Conditioning with Busulfan + Melphalan Versus Single-Agent Melphalan for Patients with Multiple Myeloma Receiving Autologous Stem Cell Transplantation: A Propensity Score-Matched Analysis

Background: For patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT), high dose melphalan has been the standard conditioning for many years. A prospective randomized clinical trial at our institution compared the outcomes of patients who received busulfan + melphalan (BuMel) to melphalan 200mg/m² (Mel200) showed longer progression-free survival (PFS) in the BuMel group [Bashir et al. Lancet Haematol. 2019]. In the present study we compared outcomes of patients with MM who received these two conditioning regimens as standard of care, off protocol.

Methods: We conducted a single-center, retrospective analysis of patients who underwent upfront autoHCT for MM and received either BuMel or Mel200 conditioning between 2005 to 2021. We conducted 2:1 propensity score matching (PSM) between Mel200 and BuMel patients, according to the following variables: age at autoHCT, year of autoHCT, cytogenetic risk (standard vs. high), R-ISS stage, HCT-CI (≤ 3 vs. > 3), type of induction treatment, hematological response prior to autoHCT and the use of post-transplant maintenance treatment. High-risk cytogenetics were defined as del17p, t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization. Clinical response, relapse, and progression were defined by the International Myeloma Working Group criteria. Primary endpoints were PFS and overall survival (OS).

Results: After matching, 262 patients in the BuMel group were compared to 524 in the Mel200 group. Patients in the two groups were well-matched for their baseline characteristics. One hundred and sixty (61%) patients in the BuMel group and 285 (54%) in the Mel200 group were male (p=0.08) and the median age at autoHCT was 59.1 and 59.4 years (p=0.53), respectively. There was no significant difference between the two conditioning groups in rates of high-risk cytogenetics (54% vs. 50%; p=0.26), revised international staging system (R-ISS) III (11% vs. 9%; p=0.42), type of induction regimen (VRD: 37% vs. 34%, KRD: 25% vs. 21%; p=0.30) or hematological response prior to autoHCT (CR: 18% vs. 16%, VGPR 45% vs. 45%; p=0.87).

There was no significant difference in CR or ≥VGPR between the BuMel and Mel200 groups at day 100 [(odds ratio (OR) 1.07, 95% confidence interval (CI) 0.79-1.45; p=0.68) and (OR 0.96, 95% CI 0.67-1.40; p=0.85), respectively] or at best post-transplant response [(OR 1.00, 95% CI 0.75-1.35; p=0.98) and (OR 1.09, 95% CI 0.66-1.79; p=0.74), respectively].

Moreover, there was no significant difference in PFS (hazard ratio (HR) 0.96, 95% CI 0.73-1.24;p=0.74) or OS (HR 1.03, 95% CI 0.72-1.46;p=0.88) between the two conditioning groups.

Within the subgroup of patients with high-risk cytogenetics, we did not observe any difference in PFS (HR 0.77, 95% CI 0.57-1.05; p=0.10) or OS (HR 0.98, 95% CI 0.63-1.52; p=0.94) between the BuMel and Mel200 groups. Similarly, within the subgroup of patients with R-ISS III, there was no significant difference in PFS (HR 1.11, 95% CI 0.57-2.17; p=0.76) or OS (HR 1.37, 95% CI 0.58-3.21; p=0.47) between the two conditioning groups.

Conclusions: In this real-world PSM analysis of patients with MM who received upfront autoHCT, we did not observe a significant difference in response rates or survival outcomes between patients who received conditioning with either BuMel or Mel200, including in subsets of patients with high-risk cytogenetics and R-ISS stage III.

Bashir:Pfizer, Inc.: Research Funding; GSK PLC: Research Funding; Stemline Therapeutics, Inc.: Research Funding. Srour:Hansa Biopharma: Consultancy; Orca Bio: Research Funding. Lee:Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Allogene: Consultancy; Regeneron: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy. Patel:AstraZeneca: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Caribou Sciences: Consultancy; Merck: Consultancy; Johnson & Johnson (Janssen): Consultancy; Takeda: Consultancy; Genentech: Consultancy; Sanofi: Consultancy; Poseida: Consultancy; Kite, A Gilead company: Consultancy, Other: scientific advisory board; BMS: Consultancy, Other: chair of scientific advisory board ; Oricel: Consultancy, Other: Chair of scientific board. Gaballa:GLG: Consultancy; Guidepoint: Consultancy; Boxer Capital, LLC: Consultancy; Bristol Myers Squibb: Consultancy. Kebriaei:Pfizer: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Thomas:Ascentage Pharma: Research Funding; Sanofi: Research Funding; Mustang Bio: Consultancy, Honoraria; Janssen: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Acerta Pharma: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar Biosciences: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; X4 Pharma: Research Funding; Abbvie: Consultancy, Research Funding. Orlowski:Sanofi, Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc, Adaptive Biotechnologies Corporation, Asylia Therapeutics Inc, BioTheryX Inc, Bristol Myers Squibb, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Therapeutics, Oncopeptides, Pf: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, CARsgen Therapeutics, Exelixis Inc, Heidelberg Pharma, Janssen Biotech Inc, Sanofi, Takeda Pharmaceuticals USA Inc; Laboratory Research Funding: Asylia Therapeutics Inc, BioTheryX Inc, Heidelberg Pharma: Research Funding; Asylia Therapeutics Inc.: Current equity holder in private company, Patents & Royalties; DEM BioPharma, Inc., Karyopharm Therapeutics, Lytica Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Myeloma 360, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sporos Bio: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shpall:FibroBiologics: Other: Scientific Advisor; Zelluna Immunotherapy: Other: Scientific Advisor; Adaptimmune Limited: Other: Scientific Advisor; National Marrow Donor Program: Other: Board of Directors/Management; Axio Research: Current Employment, Other: Scientific Advisor. Qazilbash:Janssen Pharmaceuticals: Research Funding; Angiocrine Bioscience: Research Funding; BioLineRx: Research Funding; Amgen: Research Funding; NexImmune: Research Funding.