EHA 2025 Insights: IMROZ Trial Updates On Isatuximab-Based Regimens for Transplant-Ineligible High-Risk Patients In NDMM

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The IMROZ trial provides compelling evidence for isatuximab-based quadruplet therapy in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM), with particularly impressive results in 1q21 abnormalities and extramedullary disease subgroups. The trial demonstrated nearly doubled sustained MRD negativity rates at 12 months (52% vs 23%) when isatuximab was added to VRd backbone therapy. Notably, both control and experimental arms performed exceptionally well, with the control arm showing robust progression-free survival at 40 months, highlighting the efficacy of modern backbone regimens even without CD38 targeting. The sustained MRD negativity data represent a crucial clinical end point, providing accessible and meaningful information for treatment decision-making in routine practice.

Expert discussion clarifies the important distinction between paramedullary and true extramedullary disease, with significant implications for treatment selection and prognosis. Paramedullary disease represents myeloma growth adjacent to bone marrow that has outgrown its original container, whereas true extramedullary disease occurs in locations separate from bone marrow (liver, orbital, bladder lesions). True extramedullary disease represents a different pathologic entity with altered clone characteristics and generally worse prognosis. In the IMROZ extramedullary disease subgroup analysis, despite small patient numbers, the sustained MRD negativity rates improved from 23% to 42% with isatuximab addition. However, experts caution that these patients require more intensive approaches and longer follow-up to determine true clinical benefit.

The choice between daratumumab and isatuximab in clinical practice largely depends on institutional familiarity and practical considerations rather than significant efficacy differences. Both agents have demonstrated similar benefits when added to standard backbone regimens, with no head-to-head comparative data available. Daratumumab benefits from earlier approval (2015), extensive clinical experience, and subcutaneous formulation availability, while isatuximab offers alternative options for patients with administration preferences. Experts emphasize that the agents are not interchangeable after progression - patients who progress on one CD38 antibody should not routinely switch to the other within the same class. The decision should be based on physician comfort, institutional protocols, patient convenience factors, and administration preferences rather than perceived efficacy advantages, as both agents provide substantial clinical benefit in appropriate treatment combinations.