By Candace Gwaltney
January 26, 2021
Brian Walker, Ph.D., and colleagues recently wrote “The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma,” which was published in Nature Communications.
Walker is a cancer center researcher and the Daniel and Lori Efroymson Professor of Oncology at IU School of Medicine. He answered questions about these findings.
Q. This study focuses on smoldering myeloma. First, could you explain smoldering myeloma and its relationship to multiple myeloma?
A. Smoldering multiple myeloma (SMM) is an asymptomatic stage that we believe precedes all multiple myeloma (MM) cases. Patients with SMM still have abnormal plasma cells in their bone marrow, but they don’t have any of the criteria or symptoms that define myeloma such as bone pain, anemia, hypercalcemia or renal failure. As such, most SMM patients are not treated because the side effects of the drugs could be worse than doing nothing.
On average, SMM patients progress to MM at a rate of about 10% per annum, but we also know that some patients progress faster (up to 30% per annum) and others are much more stable and have a lower chance of progression (1% per annum). There are now clinical trials looking at identifying high-risk SMM patients and treating them to see if we can reduce the rate of progression in them. The challenge is to identify the reasons why some SMM patients progress faster than others so that they can be monitored more closely or treated before symptoms begin. We wanted to look at the DNA in the SMM patient samples to see if we could find markers that could identify those high-risk patients and tell us why the patient progresses to MM.
Q. What are the key findings in your research published in Nature Communications?
A. We looked at 82 abnormal plasma cell samples from SMM patients and compared them to 223 samples from MM patients. We sequenced the DNA of the samples to find mutations and other changes in the DNA and compared the frequencies of these abnormalities. We found that many of the known high-risk abnormalities in MM were at lower frequencies in SMM. Also, mutations in the genes called NRAS, KRAS, and FAM46C were much lower in SMM patients. This suggests that having these abnormalities may promote progression to MM.
As the samples we used were collected over the past decade, we were able to look back and find out which patients had progressed to MM and see if any abnormalities were associated with a shorter time to progression. We found that mutations in the gene KRAS were associated with a shorter time progression. KRAS is one of the most frequently mutated genes in MM (about 20% of patients) and so it is important for the continued growth of the myeloma cells.
We were also able to get some samples from the same SMM patients each year. This allowed us to monitor the changes in the DNA over time. We saw that some changes that are known to be high-risk in MM patients were not present in the first samples from SMM patients, but as the years went by, they began to appear and those cells outgrew the cells without the high-risk markers. This shows that the abnormal plasma cells in SMM patients don’t stay the same, but instead they are competing with one another until a high-risk cell takes over. At this point, the patient might progress to MM. So, a SMM patient could be low risk to start with but over time could develop markers of high-risk SMM.
Q: What are the implications of this research? Are there clinical applications that could be applied in the next few years?
A. We hope that the information in our study can be used to more definitively identify SMM patients that are more likely to progress to MM, or at least be used to monitor patients with the high-risk markers more closely. It would be great for genomic information to be integrated into future clinical trials for SMM patients to see if we can stop SMM before it turns into MM.
It also shows that SMM patients should be biopsied more frequently so that they can be monitored for high-risk markers and clinical decisions can be changed based on newer information.
Q. Research in your lab focuses on the genetics of multiple myeloma using patient tumor cell samples. How does this data inform your research?
A. This is really important data for our lab, but it is just the start. Although we sequenced 82 samples from SMM patients, the dataset is still quite small. Many of the changes are only present in small numbers of patients and the patients can take a long time to progress, so it can be a challenge to get enough samples over a long enough period to make firm conclusions. We also only looked at the regions of the DNA that are known to be important in MM. We are now expanding this dataset to look at the rest of the DNA to see what else could be important in defining high-risk SMM patients.
The results also show us what to focus on in MM patients as it tells us which abnormalities drive the disease forward. If the abnormalities are important in turning SMM into MM, then targeting them might reverse the process. Ultimately, we hope that by studying both SMM and MM disease stages we can find the key triggers that promote cell growth and inhibit them.
Q. Is there anything else you’d like to add?
I would like to thank all the patients who have generously given samples to research programs. Patient material is really important for our research and without it we would not be able to make new discoveries. IU has set up the Indiana Myeloma Registry that patients with any plasma cell disorder (MGUS, SMM, MM or PCL) can join and samples can be stored for future research studies.