Myeloma Paradigm Shifts With Continued Success of Combo Regimens

Rafael Fonseca, MD

Rafael Fonseca, MD

Pivotal clinical trial findings from the past year will likely have a game-changing effect on the multiple myeloma landscape, according to Rafael Fonseca, MD. Moreover, he adds, oncologists may be looking at a future where the number of drugs in a single regimen continues to grow in an effort to further improve outcomes.

For example, in October 2016, the FDA granted a priority review designation to the monoclonal antibody daratumumab (Darzalex) in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy.

The designation was based on results from the phase III POLLUX¹ and CASTOR² studies.

In the POLLUX trial, the addition of daratumumab to lenalidomide and dexamethasone led to a 63% reduction in the risk of progression or death compared with lenalidomide and dexamethasone alone for patients with relapsed/refractory disease. Meanwhile, in the CASTOR study, adding daratumumab to bortezomib and dexamethasone was associated with a 61% reduction in the risk of progression or death versus bortezomib and dexamethasone alone for patients with recurrent or refractory disease.

Updated findings regarding another monoclonal antibody, elotuzumab (Empliciti), could also guide oncologists in determining the agent’s role in multiple myeloma.

Elotuzumab was approved by the FDA in November 2015 for use in combination with lenalidomide and dexamethasone for patients with multiple myeloma following failure on 1 to 3 prior therapies. The approval was based on data from the phase III ELOQUENT-2 trial.³ Here, the triplet regimen led to a 30% reduction in the risk of disease progression when compared with lenalidomide/dexamethasone alone.

OncLive: What were the key points of your lecture on advances in multiple myeloma?

In an interview during the 2016 OncLive State of the Science Summit on Treatment of Hematologic Malignancies, Fonseca, a professor of Medicine at Mayo Clinic, discussed several of the key recent advancements in the management of multiple myeloma.Fonseca: What I tried to accomplish is to update the audience on some of the developments that occurred over the last year with regard to clinical trials that address the treatment of the disease. We have a number of trials that have looked at frontline therapy, as well as therapy for the relapsed/refractory setting. Fortunately, we have a plethora of trials that are showing improvements in our ability to control the disease. Some of the trials that are maturing are showing improvements in overall survival.

Will we ever get to a place in which patients die with, not of, myeloma?

Perhaps, most excitedly, we do have the advent of monoclonal antibodies that are now part of the standard toolbox in our treatment against myeloma. Our next order of duty is to find out how to combine all of these agents to provide optimal disease control. In the mind of many of us, [our goal] is to control myelomaAbsolutely. The survival expectancy with myeloma continues to improve. That is not to say that it is not a serious disorder. For many patients, particularly those with high-risk disease, myeloma remains very challenging. However, more and more patients are seeing a 10-year anniversary. It’s not unusual for me to see patients who are doing 7, 8, or 9 lines of therapy now. They are still responding quite nicely to treatment.

What do you look for when you are identifying patients who are high risk?

We would like to compress that. We would certainly like to provide patients with a combination with or without transplant, and put a large number of those patients into durable remissions; some of those should translate into cures in the future. We know, from historic data, that when patients achieve a complete response (CR) after transplant, there is a subset of them—about 30%—that will remain at CR at 20 years. Now, we can put patients on stringent CRs and minimal-residual disease (MRD)¬—negative status. Our hope is that, as time goes by, more and more patients will fall into that category.Traditionally, we have looked at high-risk disease based on the genetic markers. That can be determined in 1 of multiple ways. The standard way has been through genetic testing by FISH for abnormalities; it is very important that is done properly. If a bone marrow is sent out to a lab and they don’t have a selection of cells, there is a very high risk that the results will be false negatives.

You mentioned there are a plethora of ongoing clinical trials. What are some of them?

