(SLB-013) Structured benefit-risk assessment for isatuximab in transplant-ineligible newly diagnosed multiple myeloma patients

Background: Multiple myeloma (MM) is the second most frequent hematological malignancy worldwide. It is an incurable disease with significant unmet needs for treatments that can improve patient outcomes and prolonged disease control, while considering the more fragile patients’ status.

Objectives: The aim was to evaluate the benefit-risk profile of isatuximab (I) in combination with lenalidomide (V), bortezomib (R) and dexamethasone (d) to support indication extension in newly diagnosed MM (NDMM) patients not eligible for autologous stem cell transplantation (ASCT) or with no intent for ASCT as initial therapy.

Methods: A structured semi-quantitative benefit-risk assessment (BRA) was conducted. The steps from the Benefit-Risk Action Team framework were followed: decision context definition, key benefits and risks identification, data sources selection, presentation and interpretation of the results. The BRA was mainly based on interim data of phase 3 IMROZ study in transplant-ineligible (TI) NDMM patients. The data presentation consisted of a value tree, a BR framework, and forest plots comparing IVRd and VRd for the key benefits and risks in terms of hazard ratio (HR) and absolute risk difference (RD) with 95% confidence interval (CI).

Results: For the key benefits, the comparison between IVRd and VRd showed
improvement in favor of IVRd for progression-free survival (HR=0.596; 98.5%CI [0.406; 0.876]), reflecting clinical benefits of disease control; an increased frequency in favor of IVRd for complete response (CR) (RD=10.63% [1.9; 19.36]), minimal residual disease (MRD) negativity(-) with CR (RD= 14.59% [5.25; 23.92]) and sustained MRD (-), reflecting improved depth of disease response. For overall survival, a non-significant difference in favor of IVRd was seen (data immature at this stage).
For the key risks, the comparison showed an increased frequency of neutropenia (Grade ≥ 3) and secondary primary malignancy (SPM) with IVRd and a non-significant difference for lymphopenia (Grade ≥ 3), infections (Grade ≥ 3), and tumor lysis syndrome. Exposure adjusted analysis showed that differences were largely due to increased exposure in the IVRd arm. Overall, the safety profile of IVRd is manageable and remains consistent with the known safety profiles of individual agents.

Conclusions: The analysis provides evidence that the key benefits of isatuximab in combination with VRd are clinically meaningful and outweigh the key risks in patients with NDMM TI. This example shows how the sBRA enables a comprehensive discussion of the benefits and risks while providing complete transparency regarding the origin and format of the data sources in order to support decision-making in appropriate patient populations.