Treatment Goals and Therapy Approach in NDMM

A. Keith Stewart, MB, ChB:The treatment goals in multiple myeloma will depend very much on the individual patient. We generally divide patients into those who are fit and healthy enough to withstand a more aggressive treatment approach, and those who are more frail who may need a more gentle and low-toxicity approach to their care. In the younger, healthier, and more fit patient, we tend to use a more aggressive approach with the aim of becoming free of disease by biochemical testing, looking under the microscope and at the bone marrow, looking at imaging with PET CB scanning to see that that has become normal, and now also beginning to look for molecular evidence of disease, or minimal residual disease, using very sensitive techniques. For the more frail patient, our goals of care are quite different. In this case, we hope to extend life and with the least amount of toxicity, and generally our goals do not involve trying to eradicate every last sign of disease but more symptom control and longevity of remission.

Our goals of care also change whether we’re treating the patient for the first time or their first, second, or subsequent relapse. More and more today, our goal is to try and cure the patient when we’re treating them at frontline therapy. With the new drugs we have, the new things that are emerging, we think that is an attainable goal for some of our, particularly our low genetic risk, patients. So, we’re going to be quite aggressive. We’re going to be quite prolonged in our treatment duration with the attempt to get complete negativity of their myeloma and sustain it over time. Once you relapse, that opportunity for cure has probably gone for most patients. And at that point, we’re now looking to extend remission for as long as possible using regimens that are the least toxic over time. When we get into very late relapse, we begin to worry much more about toxicity, convenience, and, sometimes today, cost.

So, my personal approach to treating myeloma is to divide patients into those eligible for aggressive therapy, including transplant, and those who are probably going to be treated more gently and with less toxicity. In the younger, fitter patient, we will use a 3-drug induction regimen and, I think soon, a 4-drug induction regimen. It will contain a proteasome inhibitor such as bortezomib, an immune modulator such as lenalidomide, and dexamethasone. I think, increasingly, we’ll see use of daratumumab in the frontline setting. But today, the combination of bortezomib, lenalidomide, dexamethasone is probably our gold standard. And for certain patients, I’ve started using carfilzomib instead of bortezomib in that population, what we call KRd. Most of those patients will go to transplant. But increasingly, we are using the same drugs after transplant—lenalidomide with bortezomib, lenalidomide with ixazomib, lenalidomide with carfilzomib—because we think that will sustain remission over a longer period of time and allow more patients to enter a molecular complete remission.

In the elderly patients, we tend to use a less dose-intense approach. So we can use the same drugs but at lower doses less frequently, something we call VRd-lite, for example. Or we can use just 2 drugs, such as lenalidomide and dexamethasone, which can also be very successful.

The other big feature that we take account of when we’re addressing a patient for the first time is the molecular basis of the disease. There are 8 different genetic types of myeloma. We can roughly put them into buckets—so, low risk, intermediate risk, and high risk—and to a certain extent, we treat those patients differently. The high-risk group is probably the one that gets our most attention because they’re most in need of a different approach. Those are the patients we believe giving a proteasome inhibitor, such as bortezomib, ixazomib, or carfilzomib, is likely to prolong their remissione, particularly if we use those drugs for longer periods of time. So, we see increasingly that we’ll start those drugs and they may stay on them for up to 2 years or longer, depending on what level of disease control they obtain.

Transcript edited for clarity.