Sunday at ASH brought us 4 more CoMMpass oral presentations.
Our first presentation was supported by the MMRF Answer Fund and focused on identification of high-risk myeloma patients—those patients who will relapse or die within two years. Dr. Benjamin Barwick of the Winship Cancer Institute in Atlanta, Georgia analyzed genomic sequences from 826 newly diagnosed myeloma patients from the CoMMpass study to tease out any genomic factors that contribute to poor outcomes (ABSTRACT 405 https://ash.confex.com/ash/2018/webprogram/Paper113585.html).
Dr. Barwick and colleagues found that translocations (that is, when segments of 2 chromosomes switch positions)—namely in the IgH and MYC regions—are the most significant structural changes that occur in patients. However, these particular translocations are not associated with poor outcomes. It was the third most commonly translocated region—found at the IgL locus—that was associated with poor survival. They found that patients with the IgL-translocation do not benefit from treatment with immunomodulatory drugs (such as Revlimid). These results suggest that the IgL translocation may serve as a marker for high-risk disease and poor prognosis and are important new insights into identifying a previously unknown group of patients at high risk for disease progression.
Dr. Yu-Hsiu Lin from the University of California, San Francisco analyzed plasma cells obtained from the CoMMpass trial to measure tumor cell signaling activity and identify signaling pathways that drive myeloma cell growth and survival (ABSTRACT 469 https://ash.confex.com/ash/2018/webprogram/Paper113683.html). Dr.Lin found that a pathway called the MAP kinase (MAPK) pathway is dysregulated in myeloma cells. This pathway is important for cell division and represents one of the arms studies in the MMRF MyDrug Trial.
Dr. Susan Bal of Memorial Sloan Kettering Cancer Center in New York City wanted to understand why patients with high levels of lactate dehydrogenase (LDH, a blood marker that reflects tumor-cell burden) is associated with drug resistance and shorter survival by analyzing the genomes from myeloma patients with high LDH from the CoMMpass study. She wanted to see if there were any associated high-risk factors associated with these patients (ABSTRACT 470 https://ash.confex.com/ash/2018/webprogram/Paper115523.html). Dr. Bal and her team identified 871 patients that had high (143 patients) and normal (782 patients) LDH levels. Her analysis found:
- High LDH levels is a poor prognostic factor for myeloma patients which might be due to the overrepresentation of the deletion of chromosome 17p in these same patients
- Patients with high LDH levels also had high expression of other genes responsible for myeloma cell growth and survival as well as genes responsible for invasion and metastasis (tumor cell dissemination)
These results suggest that drugs that target the myeloma cell microenvironment or cell division pathways may be useful strategies for patients with high LDH levels.
The last abstract focused on the mechanisms of drug resistance. Dr. Santiago Barrio Garcia from Spain wanted to identify specific genomic fingerprints of myeloma relapse so he analyzed genomic data from 57 myeloma patients from CoMMpass who had data from both diagnosis and at relapse (ABSTRACT 471 https://ash.confex.com/ash/2018/webprogram/Paper118700.html). Dr. Garcia and his colleagues observed the following genomic changes at relapse:
- As many as 23 new genetic mutations (ie, a defect or error) occur per patient on average
- The most common mutations were in the RAS pathway—which is a signaling pathway in cells that, when normal, regulate cell division
- Mutations were also found in the genes for ubiquitin (a cellular protein that targets other proteins for degradation) and histones (cellular proteins that interact with DNA)
- Some patients developed the deletion of chromosome 17 and some had a gain of chromosome 1