For those living with smoldering multiple myeloma (SMM), many uncertainties exist. These uncertainties can be whittled down to two “million dollar” questions: (a) “Will I progress to active disease?” and (b) “Should I consider treatment, and if so, how and when?” This blog is dedicated to the first question, “Will I progress?”, and what research at 64th Annual American Society of Hematology (ASH) meeting addresses this.

When diagnosed, most SMM patients hear the generalized chance for progression: 10% chance per year for the first five years after diagnosis, and then a 3% chance per year after that. We then learn about important lab values and risk factors, things like M-protein spike, free light chain ratios (FLCr), genetic translocations, deletions, and gains, and how these can impact chance of progression. Researchers have developed prediction models, most notably the Mayo- International Myeloma Working Group’s 2/20/20 model (aka 20-2-20) and the PETHEMA model.

Research by Rodriguez-Lobato and colleagues (ASH Poster 1892) has expanded the 2/20/20 model by integrating “evolving pattern” information. This evolving pattern takes into account the increase in the M-protein spike within the first year post-diagnosis. Essentially, depending on initial M-spike, if a certain percentage of increase is seen in the first year, the disease state is considered evolving, and the risk is modified (see diagram)

This model is expected to provide better risk stratification of SMM patients, and well as detect those at very high risk for the purposes of closer observation and determining early treatment. This model also has a dynamic nature to it, based on change in M-spike in first year of diagnosis. After a year, some patients may be reclassified.

In addition to the expansion of the 2/20/20 model by including evolving criteria, other researchers are examining gene signatures, chromatin landscape, body mass index (BMI), and diet, among other things. Admittedly, some of this content goes beyond my understanding. But I think it’s important for SMM patients to know that work is being done on various levels to help address the question, “Will I progress?”. For those interested in details, I’ll provide a brief summary below along with the links to the abstracts. Otherwise, I think this research highlights the quote that I heard from Dr. Thomas Martin on Friday, as it relates to SMM and understanding disease progression, “We need to view the movie, and not the snapshot.” It’s hard to be told about an SMM diagnosis and then to be told that the course of action is to “watch and wait.” But the time it takes to develop our own movie relative to our disease is important and can provide information that can be used for best decision-making. Additionally, perhaps we can use this time to focus on health and wellness, making improvements given our current fitness status and dietary habits.

Thank you to all who conduct and participate in research so that we can get closer to an answer to our million dollar question, “Will I progress?”.

Selected summaries:

  • Sun and colleagues (ASH Abstract 106) looked at progression from MGUS to MM using gene signatures examined retrospectively among a group of who progressed and a group who did not. Their profiling revealed a strong differentiation between the two groups. While I’m not certain about the feasibility of this profiling being done in clinics generally, their results provide some hope in the future regarding the question of “Will I progress?”.
  • Rahmat and colleagues (ASH Poster 1827) examined the molecular requirement of disease progression, focusing on altered chromatin states in pre-myeloma cells. They hypothesized that these might act as “priming events” for clonal expansion and lead to transition from inactive disease to active disease. Their work is ongoing but is showing promise for possible improved prediction of progression.
  • Liu and colleagues (ASH Poster 1865) examined BMI and progression of MGUS to MM using a retrospective analysis of data from 1999 to 2021, encompassing 7,700+ patients. They found a positive association between BMI and MM progression, with a 2% increased risk of progression per 1 kg/m2 increase in excess BMI/year following MGUS diagnosis.
  • Shah and colleagues (ASH Poster 2219) presented results from a pilot study using a whole foods plant based diet (WFPBD) among those with MGUS and SMM. They looked at various factors following a 12-week WFPBD, including BMI, metabolic markers, and microbiome changes, with positive outcomes occurring. This study sets the stage for further research, as patients experienced a decrease in proinflammatory cytokines as well as positive changes in microbiome, metabolic, and inflammation markers, and these might alter disease trajectory.

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