Updates -Smoldering Multiple #Myeloma from ASH 2025 | Rahul Banerjee, MD, FACP

Hi, everyone.

My name is Rahul Banerjee. I'm an assistant professor of medicine at the Fred Hutchinson Cancer Center in Seattle. I'm here at the 2025 ASH, American Society of Hematology meeting, in Orlando, Florida.

Many of you are thinking about multiple myeloma being presented here. I'll start by talking about smoldering myeloma and just what's new, what's being presented here. I'll start by what's changed in the last six months for smoldering myeloma in the United States.

And that's daratumumab, now approved as monotherapy, meaning a single-agent drug for high-risk smoldering myeloma. There are a lot of questions and answers when it comes to smoldering myeloma in the modern era. You know, I think daratumumab, in brief, if you hear nothing but this, I would say talk with your physician about it because it's complicated. For my patients with high-risk smoldering myeloma, I have to figure out who is high-risk and who's not. That is not in the package insert.

The trial that led to the approval of daratumumab, called the AQUILA study, had its own definition of high-risk smoldering that doesn't match how it is defined in 2025, and it probably won't match how it will be defined in 2028. And so it's an ongoing discussion. I joke to my patients that if they're interested in treatment for smoldering myeloma, I don't offer it to them the first time I discuss it. I have them think about it more, come back, because there are pros and cons to observation.

The vast majority of patients with smoldering myeloma can and should safely be observed. Some patients with high-risk smoldering myeloma, probably about 20–30% of my patients in that category, do opt for treatment and enroll in clinical trials or treatments. And daratumumab is now FDA approved for this. Many of you who listen to HealthTree are familiar with daratumumab; you've heard other videos talk about it. It is extremely well tolerated.

The question is, do you need it in terms of the costs, the injection time, time in clinic, infection risk, and so forth? We don't really have an update there per se. I think earlier this year, there was a paper published in JCO, led by many of the who's who in smoldering myeloma, showing that in many cases, smoldering myeloma—the cases that are actually a wolf in sheep's clothing, the cases that are destined to become multiple myeloma—you actually can tell from the moment they are diagnosed if you have the right tools to diagnose them and try to fight them appropriately.

Which is why I said earlier that smoldering myeloma will be defined very differently five years from now than how it is now. High-risk modeling in myeloma is tricky. Patients are always dealing with the stage of life where their next scan or their next set of bloodwork could show something bad going on. The analogy I give to my patients is it's like every couple of months we get a news article that there's an asteroid that has a 5% chance of hitting the Earth in 2030. And how do you approach it? Some patients prefer that, "Let's just keep an eye on it." And that's very reasonable because 5% is a very low number.

Some patients prefer the daratumumab approach. This is what I call the deflect approach, where you take a little laser, push the asteroid out of the way so the odds of it hitting Earth go from 5% down to 1%. And then there's the treatment modality of curative approach or destroy the asteroid, Bruce Willis Armageddon style—go in there, just get rid of it. That is not FDA approved yet, but the bispecific antibodies that are out there are an excellent way to do it. And there have been many studies presented this year with both teclistamab, which is a BCMA bispecific, as well as linvoseltamab, a different BCMA bispecific antibody.

Remember, bispecific antibodies are drugs that bind a T-cell, an immune cell, with one arm and a myeloma cell with the other arm, and put them together. In those trials, basically 100% of patients achieve MRD negativity, which means no abnormal cells left. 100% of those patients will never get active myeloma in their lifetime. Comes with many more side effects. Patients have to be hospitalized. They can get fevers. They can really get infections.

And so as complicated as the landscape is now for high-risk smoldering myeloma, it will get even more complicated in the coming years. Thankfully, right now, for 95% of smoldering myeloma, I think patients should and will opt for close observation, which I would say should include some form of a head-to-toe scan every year for the first couple of years. In my practice, I tend to use full-body MRIs. MRIs are probably more sensitive than PET scans and don't have any radiation exposure with them, unlike PET CT scans.

But there are patients for whom daratumumab, in the high-risk smoldering category, is entirely appropriate, and I've had patients who have opted for it because the benefit-risk ratio is actually relatively favorable. Daratumumab doesn't have that many risks, is extremely well tolerated, and works. Does it knock out every last smoldering myeloma cell? No—but it brings the risk of active myeloma down.

So ASH 2025 didn't really change high-risk smoldering myeloma, but certainly more to come.

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