What is the Best Treatment Approach for Smoldering Myeloma?

At the 2019 Lymphoma & Myeloma Congress, Joseph Mikhael, MD, MEd, FRCPC, Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona, participated in a debate about the best treatment approach for patients with smoldering myeloma.

Transcript

My name is Dr. Joseph Mikhael. I'm a professor at the Translational Genomics Research Institute in Phoenix, which is part of City of Hope. It was my privilege today to be involved in a significant debate regarding treating patients with smoldering multiple myeloma.

My side of the debate was to argue that only a few patients with smoldering myeloma should be treated. This is actually a very important and practical issue in the clinic. We have divided historically, myeloma patients into 3 categories: MGUS, or monoclonal gammopathy of undetermined significance, smoldering myeloma, and then active myeloma.

We know, of course, active myeloma patients require treatment. MGUS patients do not. The debate related to that middle group of patients, smoldering myeloma patients, should they be treated or not.

Importantly, we changed the definition of myeloma 5 years ago. A part of the category, if you will, of smoldering myeloma, has now moved into the active myeloma sphere.

We used to always say, "You have to have CRAB features to be treated with multiple myeloma." Those CRAB features are elevated calcium, renal insufficiency, anemia, and bone disease. We added 3 more 5 years ago, which if you will, made the category of smoldering myeloma smaller.

Those 3 features we added were 60% or greater plasma cells in the bone marrow, a ratio of involved over uninvolved light chains of 100 or greater, and thirdly, MRI findings of more than one focal lesion when the bone marrow is evaluated.

I made the point today in the debate, that if we used to say someone has to be falling off a cliff to be in trouble to have myeloma, we've now defined myeloma by drawing a line maybe 50 feet from a cliff and said, "If you're within that 50 feet, you're so close to falling over. As you run towards the cliff, we may as well treat you."

There have been those who have advocated that we should treat everybody far away from the cliff, all the way down to MGUS. Anyone with more than 10% plasma cells or an M spike over three.

I made a case today that that would be over treating a lot of people. Above all, we don't want to harm our patients. The strategy that most of us believe, and 84% of the voters believed, was that we should really reserve treatment for the very high-risk smoldering myeloma patients. Just like we drew the line, 50 feet away from the cliff, we may bring that line in a little bit further to capture more patients with high-risk disease.

If we go and treat a whole host of patients with smoldering myeloma, many of these patients would never have gotten into trouble, would never have developed active myeloma, and we'd be over-treating them. The evidence we have for this, really based on 2 large phase 3 trials.

I don't want to minimize the value of those trials, but treating with single-agent lenalidomide or lenalidomide and dexamethasone, is really unlikely to truly cure or totally prevent myeloma, and may, in fact, cause more trouble with time in developing lenalidomide resistance.

I think the take-home message for a training clinician today, is that we really still have to stay within the parameters of active myeloma, to decide on treatment. I do think there is a group of high-risk smoldering myeloma patients. Different models are being evaluated right now, to test them out to decide how we can move that line a little bit further away from the cliff.

Most of them relate to the size of one's M spike, the light chain ratio, the percent plasmacytosis, and high-risk side of genetics. Indeed, the International Myeloma Working Group has created a model based on those four factors, where about 20-25% of smoldering myeloma patients can be defined as high risk.

It may be worth treating those patients because their risk of developing myeloma is 50% or more over the next 2 years.

For the clinician today, I think a very important thing to remember is that unless your patient really meets criteria of CRAB plus those 3 new features, sometimes together, we call them SLiM CRAB, then it's best to continue to wait and watch so that we don't intervene too quickly in these patients.

Stay tuned because these rules will change every year, as we better understand the pathophysiology of this disease, working towards a cure.