Rafael Fonseca, MD: In multiple myeloma, it has almost been a badge of honor to be conservative. When I was in training, the mantra was that you don’t want to treat too early, and that was partly because very old studies have shown that there was no improvement for patients. But now that we have better agents, people are asking whether we are treating sometimes too late. That applies at the time of progression from smoldering or MGUS but also at the time of progression or relapse post-initial therapy. I think this is a bit confusing because people can interpret relapse in many ways. Even though there are international guidelines that have been developed, such as those of the International Myeloma Working Group, we use an N of 1 for decisions we make at the bedside. I think most people clearly feel in need of treatment if the patient has symptomatic relapse. If someone has hypercalcaemia, if someone has anemia, that patient needs treatment.

What I think is less clear is what to do when there’s biochemical relapse. There are some patients who will have a minute increase, for instance, in their free light chains. Even then, I know there can be discrepant opinions with some patients being observed and some physicians being very uncomfortable and immediately wanting to provide the patient with the best therapy. I think the step between those 2 extremes is a biochemical relapse that seems to be progressing. I think more and more, people agree that is something that should be treated. Now, to confirm this, I went to a place where everyone is testing everything, and that is Twitter. I put a poll out there to see what my myeloma colleagues would do. What I found is that the majority of them think treatment should be started at the time of progressive biochemical relapse. A few of them said just biochemical relapse. Of course, everyone agrees that you should treat when it’s aggressive, but many would say that may be too late.

One of the arts of the proper treatment of patients with myeloma is to consider the patient, unique features of their myeloma, risk stratification, comorbidities that the patient may have, personal preferences, and logistics such as the driving time to a treatment center. But another important variable is tolerance to the previous line of therapy, and I think that makes a world of difference in how we integrate all this information to decide on future lines of therapy. Everyone is unique, and I think that’s very much a cliché, but some patients will not tolerate a certain class of drugs well. We have to keep that in mind for subsequent therapy, or a patient may have had a very serious side effect, such as peripheral neuropathy with bortezomib. I think everyone would agree that we have so many options for those patients, so bortezomib should be omitted from future therapy. But again, it’s an integration of all this information. I tell my patients sometimes that managing myeloma is almost like flying a plane. It’s rarely 1 gauge but rather a combination of all that information that allows you to present an option to the patient.

Thomas G. Martin, MD: When somebody has relapsed with multiple myeloma, you really have to take a personal approach. There are many factors that you have to consider when you’re going to select a regimen for a patient. One of the first things is, is it biochemical-only progression? Or are they symptomatic? If it’s biochemical progression, you may actually be able to delay treatment for some period of time by watching them closely and making sure they have no new bone lesions or end-organ effects. You may be able to put therapy off for maybe 6 months or a year. However, if they have symptomatic disease, you obviously have to start right away.

The pace of progression is an important thing. If it’s a really slow progression, I almost always use triplets, but I tend to use triplets that are perhaps better tolerated or more convenient. I think elotuzumab, lenalidomide, and dexamethasone is a very well tolerated regimen. I use it in a lot of patients who have very slow progressive disease. Also, ixazomib, lenalidomide, and dexamethasone, or IRD, is an all-oral regimen. It’s a very convenient regimen. I tend to also use that in patients who have more of a slow progression.

On the opposite spectrum, some patients can have very rapid progression. They can double their M protein in 4 to 6 weeks, and they can also have cytopenias. For patients who have that fast and rapid a progression, I often use chemotherapy. That is the patient population for which I will use infusional chemotherapy like hyper-CVAD with VD, VD-PACE, or D-PACE: some intensive chemotherapy regimen that in general for us is given for a few days in the hospital. I really need to knock down that rapidly progressive clone and try to get better recovery of their blood counts, etc, so they’ll tolerate further therapy better.

And then there are the patients who have intermediate-paced relapse. In those patients, we have so many options. It’s really great. Carfilzomib, lenalidomide, and dexamethasone, KRD, is a common one for me. Daratumumab, lenalidomide, and dexamethasone, DRD, is a common option. If I use KRD, then I’ll use daratumumab in the next regimen, and I’ll often combine it with pomalidomide and dexamethasone. Vice versa, if I use daratumumab, lenalidomide, and dexamethasone, my next regimen is going to be pomalidomide, carfilzomib, and dexamethasone. So, we have so many agents now that we can really plan our next 2 or 3 regimens just as we go, which is really great. I think that’s mostly the strategy that I use.

The other thing I want to mention briefly is comorbidities. You always have to be worried about comorbidities. A lot of the comorbidities are in fact from their prior therapy. Sometimes, they have neuropathy. The neuropathy has come from their prior therapy. If they have significant neuropathy, I’m going to try to avoid drugs that can cause neuropathy. Certainly, bortezomib causes neuropathy. Lenalidomide sometimes causes some neuropathy. If they really have severe neuropathy, I might choose carfilzomib and pomalidomide, which both have much lower rates of neuropathy associated with them.

Sometimes, if somebody has a history of a DVT or a clot, I don’t think we need to stay away from the IMiDs unless it’s convenient to or if I have another regimen like a regimen of carfilzomib, Cytoxan (cyclophosphamide), and dexamethasone. It’s one of my favorite regimens. With that one, we don’t have to worry too much about blood clotting. But if they do have a history of blood clotting, you just have to put them on a blood thinner to get them on the IMiD-based therapy, and that’s OK.

And lastly, I’ll just comment on renal insufficiency. With renal insufficiency, the take-home point for that is you really need to dose-reduce the IMiD, specifically lenalidomide if you’re going to use lenalidomide. I don’t typically dose-reduce pomalidomide. I don’t dose-reduce carfilzomib in that setting. You just have to watch them very closely and watch their counts very closely.

Transcript Edited for Clarity