Expert Evaluates Evolving Options in Relapsed/Refractory Myeloma

Ajai Chari, MD

Altered dosing schedules and accumulating data on triplet regimens are showing greater efficacy in patients with relapsed/refractory multiple myeloma, even in those who become refractory to lenalidomide (Revlimid), explained Ajai Chari, MD.

“The management of relapsed/refractory multiple myeloma [is] really challenging; it's like a math game. We have 6 different classes of drugs with multiple drugs in each class, and you ask, how many combinations are there?” asked Chari, an associate professor of Medicine, Hematology and Medical Oncology, at Mount Sinai Hospital.

OncLive^®: What was the rationale for the ARROW trial?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Multiple Myeloma, held prior to the 2018 ASH Annual Meeting, Chari, discussed some of the available and anticipated combinations for use in patients with relapsed/refractory multiple myeloma.Chari: Initially, carfilzomib (Kyprolis) was studied at 20 mg/m² and 70 mg/m². On days 1 and 2, patients received 20 mg/m², and then received 27 mg/m² on days 8, 9, 15, and 16. It's important to remember that when the drug was being developed in the early 2000s, there was concern regarding cytokine release syndrome, tumor lysis syndrome, and renal dysfunction. Therefore, the step-up dosing, the hydration, and the tumor lysis prophylaxis were implemented. Then, the drug was approved [by the FDA] and it’s clearly an effective drug, but giving patients twice-weekly therapy indefinitely is challenging from a practicality point of view.

Are any other doses being explored with carfilzomib?

The question was whether you could give it once weekly because additional data showed that if you give the drug over 30 minutes instead of 10 minutes, you can give higher doses very safely. This was tested in the pivotal study that did a head-to-head comparison of the 2 schedules to see whether you could switch to the weekly dosing, maintain efficacy, and improve convenience without any new adverse events. We found that not only was efficacy maintained, it was actually superior by about 4 months. Response rates were higher, and there was no difference in toxicity profile. That is great for patients, when you have a drug that's more convenient and effective, but equally safe.It’s really important to pay attention to the dose schedule, duration of infusion, and combination therapy with carfilzomib. The 20/27 mg/m² dose can be administered over 10 minutes. The minute you go beyond 27 mg/m², it's imperative to give it over the course of 30 minutes. At our institution, everybody gets it over 30 minutes, so there is no confusion. If a nurse accidentally administers a dose like 70 mg/m² over 10 minutes, that can cause a lot of problems. For that reason, we just standardize it, so everybody receives it over 30 minutes.

What are the latest data with the MMY1001 trial?

The second part of the question pertains to what combination drugs are being given. The 20 mg/m² and /27 mg/m² dose can be given by itself and with every other drug. Additionally, 36 mg/m² can be pretty much given with all other drugs. I would not go beyond 56 mg/m² in a single dose with concurrent immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide (Pomalyst). A dose of 70 mg/m² is probably safe with monoclonal antibodies, but not with IMiDs.I presented the latest data of the daratumumab (Darzalex), carfilzomib, dexamethasone (DKd) component of the MMY1001 trial at the 2018 ASCO Annual Meeting. The MMY1001 trial was a great study design [that came out] when daratumumab was first being studied. It's a phase I backbone study, which basically took daratumumab and partnered it with every drug. At the 2018 ASCO Annual Meeting, we provided an update on DKd. The standard dose of daratumumab was given, although a substantial number of patients received a split-dose of daratumumab.

In the community, it can be hard to do a single infusion over 6 to 8 hours, which is the median time of first infusion. It was given in a split-dose over 2 days, for about 4 hours in each day [and that] was shown to be quite effective. The infusion-related reactions were lower in patients who received split dosing. Carfilzomib was administered at 20 mg/m² day 1 and escalated to 70 mg/m².

The overall response rate was very high at 84%. We don't have a median progression-free survival (PFS) yet, because it hasn't been reached. Even in lenalidomide-refractory patients, the median PFS was 14 months; that's very impressive given what we know about [that patient population]. In the United States, most patients are receiving triplet therapy, transplant, and then lenalidomide maintenance. If a patient is refractory to lenalidomide, he/she would not have been eligible for all of the phase III studies that we have with a lenalidomide backbone.

How does pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) fit into the sequence?

It's nice to start accumulating data about lenalidomide-refractory patients, and that's what is really good about DKd. We did not see unusual safety signals, so it's a good option. We hope it'll be approved soon, so we can give this more readily to our patients. At the 2018 ASCO Annual Meeting, Paul Richardson, MD, of Dana-Farber Cancer Institute presented the OPTIMISMM study, which examined Vd with or without pomalidomide. Historically, pomalidomide was relegated to very advanced lines of therapy. The initial MM-003 study [enrolled patients with a] median of 5 prior lines of therapy. In heavily treated patients, the response rate was only about 30%. Additionally, PFS was only about 4 months. While that’s

a very important development for patients, that's not enough.

Should the regimen be reserved for lenalidomide-refractory patients?

You need higher response rates and a higher PFS. Therefore, you need combination therapy. Historically, pomalidomide was relegated to the end of the line of therapy. OPTIMISMM showed that when you move it earlier, you get a significant improvement in PFS and response rates. Clearly, pomalidomide being used earlier is going to give you better numbers. This gives us another treatment option for patients in relapse. In myeloma [and in the trial], a substantial number of patients are refractory to lenalidomide. It's another active regimen and it’s great [for oncologists to] have choices. PVd is really appropriate for everyone. The question of lenalidomide-refractory is a relatively moot one in the United States for academic centers because of the impressiveness of the lenalidomide maintenance data. In the 2000s, both the CALGB 100104 and IFM 2005-02 studies showed that lenalidomide maintenance improved PFS. Now, a recent meta-analysis shows that not only do you improve PFS, you improve overall survival. We've been using lenalidomide maintenance for a long time in posttransplant patients. It's hard for us to do lenalidomide-based studies because everybody in our population is refractory to lenalidomide.

