A Randomized Phase III Trial of Busulfan + Melphalan Vs Melphalan Alone for Multiple Myeloma

Background:  Two recent retrospective analyses suggested that a combination of busulfan (Bu) and Mel (Bu-Mel) may be associated with a longer progression-free survival (PFS) compared to Mel alone. In this randomized phase III trial we compared the safety and efficacy of Bu-Mel vs. Mel. 

Methods: Patients were randomized to either Bu-Mel or Mel using the Pocock-Simon method. In the Bu-Mel arm, Bu 130 mg/m² was infused daily for 4 days, followed by 2 daily doses of Mel at 70 mg/m². Mel 200 mg/m² was given as a single dose in the Mel only arm. The primary endpoint was Day 90 CR (IMWG criteria) rate.

Results: Ninety-two patients (Bu-Mel: 49, Mel: 43) were enrolled from October 2011 to August 2013. Median ages at auto-HCT were 58.4 and 58.5 years in Bu-Mel and Mel arms, respectively (p=0.75). Ten (20%) and 11 (26%) patients had high-risk chromosomal abnormalities in Bu-Mel vs. Mel, respectively (p=0.62). Forty-four (90%) and 40 (93%) patients received bortezomib-based induction therapy in the Bu-Mel and Mel, respectively (p=0.71). At the time of auto-HCT, 8/0 (16%) and 7/3 (23%) patients were in CR/near (n)CR in Bu-Mel and Mel arms, respectively (p=0.44), Grade 3 non-hematologic toxicity was seen in 41 (84%) and 20 (47%) patients in Bu-Mel and Mel, respectively (p=0.0003). There was no 100-day TRM in either arm. At day 90, 8 (16%) and 15 (35%) patients had achieved a CR (p=0.05), and 13 (27%) and 20 (47%) patients had achieved a CR + nCR (p=0.05) in Bu-Mel and Mel, respectively. At day 90, 7/7 (100%) evaluable patients with CR in BU-Mel and 14/15 (93%) evaluable patients with CR in Mel also achieved a multiparametric flow cytometric (MFC) CR (p=1.00). Thirty-nine (80%) patients in Bu-Mel and 37 (86%) in Mel received maintenance therapy after day 90 (p=0.58). Median follow up was 15.7 months (range 0.8 – 28.7). No second primary malignancies have been seen in either arm so far. Bayesian multivariable lognormal survival time regression showed significantly better PFS in the Bu-Mel arm (posterior probability of the treatment effect>0.9963, 95% credible interval 0.21-1.70). Median PFS from Day 90 was not reached in the Bu-Mel arm. Median PFS from Day 90 for Mel only was 20 months. One-year survival rates in the Bu-Mel vs Mel arms were 91% (95% CI: 75-97%) and 77% (95% CI: 58-88%), respectively. A formal interim analysis of the Day 90 CR rate was conducted when 65 patients were evaluable, and at that time the Mel only arm was determined to be superior. The study was, therefore, stopped early by the Institutional DSMB. However, with a longer follow up Bu-Mel ultimately resulted in better PFS.   

Conclusions: Bu-Mel was associated with a significantly lower day 90 CR rate and a significantly higher rate of grade 3-4 non-hematologic toxicity, compared to Mel. However, after a median follow up of 15.7 months, PFS was significantly longer in the Bu-Mel arm.

Figure 1. PFS from Day 90 by Treatment Arm