A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study

Abstract

+1 relative to the day of autologous stem cell transplantation (ASCT) to a conditioning regimen with busulfan and melphalan (BuMel; 3.2 mg/kg/day busulfan on days -5 to -3 and 140 mg/m 2 /day melphalan on day -2) in patients with multiple myeloma (MM) following bortezomib-based induction chemotherapy. In phase I, doses of bortezomib (.7, 1.0, and 1.3 mg/m 2 ) with BuMel were administered to groups of 3 patients each. No dose-limiting toxicities were observed. The maximum tolerated dose of bortezomib was 1.3 mg/m 2 /day. A subsequent cohort with 41 patients was analyzed in a phase II trial to identify safety and efficacy. The phase II trial showed a 75% response rate, including very good partial response (VGPR) or better, and a 55% rate of complete response (CR) at 3 months; For post-transplantation best response, an 83% rate of VGPR or better (68% CR) was observed. With a median follow-up of 31.4 months, the median progression-free survival (PFS) was 26.8 months. The probability of 2 year-PFS was 56.5%, and median overall survival (OS) could not calculated. Specifically, high-risk cytogenetics were associated with adverse survival outcomes compared with standard-risk cytogenetics (median PFS, 12.2 months versus 35.7 months, P = .039; median OS, 26.7 months versus 73.3 months; P = .086). With a median of 11 days to neutrophil engraftment and 10 days for platelet engraftment, no graft failure or delayed engrafting were observed. The most common grade 3 or severe nonhematologic adverse events included neutropenic fever (73.2%) and stomatitis (14.6%). Except for 3 patients with transplantation-related mortality due to sepsis, other adverse events were manageable. These findings demonstrate that bortezomib is safe and has a potential role in conditioning regimens in combination with BuMel for patients with transplantation-eligible MM.

In Vitro Assessment of Antitumor Potential and Combination Effect of Classical and Molecular-targeted Anticancer Drugs

“…Bmib is mainly used as a therapeutic agent for refractory multiple myeloma in hematology clinic, due to its potent anti-tumor activity and yet-unknown biological function (16). It has been reported that Bmib caused the high incidence of neutropenia and stomatitis (17), peripheral neuropathy (18) and epidermal necrolysis (19). We also found potent cytotoxicity of Bmib against OSCC cell lines as well as normal oral cells, especially oral keratinocytes.…”

Allogeneic Stem Cell Transplantation in Relapsed/Refractory Multiple Myeloma Treatment: Is It Still Relevant?

“…For conformation of this, a further randomized, well-controlled trial is needed. In a previous multicenter autoSCT study performed in Korea (KMM 103 study), 3/41 patients (7.3%) experienced mortality within one year due to sepsis in patients who were treated with autoSCT following bortezomib-based induction chemotherapy [30]. Although this study showed relatively lower NRM compared with our study, considering that this study only included newly diagnosed MM patients, it may be a comparable outcome.…”

Busulfan, melphalan, and bortezomib compared to melphalan as a high dose regimen for autologous hematopoietic stem cell transplantation in multiple myeloma: long term follow up of a novel high dose regimen

“…Our results however seem better than other recent reports given the lack of maintenance therapy received by patients on our study, perhaps owing to the use of bortezomib in the combination and the PK dosing of the busulfan. To our knowledge, only one other group has prospectively evaluated BuMelVel as a high dose regimen for MM [17] with a much shorter reported follow up of only 31.4 months. In their phase I/II study following a bortezomib based induction, they reported a higher response rate than ours with Table 4.…”

“…Blanes et al [26] , [17] BBMT 2019 [18] BBMT 2018 Per high dose arm, pending Barta et al [28] , CLML 2017 83% of patients achieving a very good partial response (VGPR) or better but an inferior median PFS of only 26.8 months and two year PFS of just 56%. Interestingly, they reported less grade III mucositis (only 14.6%) even in the absence of palifermin and no SOS.…”