Transcript
My name is Peter Voorhees and I am a myeloma physician at Levine Cancer Institute Atrium Health in Charlotte, North Carolina. I'm here at the Great Debates in Hematological Malignancies here in Los Angeles, California. I will be debating the good Dr Mikhael on the matter of treatment of smoldering multiple myeloma, arguing in favor of early intervention.
There's 2 general schools of thought with regards to therapy for smoldering multiple myeloma. There's more of a preventative or control philosophy where we simply are trying to prevent progression of smoldering multiple myeloma into clinically symptomatic disease.
Then there's the other school of thought which is to use everything in our arsenal that we have to potentially eradicate the disease entirely and spare the patient from relapse in their lifetime. Most of the level 1 evidence that's available at this point, in fact all of the level 1 evidence that's available at this time is on the former approach. That's what I'll be discussing.
We do know that as myeloma precursor disease, MGUS transitions to smoldering multiple myeloma and then to active multiple myeloma, we see increasing levels of both cellular and humoral mediated immunodeficiency. The thought is if we can augment anti-myeloma immunity, we could potentially prevent progression to clinically active disease.
We have several agents available in our arsenal already that not only have direct effects on myeloma cells, but actually have an immunostimulatory effect as well, specifically the IMiDs, lenalidomide and pomalidomide, as well as the CD38 antibodies including daratumumab.
Lenalidomide is the agent that's been explored most extensively in randomized studies at this point in smoldering myeloma. Now we do know that while lenalidomide and daratumumab and the other myeloma agents are relatively safe, they're certainly not without toxicity. You need a system in place where you're really targeting those smoldering multiple myeloma patients that are truly at high risk of progression to clinically active disease.
I think the modified 2018 Mayo Clinic criteria for defining high risk smoldering multiple myeloma are actually quite useful. In this particular paradigm you look at 3 risk factors. Does the patient have more than 20% plasma cells in their bone marrow? Is their M spike greater than 2 grams per deciliter? Is the affected divided by the unaffected free light chain ratio in the serum greater than 20?
If you have none of those risk factors, you're low risk. If you have 1, you're intermediate risk. If you have 2 or more, you're high risk. In the high risk patients, there's approximately a 50% likelihood of going on to developing active disease within the first 2 years. That's really the patient population that I think we should be most interested in.
The initial foray into this in the randomized setting was the Spanish myeloma group where they took patients who were considered to have high risk smoldering multiple myeloma and they randomized them to an intervention strategy versus an observation strategy.
What they did in the intervention strategy is that patients received 9 cycles of lenalidomide and dexamethasone followed by lenalidomide maintenance therapy, the totality of that treatment, both the induction and the maintenance consisting of 2 years of treatment.
They did a second intervention in that particular arm of the study, specifically those patients who were on lenalidomide maintenance who had by chemical progression could have their dexamethasone added back into the regimen to recapture control.
Both groups of patients had their myeloma evaluated on a monthly basis, so both groups were looked at very carefully. The primary endpoint was time to the development of clinical symptoms of multiple myeloma, or CRAB, so hypercalcemia, renal dysfunction anemia, bone disease.
What they showed in this particular study is that there's an approximately 75% reduction in the risk of progression to clinically symptomatic multiple myeloma with the intervention that they chose to pursue. Not only that, but they saw an improvement in overall survival as well.
One of the things we're always concerned about when we intervene early in smoldering multiple myeloma is how is the disease going to behave at the time of progression?
With very long follow-up in this particular study that was published back in 2016, what they're able to show is that the overall survival was the same at the time of progression whether you got the interventional strategy of lenalidomide and dexamethasone or whether you're on observation. It didn't look like intervening early in smoldering myeloma had a clinically adverse effect on the ability of patients to respond to treatment subsequently.
There's a couple of criticisms of this particular trial. First off, they only used plain radiographs to look for bone disease. The thought is that there's probably some patients who would have had active myeloma if more advanced imaging techniques had been used such as CT MRI, PET CT, etc.
The other thing is that it's a little unclear what impact the 2 different interventions had, both the initial therapy versus the reintroduction of dexamethasone for biochemical progression. Recognizing that those in the observation arm could not get therapy for biochemical progression.
Enter the ECOG study that was just published in the "Journal of Clinical Oncology." This was a study that was spearheaded by Dr. Sagar Lonial. What they did is they took patients with smoldering multiple myeloma at varying levels of risk of progression to active disease and they randomized them to either lenalidomide monotherapy until disease progression or the emergence of unacceptable side effects or observation.
There was no escalation of therapy in the lenalidomide arm if biochemical progression was seen. The primary end point was progression free survival, which in this study was defined as not only the development of CRAB criteria but biochemical progression as well. You had to have both.
What they showed, very similar to the Spanish study, was that there was about a 75% reduction in the risk of progression to clinically active disease. When you look at both of the studies and you look at the types of events that they prevented with the lenalidomide arm, in particular there was a decreased number of patients with new bone lesions and there was a decreased rate of patients with anemia at the time of progression.
There was also a small number of patients who developed renal failure and hypercalcemia more so in the observation arms than in the lenalidomide arms of both of those studies.
The other thing that I'll point out about the ECOG study is that when you look at how these patients fared when you classified them into low, intermediate, and high risk based on the revised 2018 Mayo Clinic criteria, what you see is that the patients who had high risk disease were really the ones who truly benefited the most as far as progression to clinically active disease.
In fact, in that group of patients the hazard ratio was .09, so you're looking at a 91% reduction in the risk of progression to clinically active disease in that group of patients. Whereas there wasn't so much of an effect in those with intermediate or low risk smoldering myeloma.
I think suffice it to say that for patients with smoldering myeloma that's at high risk of progression, the use of lenalidomide dramatically cuts down on the risk of progression to active disease.
For that reason, I think those patients that have high risk smoldering multiple myeloma as defined by the 2018 Mayo Clinic criteria should be considered for lenalidomide monotherapy or lenalidomide with dexamethasone and that's a conversation that we have to be having with our patients.
