Niels Weinhold

Abstract In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of “fitter” clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53 , and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.

PURPOSE: To evaluate magnetic resonance (MR) imaging-guided laser-induced thermotherapy (LITT) of liver metastases. MATERIALS AND METHODS: In a phase II study, 20 patients with 33 metastases from colorectal carcinoma (75%) or other primary tumors (25%) underwent LITT. MR thermometry performed with fast low-angle shot sequences was used to monitor therapy on-line, and dynamic and static contrast material-enhanced MR images enabled estimation of the degree of resultant necrosis. Follow-up studies were performed 3 months after thermotherapy. RESULTS: The thermosequences enabled accurate on-line monitoring in 85% of lesions. In 69% of lesions 20 mm in diameter or smaller, contrast-enhanced MR images depicted substantial necrosis, with a local tumor control rate of 69% after 6 months and 44% after 12 months. Among lesions larger than 20 mm, necrosis was frequently incomplete, with a local control rate of only 41% after 6 months and 27% after 12 months. CONCLUSION: MR imaging-guided LITT of liver metastases is a safe and promising therapy for liver metastases.

< .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers.

Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but the immunological mechanism and molecular determinants of primary and acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors of bone marrow-residing T cells in multiple myeloma patients undergoing BCMAxCD3 TCE therapy. We show that the immune repertoire reacts to TCE therapy with cell state-dependent clonal expansion and find evidence supporting the coupling of tumor recognition via major histocompatibility complex class I (MHC class I), exhaustion, and clinical response. We find the abundance of exhausted-like CD8+ T cell clones to be associated with clinical response failure, and we describe loss of target epitope and MHC class I as tumor-intrinsic adaptations to TCEs. These findings advance our understanding of the in vivo mechanism of TCE treatment in humans and provide the rationale for predictive immune-monitoring and conditioning of the immune repertoire to guide future immunotherapy in hematological malignancies.