Bart Barlogie

Imaging of Multiple Myeloma, Solitary Plasmacytoma, MGUS, and Other Plasma Cell Dyscrasias

The significance of medical imaging in multiple myeloma was established in 1975 with the classic description of the Durie–Salmon staging system which incorporated the presence and number of focal osteolytic lesions in the staging scheme. A third of a century later, this staging system remains in use, though augmented by advances in medical imaging. By the early 1980s, CT imaging demonstrated more focal bone lesions than were seen with standard radiographs as well as extramedullary disease. By the 1980s, MRI imaging revealed skeletal disease that was not apparent by either standard x-rays or CT, focal plasmacytomas in bone that had not yet produced focal osteolysis, and diffuse marrow infiltration. Subsequent work throughout the 1990s developed and established MRI as a very powerful tool to demonstrate the full extent of skeletal disease with resolution approaching a few millimeters. MRI was also used to direct biopsies of focal lesions which increased the detection rate of clinically relevant information compared to random marrow biopsies. However, standard MRI lacked the wide field of view of CT and was both considerably more expensive and less widely available than CT. An additional weakness of standard x-rays, CT, and MRI was their limited utility in the demonstration of response to treatment. By the mid- to late 1990s, the utility of 18F-FDG PET and (after 2000) PET/CT was apparent. PET/CT was particularly powerful since it provided a “whole-body” examination combining the utility of CT (“anatomy”) with a “metabolic” image that was linked to the Warburg physiology of tumors, at a fraction of the cost of an extensive MRI. Thus, PET and PET/CT can demonstrate both active disease and, very importantly, response to treatment. The PET image fused to the CT portion of the PET/CT also provides a “free” whole-body metastatic bone survey that can reveal not only focal bone lesions but also additional clinically relevant findings (fractures or impending fractures, additional malignancies, occult infections, unsuspected regions of tumor involvement such as extramedullary tumor). Recent work has established the fundamental importance of 18F-FDG PET and PET/CT for the baseline evaluation of patients with multiple myeloma and related plasma cell dyscrasias, as well as for subsequent evaluations related to patient management. Future directions for imaging research in multiple myeloma will include PET imaging with isotopes other than 18F-FDG and whole-body MRI.

Precision Medicine for Relapsed Multiple Myeloma on the Basis of an Integrative Multiomics Approach

Purpose Multiple myeloma (MM) is a malignancy of plasma cells, with a median survival of 6 years. Despite recent therapeutic advancements, relapse remains mostly inevitable, and the disease is fatal in the majority of patients. A major challenge in the treatment of patients with relapsed MM is the timely identification of treatment options in a personalized manner. Current approaches in precision oncology aim at matching specific DNA mutations to drugs, but incorporation of genome-wide RNA profiles has not yet been clinically assessed. Methods We have developed a novel computational platform for precision medicine of relapsed and/or refractory MM on the basis of DNA and RNA sequencing. Our approach expands on the traditional DNA-based approaches by integrating somatic mutations and copy number alterations with RNA-based drug repurposing and pathway analysis. We tested our approach in a pilot precision medicine clinical trial with 64 patients with relapsed and/or refractory MM. Results We generated treatment recommendations in 63 of 64 patients. Twenty-six patients had treatment implemented, and 21 were assessable. Of these, 11 received a drug that was based on RNA findings, eight received a drug that was based on DNA, and two received a drug that was based on both RNA and DNA. Sixteen of the 21 evaluable patients had a clinical response (ie, reduction of disease marker ≥ 25%), giving a clinical benefit rate of 76% and an overall response rate of 66%, with five patients having ongoing responses at the end of the trial. The median duration of response was 131 days. Conclusion Our results show that a comprehensive sequencing approach can identify viable options in patients with relapsed and/or refractory myeloma, and they represent proof of principle of how RNA sequencing can contribute beyond DNA mutation analysis to the development of a reliable drug recommendation tool.