Regulatory Decision Summary for KYPROLIS

The primary source of data supporting the use of Kyprolis in the treatment of multiple myelomais one pivotal Phase III study (ASPIRE; PX-171-009). This study enrolled 792 patients with relapsed multiple myeloma who had received between 1 to 3 prior lines of therapy. Patients were randomized 1:1 to receive either Kyprolis plus lenalidomide and dexamethasone (KRd) or lenalidomide and dexamethasone alone (Rd). The primary endpoint was progression-free survival (PFS) determined by an Independent Review Committee (IRC) using standard objective International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria.

Results from the Phase III study demonstrated a benefit to adding Kyprolis to lenalidomide and dexamethasone therapy. Patients receiving KRd had improved PFS compared to patients treated with Rd (hazard ratio [HR] = 0.69, 1-sided p value <0.0001). This represents a 45% improvement, or a 31% reduction, in the risk of disease progression or death. The median PFS was 26.3 months in the KRd arm compared to 17.6 months in the Rd arm. The PFS benefit of KRd over Rd was observed consistently in all subgroups.

The secondary efficacy endpoint of overall response rate (ORR) was higher in the KRd treatment arm compared to the Rd arm (87.1% versus [vs.] 66.7%). Combined complete responses (CR) and stringent CR (sCR) were reported in 31.8% and 9.4% of patients in the KRd and Rd arms, respectively, indicating not only a higher ORR, but a greater depth of response in patients treated with KRd. There was a trend for an overall survival (OS) benefit in patients treated with KRd at the final PFS analysis, but this interim OS analysis did not meet the protocol-specified early stopping boundary for statistical significance (which was a p-value of 0.0051).

Approximately 20-40% of multiple myeloma patients have significant renal impairment as defined by creatinine clearance (CrCL) <50 mL/min. These patients were excluded from the Phase III study as were patients who progressed during prior therapy with a bortezomib-containing regimen. Therefore, there is more uncertainty as to the effectiveness of the KRd regimen in these patients when compared to Rd therapy alone. This information is included in the Indication section of the Product Monograph.

The Product Monograph is the primary risk management strategy to manage the risks associated with Kyprolis. It provides the necessary warnings pertaining to the adverse events reported in clinical trials and in the post-marketing setting, and recommends appropriate dose adjustments (reductions/interruptions) and, when necessary, permanent discontinuation of Kyprolis to manage side effects. A Serious Warnings and Precautions box is included in the Product Monograph highlighting the following serious adverse events: cardiac toxicities, pulmonary toxicities, hepatic failure, thrombotic microangiopathy, posterior reversible encephalopathy syndrome (PRES), hemorrhage, and venous thromboembolism. Due to the risk of thrombosis in patients receiving Kyprolis in combination with lenalidomide and dexamthasone, which was increased over that associated with lenalidomide and dexamethasones in the pivotal Phase III study, it is recommended that patients receive antithrombotic therapy (that is [i.e.], aspirin) during treatment with the KRd regimen.

A Risk Management Plan (RMP) for Kyprolis was submitted by Amgen Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and, when needed, to describe measures that will be put in place to minimize risks associated with the product.

Of note, Kyprolis as a monotherapy did not show a benefit over an active comparator (corticosteroids and cyclophosphamide) in a Phase III trial in patients with relapsed and refractory multiple myeloma There were no differences in OS or PFS between the two arms, and therefore Kyprolis is not indicated as a monotherapy for the treatment of relapsed and refractory multiple myeloma.

Overall, the benefit-harm-uncertainty profile for Kyprolis in combination with lenalidomide and dexamethasone is considered positive for the treatment of relapsed multiple myeloma patients who have received 1 to 3 prior lines of therapy.