Regulatory Decision Summary for Kyprolis

This Supplement to a New Drug Submission (SNDS) for Kyprolios (carfilzomib) was filed proposing the addition of a new indication for carfilzomib in combination with isatuximab and dexamethasone (IsaKd) for the treatment of patients with multiple myeloma who have received 1 to 3 prior lines of therapy.

Kyprolis in combination with isatuximab and dexamethasone (IsaKd) was studied in IKEMA, a multicenter, multinational, randomized, open-label, 2-arm, phase III study in adult patients with relapsed and/or refractory multiple myeloma who had received 1 to 3 prior lines of therapy.

At the pre-specified interim analysis, the study met its primary endpoint and demonstrated a statistically significant improvement in progression free survival (PFS) in patients who received IsaKd compared to patients who received carfilzomib and dexamethasone (Kd). The median PFS was not reached (95% confidence interval [CI]: not reached [NR] – NR) in the IsaKd group compared to 19.15 months (95% CI: 15.77-NR) in the Kd group (hazard ratio = 0.531; 95% CI: 0.318-0.889; p = 0.0013), representing a 46.9% reduction in the risk of disease progression or death in patients treated with IsaKd compared to patients treated with Kd.

Although some uncertainties might affect the long-term benefit, the improved PFS and very good partial response together with minimal residual disease (MRD) negativity reduction outweigh the risks. Overall, the results represent clinically meaningful improvement in PFS in patients with relapsed or refractory disease.

The combination of isatuximab with Kyprolis and dexamethasone resulted in a higher incidence of Grade ≥ 3 adverse reactions (76.8% in the IsaKd group vs 67.2% in the Kd group); however, serious adverse reactions occurred at similar rates (59.3% in the IsaKd group vs 57.4% in the Kd group). Second primary malignancies (SPMs) were reported more frequently in the Isa-Kd group (7.3%) compared to the Kd group (4.9%). A warning regarding the risk of SPMs was added to the Warnings and Precautions section of the Kyprolis Product Monograph. Overall, the differences in the incidence of adverse reactions between the IsaKd group and the Kd group are consistent with the nature of a triplet therapy versus a doublet therapy, and the safety profile of the IsaKd regimen was generally consistent with the known safety profile of Kyprolis and that of isatuximab in combination with dexamethasone. The addition of isatuximab to Kd did not increase the rate of permanent treatment discontinuation relative to Kd.

Routine pharmacovigilance activities and routine risk minimization activities are considered sufficient for all safety concerns by the Market Authorization Holder in both the Kyprolis Core RMP v9.0 and Canadian RMP Addendum v2.0, at this time. Therefore, no additional pharmacovigilance activities or additional risk minimization activities are proposed by the MAH, at this time. Overall, the Kyprolis Canadian RMP Addendum v2.0 (dated May 25th, 2023) to the Core RMP v9.0 (dated October 23rd, 2020) was considered acceptable and no changes or additional activities are required at this time.

Key clinical findings are adequately described in the final approved Kyprolis Product Monograph. The submission was considered acceptable with respect to the labelling documents reviewed.

Overall, the benefit/risk profile for Kyprolis, in combination with isatuximab and dexamethasone, is considered favourable for adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.

For further details about Kyprolis, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.