Expert Summarizes Strides in Relapsed Myeloma, Says More to Come

Peter Voorhees, MD

Triplet regimens have become the preeminent means of treatment for patients with relapsed multiple myeloma, and Peter Voorhees, MD, explained that the results of the phase III OPTIMISMM trial of bortezomib (Velcade) and dexamethasone with or without pomalidomide (Pomalyst) may give physicians yet another 3-drug regimen to use in earlier lines of therapy.

As the landscape continues to evolve, Voorhees said that physicians “need to refine the definition of high-risk disease, and in particular, better identify those patients who have ultra—high-risk disease.”

Additionally, Voorhees noted that the phase III trials that resulted in FDA-approved triplet therapies examined a very heterogeneous group of patients. He said more focus needs to be placed specifically on patients with high-risk cytogenetic subtypes.

“It’s hard to make clear, concrete conclusions when you're just looking at a very small population of the overall group,” said Voorhees, a physician at Levine Cancer Institute and an associate professor in the School of Medicine at University of North Carolina-Chapel Hill.

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Voorhees discussed treatments for patients with early relapsed multiple myeloma and previewed future research efforts.Voorhees: I spoke about treatment options for patients with early relapsed multiple myeloma, and by early relapse I mean patients in first- or second- relapse who require second- and third- line therapy. There are more available options for patients with relapsed multiple myeloma than there have ever been.

At this point, it's very clear that, just like in the frontline setting, triplet therapies consistently outperform doublet therapies. The perfect example of this are the lenalidomide (Revlimid) and dexamethasone triplets which include either ixazomib (Ninlaro), elotuzumab (Empliciti), daratumumab (Darzalex) or carfilzomib (Kyprolis). The third agent uniformly improves response rate, depth of response, and progression-free survival (PFS).

Now, we have more mature data showing an overall survival signal in the ASPIRE trial. The other thing that is important to recognize is that while it's important to avoid toxicity in frail patients, the monoclonal antibodies—in particular elotuzumab and daratumumab—are very easily added to backbone doublets of lenalidomide and dexamethasone. As such, many of our frail patients who we would typically reserve doublets for may be perfectly appropriate candidates for triplets in particular situations.

One of the challenges in the United States is that patients are typically on a lenalidomide-based therapy until disease progression as part of their first-line therapy, so a lot of these lenalidomide/dexamethasone regimens don’t pertain to that group of patients. In other words, those patients would have never been eligible for any of those phase III trials. There are a number of non—lenalidomide-based platforms, specifically carfilzomib and dexamethasone as a doublet; I [might give] bortezomib and dexamethasone. Daratumumab with bortezomib and dexamethasone outperforms bortezomib and dexamethasone, so those are certainly reasonable options.

Do a high percentage of patients experience early relapse?

Also, we are going to see an increase in the use of pomalidomide-based therapy in earlier lines of therapy. Mayo Clinic and Dana-Farber Cancer Institute presented very impressive results from phase I/II studies of pomalidomide, bortezomib, and dexamethasone. The phase III OPTIMISMM trial looked at bortezomib and dexamethasone with or without pomalidomide. We don't have the results of that at this point, but there was a press release a number of months ago demonstrating that it had met its primary endpoint of PFS. We're cautiously optimistic that pomalidomide, bortezomib, and dexamethasone will be yet another triplet that we can use in earlier lines of therapy for relapsed patients. When I talk about early relapse, I'm talking about patients who are progressing either for the first time and need a second-line therapy, or are progressing for the second time and need a third-line therapy. Then, there are the patients who have a short remission following their initial therapy.

What are some of the commonalities among patients in some of these pivotal phase III studies?

