Myeloma Expert Highlights Practice-Changing ASH Findings

C. Ola Landgren, MD, PhD

The landscape of multiple myeloma continues to shift with more drug approvals, but pivotal results out of the 2016 ASH Annual Meeting will likely alter it even further, according to C. Ola Landgren, MD, PhD.

Regarding the monoclonal antibody daratumumab (Darzalex), updated results from the phase III CASTOR and POLLUX studies continued to show positive results in patients. In CASTOR, daratumumab was added to a backbone of bortezomib (Velcade)/dexamethasone while the POLLUX trial investigated the monoclonal antibody with lenalidomide (Revlimid)/dexamethasone.

Additionally, interim findings of an investigational anti—B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy also showed encouraging, yet early, activity in patients with relapsed/refractory multiple myeloma (NCT02658929).

Venetoclax (Venclexta), a BCL-2 inhibitor already FDA approved in the space of chronic lymphocytic leukemia (CLL), was also found to have notable findings in myeloma abstracts presented at the meeting, Landgren explains.

Landgren gave a lecture on these exciting studies and more in multiple myeloma during the 2016 OncLive® State of the Science Summit on Hematologic Malignancies.

OncLive: Can you provide an overview of your lecture in myeloma?

In an interview during the meeting, Landgren, chief of Myeloma Service at Memorial Sloan Kettering Cancer Center, picks apart some of the top presented abstracts in multiple myeloma from the 2016 ASH Annual Meeting, as well as what’s in store for the field.Landgren: It included selected highlights from the 2016 ASH Annual Meeting. I first talked about the updated CASTOR and POLLUX studies that are based on daratumumab, both in combination with lenalidomide/dexamethasone and bortezomib/dexamethasone in the 2 studies, respectively. These combos were recently FDA approved for patients with 1 or more prior lines of therapy.

The presentation today was an update on the follow-up with particular focus on minimal residual disease (MRD) status. It shows the patients can obtain MRD negativity on both the experimental arm and the control arm. Patients treated with or without daratumumab on both of these studies obtained MRD negativity, but the rate of MRD negativity is higher in the experimental arm in both studies.

Secondly, there was an update on CAR T-cell therapy. At ASH, we heard from the BCMA CAR T-cell therapy regarding the first 9 patients treated in the first cohort.

We have heard about the POLLUX/CASTOR studies often. What questions still need to be answered regarding those studies?

The third is the use of venetoclax, an oral BCL-2 inhibitor. It was recently approved for other B-cell malignancies. There was updated information on single-drug use in a phase I trial for patents with myeloma. In patients with an 11;14 translocation who typically have activation of BCL-2, they seem to have pretty good response to this drug.It is very exciting to see how the monoclonal antibodies are coming at full speed into the myeloma field. The FDA approved the use of daratumumab as a single agent in November 2015 and now the agency gave approval of daratumumab in combination with lenalidomide/dexamethasone and bortezomib/dexamethasone, which is exactly what the CASTOR and POLLUX studies show.

It is definitely changing the treatment landscape here in the United States. A lot of patients will start receiving monoclonal antibodies as their relapsed treatment. They probably will be treated, if they come to academic centers, typically with 3-drug combinations, an immunomodulatory (IMiD) proteasome inhibitor, and a low-dose steroid with or without transplant. If they relapse, then daratumumab in combination with either lenalidomide/dexamethasone or bortezomib/dexamethasone are very valid options. That will change the field.

What challenges are oncologists still facing with these daratumumab regimens?

I would like to emphasize that a lot of the other options remain very valid, as well. The ASPIRE, TOURMALINE-MM1, and ELOQUENT trials are also comprised of regimens that are other great options.Daratumumab is a very well-tolerated drug. I prescribe it a lot; I see a lot of patients myself. One of the key problems, if we use the word problem, is that the first infusion can take a little while. That is because patients can have infusion reactions. Typically, if patients have infusion reactions, it typically will involve some shortness of breath, swelling in the mouth, itching, or a drop in blood pressure.

What progress is being made with CAR T-cell therapy?

