezomib (BTZ) prior to and as maintenance therapy after autologous stem cell transplant (ASCT) in multiple myeloma (MM): Long-term follow-up of a phase II study.’ Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8044
2. Harousseau JL et al, for the DOXIL-MMY-3001 Investigators. ‘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.’ Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8002
3. Mazumder A et al. ‘The effect of induction therapy with novel agents on stem cell mobilization in multiple myeloma.’ Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8102
4. Richardson PG. ‘Velcade (bortezomib)’ [online], Multiple Myeloma Research Foundation. 2006. Available at URL: http://www.multiplemyeloma.org/treatments/3.05.php (last accessed 30/7/07)
5. Rosinol L et al. ‘ Final results of a phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen prior autologous stem cell transplantation (ASCT) in younger patients with multiple myeloma (MM): Efficacy and clinical implications of tumour response.’ Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8024