The Changing Landscape of Multiple Myeloma Treatment
How has the influx of newly available multiple myeloma treatment options complicated the treatment landscape?
You can look at it that way, or you can say that it has given us more opportunities. If you look at the progression of myeloma options over time, you see that we went through many years—essentially from 1958 to about 2000—there were not a lot of choices there. We had alkylating agents, there were steroids, interferons were being used, but there were not many options. And if a patient relapsed and didn’t respond to one of these interventions, you were out of gas. What happened in 1999 with the publication of the thalidomide data was that, within a few years, we had three new drugs to work with. And in the last 4 years, things have exploded. We have a lot more regimens we can consider, and it does get difficult with the different combinations. So you have to have an idea in mind of how you want to approach this.
One of the guidelines from the National Comprehensive Cancer Network [Clinical Practice Guidelines in Oncology®]4 is that if you have decided a patient needs treatment, you go back to the question of how bad the relapse is. An aggressive relapse may require a triplet intervention, whereas a later relapse might only need a couple of agents. But the increase in drug availability should be looked at as giving us more treatment options, rather than fewer.
We are now in a position where there are some early relapse phase 3 trials that give us some strong data about what to do with myeloma patients who may be in their first relapse. These are the kinds of patients whom we do not usually consider very refractory. These would include the ASPIRE trial5 and the ELOQUENT trial,6 among others. All of these trials gave very strong signals that the triplet was better for progression-free survival and, usually, overall survival. So I think in most cases, if the patient is not lenalidomide-refractory, it is considered better to use one of these combinations upfront. The highest response rate was seen in the POLLUX trial7 with daratumumab, lenalidomide, and dexamethasone, which had about a 93% response rate.
In patients with early relapse who are lenalidomide-refractory, bortezomib is usually considered a good option. Here you have the CASTOR trial,8 which is daratumumab, bortezomib, and dexamethasone; PANORAMA,9 which is panobinostat with bortezomib and dexamethasone; and of course, there is the ENDEAVOR trial,10 which uses carfilzomib and dexamethasone vs bortezomib and dexamethasone. Those have pretty reasonable data for an early relapse, and I think most people would say that in a relatively fit patient, any of those trials would be very good ones to consider. We have a lot of very strong data in the early relapse setting, but what we really lack is a testing mechanism for what will or won’t work when a patient gets to their third or fourth relapse.
What is the role of stem cell transplant within the new treatment landscape?
Prior to some of these newer drugs that started to appear in 2013, one of the options that has been present for years has been a second autologous stem cell transplant. The use of second transplants has been around for easily more than a decade, but there really hasn’t been any randomized data to say this is a reasonable approach. There was a study from the Medical Research Council11 in Great Britain, which looked at second transplant for patients at least 18 months removed from their first transplant. All of these patients were treated with a regimen of bortezomib, doxorubicin, and dexamethasone, and were then randomly assigned to second transplant or maintenance treatment with cyclophosphamide. They showed advantages in progression-free survival and overall survival for patients going through that second transplant. This particular study has been criticized, though, because oral cyclophosphamide maintenance is not something that is typically used in the United States. However, I think most myeloma experts would say that a second transplant can be quite helpful for a patient who is 2 years or more out from their first transplant.
One of the things I really like about a second transplant is that it gives them an opportunity to go on second maintenance, which can really improve their quality of life. It is one thing to be coming in once or twice a week for therapies that are effective, but it is still a lot of time out of your schedule. It’s another thing to have a second transplant and be on low-intensity maintenance, which few clinic visits. I have also found that if you really have a patient who is quite refractory, a second transplant can often reset the clock, getting a patient with active disease down to a more manageable level. That interval between first progression and second transplant is going to be shorter, but it can still be a very good strategy in well-selected patients.