Study highlights previously unknown mechanisms involved in myeloma resistance

A group of researchers led by Maximillian Merz, MD, Assistant Professor of Oncology with the Myeloma team at Roswell Park Comprehensive Cancer Center, conducted the first prospective clinical trial investigating spatial heterogeneity in patients with either relapsed/refractory or newly diagnosed multiple myeloma.

Findings from the study will be presented today at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, which is being held virtually.

The trial, which included 18 patients, demonstrated spatial evolution, or migration of cancer cells to new locations, and reduced T-cell receptor diversity, particularly in patients with relapsed/refractory multiple myeloma and/or extramedullary disease, or myeloma that forms outside the bone marrow.

Enrolled patients agreed to imaging-guided biopsy of an osteolytic or soft-tissue lesion as well as regular bone marrow sampling. Thirty-seven different locations were biopsied initially. Follow-up samples were collected from five patients who were in remission following therapy.

The researchers, a team of collaborators from the departments of Immunology, Radiology, Medicine, Biostatistics and Flow Cytometry, the Blood and Marrow Transplant Program and Center for Personalized Medicine at Roswell Park, performed whole-exome sequencing and single-cell RNA sequencing on plasma cells.

Whole-exome sequencing uncovered more mutations in relapsed/refractory multiple myeloma compared to newly diagnosed disease. Single-cell RNA sequencing of more than 150,000 plasma cells from 10 patients and 21 locations showed multiple clones. The investigators also examined spatiotemporal differences of immune cells.

The estimation of median T-cell receptor richness showed significantly lower values among patients with relapsed/refractory disease when compared to those with newly diagnosed multiple myeloma and healthy individuals.

Our study is clinically significant because we were able, for the first time, to integrate a single-cell analysis in a prospective clinical trial in multiple myeloma. By doing so, we show that myeloma patients harbor different clones of plasma cells clones responsible for the osteolytic lesions that characterize multiple myeloma, which can cause resistance to treatment. Furthermore, this study demonstrates that patients with relapsed myeloma suffer from an impaired immune system, and we know that successful treatment can help restore immune function for greater control of plasma-cell growth."

Maximillian Merz, MD, Assistant Professor of Oncology, Roswell Park Comprehensive Cancer Center

"Next-generation tools are opening the window to a number of myeloma processes and defense mechanisms that we were not aware of just a few years ago," notes the study's senior author, Jens Hillengass, MD, PhD, Chief of Myeloma at Roswell Park. "We hope that this precision-medicine approach will help us to eradicate residual disease in the future by pointing the way to strategies for attacking resistance mechanisms and supporting the immune system."

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