Current Approach for the Management of Smoldering Multiple Myeloma | Vincent Rajkumar, MD | IMS 2024

Hi, I'm Vincent Rajkumar. I'm here at the annual meeting of the International Myeloma Society in Rio in Brazil. I presented on the opening day on how to treat smoldering multiple myeloma. Smoldering multiple myeloma is a condition that was first described in 1980 by Dr. Kyle and Dr. Greit. It is defined by the presence of 10% or more plasma cells in the bone marrow, but there is no end organ damage, there are no myeloma defining events, so it's in between MGUS and multiple myeloma. Patients generally are watched every three to four months to make sure that the protein level is not going up and then we institute therapy when there is progression. The problem with our care for smoldering myeloma so far is that we've been delaying therapy until end organ damage. That means we start treatment only after the patient has renal failure or bone disease or similar events, which was fine when we did not have good drugs to treat myeloma, but now we have a lot of really good, safe drugs to treat multiple myeloma and many of us feel that early intervention will prolong the time to end organ damage, maybe prevent the formation of end organ damage and even improve overall survival. So we've been doing some risk stratification studies to see who are the patients with smoldering multiple myeloma who might benefit from early treatment. Some of these risk stratification tools allow us to discriminate high-risk smoldering myeloma from low-risk or intermediate-risk smoldering myeloma. Patients with high-risk smoldering multiple myeloma have a 50-50 chance of progressing to active disease within two years. This is the group that we think early intervention would really most benefit. A lot of clinical trials have been done in this group. The two trials that really had an impact were one done in Spain with the lenalidomide dexamethasone regimen. They found an 80-plus percent reduction in the risk of end organ damage by just lenalidomide dexamethasone compared to observation, and they also found an improvement in overall survival. There's another trial that was done in the U.S. and this looked only at single-agent lenalidomide, just a simple pill, and given for about two years was able to reduce the risk of end organ damage by 90 percent. Based on the result of these two trials, personally I do recommend therapy for patients with high-risk smoldering multiple myeloma. At the same time, I do not recommend therapy for intermediate or low-risk smoldering myeloma. Those patients still need to be observed. If you look at all patients with smoldering multiple myeloma, only one-third will have high-risk disease, and there are many risk stratification models that you can use to identify who these patients are. One is the 22-20 system, which looks at the bone marrow plasma cell percentage, the free light chain ratio, and the size of the monoclonal protein. We also can take into account the cytogenetic abnormalities. For patients and physicians, probably the easiest way to estimate risk would be to go to a website called myelomarisq.com. There's a tab for smoldering multiple myeloma where you can enter your own values, and it will give an approximate risk of progression. Again, these values have to be from the time of initial diagnosis. If somebody's already had smoldering myeloma for a year or two, the risk of progression actually goes down. So the value that you should use to enter is actually the initial diagnosis value. Now there are people who think that instead of just giving lenalidomide or lenalidomide dexamethasone, maybe we should give myeloma-like therapy for high-risk smoldering myelomas. I usually don't prefer that approach because we have clinical trials going on that are comparing just Len dex to a myeloma-like therapy with a triplet regimen. There's also a trial that's already been completed called the ITACA trial, which looked at Len dex versus a triplet with isatoxamide. So those trials will tell us whether we should do more than just one or two drugs. High-risk smoldering myeloma is also a place where some patients may want a more aggressive curative strategy. We don't know still whether by intervening early whether we can cure patients, but it's a hypothesis that we have that if you treat early, perhaps some patients can be cured. So there are clinical trials going on in that category. Two of them have been completed. One is the SESAR trial. One is the ASCEND trial. Early results are good, but it'll take a while, many years, before we find out whether we have really cured patients. So in a nutshell, when there are patients with newly diagnosed smoldering myeloma, we try to classify into high-risk versus the rest. High-risk is one third, and those patients should be considered for clinical trials or for early intervention. Like everything else in medicine, it is a shared decision making. Patients should know the pros and cons of therapy, the risks that they take on with interventions. There are some really interesting trials which we'll read out soon. One of the most important being the Aqila trial. The Aqila trial compared just daratumumab alone versus observation. This trial enrolled almost 400 patients with high-risk smoldering myeloma. I am one of the lead investigators of this trial, along with Dr. Demopoulos and Dr. Pete Orpheus. We are hoping to have the results soon. Stay tuned, and that will inform practice. Thank you so much for your attention.