We can also use gene expression profiling; more recently, some international groups are combining variables. We are looking at the International Staging System, plus cytogenetics, plus elevated lactate dehydrogenase. At the end of the day, we search for a marker in a patient who may have high-risk disease or not. We certainly take into consideration what happens in the clinic. For a patient who is progressing on frontline therapy—whether they have genetic markers or not—we consider them to be high risk.What we are seeing with the trials being presented is that many of them use a backbone of lenalidomide/dexamethasone; a few years ago, it was mainly bortezomib/dexamethasone. That can include agents such as proteasome inhibitors, which are still very recent, and includes carfilzomib (Kyprolis) and ixazomib (Ninlaro).

The 2016 ASH Annual Meeting is approaching. What data out of this conference are you excited about?

There is also the addition of monoclonal antibodies, such as elotuzumab, which has been combined in clinical trials. Most recently there was daratumumab, which was combined with lenalidomide/dexamethasone. The clinical trial that came out of that is probably—in my opinion—one of the most impressive, if not the most impressive, clinical trials in the last several years. Up to 43% of patients achieved a CR, with duration of disease control that had not yet been reached, but is estimated probably next to 40 months.At the upcoming ASH meeting, we will see an update in clinical trials. I’m particularly interested in understanding the data of elotuzumab in combination with lenalidomide/dexamethasone from the ELOQUENT-2 trial, specifically for the elderly.

That is a population that does not frequently have high-risk genetic markers; they frequently are hyperdiploid, which in consequence would make them very sensitive to a combination such as lenalidomide and dexamethasone. If we could augment that with the addition of elotuzumab, that would make a very attractive, nonintrusive, nontoxic regimen for the elderly. I’m looking forward to hopefully seeing that at the 2016 ASH Annual Meeting.

Right now, we seem to be heavily interested in triplet regimens. Would we ever explore therapies with 4 or more agents combined?

There are other combinational approaches with daratumumab. We are very keen on hearing about daratumumab plus pomalidomide (Pomalyst), given the experience with lenalidomide.

I think we will. For example, everyone expects daratumumab to move upfront. Lymphoma doctors have their R-CHOP, so we are going to have dVRD (daratumumab, bortezomib, lenalidomide, dexamethasone), dKRD (daratumumab, carfilzomib, lenalidomide, dexamethasone), and the clinical trials are being developed. In particular, monoclonal antibodies lend themselves very well for combinations. Historically, we thought 3 drugs were the limit, but that’s without consideration of monoclonal antibodies.

Are there sequencing challenges for later lines of therapy?

I see a future where frontline is going to be daratumumab plus something else. If I had to bet right now, it would probably be the KRD, although there still needs to be something worked out regarding the use of KRD upfront.One of the biggest challenges we have in myeloma right now is sequencing. From the get-go, we go from this notion that we are going to try to put the patient into a very deep response and get them into the MRD-negativity state and get them through the transplant.

With maintenance therapy, many patients can be looking at 4 to 6 years and more of disease control. Again, a few of patients will have very durable CRs, so they don’t need intensive therapy anymore; they’re potentially cured. However, if they relapse, then the patient will require constant therapy. How we sequence them then becomes incredibly important. We want to put the best foot forward when we are doing the initial planning.

In sequencing, we also don’t want to leave out agents that may be used for the given point but may not be used down the line. For a patient who relapses on frontline therapy, he or she might be a good candidate otherwise for elotuzumab; it might be an attractive idea. However, someone might say the data from the clinical trials seems to be better with daratumumab. But, elotuzumab is unlikely to be of benefit further down the line.

What is the most important takeaway for community oncologists?

This is a bit of a philosophical perspective, but I can see that someone who gets elotuzumab will get MRD and get several years of disease control. Then, I still know I would have daratumumab for maybe down the line. This is an approach of maximizing the duration of disease control.For our partners in the community, we want to continue the dialogue. This is very challenging; myeloma is a field in and of itself. I have a hard time keeping up with all of the literature, so I cannot imagine [how it is] for someone who has a private practice where myeloma is only a small portion of his or her practice. We can’t have enough of these meetings and enough of these dialogues to share information to provide to these practices. That’s really what we are trying to do.

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.
2. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
3. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-631.