Regulatory Decision Summary for Darzalex SC

This Supplement to a New Drug Submission (SNDS) was filed to obtain market authorization for Darzalex SC (daratumumab injection), to be used in combination with bortezomib, lenalidomide, and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are not undergoing autologous stem cell transplant as initial therapy.

After evaluation of the submitted data package, Health Canada authorized Darzalex SC for the following indication: Darzalex SC (daratumumab injection) is indicated in combination with bortezomib, lenalidomide, and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are not candidates for autologous stem cell transplant.

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The median age at diagnosis is 69 years. Patients with newly diagnosed multiple myeloma (NDMM) are stratified as transplant eligible (TE) or transplant ineligible (TI), with a substantial proportion deemed ineligible for autologous stem cell transplant due to age, comorbidities or frailty. Development of combination regimens incorporating novel agents - proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies (mAbs) - have improved progression-free survival (PFS) and overall survival (OS). Depth of response to treatment is evaluated using conventional criteria such as complete response (CR), and more recently, minimal residual disease (MRD) negativity.

The efficacy of the quadruplet regimen, Darzalex SC (daratumumab) in combination with bortezomib, lenalidomide and dexamethasone (D-VRd) was evaluated in a randomized, controlled trial (CEPHEUS) in NDMM patients for whom autologous stem cell transplant was not planned as initial therapy. D-VRd demonstrated a-a stastistically -asignificant improvement in the primary efficacy outcome of overall MRD negativity rate compared to bortezomib, lenalidomide and dexamethasone (VRd) (D-VRd 53.3%, VRd 35.4%; Risk Ratio = 1.51 [95% confidence interval [CI]: 1.20, 1.90]). This was supported by a statistically significant improvement in PFS. At the time of the interim PFS analysis, treatment with D-VRd resulted in a 39% reduction in the risk of disease progression or death compared to VRd (Hazard ratio = 0.61; 95% CI: 0.42, 0.90). Median PFS was not reached in either treatment arm. D-VRd also demonstrated improved outcomes across other key secondary efficacy endpoints: CR or better and sustained MRD negativity. At the time of analysis, overall survival data were immature.

Treatment-emergent adverse events (TEAEs) observed with D-VRd were generally consistent with those seen in the VRd arm, but occurred at a higher incidence. The incidences of Grade 3/4 TEAEs, treatment-emergent serious adverse events (TE-SAEs), and TEAEs with an outcome of death were higher in the D-VRd arm. When adjusted for treatment duration, the incidence of TEAEs with a fatal outcome was comparable between the two arms. Infections, including COVID-19, were the leading cause of fatal TEAEs. Other significant TEAEs included neutropenia and thrombocytopenia, which are consistent with the established safety profile of Darzalex SC.

A statistically significant improvement in overall MRD negativity rate, supported by a significant PFS benefit and a safety profile consistent with known data for daratumumab and VRd, supports a favourable benefit-risk profile for D-VRd in patients with NDMM, who are not candidates for autologous stem cell transplant.

An updated Risk Management Plan (RMP) for Darzalex SC was reviewed by Health Canada and considered acceptable.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Darzalex SC for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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