Multiple Myeloma With Symptomatic Progression: Case 2 - Episode 2
Sagar Lonial, MD: One of the issues that comes up oftenagain, a discrepancy between the United States and the European approach—is what makes a patient suitable for transplant. And I’ll tell you in our books, in our view, it’s really about performance status more than anything else. I think this patient quite clearly was a transplant candidate—54 years old, but we will actually say yes to transplants in patients as old as 78. And so, it’s really not an age-based cutoff as it is in Europe where if you’re over 65, transplant is really not an option for you. I’ve said yes to 75-years-olds, I’ve said no to 54-year-olds. So, I think it really has to do with functional status, support at home, what is the social environment, and what is the social environment that allows this patient to potentially go through a transplant. But transplants now, particularly for myeloma, are really not terribly aggressive treatment approaches, certainly not an allotransplant, and not even at the level of a transplant for lymphoma. And so, I think these should be considered for most appropriate patients where they are fit enough to undergo this process.
When we begin to think about how to approach treatment, I think the 2 factors in my mind that really come to play are, what are the patient’s genetic risk meaning do I need to come in with really aggressive upfront initial therapy, and what is the patient’s performance status? Because those 2 together will dictate where I’m trying to go. I think when you’re seeing a patient with newly-diagnosed myeloma, the thought process has to be, what am I going to do, not just this time, this week, this month, but what is my 2-year and 3-year plan of treatment for this patient? Because when we begin to think about management of myeloma patients, it is now a median survival of 7 years. In our case, for standard-risk patients, it’s well above 10 years. And so, not only do you have to think about “What am I going to do at this moment?”, it’s “How is what I’m going to do right now going to impact where I am in 5 years?” And so, understanding all of those pieces that go in to choosing therapyrisk, biology, genetics, performance status, host factors, social support—those all go into the continuum of choosing therapy over the course of a patient’s treatment.
Management of patients with deletion of 17p can often be quite challenging, and so if a patient progresses following an aggressive induction with VRd, transplant, as well as aggressive consolidation or maintenance, there are a couple of options one could consider. One option might be to switch to carfilzomib and pomalidomide, another very active combination, particularly in high-risk myeloma, taking more potent second- and third-generation proteasome inhibitors and IMiDs. Of late, a regimen that we’ve actually used a fair amount in these high-risk patients has been a combination of daratumumab with pomalidomide. And the reason we really like this approach is that the daratumumab has an effect on the outside of the cell and may in some ways be what I call “risk agnostic.” And what that means is that the mechanisms of drug resistance are often internal to the cell, particularly 17p deletion and other genetic abnormalities. Whereas daratumumab doesn’t work internally in the cell, it works purely externally, allowing for immune function to try and kill the cell.
When you partner that with pomalidomide, which clearly has preferential activity in 17p deletion, the activity that you see in pomalidomide/daratumumab/dexamethasone is really quite striking. We’ve had many patients who have done quite well for long periods of time, and for that reason, I think this becomes a really attractive potential option for high-risk patients in the context of relapse.
The third option that I’ll mention, because it actually is somewhat unique to this patient, is the use of venetoclax. And this is a patient who has an 11;14 translocation. We know that venetoclax is a single agent, works about 40% of the time in patients with 11;14 translocation; when you combine it with dexamethasone, it works about 60% of the time. And, in fact, at our center, we have an in vitro assay where we can actually profile the patient’s myeloma cells to determine whether their sensitivity is high or low. If they’re high sensitivity, I think somewhere around 11 out of 12 patients have gone on to have quite good responses that can be quite durable. This occurs even when 17p deletion appears to be present. And so, the identification of 11;14 patients, potential use of venetoclax with or without dexamethasone represents a really important option and actually may have activity not just in regular myeloma but in plasma cell leukemiaabout 50% of which have 11;14 translocation—as well as in amyloid where a significant fraction will have 11;14 as well. And this represents a new option for patients.
Transcript edited for clarity.
Multiple Myeloma With High-Risk Features