Rafael Fonseca, MD: One of the most interesting and pressing questions we have in myeloma right now is whether patients who have smoldering multiple myeloma should receive therapy. As of now, the standard has been that patients should only be observed. As time has gone by, we really are analyzing the statement and seeing if there’s a subgroup of patients that would require therapy. Effectively, this was changed in 2014, where the International Myeloma Working Group changed the criteria. The thought process was very logical. If you’re going to progress within the next 2 years, why wait until a patient develops a complication? So there were 3 new criteria added for what would be considered multiple myeloma in need of therapy. That was patients who had a very elevated free light chain, 2 or more abnormalities on an MRI [magnetic resonance imaging], which effectively we all take the PET [positron emission tomography] scan as evidence for that, or extreme plasmacytosis.

At last year’s ASH [American Society of Hematology annual meeting], in 2017, Dr C. Ola Landgren, MD, PhD, made a provocative statement which really stuck with me, saying that probably smoldering is going to disappear. And I have to say that I agree with that. I think there’s some smoldering patients that will have maybe 15% plasma cells. Whereas there’s smoldering patients who have either evolving disease or high-risk markers, or markers of cell proliferation, and I think more and more we’ll consider patients who are requiring therapy. So we have a large number of clinical trials that are exploring therapy for smoldering disease, but as of now the standard remains observation.

When I was in training people used to think of smoldering as, “Oh it’s smoldering, it can’t progress sometimes for many years,” almost like a pat on the back to a patient. We really should question that. For the average smoldering patient, based on some of the very elegant data that we have from the Mayo Clinic in Rochester, they have a 65% risk of progression at 10 years. So if you’re age 55, there’s a high likelihood you’re going to be dealing with myeloma therapy, and if that is the case, we want to intervene before there are fractures or renal failure or anything like that.

Kenneth C. Anderson, MD: Right now, smoldering multiple myeloma patients do not receive systemic therapy outside of a clinical protocol. It turns out in myeloma, since we have these effective agents—the immunomodulatory drugs, proteasome inhibitors, an HDAC [histone deacetylase] inhibitor, and monoclonal antibodies—they’re effective and don’t have a lot of adverse effects, that we have now changed the definitions of who has active myeloma. To be more clear, patients in the past were only treated when they developed complications of the disease—high blood calcium, kidney problems, anemia, or bone disease. But nowadays, even in the absence of those clinical sequelae, we treat patients who have more than 60% bone marrow plasma cells, a higher kappa/lambda ratio of 100-fold or greater, or who have bone lesions on sensitive imaging.

Those patients now are treated. So the patients who have smoldering multiple myeloma traditionally are not treated. However, in that group of what is now smoldering myeloma, if they have more than 20% plasma cells, if they have a kappa/lambda ratio of 20-fold abnormal or greater and still don’t have the calcium, kidney, anemia, and bone disease, they are at high risk to transform or to progress to myeloma. So those patients are treated on protocol.

For example, there is one particular protocol I’ll mention to you, from our institution, the elotuzumab monoclonal antibody combined with lenalidomide and dexamethasone given to 50 patients who have this risk of progressing to active disease. And when that was given we have high response rates, as you would expect—monoclonal proteins decreasing 84% of the time. And we have very little, if any, progression to active myeloma at this time, although it’s still very early. But the concept is here. We can now take active medicines, move them earlier, and we may be able to delay, and maybe someday prevent the development of active disease.

Noopur S. Raje, MD: Smoldering multiple myeloma is kind of a precursor disease state. It’s where you have all of the diagnostic criteria for multiple myeloma, but yet, we do not have any evidence of end organ damage. So known evidence of bone disease by much more refined imaging in the way of MRIs, CT [computed tomography] scans, and PET scans. You do not have a significantly elevated free light chain ratio. And this is important to recognize because we have the newer diagnostic criteria for what is actually symptomatic multiple myeloma.

So even as of today, which is 2019 now, smoldering myeloma should not be treated. The standard of care for smoldering multiple myeloma is watch and wait. It’s a space where we have a lot of different clinical trial options, and we have people who are doing a lot of research in this space, given that it is a precursor disease state. And if you think about wanting to cure a plasma cell disorder, it makes perfect sense to try and address smoldering myeloma. So try and treat it at its early stages.

Part of the problem with this is we don’t completely understand who are going to progress to develop active myeloma, and that’s why it’s still an area of research. We have come up with certain diagnostic features where we refer to these smoldering myeloma patients as high-risk patients based on their genetics, based on protein studies, and so on and so forth, where about 50% of these will progress within the next 5 years. And these are the ones that we’re using clinical trials to treat with.

We have a spectrum of clinical trials. We have fairly early-stage clinical trials. At Mass General [Massachusetts General Hospital], I’m using a vaccination approach with the idea of using an immunological approach to try and train the T cells to recognize myeloma sporing so that myeloma does not become active again. And then you have the other end of the spectrum where we’re treating smoldering myeloma like full-blown myeloma, and that’s the GEM-CESAR study which is being done by Maria-Victoria Mateos, MD, PhD, over in Spain, and that includes KRd [carfilzomib/lenalidomide/dexamethasone], a transplant, followed by KRd, with the idea of getting rid of the disease completely.

And then in between these 2 strategies you have all kinds of clinical trials where patients can try something depending on what is available to them. It is an area of very active research. But as of today, it is an area that unless you’re on a clinical trial you should not be getting treated for smoldering multiple myeloma.

Transcript Edited for Clarity