Rafael Fonseca, MD: Another question that could come up is, how do we sequence the agents? Sometimes we have agents that are going to hit the same target. You can think, for instance, carfilzomib is going to hit the same proteasome inhibitor as bortezomib would hit. As it turns out, not all drugs are the same. Often, people will talk about some of the drugs that are used in medicine as “me too” drugs, but it turns out they’re completely different. So, carfilzomib has shown some features that make it different from bortezomib, including no peripheral neuropathy and a greater power to inhibit the proteasome, which is actually translating into improvements in clinical outcomes.

There are some early clinical trials, such as the ENDEAVOR trial, that showed the superiority of carfilzomib versus bortezomib. We have very clear documentation with regards to the toxicity. Now, it does bring other issues we need to be mindful of, such as hypertension and issues associated with potential cardiac toxicity. This is fortunately a small minority of patients but something that a clinician needs to be aware of.

The same is true with IMiDs. Not all IMiDs are the same. With thalidomide, if you use it long enough, all patients will develop peripheral neuropathy, and we don’t see that with lenalidomide or with pomalidomide. But in fact, if you look at in vitro studies and studies in which we have participated, you can have situations where someone is going to be “refractory” to lenalidomide and yet go on to show responsiveness to pomalidomide. The reality is that for many of these agents, the issue of sensitivity or resistance is more one of degree rather than a binomial.

Thomas G. Martin, MD: Once relapse has occurred, we have to assess the patient on whether or not that person is refractory to a certain drug or whether they’re still sensitive to a certain drug or a class of drugs. We use those data to select the next therapy for them. For instance, many patients are on lenalidomide either at full doses or at maintenance doses in the United States when they progress. At that point in time, especially with the ones who are on full-dose lenalidomide—at least 15 mg daily or more—we would say that person is refractory to lenalidomide.

We’re lucky in that drugs like pomalidomide, which is a second-generation IMiD, can still likely bind the important protein inside the cell cereblon. Because it’s a more potent drug, it can still bind cereblon. It can still cause the downstream effects of binding cereblon, which is decreasing the expression of c-MYC and IRF4, which leads to more cellular apoptosis. Despite that they’re lenalidomide resistant—and lenalidomide works with cereblon—pomalidomide is a better and a more potent binder of cereblon. So, it can even bind in patients who have lenalidomide resistance.

When a patient has a relapse, we often will use proteasome inhibitors as their therapy. Whether it’s the first, second, or third relapse, we often will use a proteasome inhibitor at that time. We do look at their treatment history to see whether they are refractory to bortezomib. Bortezomib is a reversible inhibitor of the proteasome. The way some cells become resistant to bortezomib means they can upregulate some of the subunits, and a reversible inhibitor is more apt to have resistance.

We have second-generation drugs now. We have drugs like carfilzomib. Carfilzomib is an irreversible inhibitor of the beta subunit, and it basically can be given 2 days in a row because it doesn’t have toxicity, including neurotoxicity. And so, I think carfilzomib works in bortezomib-resistant patients because it’s a better binder of the subunit in that it’s an irreversible inhibitor and we can give it multiple days in a row. We know that from carfilzomib’s initial approval. It was approved in the space of Velcade or bortezomib-refractory disease, which is great.

Now we have another proteasome inhibitor, ixazomib. Ixazomib’s approval was really based on a bortezomib-sensitive population. I would say that we don’t have randomized data of ixazomib in bortezomib-resistant patients or in carfilzomib-resistant patients. So, that’s my personal strategy when I’m choosing a proteasome inhibitor in relapsed and refractory diseases. If they are bortezomib resistant, I certainly will choose carfilzomib. If they’re bortezomib sensitive, then I think we have the opportunity to use bortezomib again; we have the opportunity to use ixazomib, which is oral and quite convenient; and we also have the opportunity to use carfilzomib, especially if they have a very potent relapse or a very rapid relapse.

Rafael Fonseca, MD: In addition to the proteasome inhibitors and IMiDs, we have been very fortunate in that we now have monoclonal antibodies and other drugs such as HDACs. The monoclonal antibodies are very interesting because they attack the cell from, obviously, the extracellular compartment. The possibility has been raised that the mechanism of resistance that cells would normally have for drugs that signal at the intracellular level may not be as important for monoclonal antibodies because the apoptosis process may not be as dependent on p53 and other elements. There’s this loose term that’s been thrown around called “extragenomic approaches”, which is what the monoclonal antibodies would do. Now, evolution prevails, so it could be that cells will become negative for some of the surface markers, the CD38. There are, in fact, teams that are looking at ways to increase the expression of CD38, so there are more molecules that you could target with this antibody. But I think it’s going to be different from what we traditionally see with the smaller molecules.

Panobinostat is a very interesting drug. It has not had as much traction in the market, mostly because of the toxicity that was presented in the way that it was originally developed. However, it’s like a fairy-tale story about drug development because it really went from bench to bedside with the sign of phase III clinical trials that were positive. But the myeloma community was a little bit reluctant, and I always say if this drug had been approved for lung cancer 5 years ago, there would have been multiple parties, and people would be so happy. And yet the bar has been so high in myeloma that people are exploring new ways to use panobinostat, different combinations and different dosing schedules. In fact, some of my colleagues, myeloma experts, do report positive outcomes with the combinations. Now, I haven’t used a lot of it, but I’m very interested. In a few patients, we have started to try some of those agents, particularly for those who have no further standard options.

Thomas G. Martin, MD: We now have other novel therapeutics for the treatment of relapsed and refractory myeloma. We now have monoclonal antibodies. We have 2 approved monoclonal antibodies. We have daratumumab, which targets CD38, and we have elotuzumab, which targets SLAMF7. These drugs are drugs that work through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. So, they don’t really have direct toxic effects on the tumor cells but rather indirect effects by bringing in the immune system. These mechanisms are not necessary for patients who have just IMiD-based therapy or proteasome-based therapy. These are novel mechanisms that should be able to be used in patients who have resistant disease. In fact, daratumumab was approved for use initially as a single agent in patients who essentially were double refractory to bortezomib and lenalidomide and had a response rate upward of 25% to 30%. So, it had a very impressive response rate as a single agent.

We tend to use elotuzumab in a more sensitive group of patients. It’s mostly been approved in patients who are lenalidomide sensitive. They can be bortezomib resistant. But it works together in synergy with lenalidomide. So, in a bortezomib-resistant population, elotuzumab and lenalidomide are a great regimen.

There are other approved novel drugs. One of them is a histone deacetylase, or an HDAC inhibitor. Panobinostat is the drug of choice at the current time in multiple myeloma. It can overcome bortezomib resistance, and that’s the platform that it has been approved for use in. Bortezomib itself does cause problems with protein production and also with degradation of proteins. These misfolded proteins build up in the cell, and that’s really the signal that the cell should undergo apoptosis.

Now, there’s a secondary protein homeostasis pathway called the autophagy pathway. That can really help break down some of these misfolded proteins. Sometimes with bortezomib, when you get a buildup of the proteins, this autophagy pathway will start to degrade some of those proteins and really cause bortezomib resistance. HDAC inhibitors can actually shut down this autophagy pathway. So, they can work together with bortezomib. HDAC inhibitors can work very well with bortezomib and can work in patients who are bortezomib refractory. We also have some clinical data showing that in fact, they may work well with IMiDs too. So, it’s not currently approved for use in that regard, but certainly there are going to be more data and more studies with HDAC inhibitors together with lenalidomide and pomalidomide.

Transcript Edited for Clarity