That's why I think in most academic centers and in a majority of United States practices, where lenalidomide maintenance is used, it is an important issue. We have such a plethora of published phase III studies that are high-impact in the New England Journal of Medicine and Lancet—that it's difficult for community doctors to pick. The 4 pivotal studies based on lenalidomide were the POLLUX study with daratumumab/lenalidomide/dexamethasone (DRd) versus lenalidomide/dexamethasone (Rd); TOURMALINE-MM1 with ixazomib (Ninlaro)/lenalidomide/dexamethasone versus lenalidomide/dexamethasone; ELOQUENT with elotuzumab (Empliciti)/lenalidomide/dexamethasone versus lenalidomide/dexamethasone; and ASPIRE with KRd versus Rd.

What were the implications of the FDA approval of the elotuzumab triplet?

The problem is all of these have an Rd backbone, so if you’re given lenalidomide maintenance and you progress, you're not eligible for any of those studies. That's why you need studies like the PVd versus Vd, DKd, and other regimens, to try to understand what we can do for those patients. This study is really important because other than the pomalidomide/dexamethasone versus dexamethasone study, we really have no randomized studies with pomalidomide. This is the first randomized study. Although it's a randomized phase II trial, the results are quite impressive and stand on their own. We saw an improvement in response rates. That's important because previous elotuzumab studies have shown that elotuzumab does not have single-agent response. It only works by augmenting the efficacy of IMiDs. We really didn't see that much difference in elotuzumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone.

Here, EPd versus Pd showed a significant improvement in response rates, which translated into a PFS benefit from about 4 months to 10 months. That's really impressive; it was a 45% improvement. What's perhaps is as compelling is the lack of toxicity. The addition of elotuzumab had no additional toxicity. In fact, neutropenia rates, which can be as high as 75% to 98% in some of the pomalidomide-containing regimens, was lower with the addition of elotuzumab. That may be because the marrow was cleared up and resulted in better efficacy. Be that as it may, this is a great regimen and another option for patients.

What is the optimal place for daratumumab?

Historically, elotuzumab was only approved in combination with lenalidomide. If somebody had progressed on lenalidomide, what was the role of elotuzumab? Now, we have another option. It's not as much of a use-it-or-lose-it [option]; you can still use elotuzumab in combination with pomalidomide. It's another good option for patients. There are impressive data for daratumumab in the upfront setting. [Results from the] MAIA study showed better outcomes with DRd versus Rd. If this daratumumab [regimen] moves into the frontline setting, and patients progress on DRd, then what do you do? There may be a role, admittedly in the future, [for elotuzumab there]; however, we don't have those data.

What are the biggest challenges that still need to be addressed in the space?

Are there trials focusing on these populations?

What else are you excited about that’s coming down the pike?

There were very few people who were daratumumab-refractory who were enrolled into the ELOQUENT-3 study. We don't know how patients who fail on daratumumab do with elotuzumab. Preclinical data suggest that if you wait 3 to 6 months, you'll probably get pretty good natural killer/T-cell recovery and see good responses, but that needs to be studied clinically. If daratumumab moves up to the first-line space, the whole relapse segment is up for grabs for another monoclonal antibody, such as elotuzumab. The biggest unmet medical needs in myeloma are the frail and elderly population, specifically patients with renal failure and those with high-risk disease. We still have [a lot of] work to do. For high-risk patients in particular, many regimens have improved outcomes, but none of them match those of standard-risk patients. They're doing better than they would without the drug, but they still lag behind. I'd like to see the point where they do just as well. The same thing is true for the frail and elderly population and those with renal failure. If we can get these Kaplan- Meier curves to be the same for everybody, [we would be] making huge progress. There are no specific studies focusing on these patients, [partly because of how complex it is to perform] these studies. Elderly and frail patients are hard to enroll. They may be [living] in a community and not easy to get to academic medical centers. Patients with renal failure are often excluded from clinical trials, which is one of my pet peeves. All clinical trials should explore the renal failure cohort. High-risk patients are a small subset; it’s complex to do a study just with those patients. To do a good study for this population, you need all 4 groups represented. You need standard-risk and high-risk patients to receive standard therapy, and standard-risk and high-risk patients to receive novel therapy. If you don't have all 4 groups, you can't tell if the high-risk patients are just doing better or if you've really overcome [their poor prognosis]. It's a complex study design, but work is being done. I'm really excited about 3 agents that have gotten breakthrough therapy designations from the FDA. Selinexor received a fast track designation for a population that is impossible to treat; these patients are essentially penta-refractory. Ninety-seven percent of patients were refractory to carfilzomib, pomalidomide, and daratumumab. If a patient is refractory to those, what do you do in 2018? We don't really have a good drug [available]. Selinexor is being reviewed by the FDA and showed response rate of 25%. PFS was around 3 to 3.5 months. While those numbers sound modest, it's important to remember who these patients are. Some of these patients would have gone to hospice. It's [becoming increasingly difficult] to hit those benchmarks as patients become more refractory.

The second impressive designation from the FDA is the Glaxo-Smith-Kline compound GSK2857916, which is an antibody-drug conjugate (ADC). It's targeting BCMA, but it has a cellular toxin called auristatin, which inhibits cell cycle. That ADC received a breakthrough designation because it demonstrated a 60% response rate in heavily pretreated patients. These patients had received 5 prior lines of therapy, including some penta-refractory patients. We have to watch for ocular toxicities with that one. Lastly, of course, the chimeric antigen receptor T-cell therapy [bb2121] received a breakthrough designation.