Treating Relapsed Myeloma Is Not One-Size-Fits-All

There are numerous ways to treat patients with relapsed or refractory multiple myeloma, with even more options being studied in ongoing clinical trials.

Most recently, triplet regimens have been largely established as an optimal approach for treating these patients.

“If you’re going to treat a patient with relapsed or refractory myeloma, it is generally better to use three drugs over two drugs,” Leif Bergsagel, M.D., a professor of medicine and consultant in the division of hematology/oncology in the department of internal medicine at the Mayo Clinic in Phoenix, Arizona, said in an interview with OncLive, a sister publication of CURE.

While triplet regimens have been established as an excellent choice for this group of patients, one combination, in particular, is exceptionally promising, according to Bergsage. That combination includes Darzalex (daratumumab), Revlimid (lenalidomide) and dexamethasone, which was granted FDA approval in 2016 based on findings from the phase 3 POLLUX study.

“The results of the randomized clinical trials almost looked as though they were treating newly diagnosed patients because they did so well,” he added. “You have to ask yourself, ‘Why isn't that the regimen you are using?’”

In the POLLUX study, the addition of Darzalex to the combination regimen reduced the risk of progression or death by 63 percent compared to Revlimid and dexamethasone alone.

However, while this triplet is very promising, it should not be the automatic go-to for all patients with relapsed or refractory disease. Bersagel mentioned that patient risk factors, previous treatment and anticipated side effects should be considered when patients and providers are deciding on the next line of therapy.

Luckily, though, therapies coming down the pipeline are generating excitement — and good response rates.

“Some of the newer experimental things that aren’t approved are CAR-T cells, which everyone is really excited about. There are very high response rates, but there is a question about durability of response,” Bergsagel said. “Clinical trials are ongoing. There is one other clinical trial that is very exciting right now, which is an antibody targeted to BCMA.”

Of note, Bergsagel highlighted the study of the investigational B-cell maturation agent antibody-drug conjugate (GSK2857916), which was granted a breakthrough therapy designation for patients with relapsed or refractory myeloma who failed at least three lines of prior therapy, including an anti-CD38 antibody, and are refractory to a proteasome inhibitor and an immunomodulary agent in November 2017. According to findings from the phase 1/2 DREAMM-1 study, the agent induced an overall response rate of 60 percent in heavily pretreated patients with relapsed or refractory multiple myeloma.

Although CAR-T cell therapy is the latest buzz in treating blood cancers, much remains unknown about its use in myeloma, according to Bersagel, particularly about the duration of response, how long the CAR-T cells last in the body, and if patients relapsed on them, whether or not they can be given another similar agent. “There are a whole lot of things we need to learn,” he added.

In the meantime, physicians must consider a patient’s health and history when determining which agents they’ll receive, as well as the order in which they’ll be administered.

For example, once a patient has relapsed, physicians may want to use an incremental approach: Following relapse on lenalidomide, add dexamethasone and ixazomib (Ninlaro), and then more aggressively add carfilzomib (Kyprolis), or if all of those options fail, go with daratumumab. Or, if a patient relapses on Revlimid, physicians might prescribe their patients Kyprolis plus cyclophosphamide.

“In different situations, each of these approaches may be appropriate depending on how the patient is doing,” Bergsagel said.

And when patients are considered to have high-risk disease, Bergsagel said that he would consider four-drug combinations. “There are not a lot of data, but I do have thoughts about it. When I have had a patient with very high-risk disease, the more drugs that I can give them at the same time to control the subclones that may be present, the better,” he said.

In that situation, Bergsagel noted that he would use a combination of Pomalyst (pomalidomide), Kyprolis, Darzalex and cyclophosphamide.

Since treating relapsed or refractory myeloma is not a one-size-fits-all approach, it is crucial that patients talk with their health care team to determine the best regimen for them moving forward.