BACKGROUND: A rapid and early monoclonal (M) protein response during initial therapy in patients with multiple myeloma had been identified as a predictor of superior long-term outcome in some-but not all-studies. METHODS: To determine if the parameter of M protein reduction was of value in the relapsed and/or refractory setting, retrospective landmark analyses were performed at the end of cycles 2 and 4 of a phase 3 study, which randomized such patients to receive bortezomib alone or pegylated liposomal doxorubicin (PLD) with bortezomib. RESULTS: Compared with a <25% reduction in M protein at the landmark time point, patients with a 50% to <75% reduction after cycle 2 had a significantly lower hazard ratio (HR) for time to progression (HR = 0.41; 95% confidence interval [CI], 0.26-0.64; P <.001), as did those with a >= 75% reduction (HR = 0.26; 95% CI, 0.15-0.45; P < .001). In all of these groups, PLD + bortezomib provided superior outcomes to bortezomib alone, and did so without an increase in the risk of adverse events overall and with a predictable toxicity profile. CONCLUSIONS: These analyses supported the possibility that a robust early M protein response is a good prognostic factor for long-term outcome of myeloma patients with relapsed and/or refractory disease receiving bortezomib or PLD + bortezomib. Cancer 2011;117:3758-62. (C) 2011 American Cancer Society.