Bortezomib and high-dose melphalan conditioning regimen in frontline multiple myeloma: an IFM randomized phase 3 study

Abstract

High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days −6, –3, +1, and +4 and melphalan (200 mg/m2 IV) on day –2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM–treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.

Busulfan, melphalan and carfilzomib high‐dose chemotherapy and autologous haematopoietic stem cell transplantation in multiple myeloma

“…When a dose‐limiting toxicity (DLT) was determined, the maximum tolerated dose (MTD) was the prior dose, and an additional 10 patients were enrolled at that level. The busulfan was administered for 4 days over 3 h for each dose 17,27 . On Day‐7 and on Day‐6, busulfan was given at 130 mg/m 2 and on Day‐5 and on Day‐4, the doses were adjusted by PK analysis after the first two doses in order to yield a systemic plasma drug exposure represented by a daily area under the plasma concentration versus time curve (AUC) of approximately 5000 mMol‐min per dose for a total of 20 000 mMol‐min.…”

“…The busulfan was administered for 4 days over 3 h for each dose. 17,27 On Day-7 and on Day-6, busulfan was given at 130 mg/m 2 and on Day-5 and on Day-4, the doses were adjusted by PK analysis after the first two doses in order to yield a systemic plasma drug exposure represented by a daily area under the plasma concentration versus time curve (AUC) of approximately 5000 mMol-min per dose for a total of 20 000 mMolmin. Melphalan was given at a dose of 140 mg/m 2 on Day −3, as is the standard for BuMel combinations.…”

“…Combination therapy with bortezomib and melphalan noted synergistic effects in vitro 15 ; however, it failed to achieve meaningful differences in all end-points in an Intergroupe Francophone du Myélome (IFM) study when compared to single-agent melphalan possibly due to schedule dependency of effect and the timing of bortezomib given in these trials. 16,17 Our own group has previously investigated bortezomib in combination with the dual alkylator backbone of BuMel (BuMelVel). When compared to a cohort of matched CIBMTR controls, we noted an improved PFS with a 5-year PFS of 47%, even without IMiD maintenance, with 7-year follow-up continuing to show this advantage.…”

“…Recently, newer agents have been combined with high‐dose melphalan to varying degrees of success. Combination therapy with bortezomib and melphalan noted synergistic effects in vitro 15 ; however, it failed to achieve meaningful differences in all end‐points in an Intergroupe Francophone du Myélome (IFM) study when compared to single‐agent melphalan possibly due to schedule dependency of effect and the timing of bortezomib given in these trials 16,17 . Our own group has previously investigated bortezomib in combination with the dual alkylator backbone of BuMel (BuMelVel).…”

Updates on Multiple Myeloma: What’s New in Risk Stratification, Treatment, and Prognosis

“…The sCR/CR rates at day 60 post-transplant was 22.1% in bortezomib arm versus 20.5% in the control arm (P = 0.844), with no differences in undetectable minimum residual disease rates; 41.3% versus 39.4% (P = 0.864). Median progression-free survival was 34 months versus 29.6 months for bortezomib and HDM, respectively (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = 0.244) with an estimated 3-year overall survival of 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = 0.374) [25].…”