It is sort of like using rituximab (Rituxan) many years ago for lymphoma therapy. We are quite used to giving these types of drugs; once the nurses give the drug in the infusion room for the first time and are used to it, they know how to start, slow down, and start again. It probably happens in 30% to 50% of patients. After that, the second, third, and fourth infusion usually goes much faster. I myself have not seen any infusion reactions for the subsequent doses, and that is coinciding with the literature.CAR T-cell therapy has been talked about a lot in the past few years. In myeloma, the first presentation was given at the 2015 ASH Annual Meeting by the NCI. This year, it was Adam D. Cohen, MD, out of the University of Pennsylvania who gave the update. This update from the University of Pennsylvania used the same target—BCMA—that the NCI group used. It is a little bit of a different construct used, but the target is the same.

We have seen the potential of venetoclax in CLL. What do you predict it will do in myeloma?

Also, there is not any conditioning therapy. People have used cytoxan and there have been other CAR T-cell studies, and they used cytoxan and fludarabine, or they used melphalan with stem cell transplant as the conditioning regimen. The first cohort of 9 patients had no conditioning. In 7 of the patients, they were able to see expansion of the CAR T cells in the patient, but 2 patients did not have that. In the second and third cohorts going forward, researchers are adding cytoxan as the conditioning therapy to see if they can increase the expansion.Venetoclax was FDA approved for the indication of the CLL, and now we have started seeing it in other diseases. There were 2 presentations with patients at the 2016 ASH Annual Meeting; one of them was a phase I trial with a dose-escalation cohort and then an expansion cohort with around 60 patients. What they found was the overall response rate (ORR) was in the range of 20%—specifically if you stratify patients by different subtypes using cytogenetics and fluorescence in situ hybridization—that virtually all of the responses were in the group of patients with an 11;14 translocation. That makes perfect biological sense because, in patients with an 11;14 translocation, that is where you see expression of BCL-2. Therefore, that is why the BCL-2 inhibitor works.

In the study looking at the combination of venetoclax with bortezomib and dexamethasone, they treated patients independent of the cytogenetic risk status. They reported that the ORR was very similar in patients independent of their cytogenetic risk status.

Do you envision immunotherapy having a larger role in the field?

However, there were quite a few patients with 11;14 and patients were heavily pretreated. Therefore, it’s hard to really evaluate a study when you have a drug like bortezomib that hits independent of the cytogenetic risk group, and then you add another drug that really focuses on a mechanist that’s not in every patient. Then, you have patients who are heavily pretreated. The results are a little more difficult to understand in that study. We need a larger study so we can stratify and look at it in more detail.Immunotherapy has already entered the myeloma space. Depending on how you define immunotherapy, if you include IMiDs, you can claim that immunotherapy started in the late 1990s. If you restrict it to lenalidomide, then you say 2006 is when immunotherapy came to myeloma.

But if you are talking about monoclonal antibodies, then we’re talking November 2015. That is when elotuzumab (Empliciti) and daratumumab entered the myeloma scene. We will continue to see more antibodies. PD-1/PD-L1 inhibitors have already been found to seemingly work, but they don’t work as single drugs. If you add an IMiD with dexamethasone, though, you can see evidence of synergy. There is evidence from small randomized trials that showed that the combination of pomalidomide (Pomalyst)/dexamethasone with pembrolizumab (Keytruda) demonstrated a better response rate than just pomalidomide/dexamethasone alone.

What is important for the community oncologist to know about the rapidly evolving field right now?

There are additional antibodies that will continue to come out—antibody-drug conjugates. This is a field that will continue to expand. We are just in the beginning of seeing all of these new antibodies entering the myeloma field. My projection is that they will be used in combination with other drugs in the upfront and relapsed settings, and will probably also be used in some type of maintenance, as well. The future will tell.ASH goes on for so many days. If you ask to summarize myeloma from the 2016 ASH Annual Meeting in 20 minutes, you either have to cheat or lie, or you have to just pick a few things. I don’t like to cheat or lie, so I picked a few things.

Daratumumab has really put down its foot in the myeloma space. It is important to show what that drug delivers, and it’s the first of 2 antibodies. MRD also has come to myeloma to stay; it will soon become a regulatory endpoint.

I wanted to shed light on CAR T-cell therapy, because there is so much interest in it, and it is important to give an update on where we are right now.

With venetoclax, we know that myeloma is not just 1 disease. Patients with myeloma, on average, have mutations in exomes of more than 50 genes at diagnosis. If you use that genetic information, you can see that every patient who walks in the door with myeloma has 10 or more parallel clones at diagnosis to begin with. Venetoclax is an example of the fact that there are proportions of patients with certain subtypes where drugs work. That is the message: we need to find the right patient and couple him or her with the right drug. We need to monitor for the depth of response, and the role of immunotherapy is important.