Melphalan at a dose of 200 mg/m ² is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m ² is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m ² and melphalan 140 mg/m ² are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m ² (n=245) and melphalan 200 mg/m ² (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m ² in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m ² versus melphalan 140 mg/m ² : 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m ² for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m ² and melphalan 140 mg/m ² patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m ² or melphalan 140 mg/m ² for key transplant outcomes (NCT01362972).