Regulatory Decision Summary for KYPROLIS

The safety and efficacy of Kyprolis in combination with dexamethasone for treatment of patients with relapsed multiple myeloma were evaluated in a randomized open-label study (referred to as ENDEAVOR) in which Kyprolis plus dexamethasone (Kd) was compared to bortezomib plus dexamethasone (Vd). A total of 929 patients were randomized (464 in the Kd arm, 465 in the Vd arm). The study evaluated Kyprolis at an initial dose of 20 mg/m², which was increased to 56 mg/m² on Cycle 1, Day 8, administered twice weekly as a 30-minute intravenous infusion until disease progression or unacceptable toxicity. The primary efficacy endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC) blinded to treatment arm. Key secondary efficacy endpoints were overall survival (OS) and overall response rate (ORR).

The study met its primary efficacy endpoint demonstrating the superiority of Kd over Vd based on a 47% reduction in the risk of progression or death (hazard ratio 0.53; 95% CI: 0.44, 0.65; p-value <0.0001). The improvement in median PFS was 9.3 months (18.7 months in the Kd arm versus 9.4 months in the Vd arm). The OS data are not yet mature and patients continue to be followed for this endpoint. The ORR in the Kd arm was significantly higher than that in the Vd arm (77% versus 63%).

The adverse events reported in this study were generally consistent with the known toxicity profiles of Kyprolis, bortezomib, and dexamethasone. There was no difference in the incidence of treatment discontinuations and on study deaths between study arms despite a longer duration of therapy for the Kd arm. No new safety signals were identified with the use of a higher Kyprolis dose (56 mg/m²) as part of doublet therapy with dexamethasone when compared to Kyprolis dosed at 27 mg/m² used in combination with lenalidomide and dexamethasone.

The Product Monograph is the primary risk mitigation measure and has been updated with the benefits, harms and uncertainties for Kyprolis used in combination with dexamethasone alone. The serious warnings and precautions box highlights the different dose and infusion times for Kyprolis between the two recommended combinations.

Based on the data reviewed, the benefit-harm-uncertainty profile is considered favourable for Kyprolis in combination with dexamethasone as treatment of relapsed multiple myeloma. Kyprolis, used in combination with either lenalidomide and dexamethasone or dexamethasone alone, provides effective treatment options for patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy.