Isatuximab Improves MRD Negativity in Newly Diagnosed Multiple Myeloma: EMN24 IsKia Trial Results

A phase 3 clinical trial published in Nature Medicine on April 6, 2026, has found that a quadruplet therapy regimen significantly improves the rate of measurable residual disease (MRD) negativity in transplant-eligible patients with newly diagnosed multiple myeloma.

The EMN24 IsKia trial evaluated the effectiveness of adding isatuximab to a standard combination of carfilzomib, lenalidomide, and dexamethasone (known as KRd) for patients aged 70 years or younger.

The study focused on patients undergoing pretransplant induction and post-transplant consolidation. The primary objective was to measure the rate of MRD negativity using next-generation sequencing (NGS) after the consolidation phase.

Comparative Trial Results

The trial randomized 302 patients to receive either the quadruplet therapy (Isa-KRd) or the triplet therapy (KRd). The results indicated that the addition of isatuximab led to significantly higher rates of MRD negativity at two different sensitivity levels.

At a sensitivity of 10−5 or better, the MRD negativity rate was 77% for the Isa-KRd group compared to 67% for the KRd group.

At a higher sensitivity of 10−6 or better, the difference was more pronounced, with 68% of patients in the Isa-KRd arm achieving negativity compared to 48% in the KRd arm.

Speed and Durability of Response

Researchers observed that deep MRD responses were achieved more rapidly with the quadruplet therapy. Following induction, the rates of MRD negativity were higher for Isa-KRd than for KRd at both sensitivity levels:

• At 10−5 sensitivity: 46% for Isa-KRd versus 27% for KRd.
• At 10−6 sensitivity: 28% for Isa-KRd versus 14% for KRd.

The study also assessed the durability of these responses. One-year sustained MRD negativity at the 10−6 sensitivity level was reported in 52% of the Isa-KRd group, compared to 38% in the KRd group.

Safety and Tolerability

The trial monitored for adverse events to determine if the added complexity of the quadruplet regimen increased patient risk. According to the findings, Grade 3–4 non-hematologic adverse events were similar between the two treatment arms.

the rates of treatment discontinuations and deaths resulting from adverse events were similar across both the Isa-KRd and KRd groups, suggesting a manageable safety profile for the quadruplet approach.

Clinical Context and Limitations

Induction and consolidation using a combination of a CD38-targeting monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug, and dexamethasone is considered a standard-of-care treatment for transplant-eligible patients with newly diagnosed multiple myeloma. However, the specific selection of drugs for these combinations remains a subject of medical debate.

While the EMN24 IsKia trial demonstrated significant improvements in MRD negativity, some data remains incomplete. At the time of the report, progression-free survival (PFS) data were described as immature.

The use of MRD as a surrogate endpoint in such studies has also sparked broader debate within the oncology community regarding how these markers translate to long-term patient outcomes.