Expert Sheds Light on Rapid Progress in Relapsed/Refractory Myeloma

Ivan M. Borrello, MD

Given the number of treatment regimens that have become available to patients with relapsed/refractory multiple myeloma, the decision of which strategy to pursue should be grounded in the nature of the relapse, the setting in which it occurs, and any comorbidities that may present contraindications to specific agents, explained Ivan M. Borrello, MD.

“We can now combine several classes of drugs and get an additive, if not synergistic, effect at times to improve overall survival (OS),” said Borrello. “Evidence also suggests that some drugs can molecularly target certain chromosomal abnormalities.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Borrello, an associate professor of oncology at Johns Hopkins Medicine, discussed the most impactful agents that have entered the relapsed/refractory setting of multiple myeloma and detailed some of the guiding principles of treatment selection.

OncLive: Could you discuss treatment approaches in relapsed/refractory multiple myeloma?

Borrello: Multiple myeloma has really turned into a chronic disease. There is an increasing recognition of the concept of clonal evolution, which is the idea that myeloma at diagnosis is very different than myeloma at third or fourth relapse. This has been coupled with the fact that there has been a significant increase in the drugs that have become available—not just more drugs in one family but new families of drugs.

As a result, we have made significant advances in treatment that have translated into improvements in progression-free survival and OS. Theoretically, [the number of treatment regimens that are available to patients] is almost infinite. The reality is that we are probably seeing [patients] go onto 9 or 10 lines of therapy with the various combinations we could give.

Moreover, venetoclax (Venclexta) has shown impressive activity in patients whose disease harbors 11;14 translocation (t(11;14) compared with those who don't. That is one of the more interesting targeted approaches in myeloma. [Granted, myeloma] lags behind targeted therapy in lung cancer and acute myeloid leukemia.

Do you anticipate venetoclax having a role in all-comers or only those with t(11;14)?

According to the data, patients without t(11;14) also respond to venetoclax; however, the objective response rate is significantly lower in these patients. The difference in response between those who have t(11;14) and those who don’t is so great. So many other options are becoming available as well. If I had myeloma and didn’t have t(11;14), I would opt for venetoclax after I exhausted all my options. [Not having t(11;14) is not an absolute contraindication, but other therapies would be [just as, if not more effective] in that patient population.

What are some of the most promising regimens in the relapsed/refractory setting?

There are a lot of them. The use of carfilzomib (Kyprolis) in a triplet regimen with either lenalidomide (Revlimid) or pomalidomide (Pomalyst) is interesting and has shown a benefit compared with carfilzomib and dexamethasone alone. The fact that daratumumab (Darzalex) is showing a significant amount of activity [in combination with other agents] in the relapsed setting, and now, more recently, in the upfront setting is [encouraging]. With daratumumab, we’re seeing a significant percentage of complete remissions as well as a higher incidence of minimal residual disease negativity. That is very exciting.

We recently saw the FDA approval of selinexor (Xpovio), which [is indicated] for patients with [heavily pretreated] disease. The drug has a completely novel mechanism of action, which offers a whole new realm of possibilities for patients. Additionally, the oral proteasome inhibitor ixazomib (Ninlaro) has shown significant activity in combination with immunomodulatory drugs and dexamethasone, even in patients with high-risk features.

How does CAR T-cell therapy compare with selinexor? Are these competing strategies?

Those are very different [modalities]. CAR T-cell therapy has a significant complexity in terms of manufacturing and delivering treatment. We’ve seen very impressive results with [CAR T-cell therapy]. In the clinical trials that were done, it was given as a one-time therapy. One of the interesting things about BCMA-targeted CAR T cell therapy is that, in contrast with diffuse large B-cell lymphoma and pediatric acute lymphoblastic leukemia, we are not seeing the plateaus that we saw in those two diseases. How we're going to integrate that therapy will require further investigation.

Selinexor is a different drug. I can prescribe selinexor today and give it to the patient tomorrow. You certainly cannot do that with any autologous cell-based therapy. That’s not to say that in the future that might not change, but currently, this is what the situation is.

Does your recommended treatment regimen differ in a patient who has an early relapse versus a late relapse?

Whether the relapse is early or late is not as important as whether it's aggressive or indolent and in what setting it occurs, specifically in the posttransplant setting or in those who have never received a transplant. The kind of comorbidities that the patient has [must also be considered]. Patients with myeloma have a median age of 65, so a significant number of patients do have comorbidities. Preexisting neuropathy would preclude, or at least reduce, the enthusiasm of using proteasome inhibitors, such as bortezomib (Velcade) and ixazomib, as they may cause neuropathy. You would want to be careful about using carfilzomib in patients with preexisting cardiac dysfunction. Carfilzomib isn’t necessarily contraindicated [for any of these comorbidities], but you want to be careful.

In addition, we have to take into account the patient’s response to prior therapy and any kind of toxicities they may have experienced. There are situations in which an indolent relapse could be treated with the addition of one drug superimposed onto what they’re already receiving. There are also more aggressive relapses in which one could justify, and perhaps even mandate, completely switching regimens.

Does prior exposure to one drug preclude its use in another setting?

No, it wouldn't, especially if a patient responded to a therapy, went onto transplant, and then relapsed afterwards. Theoretically, they could be treated with the same regimen they had initially responded to, or parts of that regimen in combination with other drugs.