P-361: Busulfan Plus Melphalan versus Melphalan Alone as Conditioning Before Autologous Hematopoietic Cell Transplantation for Multiple Myeloma: Long-Term Follow Up of a Randomized Phase III Trial

Introduction: In a phase III randomized trial for conditioning regimen for autologous hematopoietic stem cell transplantation (auto-HCT) for patients with newly diagnosed multiple myeloma, we showed that busulfan plus melphalan (Bu-Mel) was associated with longer progression-free survival (PFS) compared to melphalan alone (Mel alone). Here we report updated results for this trial based on long-term follow up.

Methods: Patients were randomized to either Bu-Mel or Mel using dynamic adaptation to balance on patient covariates. Eligible patients, aged 70 years or younger, with at least stable disease, were randomly assigned to either Bu-Mel, with a pharmacokinetically adjusted doses of Bu on days –7, –6, –5, and –4 to achieve a target daily area under the curve (AUC) of 5000 µmol-minute and Mel 70 mg/m² per day on days –2 and –1 or a Mel dose of 200 mg/m² on day –2. The primary objective was to compare PFS between the two arms.

Results: Between Oct 2011, and March 2017, 202 patients received the treatment: 104 in the Bu-Mel group and 98 in the Mel alone group. There was no significant difference between the two arms in age, gender, race, cytogenetic risk status, R-ISS stage, induction regimens, response to induction, or maintenance therapy. Overall, 28 of 101 (28%) patients and 27 of 93 (29%) patients had high-risk cytogenetics, defined as t(4;14), t(14;16), del17p, and 1q gain or amplification, in the Bu-Mel and Mel arms, respectively. There were no treatment-related deaths by day 100 in either group. Grade 1-3 mucositis (96% vs. 49%, p < 0.001), rise in ALT (33% vs 1%, p < 0.001) and neutropenic fever (71% vs. 30%, p < 0.001) were seen at a higher rate in the Bu-Mel arm. At day 90 after auto-HCT, 29 (28%) and 34 (35%) patients had achieved complete remission (CR), which increased to 61 (59%) and 63 (64%) patients at best post-transplant response evaluation in Bu-Mel and Mel arms, respectively. The median follow-up in the Bu-Mel group was 96.6 months (5.6–146.7) and 88.4 months (10.7–146.2) in the Mel alone group. Median PFS was 62.2 months (95% CI: 48.1–81.9) in the Bu-Mel versus 56.8 months (95% CI: 34.7–82.5) in the Mel alone. Median overall survival has not been reached in either group. Second primary malignancies were seen in 17 (16%) and 15 (15%) patients in the Bu-Mel vs. Mel alone arms, respectively. In a fitted Bayesian regression model for PFS, there was no meaningful Bu-Mel vs. Mel alone effect, with a 55% posterior probability of benefit for Bu-Mel. Only high-risk cytogenetics was predictive, with a 99% posterior probability of shorter PFS.

Conclusions: Contrary to our original report, after a longer follow up of almost 8 years, there was no significant difference in PFS between the Bu-Mel and Mel alone arms. Mel 200 mg/m² remains the standard conditioning regimen for auto-HCT for multiple myeloma.