A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma

Abstract

Carfilzomib is a next-generation

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

“…Carfilzomib has demonstrated anti‐tumour activity in patients with MM at doses ranging from 15 to 56 mg/m 2 (Siegel et al , 2012; Vij et al , 2012a,b; Badros et al , 2013; Papadopoulos et al , 2013, 2015). In phase I and II trials, only the LLVY‐AMC assay was used in a limited number of patient samples to measure CT‐L activity alone (O'Connor et al , 2009; Badros et al , 2013; Niesvizky et al , 2013; Papadopoulos et al , 2013).…”

“…Kuhn et al (2009) have shown that LMP2‐selective inhibitors can induce myeloma cell death, and multiple reports have demonstrated synergistic tumour cell killing with carfilzomib or bortezomib and either an LMP2/β1 or MECL1/β2 selective inhibitor (Britton et al , 2009; Mirabella et al , 2011). It is possible that the simultaneous inhibition of multiple i20S subunits contributes to the potent anti‐tumour activity of carfilzomib in patients with MM, including patients that are refractory to bortezomib (Siegel et al , 2012; Vij et al , 2012a), particularly given that approximately 75% of the proteasomes in isolated myeloma cells are i20S.…”

Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy

“…3 In July 2012, the proteasome inhibitor (PI) carfilzomib was approved as a single agent in the United States for the treatment of relapsed and refractory MM based on the findings from the pivotal PX-171-003-A1 (#NCT00511238)) trial. 4,5 In this study, nearly all patients who received carfilzomib had received prior therapy with bortezomib, a first-generation PI. 4 Among patients who were refractory or intolerant to bortezomib and lenalidomide, the ORR was 20.1% (95% confidence interval (CI): 14.9-26.1).…”

“…4,5 In this study, nearly all patients who received carfilzomib had received prior therapy with bortezomib, a first-generation PI. 4 Among patients who were refractory or intolerant to bortezomib and lenalidomide, the ORR was 20.1% (95% confidence interval (CI): 14.9-26.1). Similarly, many relapsed and refractory MM patients who received single-agent carfilzomib in the PX-171-004 study (#NCT00530816) had also received bortezomib and had an ORR of 17.1%.…”

“…16 These preclinical studies provided the rationale for evaluating whether replacing a PI for one that is ineffective in a combination treatment can achieve clinical efficacy for patients with MM. In this context, carfilzomib treatment for patients that failed bortezomib therapy in an otherwise novel treatment combination has shown clinical activity, 4,6 yet the concept of substituting PI with another into an otherwise unchanged combination treatment in an attempt to overcome PI resistance has not been investigated in the clinic. Given that single-agent carfilzomib can produce responses in some bortezomib refractory patients 4 and shows high response rates when combined with other agents, 17,18 we hypothesized that carfilzomib would be an effective and well-tolerated replacement for bortezomib among MM patients who had failed bortezomibcontaining combination regimens.…”