Overview of Smoldering Multiple Myeloma


Paul G. Richardson, MD:Welcome to this OncLive® Peer Exchange titled, “Multiple Myeloma Management in 2021.” My name is Dr Paul Richardson, and I am from the Dana-Farber Cancer Institute in Boston, Massachusetts. It is my pleasure to introduce to you and to welcome in this virtual discussion my colleagues, Dr Nina Shah from the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco; Dr David Siegel from the Hackensack Meridian John Theurer Cancer Center in Hackensack, New Jersey; and Dr Saad Usmani from the Atrium Health Levine Cancer Institute in Charlotte, North Carolina. Today we’ll discuss modern approaches to management of multiple myeloma [MM], and we’ll reflect on the latest data, including some very exciting new information from the ASH [American Society of Hematology] 2020 virtual meeting. Let’s get started on our first topic.

It’s my pleasure to ask Saad to lead our first segment on smoldering multiple myeloma [SMM] and newly diagnosed MM. Saad, should patients with SMM receive treatment?

Saad Z. Usmani, MD:Thank you so much, Paul, for having me as part of this esteemed group for discussion. Despite the challenges from what we’ve observed in 2020, many of these important questions, such as whether SMM should be treated, the work that we were doing in our respective institutions and as a collective has been coming to the fore. This debate started when our colleague, Maria-Victoria Mateos, MD, PhD, published the initial QuiRedex trial, demonstrating that you can delay the progression to active MM by treating patients with lenalidomide and dexamethasone. Notably, even though it was a small and underpowered study, they did see an overall survival [OS] benefit.

As of last year, Sagar Lonial, MD, FACP, presented the ECOG trial, which had compared LEN [lenalidomide]-only treatment versus observation in high-risk smoldering MM patients, demonstrating a delay in progression to active MM, specifically for the high-risk SMM, even by the newer criteria. As such, the debate is certainly heating up, and we are seeing more data emerge.

The focus of the debate is, if we are going to treat smoldering myeloma patients, what is the goal? Is the goal to delay the next line of therapy or active disease? Or, are we looking for long-term remissions and potentially even curing a proportion of them? There have been several different approaches to treating SMM. Specifically, there has been an active MM approach where you’re using a triplet or quadruplet therapy with or without stem cell transplant, and then extended maintenance for 2 years, which Maria-Victoria, has reported on. Additionally, there is the C. Ola Landgren, MD, PhD, approach of treating with a 3-drug combination, utilizing KRd [carfilzomib, lenalidomide, dexamethasone] for 8 cycles, and then moving on to maintenance.

Each of these strategies is showing that you can get good responses in these patients and delay the progression to active disease. However, what we do not understand is which patients benefit from the less intensive approach versus the more intensive approach. This is where I think you must marry the disease biology with the immune status of the patient. I think we can have a very nice discussion with the group. I simply wanted to lay out the entire debate and discussion considering everything that’s been going on in the field.

Paul G. Richardson, MD:I think we’ve all become very comfortable with the IMWG [International Myeloma Working Group] 2/20/20 risk stratification model and the IMWG position that Maria-Victoria has led with a number of investigators, in that it simplifies things and it helps us think very rationally for patients at the bedside about what we can offer in terms of “the patient with high-risk SMM.” I would love comments from Nina. How do you approach “a high-risk patient,” what do you consider them to be, and how do you think about them in terms of follow-up?

Nina Shah, MD:Thank you so much for having me. I’m so sad that we couldn’t all be together in person, but this is almost the next best thing, and I really enjoy getting together with all of you to talk about what we’ve learned. SMM is ironically one of the most controversial topics in MM because it seems like you get 4 myeloma doctors and you get 4 different opinions.

One of the things I think is so hard about SMM is regarding all the trials, similar to the rest of MM, they start out one way, and then our field goes beyond that very quickly before results are apparent. One of the places that’s been true for me is even in defining high-risk SMM. I think this 2/20/20 model is easy and is something you can do right away, the first time you meet the patient, and you don’t have to go through all the data, it’s very easy to go through these things that they have. When I find somebody who has 2 or 3 of these characteristics, I do talk to them about their likelihood of progressing to MM.

I’m still in the camp that I don’t treat these people yet, but I do change my follow-up. I traditionally, in general with SMM, particularly if they have 2 or 3 of these criteria of the 2/20/20, I would elect for annual imaging and annual bone marrow as these are things that I might miss on a simple laboratory examination. I think it’s important to catch these things early because that’s what we want to do for these people that know they have something going on, but maybe don’t want to have chemotherapy right away.

As Saad said, there are so many factors that go into that, because if a patient is older and never wants to have chemotherapy again, then this is a good option for them to just watch and wait. Other patients who are younger may want to be as aggressive as possible, which is a different discussion.

Paul G. Richardson, MD:I completely agree, Nina. For our audience, the 2 grams per dL is the “2.” Traditionally, we say 2/20/20. The second figure “20” is the free light-chain ratio greater than 20, and the degree of plasmacytosis is the last piece, at 20%. Regarding the ASH meeting, Saad, what did you make of the paper where they examined whole-genome sequencing? Overall, might whole-genome sequencing data inform clinical identification of patients with progressive versus indolent myeloma based on that data?

Saad Z. Usmani, MD:I thought that was a very interesting paper. If I remember correctly, the study consisted of a smaller number or patients. I recall there were around 30 patients in that group. I believe it was close to 150X depth of the whole-genome sequencing done in the groups, where they identified indolent versus early progressive and focusing in on disease biology. I think they came up with 2 targetable gene mutations; one was APOBEC. While I do not recall the other, they did identify distinct clinical behaviors and were able to link them to specific gene mutations that have not been previously reported.

Paul G. Richardson, MD:I couldn’t agree more. Your memory, Saad, is excellent. It’s the APOBEC, which was detectable and characterized by a higher ratio, and that was associated with greater mutational activity. Essentially, in the MAF-translocated patients, this is something that’s particularly important. Obviously, they were then able to identify features from the whole-genome sequencing that might point to a more indolent picture and so take us to the next step. I think you’re right, it symbolizes a more tailored approach.

Transcript Edited for Clarity

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