Single-cell immune landscape associated with isatuximab, carfilzomib, lenalidomide, and dexamethasone induction efficacy in newly diagnosed myeloma

Abstract

Abstract Introduction: 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 performed single-cell RNA sequencing (scRNA-seq) on CD45⁺ bone marrow immune cells from 85 NDMM patients enrolled in the Intergroupe Francophone du Myélome (IFM) phase III “MIDAS” trial, treated with Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (IsaKRD). Paired samples collected at baseline and post-induction were analyzed to assess transcriptional and compositional changes across immune subsets. Remodeling patterns were correlated with 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 of inflammatory myeloid populations. MRD-positive patients exhibited a distinct enrichment of monocytes characterized by NF-κB activation, HIF1A-associated transcriptional profiles, and IL1b upregulation, indicating a skewing toward a pro-inflammatory and hypoxic myeloid niche. 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 post IsaKRd induction that differed between MRD-negative and positive patients. MRD-positive patients displayed an enrichment of Tregs and resident memory–like CD4⁺ and CD8⁺ T cells, along with a reduction in cytotoxic CD8⁺ T cells. In contrast, MRD patients preserved CD8⁺ T cell cytotoxicity and showed an expansion of CD4⁺ T cells with effector memory signatures highlighting divergent remodeling patterns based on treatment response. Integration of these findings through multivariate modeling underlines a coordinated immune remodeling involving inflammatory myeloid cells, regulatory T cells, and bone marrow–resident NK and T cell subsets as a hallmark of MRD persistence. 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.