There are relatively few effective treatment options for patients with multiple myeloma. Traditional treatment includes combination chemotherapy with melphalan/prednisone and vincristine/doxorubicin/dexamethasone. Myeloablation with high-dose chemotherapy and subsequent rescue with ASCT is a mainstay for patients fit enough to withstand the regimen, usually patients less than 65 years of age. The immunomodulators, thalidomide and lenalidomide, alone or in combination with dexamethasone, have been shown to be effective in multiple myeloma.
Bortezomib is a first-in-class proteasome inhibitor that has shown remarkable efficacy in multiple myeloma. Bortezomib specifically targets the ubiquitin-proteasome pathway; the proteasome plays a key role in the degradation of ubiquinated proteins in general, and specifically proteins that control tumor cell growth and survival. By targeting the proteasome and acting on the multiple myeloma cells as well as the microenvironment, bortezomib has been shown to increase response in patients with multiple myeloma, especially in patients with relapsed and refractory disease. Bortezomib was first indicated for the treatment of relapsed and refractory multiple myeloma, including use as second-line treatment after first relapse.
Bortezomib has shown activity as first-line treatment in newly diagnosed, untreated multiple myeloma in two phase II studies. In one study, overall response after more than 2 cycles of therapy (n = 22) was 64%. Peripheral neuropathy occurred in 21% of patients and was mainly grade 2 and managed with dose modification.
In the second study, patients (completed, n = 23) received single-agent bortezomib with added dexamethasone for less than PR after 2 cycles or less than CR after 4 cycles of treatment . Overall major response was 83%. Best response was recorded for 43% of patients after cycle 2, 39% after cycle 4, and 13% after cycle . The addition of dexamethasone (61% of patients) increased response in 9 patients. Peripheral neuropathy (grades 1-3) occurred in 56% of patients; 12% had neuropathic pain, which resolved when treatment was discontinued.
A number of phase I/II clinical trials have investigated the use of bortezomib in combination with chemotherapy, including dexamethasone, for induction treatment prior to ASCTThe conclusion from these studies is that bortezomib is an effective adjunct to standard induction regimens, with excellent response, successful mobilization of peripheral blood stem cells, and good tolerance. Based on this data, NCCN recommends bortezomib/dexamethasone as primary (front-line) therapy for transplant candidates. Newer studies suggest that it is a superior front line treatment and FDA approval has been granted.
Rami Manochakian, Kena C. Mis iller, Asher A. Chanan-Khan Clinical Impact of Bortezomib in Frontline Regimens for Patients with Multiple Myeloma The Oncologist, Vol. 12, No. 8, 978-990, August 2007;
Mario Dicatoa et al, Management of Multiple Myeloma with Bortezomib: Experts Review the Data and Debate the Issues Oncology Vol. 70, No. 6, 2006
Reece DE, Rodriguez GP, Chen C, et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. Journal of Clinical Oncology 2008;26:4777-4783.