High-Dose Melphalan Plus Thiotepa as Conditioning Regimen before Second Autologous Stem Cell Transplantation for “De Novo” Multiple Myeloma Patients: A Phase II Study

Abstract

High-dose melphalan (MEL) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be identified. Thiotepa (THIO) appears to be a potentially effective option, with broad-spectrum antitumor efficacy that can be added to myeloablative multiagent regimens for ASCT in hematopoietic tumors. We conducted a phase II trial, adding THIO (275 mg/m(2)) to high-dose MEL (140 mg/m(2)) before a second ASCT, in a tandem ASCT strategy, in 64 patients with "de novo" MM. Overall, there was no transplant-related mortality. The incidence of neutropenic fever and mucositis (grades 3 to 4) was 39% and 9%, respectively. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response improved to 43.8%. Overall response rate was 86%. After a median follow-up of 18.1 months, 13 patients had progressed and 3 died from MM. Median progression-free survival was not reached, and actuarial 2-year rates of progression-free and overall survival were 71% and 88.9%, respectively. Our results suggest that THIO/MEL is a feasible and safe conditioning regimen for ASCT in MM and should be explored for efficacy in a phase III study.

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.…”

Gain of chromosome 1q portends worse prognosis in multiple myeloma despite novel agent-based induction regimens and autologous transplantation

“…Recent studies of modern induction including proteasome inhibition followed by tandem HCT in patients with high-risk disease have shown three-year PFS between 35 and 69%. [14,29] In addition, studies adding bendamustine or thiotepa to melphalan as conditioning for the second HCT suggest that these options are feasible,[30,31] though their impact is unknown as only 10% of patients in each trial had high-risk disease by current cytogenetic risk classification. Pharmacokinetic targeted dosing of melphalan may also improve outcomes while limiting toxicity.…”

Dose‐intensified bendamustine and melphalan (BenMel) conditioning before second autologous transplantation in myeloma patients

“…Whereas high‐dose melphalan at 200 mg/m 2 (Mel) is considered the standard HDCT regimen, various strategies were investigated to improve the results of Mel HDCT. Examples were dose escalation or addition of a second compound including busulfan, thiotepa, bortezomib, or even TBI, with none of them turning out to be decisively superior to Mel HDCT …”