Myeloma Regimens Require Coping Mechanisms for Toxicity

Multiple myeloma treatment has made significant strides, but many of the regimens cause considerable toxicity, making it a priority to optimally manage the associated adverse events (AEs) or create less-toxic approaches, explained Adam J. Waxman, MD, MS.

“In the last year or so, there was a real explosion of randomized data for patients with multiple myeloma, including new data for newly diagnosed patients with the addition of daratumumab (Darzalex) and of carfilzomib (Kyprolis) as initial therapies on the transplant-eligible and -ineligible patients. The addition of daratumumab showed progression-free and, in some cases, overall survival (OS) benefits,” said Waxman. “We need to find better ways to manage the toxicities of the drug classes we're using with additional drugs, as well as developing new classes [of drugs] to treat patients where we have efficacy issues.”

Additionally, selinexor (Xpovio) was approved by the FDA in July 2019 after showing an overall response rate of 25.3% (95% CI, 16.4-36.0) in patients whose disease was refractory to bortezomib (Velcade), carfilzomib, lenalidomide (Revlimid), pomalidomide (Pomalyst), and daratumumab. However, the data did raise safety concerns after treatment-emergent AEs and serious AEs resulted in patient deaths.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Waxman, an assistant professor of clinical medicine at the University of Pennsylvania, discussed new and upcoming multiple myeloma treatments and how to optimally manage toxicities from these regimens.

OncLive: How do you determine whether a patient is eligible for transplant?

Waxman: When I meet a patient for the first time, I ask if this is someone who could tolerate receiving a high dose. I usually tell patients, "I'm going to set a nuclear bomb off in your bone marrow, and the only way you're going to live through it is by me giving you your stem cells back afterwards."

The major things I'm thinking about are their organ function and age. I generally tell patients they are allowed to have one of the following things: they can be older than 70 years old and have heart problems, lung problems, or kidney problems. If they have more than one of these criteria, we're going to be really careful about what we're doing.

It's important to remember that age is a very common factor because usually most of our transplant data go up to patients at age 70. We have a pretty good idea that up to age 75 is safe [for transplant]. In a lot of the transplant-ineligible studies, one of the biggest groups includes patients who are older with a lot of comorbidities. In a lot of ways, that ends up being a surrogate when we're thinking about who can safely receive transplant. It's something we want to be somewhat aggressive towards, because we've shown transplant has benefit, regardless of all the new drugs. However, it is important to note that it's a noncurative therapy and we want to have minimal risk for doing it.

Could you highlight some promising novel approaches in multiple myeloma?

In terms of the novel approaches, they are largely being seen in the late relapse setting. The STORM trial of selinexor only included patients [with multiple myeloma] who had been exposed to and refractory towards most of the approved drugs for myeloma. We're taking a group that is underserved. We now have a drug approved that about one-quarter of patients will respond to and about half of those patients will have somewhat durable responses, giving a clear clinical benefit. The data from a single-arm study of about 120 patients showed that we have a reasonable number of people with some significant toxicities associated with this drug. Managing that is going to be one of our challenges moving forward.

Other approaches that are important include looking at the targeting of the B-cell maturation antigen (BCMA), of which there are a number of ways to target. Initially, when CAR T cells were being used, we would genetically engineer the T cells to attack the myeloma cells. It held a tremendous amount of promise because in lymphoma and acute lymphoblastic leukemia, this can be a curative therapy in very relapsed patients.

Thus far in myeloma, while we have high response rates of 70%, 80%, or 90% seen in two published studies, the challenge remains that [CAR T cells] are not durable and patients with myeloma continue to relapse. We are looking at many additional ways of seeing how that strategy can be perfected.

We are also looking at other methods of targeting that may be easier, because one of the major challenges with CAR T cells is that you have a long period of time when patients need to have their cells collected, you need to have adequate lymphocytes to collect, and you end up needing to reinfuse lymphocytes within a certain time period.

In the studies that we have looked at, patients progress in the time period where their cells are being manufactured in the first place. It’s important to look at other [treatment options], such as an antibody-drug conjugate (ADC) that looks very promising. However, similar to selinexor, there is very real toxicity affecting the cornea associated with using the ADC.

All of our strategies are promising. We have a lot of drugs with very real responses and real toxicities. Balancing how that happens is going to be very individualized for patients. Hopefully, as we have more of these approaches approved and ready to give people, we will have more options to individualize the care of myeloma, from the beginning to the end.

How do you anticipate the treatment landscape of multiple myeloma changing in the future?

If we're looking in the near future, as we have more data on quadruplet therapy, the addition of daratumumab to proteasome inhibitors and immunomodulatory drugs together, will hopefully lead to some PFS benefits. If we find an OS benefit, that will change the standard of care for most patients.

Daratumumab is very well tolerated. Even in older patients, the landscape is changing. A year ago, [older] patients might have received a doublet, but they likely couldn't handle lenalidomide and bortezomib; now, these patients probably can get daratumumab and either lenalidomide or bortezomib.

In the future, there will likely be the solidification of almost all patients receiving at least the triplet—some getting quadruplets, including a monoclonal antibody. In the relapse setting, there will be more combinations of drugs. We have a lot of treatments. Most patients, because this is a noncurative disease, are going to receive most drugs in combination. In the next few years, we hope to see the approval of BCMA-directed targeted therapies and CAR T cells for the treatment of patients with myeloma and have them moved earlier in the treatment line.

What is the key takeaway for physicians working in this space?

We need to learn how to manage patients who are unable to receive drugs due to known adverse events. These are patients who come to me already having peripheral neuropathy or autoimmune disorders; patients with peripheral neuropathy can't get bortezomib. We're meeting that need with carfilzomib, but [not having bortezomib is] one less drug you have. This is a disease that patients live with for a long time and you want to maximize their quality of life.

We need to continue thinking of how to help [manage] the very real toxicities, especially as we deal with a frailer and older population, be it newly diagnosed patients or those who were diagnosed and have been living with this disease for a decade or more.

Karyopharm Announces FDA Approval of XPOVIO™ (selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Karyopharm. Published July 3, 2019. https://bit.ly/2XMo1k0. Accessed October 10, 2019.