Patients who have a very short remission after receiving modern triplets in the frontline setting comprise a very select group of what I would consider as ultra—high-risk patients. They would certainly be patients who we would consider for a novel triplet-based platform at the time of disease progression. I would also argue that that group of patients likely does not have the same magnitude of benefit from those strategies as a patient who perhaps had a longer remission from their first-line therapy. We need to better understand the mechanism of resistance in those higher-risk patients and develop strategies to overcome that.The CASTOR trial looked at bortezomib and dexamethasone with or without daratumumab, and then carfilzomib/dexamethasone versus bortezomib/dexamethasone. There’s also the ENDEAVOR trial. Typically, patients had to have received at least 1 prior therapy for their disease, and several studies required that patients have 1 to 3 prior lines of therapy. Other studies, such as POLLUX and CASTOR, allowed 1 or any number of regimens beyond that. In general, patients on these phase III trials received anywhere from 1 to 3 prior regimens for their disease.

The proportion of patients who had high-risk cytogenetics in each of the individual trials was a distinct minority of patients. There is probably somewhat of an underrepresentation of high-risk cytogenetic patients in clinical trials. Often, those are the patients who may not have time to go through the screening procedures that are required for a trial. The proportion of patients with high-risk disease in each of the individual trials was similar.

It's important to realize that, in a number of studies where they've looked at this, patients with high-risk cytogenetics benefited from the newer therapy compared with standard of care. For example, in all 4 of the phase III lenalidomide/dexamethasone triplet studies, there was an improvement in PFS for those patients who had high-risk cytogenetic disease.

There have been published data carefully looking at that in the ASPIRE trial as well as the TOURMALINE-MM1 trial. There is absolutely no question that the addition of the proteasome inhibitor benefits high-risk patients—in particular, those patients with 17p deletion. In the TOURMALINE-MM1 trial, the patients with 17p deletion seemed to do just about as well as the patients who had standard-risk disease. We also saw a clear improvement in PFS in the patients with 17p deletion with the addition of carfilzomib in the ASPIRE trial.

Has there been a push toward oral and subcutaneous methods of administration to avoid the cumulative toxicity seen in long-term treatment?

That said, they didn't do quite as well as the patients who had standard-risk disease. It tells us that these regimens are performing better in high-risk cytogenetic patients just as they are in standard-risk patients. However, they may not completely overcome the adverse effect of high-risk cytogenetic disease. With regard to bortezomib, certainly the subcutaneous approach has performed better from a toxicity perspective compared with an intravenous (IV) approach. Worldwide, the vast majority of providers are administering [bortezomib] subcutaneously.

Ixazomib, an oral proteasome inhibitor is very well tolerated, generally speaking. When you look at the adverse events (AEs) in the phase III study of lenalidomide/dexamethasone with or without ixazomib, ixazomib adds some hematologic toxicities, gastrointestinal toxicity, a little more rash, and perhaps a bit more fatigue. In general, most of those AEs were low grade and manageable.

Is there anything else you would like to address?

Oral proteasome inhibitors have performed well, but we should get away from this notion that IV therapy is more toxic therapy. The antibodies are IV, at least up to this point, and they're very well tolerated. Carfilzomib, for those patients who don't have severe preexisting cardiovascular disease, can be well tolerated with less neuropathy than bortezomib does. It is an agent that lends itself to long-term dosing in select patients. Hopefully, subcutaneous daratumumab will come. It's not going to be less toxic, per se, although there is a signal for decreased risk of infusion reactions. It's going to be a heck of a lot more convenient to administer. We need to better understand how to treat patients with higher-risk disease. The patients who develop resistance to lenalidomide and proteasome inhibitors earlier in the course of their disease clearly fit that bill. [We need to know] what the genetic makeup of their disease is, why it’s happening, and if there are ways we can overcome that. We need to focus a lot more attention on those particular groups of patients.

The other thing that is a bit of a challenge in the existing phase III trials is that everybody is treated the same, though you have a heterogeneous group of patients with the exception of perhaps similarities in age and prior lines of therapy. For example, there may be a very small percentage of patients in an individual trial who have a t(4;14) translocation, and a very small percentage of patients who have 17p deletion. We need to have more studies that specifically target patients with particular high-risk abnormalities so we can better understand how these regimens are performing in those groups.