Safety and efficacy of bortezomib and melphalan combination in patients with relapsed or refractory multiple myeloma: updated results of a phase 1/2 study after longer follow-up

Abstract

Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m(2)) on days 1, 4, 8, and 11 and oral melphalan (0.025-0.25 mg/kg) on days 1-4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m(2)) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1-24), and overall survival was 32 months (range, 1-54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity.

A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma

“…1 --3 Improvements in efficacy have been found in combination therapies using these newer agents by showing superior response rates compared to single-agent therapies for MM, likely because of synergistic effects of these newer agents when combined with chemotherapeutic agents such as alkylating agents, anthracyclines or glucocorticosteroids. 4 --8 This has led to a proliferation of combination regimens such as combining the proteasome inhibitor bortezomib with doxorubicin, 9 melphalan, 10 dexamethasone plus cyclophosphamide 11 and pegylated liposomal doxorubicin (PLD) plus dexamethasone (DVD). 12,13 As efficacy seems to increase as more active agents are combined, preclinical and clinical studies have also evaluated the addition of a fourth drug to the three-drug regimens in an attempt to further enhance their efficacy.…”

Better quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in patients with relapsed or refractory multiple myeloma

“…In the last few years, CR rates have improved with the emergence of novel therapies such as bortezomib, thalidomide and lenalidomide, and can be even further improved if these drugs are used in combinations, for example bortezomib with melphalan, 17 cyclophosphamide and prednisone, 18 dexamethasone, 19 vorinostat, 20 and lenalidomide. 21 Whereas the more aggressive goal to achieve CR may be justified in high-risk patients, the impact of CR on outcomes seems to be less important in indolent disease and elderly patients, in whom the toxicity of multiple drug regimens may outweigh treatment benefits.…”

Delayed Onset Tumor Lysis Syndrome after Initial Pomalidomide Treatment in a Patient with Refractory Multiple Myeloma

“…Six of these patients had a high tumor burden and four patients had 13q deletion. There have also been additional reports of TLS after bortezomib treatment [3][4][5][6][7][8][9], almost all of whom suffered from relapsed/refractory MM, and had been pretreated by several courses of treatment, including autologous stem cell transplantation.…”

“…TLS was previously considered extremely rare (~1%) in multiple myeloma (MM) patients [1], but several reports have been published after the introduction of new agents [2][3][4][5][6][7][8][9][10][11][12]. Hyperproliferative diseases in bone marrow, circulating plasmablasts, and 13q deletion have been identified as risk factors for TLS in MM [1].…”