Sequencing Challenges Emerge in Myeloma as Options Expand

Omar Nadeem, MD

As more novel agents are added to the treatment paradigm for relapsed/refractory multiple myeloma, Omar Nadeem, MD, stressed that the big challenge lies in determining how best to sequence these therapies.

“The most important thing is going to be determining how to sequence therapy in myeloma,” said Nadeem. “As more drugs become available, we have to be a bit logical about how we expose patients to them. Patients with myeloma are living longer and longer, and exposure to agents at the right time is extremely important.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Nadeem, a physician at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, highlighted exciting approaches that have emerged in relapsed/refractory myeloma, such as CAR T-cell therapy, and shared unanswered questions that future research should address.

OncLive: What are some active areas of research in the relapsed/refractory multiple myeloma setting?

Nadeem: There have been many advances made in the relapsed/refractory myeloma setting. The good news about the advances that are being made is that the targets are quite varied in terms of what's being studied. We're looking at different combinations of drugs that have already been out there, certain immunomodulatory drugs and proteasome inhibitor combinations, but what's even more exciting is the novel mechanisms that we're using to target the myeloma cell. That includes CAR T-cell therapy and anti—BCMA-targeted drugs, antibody-drug conjugates targeting BCMA, and bispecific antibodies targeting that same family. We also have several other drugs, such as melflufen and selinexor, in development.

What is the current approach for sequencing these agents and what challenges do you foresee?

There are several issues. First, it's always what the patient is able to tolerate. As patients are exposed to any of these drugs, there are potential toxicities that can develop. We always look at patient factors when we're choosing what the next best regimen for somebody would be. We look at their disease. We look to see how much benefit they received from prior therapy and if they received a very long-term benefit from a very specific class of medications, then it's possible that they will receive similar benefit if we change them to a different medication in the same class. Those are some patient factors and disease factors that we consider.

We also look at their cytogenetic risk to see if they have developed or acquired some new high-risk mutations. We tend to reach for our most effective and potent therapy with the hopes of offsetting that as much as we can. However, at this point, we haven't quite gotten into where we can use that data to specifically target any of those mutations.

Venetoclax (Venclexta) is a medication that does have very significant activity in patients with t(11;14) disease, although there are some safety concerns with that agent that are hopefully going to be teased out [in the future]. That is one example of a targeted drug that is hopefully going to be available in the future for patients who carry that particular mutation. Hopefully, more [agents] will be discovered and there will be more to come in that particular space.

What key trials are you particularly excited about?

In the relapsed/refractory state, we've had a lot of data come out recently looking at various combination therapies of [agents that are] already available. We looked at some smaller phase II studies looking at some of these medications, such as melflufen and selinexor, and there will be more of that to come. We're looking at many daratumumab-based combinations that are being used in various platforms, and we’re even looking at 4-drug regimens that we never really considered using previously. We're seeing lots of potent activity and we're seeing a fairly decent tolerability for these drugs. Therefore, hopefully, going forward, we'll get more data as time goes on.

Could you speak to the work being done with CAR T-cell therapy in myeloma? What is the hope for this approach in the space?

By far, the biggest buzz in myeloma and a lot of hematologic malignancies over the last couple of years has been CAR T-cell therapy. BCMA-targeted CAR T-cell therapy in particular has made some advances over the last several years, as we have more and more data for patients who are treated with this particular protocol. What we know is that this treatment modality is extremely effective. Most patients do respond, and these are patients who have been very heavily pretreated and are extremely refractory, where no other prior therapy has yielded the types of responses that we're seeing with some of these CAR T-cell platforms.

However, what we're also seeing is the toxicity associated with it. With that [therapy], comes hospitalization, cytokine release syndrome—which is pretty common—and then neurotoxicity, which is less common than we're seeing with some of our other diseases that have used CAR T-cell therapy. However, this is still a risk for patients going forward.

All of us were waiting to see what the actual duration of response (DOR) would be [with CAR T-cell therapy]. When the data first came out several years ago, we [were all excited about its] activity, but we didn't know how long that was going to last. Now, we have some data showing that [DOR with this approach is] roughly 1 year, and longer for some patients who achieve MRD negativity.

However, it certainly needs more work. It needs more tweaking along with different mechanisms to prolong that response for patients going forward, but clearly the signal is quite active. We need to fine tune it and also start to think about where we want to use this particular platform. [Do we want to] use it in the current space where it is, which is this refractory population, or do we move it into earlier lines of treatment? Doing that may yield potentially longer responses in patients.

What are some key unanswered questions that future research needs to address?

As more and more medications are available, we have to think about how to sequence these medications. In the relapsed setting, that’s by far the most important thing. As 4-drug regimens emerge in the frontline setting—and trials are ongoing, we think that may be where the field is headed—we then have to see, what does that mean? Does that mean that stem cell transplantation is still a standard of care or not? We have to be very careful about when we make those decisions to ensure that we are doing the right things for the patients.

The other [challenge] is escalation and de-escalation of therapy. We need tools that will tell us when somebody starts with 4 medications, intensive therapy, can we de-escalate their therapy? These are some questions that we have not ever fully asked before, because we never really had these types of medications and platforms to start with.

My hope is, with time, we will get more and more medications and develop better tools to individualize therapy for patients. In my opinion, no 2 patients with myeloma are alike and [each patient] really does require a very individualized [treatment] plan. As we get more of these approvals, we have to make sure that we keep that in mind.

As more medications with novel mechanisms of actions become available, we all have to work as a big collaborative team. We all treat this disease because we care for our patients and we want our patients to do well for a long, long time, until hopefully, we can reach a cure for this disease. All of us need to work together to figure out the right tools, the right combinations, and the right modalities so that we can get these patients to enjoy their lives.