Institution: Sylvester Comprehensive Cancer Center ASCO 2025 | Where is the smoldering myeloma field moving, and what does future management look like?

For a long time, the field has had different definitions for multiple myeloma, smoldering myeloma, and the monoclonal gammopathy, or MGUS. The precursor states go all the way back to the 1970s and 1980s. In 1978, the monoclonal gammopathy, or MGUS, was proposed, and only two years later, based on six patients, it was proposed that maybe there is something called smoldering myeloma. These were patients that didn’t fit the bill for the monoclonal gammopathy, but they also did not have multiple myeloma. For a long time, the thinking was that you could have this so-called smoldering myeloma and it’s just more precursor disease, but you may not need any treatment. It turned out over time that that was not the correct hypothesis. Patients with the so-called smoldering myeloma, they had a much higher risk of developing multiple myeloma than the monoclonal gammopathy. And that triggered the development of clinical trials in this space. 

The first trials were negative. In the 1990s, there were early randomized trials using old chemotherapy, and it didn’t really work. It took all the way till 2012 when the Spanish group did lenalidomide dexamethasone versus observation and showing that maybe doing an early intervention is better, better progression-free, and they even showed overall survival benefits. We worked on the addition of carfilzomib, lenalidomide, dexamethasone, in the same space when I was at the National Institutes of Health, at the National Cancer Institute. And we were the first to show in a three-drug combination that you could achieve very deep responses that were durable. Other groups continued to build on that. The Spanish group added transplantation to what we did, and Mayo Clinic, they tried to add antibodies as well. 

The study we did at the National Cancer Institute showed that eight years after stopping therapy, 70% of patients sustained their MRD negativity, which could indicate that could even be some potentially cured patients, but that remains to be proven. 

In parallel, work has been done and I was involved in the work for the CENTAURUS trial, which was the first randomized study using daratumumab in smoldering myeloma, both intermediate and high-risk disease. And we published that for the first time in 2020, and we showed that if you give daratumumab as a single drug, that you can significantly delay progression of the disease into multiple myeloma. This in turn led to the development of a large randomized registrational trial, the AQUILA trial, and that read out in December of 2024. And this has now been voted on by ODAC in the late spring of 2025. So when we do this recording, we are still waiting for the final decision by the FDA. But ODAC was in strong support of going forward with daratumumab for the indication of smoldering myeloma. The FDA will make the decision and they may choose to do only high risk or they may do intermediate risk. We will see. But the data suggests that you can significantly delay progression of smoldering myeloma into multiple myeloma. 

I should lastly say that there are additional studies going on. We have one study at Sylvester Comprehensive Cancer Center at the University of Miami, where we are using daratumumab in combination with teclistamab. This is a study called the REVIVE study. And we have extremely high rates of deep responses. You do not see deep responses with daratumumab, but you delay progression. So is delay the way to go, or is it eradication? Is that the way to go? And these and many other questions remain for the future. 

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