Immune remodeling after Isa-KRd in newly diagnosed multiple myeloma

In the plenary session of IMS 2025, Dr Ludovic Martinet, Director of Research at the Toulouse Cancer Research Center, presented the result of his research into the response of the immune system following quadruplet therapy in multiple myeloma (MM) patients. In these quadruplets, an immunomodulatory drug is combined with a proteasome inhibitor, an anti-CD38 antibody, and dexamethasone. While several studies have convincingly demonstrated that these regimens are highly effective, their precise impact on the immune system remains unclear. Gaining more insights into this effect is of particular relevance given the role of the immune environment as a foundation for future T-cell-based immunotherapies such as CAR-T therapy and bispecific antibodies.

For this research, Martinet and colleagues performed an immune profiling before and after treatment for 84 patients enrolled in the MIDAS trial. An analysis of these profiles revealed significant alterations in the immune landscape after therapy. In fact, these was a notable increase in myeloid populations and a decrease in lymphoid populations, particularly B cells and both CD4+ and CD8+ T cells. Furthermore, cytotoxic natural killer (NK) cells were observed to shift toward an inflammatory, bone marrow-resident phenotype.

The study also identified a depletion of naïve and cytotoxic CD8+ T cells, alongside an expansion of CD8+ T cells with an exhausted and inflammatory profile. Contrary to expectations, the therapy did not reduce inflammation but rather increased the expression of inflammatory genes and pathways across multiple immune cell types.

Interestingly, patients who failed to reach minimal residual disease (MRD) negativity, indicating an in complete response, showed higher levels of inflammation, immunosuppression, and immunomodulation. 

Dr Martinet concludes that quadruplet therapies induce a profound immune dysregulation. A better understanding of these immune effects is crucial not only to optimize current therapies but also to improve the sequencing and design of future immunotherapies.