Despite the initial efficacy of these therapies against multiple myeloma (MM), relapse is invariably the rule. Bortezomib (Velcade, formerly PS-341, Millennium, USA) is a novel first-class agent that inhibits the proteasome, a multicatalytic cellular enzyme whose activity entails several molecular mechanisms, including, in particular, the NF-kB pathway.
Currently, bortezomib, alone or in combination with dexamethasone and doxorubicin, is under investigation as first-line and maintenance therapy. However, previous studies on advanced disease included a mixture of patients with multiple and heterogeneous previous regimens. Therefore, in order to obtain more careful information about the efficacy and tolerability of this drug in more homogeneously and less heavily pre-treated patients, researchers from Italy focused on the effects of bortezomib on a selected cohort of MM patients who had progressive disease after previous treatments including exclusively AuSCT and thalidomide. They focused on the effects of bortezomib as third line treatment (second salvage therapy) in a very homogeneous group of MM patients induced by AuSCT and relapsed or refractory after thalidomide employed as second line treatment (first salvage therapy).
For the study to be published in the journal Leukemia Research (available online 18 August 2005), twenty-one patients with multiple myeloma, all relapsed after frontline autologous stem cell transplantation and all relapsed again after or resistant to thalidomide (employed as second line treatment) received bortezomib without adjunct of steroids as third line therapy. Three patients died of progressive disease during the first 2 cycles with bortezomib. Eighteen patients received at least 2 cycles and were evaluated for response. According to EBMT criteria, 2 complete (negative immunofixation) and 7 partial remissions were achieved. Duration of response lasted from 2 to 14+ months. Grades 3?4 toxicities (thrombocytopenia, leucopenia, peripheral neuropathy and vasculitis) were observed in 7 patients, but no patient interrupted the treatment due to side effects.
The study indicates that the use of bortezomib, in this specific setting, is generally safe and may be effective in a relevant proportion of cases. The authors conclude that bortezomib alone may induce high quality responses as third line salvage therapy with acceptable toxicity in a significant proportion of homogeneously pre-treated myeloma patients with progressive disease after autologous transplantation and thalidomide.