(OA-30) Single-Cell Immune Landscape Associated with Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone Induction Efficacy in Newly Diagnosed Myeloma

Quadruplet regimens combining CD38-targeting monoclonal antibodies, such as Isatuximab or Daratumumab, with proteasome inhibitors, immunomodulatory drugs (IMiDs), and dexamethasone have recently emerged as the standard-of-care induction therapy for newly diagnosed multiple myeloma (NDMM). Despite significant clinical advances, many patients experience incomplete responses, resistance, or relapse. Increasing evidence highlights the critical role of the immune microenvironment in modulating treatment efficacy. However, the immunological impact of quadruplet therapy and the mechanisms underpinning therapeutic resistance remain poorly defined. A deeper understanding of immune dynamics in response to treatment could inform novel immunotherapeutic strategies aimed at enhancing long-term disease control.

Methods: We analyzed longitudinal samples from the phase III IFM2020-02 “MIDAS” trial, investigating the immune effects of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (IsaKRD) in NDMM. Bone marrow aspirates were collected at baseline and after six cycles of induction. We performed single-cell RNA sequencing (scRNA-seq) on paired samples from 85 patients collecting over 200,000 CD45⁺ immune cells and applied integrative bioinformatic pipelines to assess transcriptional and compositional changes across immune subsets. Immune remodeling patterns were correlated with treatment response, focusing on minimal residual disease (MRD) status.


Results:

IsaKRD therapy profoundly reshaped the bone marrow immune landscape. This remodeling was marked by a significant reduction in B cells, NK cells, and T cells, coupled with an expansion of myeloid populations—particularly inflammatory monocytes exhibiting NF-κB activation and hypoxia-associated transcriptional profiles, which were specifically enriched in MRD-positive patients. Cytotoxic NK cell subsets were selectively depleted following treatment, especially in MRD-positive individuals, who instead showed an increase in inflammatory, bone marrow–resident NK cells. CD4⁺ and CD8⁺ T cells also underwent transcriptional reprogramming toward activated and pro-inflammatory states. MRD-positive patients displayed an enrichment of regulatory and T follicular helper–like CD4⁺ subsets, along with a reduction in cytotoxic CD8⁺ T cells. In contrast, MRD-negative patients preserved CD8⁺ T cell cytotoxicity and showed an expansion of CD4⁺ T cells with tissue-resident memory signatures highlighting divergent remodeling patterns based on treatment response.

Conclusions: Our study provides a comprehensive single-cell atlas of the immune microenvironment in NDMM patients before and after IsaKRD induction. We reveal coordinated reshaping of both lymphoid and myeloid compartments, with immune signatures that correlate with MRD status and treatment efficacy. These findings underscore the importance of immune remodeling in shaping therapeutic outcomes and offer potential avenues for biomarker development and immune-based interventions in multiple myeloma.