PAD combination therapy (PS‐341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma

Abstract

SummaryBortezomib (formerly PS-341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21-d cycles of PAD, comprising bortezomib 1AE3 mg/m 2 on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1-4, 8-11 and 15-18 during cycle 1 and days 1-4 during cycles 2-4. During days 1-4, patients also received 0, 4AE5 or 9 mg/m 2 of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high-dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention-to-treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials.

Thalidomide in newly diagnosed multiple myeloma: influence of thalidomide treatment on peripheral blood stem cell collection yield

“…33 Clinical phase III trials are now ongoing to investigate further the efficacy of lenalidomide and bortezomib in newly diagnosed MM before high-dose therapy. However, as there are still just a few data published regarding the influence of lenalidomide or bortezomib on PBSC, 34 the analyses of these trials should also focus on the influence of these novel agents on PBSC, with a maximum of 4-6 cycles to prevent negative effects on CD34 þ yield.…”

Proteasome inhibitor bortezomib for the treatment of multiple myeloma

“…In these studies, the role of bortezomib was explored as singleagent therapy or, more frequently, in combination with other drugs ( 47,48 In particular, great efforts have been devoted to the development of bortezomib-based combination regimens aimed at enhancing the rate, rapidity and magnitude of response in patients who are candidates to receive autologous stem cell transplantation. In addition to response, important end points of these studies also included safety and toxicity profile, with particular considerations for harvesting peripheral blood stem cells (PBSCs).…”

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

“…Carfilzomib, a secondgeneration proteasome inhibitor, has shown to have reduced offtarget activity compared with bortezomib, which can eliminate the dose-limiting side-effects seen with bortezomib, such as peripheral neuropathy (20)(21)(22). Although numerous studies have been performed with bortezomib and doxorubicin, combination studies involving carfilzomib and anthracyclines have not been pursued to date (23)(24)(25). In addition, the incorporation of these therapeutics into a single nanoparticle has the potential to further improve the therapeutic efficacy by selectively delivering the drugs to the tumor site at their optimal drug ratio.…”