Triplets Reign Supreme in Relapsed/Refractory Myeloma

Leif Bergsagel, MD

Triplet regimens have been largely established as an optimal approach for treating patients with multiple myeloma who have relapsed. According to Leif Bergsagel, MD, the triplet that stands out from the pack is daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone.

The FDA granted approval to this triplet in 2016 based on findings from the phase III POLLUX study.¹ Results showed that in patients with relapsed/refractory myeloma, adding daratumumab to lenalidomide and dexamethasone reduced the risk of progression or death by 63% versus lenalidomide and dexamethasone.

Chimeric antigen receptor (CAR) T-cell therapy is another exciting avenue of investigation for patients with relapsed/refractory disease. For example, data from the 2017 ASH Annual Meeting showed that the BCMA-directed CAR T-cell therapy bb2121 induced complete remissions for 56% of patients with relapsed/refractory multiple myeloma.² Other clinical trials with CAR T-cell therapy are currently underway in this indication, says Bergsagel.

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Multiple Myeloma and Myeloproliferative Neoplasms, Bergsagel, professor of medicine, consultant, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, discussed the treatment evolution for patients with relapsed/refractory multiple myeloma.Bergsagel: There are a lot of choices, and it can be confusing for oncologists to choose one over the other. The choices can depend a lot on the patient and what the risk factors are, what the previous treatment was, and what the anticipated adverse events (AEs) are. Summarized, if you are going to treat a patient with relapsed/refractory myeloma, it is generally better to use 3 drugs over 2 drugs.

With the available choices, what are some of the go-to regimens?

Once a patient has relapsed, what are the considerations for sequencing?

What are some of the AEs to look out for?

What are your thoughts on 4-drug regimens?

CAR T-cell therapy is showing excitement in this field. Is there anything other than bb2121 that is looking promising?

What are some of the remaining questions with CAR T-cell therapy that need to be answered?

Is this something that you anticipate using only in heavily pretreated patients?

Is there anything else that you would like to emphasize?

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. Clinical trials are ongoing. There is one other clinical trial that is very exciting right now, which is an antibody targeted to BCMA. There is one regimen that stands out in comparison with the others, which is daratumumab, lenalidomide, and dexamethasone. The results of the randomized clinical trials almost looked as though they were treating newly diagnosed patients because they did so well. You have to ask yourself, “Why isn't that the regimen you are using?”[We ask]: do you gradually introduce 1 drug, and then a second? If a patient is relapsing on lenalidomide, you might add dexamethasone and ixazomib (Ninlaro), and then you might get more aggressive with carfilzomib (Kyprolis). When all of that fails, you might then go with daratumumab. That is a sort of incremental approach. The alternative is to switch completely to something else after relapse on lenalidomide—perhaps carfilzomib with cyclophosphamide. In different situations, each of those approaches may be appropriate depending on how the patient is doing.The use of carfilzomib can result in some unpredictable cardio or renal side effects. About 1% to 2% of patients can get hypertension or heart failure. The first infusion of daratumumab is associated with infusion reactions. With ixazomib, there is nausea and vomiting [associated with it].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. I would use cyclophosphamide, pomalidomide (Pomalyst), carfilzomib, and daratumumab—some combination of those. There is a CAR T-cell therapy, manufactured by Juno Therapeutics, that does not have much data. There is also the [product] from China, data of which was presented at the 2017 ASCO Annual Meeting. There are several studies that have showed promising results other than bb2121, but there are still a lot of clinical research to be done.[There are questions with] the duration of response, which may correlate with how long the CAR T cells persist in the body, and whether when patients relapse, can you give them more CAR T cells? Does the antigen persist or does it go away? Do you need to move beyond BCMA to a new target? There are a whole lot of things that we need to learn.Initially, I would use it in the heavily pretreated patients, so we get more experience with it and are more comfortable with managing the AEs, and maybe find the optimal way to use it. In the long term, I would like to see it replace transplant, but we are not there yet. People should know that there was an increase in mortality with the use of checkpoint inhibitors in multiple myeloma when compared with lenalidomide and dexamethasone. They probably should not be used outside of a clinical trial. That does not mean that there is no promise; we just need to learn why there was a toxicity and find the safe way to use them.

A full analysis has not been presented explaining why the patients were dying. Until we have that, it is hard to know the issue. However, some things that are different about this study compared with the other tumors is that this one used a lot of dexamethasone—which is unusual—so perhaps that led into it. It also used lenalidomide, which may have augmented the effects.

References

1. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi: 10.1056/NEJMoa1607751.
2. Berdeja JG, Lin Y, Raje N, et al. durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-BCMA CAR T cell therapy. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 740.