Optimizing the Management of Transplant-Ineligible NDMM: Depth and Durability of Response

Practical advice on strategies to improve care for patients with transplant-ineligible multiple myeloma regarding induction and maintenance therapy, and aiming for deep and durable responses.

Rafael Fonseca, MD:
A common question is what to do after awhile when you start a patient in a triplet regimen, such as RVd [lenalidomide, bortezomib, dexamethasone] or MAIA. Most people have switched to a convenient, simple oral regimen for maintenance. Historically that’s been in the form of lenalidomide. The reason we’ve done that is 2-fold. First, because of the data we have, we know their settings. We know that lenalidomide has proven to be an effective maintenance drug in both transplant and nontransplant patients. But the thought is that you have a pill, and the person can be emancipated from the treatment center, so they need to come less often. With an oral regimen, the maintenance can have them be more detached from the treatment center and more able to resume their normal activities.

Several concepts are being challenged. The first is that in this regimen, we always have 3 drugs. We tend to forget the third drug, which is dexamethasone. Several studies show that dexamethasone, while it can be very powerful and is critically important as you start therapy, the reduction or ultimate discontinuation seems to pay off because of the patient’s ability to stay on treatment. The other side of that coin is that patients who stay on dexamethasone, who start experiencing, prolonged toxicity, neurocognitive toxicity, and so forth, are more likely to say, “I’m going to stop all treatment.” That’s the low-hanging fruit: dose adjustments or discontinuation of dexamethasone.

The other question that’s coming to the forefront is that people say, “You’re treating maintenance with an oral agent.” But it turns out the oral agent, while it seems simple, does carry a burden. Lenalidomide has a burden for patients with regard to toxicity. That burden includes the neurocognitive toxicity—slower thinking, not as sharp—and also the possibility of chronic diarrhea. Those are 2 things we see in patients who are getting therapy for the longer term with lenalidomide.

The question that’s been asked: are there some patients for whom you could stop lenalidomide and maintain the daratumumab? That’s a possibility. In fact, I’ve been asking some of my patients. The question I get is variable, but some of them seem to think it would be a lot better to go in and out and get that shot than to think about the continuation of therapy with lenalidomide.

We have a number of clinical trials looking at maintenance approaches, including daratumumab. For instance, we have the AURIGA clinical trial, which is daratumumab and lenalidomide vs lenalidomide alone. That will help illustrate some of these concepts. In the meantime, clinical judgment is important for the treating physician.

We like to continue therapy for as long as possible, especially with the transplant-ineligible population, because the ability to induce deep responses is not as high as what we can do with patients who are transplant eligible. For instance, when you look at MAIA, about 25% of patients achieve MRD [minimal residual disease] negativity, but this is 10-5. If you go to 10-6, the number would have been lower. If you asked that question, you would say, “The majority of patients, at least 75%, have some residual disease if we go by that 10-5 threshold,” so we try to do that.

There’s a bit of an art in trying to maintain therapy. I always tell my patients that you want to stay on therapy as long as 2 things happen. A) you’re responding, and B) we’re not facing undue toxicity. It’s a combination of those 2 things. We’re all hoping for a future when you could treat for a certain period of time, and if you achieve a response of X quality, maybe that’s an MRD of 10-6 and we can discontinue therapy. But in general, knowing there’s a Cs in the background, we like to go for as long as possible.

Everyone in the field is hoping that we’ll have MRD testing from peripheral blood in the near future. It’s available, but the framework for the decisions is still evolving. MRD testing can be done through various mechanisms. Flow cytometry is not very good when we look at peripheral blood because of the sensitivity, although it can be done. The 2 other options include next-generation sequencing—we have the FDA-approved assay of the clonoSEQ—and the mass spectrometry analysis for small proteins in the peripheral blood.

I’ve started doing peripheral blood MRD testing, and the reason is 2-fold. If you have someone who has a significant disease burden, then they’re positive in the blood and there’s no point in doing the bone marrow. The second is that the bone marrow is more complicated. It’s a more involved, potentially painful procedure, so if we could get away with the blood, that would be great. But one has to consider that the blood—this has to do with the biology of myeloma, so there’s no technology that can improve this—will have a propensity to stay in the bone marrow. Because of that, you have about 1 long difference in sensitivity. You can estimate that whatever you’re seeing in the blood, in general, would be 10-fold less than what you’re seeing in the bone marrow. I say in general because there could be some myeloma subsets where you could find peripheral blood markers, and maybe they correlate very well with what’s going on in the bone marrow. Maybe there are some myelomas with a high preference for the bone marrow niche, where the peripheral blood is going to be negative.

Interestingly, for a few patients who are nonsecretors, I’ve started using the peripheral blood MRD testing with a clonoSEQ assay to see if I can use that as a biomarker. One thing most people don’t realize is that MRD testing isn’t positive or negative; it gives you a number. From the peripheral blood, I could get a number of 100, and then next month that patient is going to show me 20. I’m going down the copy number, and I’m going to presume that we’re delivering effective therapy for that patient. In particular, the numbers I gave you correspond closely to 1 patient I’m treating now who is a nonsecretor and for whom the peripheral blood clonoSEQ is informing what we’re doing with therapy.

Transcript edited for clarity.

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