Minimal residual disease and imaging-guided consolidation strategies in newly diagnosed and relapsed refractory multiple myeloma.

Measurement of minimal residual disease (MRD) by next-generation flow cytometry (NGF) is an important tool to define deep responses in multiple myeloma (MM). However, little is known about the value of combining NGF with functional imaging and its role for MRD-based consolidation strategies in clinical routine. In the present study, we report our experience investigating these issues with 102 patients with newly diagnosed (n = 57) and relapsed/refractory MM (n = 45). Imaging was performed using either positron emission tomography or diffusion-weighted magnetic resonance imaging. In all, 45% of patients achieved MRD-negativity on both NGF and imaging (double-negativity), and 8% and 40% of patients were negative on either NGF or imaging respectively. Thus, in a minority of patients imaging was the only technique to detect residual disease. Imaging-positivity despite negativity on NGF was more common in heavily pretreated disease (four or more previous lines) compared to newly diagnosed MM (p < 0.01). Among the 29 patients undergoing MRD-triggered consolidation, 51% responded with MRD conversion and 21% with improved serological response. MRD-triggered consolidation led to superior progression-free survival (PFS) when compared to standard treatment (p = 0.04). In conclusion, we show that combining NGF with imaging is helpful particularly in patients with heavily pretreated MM, and that MRD-based consolidation could lead to improved PFS.

Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract.

Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.