A Phase 1 Study of Bendamustine and Melphalan Conditioning for Autologous Stem Cell Transplantation in Multiple Myeloma

Abstract

Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200mg/m2. Twenty-five subjects were enrolled onto 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225mg/m2 + melphalan 200mg/m2 was expanded to further evaluate safety. Overall, there was no transplant related mortality and only 1 grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment was 11 (9-14) and 13 (10-21), respectively. Disease responses at day +100 post-transplant were: progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with preexisting high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after ASCT. Bendamustine up to a dose of 225mg/m2 added to autologous stem cell transplant conditioning with high dose melphalan in multiple myeloma did not exacerbate expected toxicities.

A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy

“…The median number of days with ANC ⩽ 0.1, ⩽ 0.5 and ⩽ 1 × 10 9 /L was 3 (range 2-8), 5 (range 3-10) and 6 (range 3-13), respectively. The median duration of hospitalization after stem cell infusion was 16 days (range [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The engraftment kinetics observed for BENDA plus HDM conditioning at second transplant were similar to those reported previously with the first HDM (200 mg/m 2 ) conditioning regimen ( Table 2).…”

“…3,14 HDM at a dose of 200 mg/m 2 is considered to be the standard conditioning regimen. 14,17,18,30 However, a variety of strategies has been explored with the aim of improving the results of HDM 200 mg/m 2 , including dose escalation, 22 addition of other agents such as busulfan, thiotepa or TBI 14,15,[17][18][19][20][21][22] or, conversely, dose reduction as part of a tandem auto-SCT procedure, 20 with overall mixed results. Further evidence is however necessary on the best conditioning regimen.…”

“…Although many studies have been performed in the induction, consolidation and maintenance settings, few trials have been dedicated to conditioning regimens before ASCT; [14][15][16][17][18][19][20][21][22] and the current standard conditioning regimen is considered high-dose melphalan (HDM). 14 Bendamustine (BENDA) (Ribomustin/Levact; Mundipharma International Ltd, and Treanda; Cephalon) is a synthetic chemotherapeutic agent that combines the alkylating properties of a mustard group with the antimetabolic activity of a purine analog.…”

“…23 BENDA has proven activity in both newly diagnosed and relapsed/refractory MM; 24 and it has already been shown to be a feasible part of a modified BeEAM (bendamustine, etoposide, cytarabine, melphalan) ASCT conditioning regimen for non-Hodgkin lymphoma with acceptable safety and promising efficacy. 25 Recently, Mark et al 19 published a phase I trial on escalating doses of BENDA added to the current standard conditioning of HDM at 200 mg/m 2 in patients with MM at their first transplant. We report herein the results of a phase II trial evaluating the safety and efficacy of BENDA plus HDM as the conditioning regimen for ASCT after induction therapy in MM patients.…”

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

“…More recently bendamustine, which has shown single agent activity in relapsed myeloma, was combined with Mel200 at escalated doses reaching 225mg/m 2 with only one dose-limiting toxicity in the first 100 days post-transplant. (Mark et al, 2013) Melflufen is a dipeptide pro-drug of melphalan, which by virtue of increased intracellular hydrolysis is concentrated in myeloma cells. Melflufen induces apoptosis in melphalan-resistant cells and is highly effective in mouse models (Chauhan et al, 2013).…”