Myeloma Update -- Part 1: Carfilzomib and Panobinostat

Sagar Lonial, MD; Gabriel Miller


December 24, 2014

Editor's Note: The 56th annual meeting of the American Society of Hematology (ASH) featured several important studies in multiple myeloma, including trials of new triplet regimens, monoclonal antibodies, and an all-oral regimen.

At the meeting, Medscape spoke with myeloma expert Sagar Lonial, MD, about the clinical implications of these studies and the research direction of the field more broadly.

Medscape: One of the most newsworthy studies in myeloma presented this year was the ASPIRE trial,[1] which compared the triple combination of carfilzomib plus lenalidomide and dexamethasone (CRd) with the standard combination regimen of lenalidomide and dexamethasone (Rd) in patients with relapsed disease.

Dr Lonial: We learned a couple of things from ASPIRE. The first is that the control arm of lenalidomide/low-dose dexamethasone had a median progression-free survival (PFS) of about 16-17 months, which is longer than I think many of us had anticipated. We thought that was going to be closer to 11 months, which is what we saw with the original studies with lenalidomide plus high-dose dexamethasone.

The second thing we learned is that the addition of carfilzomib for a fixed duration of, I believe it was 2 years in that trial, improved the PFS to 27 months. That is now the longest PFS that's been reported in a large phase 3 trial in relapsed myeloma.

There are also hints of improvement in overall survival. The question in my mind becomes whether, in newly diagnosed myeloma, we believe that three drugs is better than two, because depth of response correlates with long-term outcomes. The ASPIRE trial is the first of several trials in the early relapsed setting—one to three prior lines—where that same principle may start to hold up as well. That is, that more is better.

We've always used doublets in the early relapsed setting, saying that once the disease comes back, you just sort of placate it; there's no reason to go for broke. This is pretty significant evidence that may suggest that hitting with three drugs and getting a really deep response may translate to a better PFS, and maybe even better overall survival. So I think that's a really important point.

Medscape: Considering that there was such a significant improvement in PFS, the risk/benefit balance obviously favors using the triplet vs the doublet. Are there clinically relevant side effects that should be noted?

Dr Lonial: One of the questions that has come up with carfilzomib since its approval a little while ago was the issue of cardiac toxicity. That's been something that we've seen in small phase 2 studies. We've not really had a phase 3 experience to fully explore that.

This trial puts some of that to bed, in the sense that if you look at cardiac-related adverse events, it was 6% in the CRd arm and it was 4% in the Rd arm. So, there was not a wealth of cardiac toxicity associated with the infusion of carfilzomib. That's also an important toxicity take-away, because one idea swirling around about carfilzomib was that there were lots of cardiac issues.

Medscape: Are there other regimens that could be considered contenders in the early relapse setting? And how do these data compare with those other contenders?

Dr Lonial: There are a whole host of large phase 3 trials that have treated this exact same population: patients with early relapse. The trial of elotuzumab/lenalidomide/dexamethasone vs Rd[2] is treating a similar patient population with one to three prior lines of therapy. Those data are not out yet. The trial of ixazomib/lenalidomide/dexamethasone vs Rd[3] is using an oral proteasome inhibitor and applying the same principle: three vs two, following one to three prior lines of therapy.

The hard part about comparing across trials—ASPIRE with the Tourmaline MM1 and ELOQUENT trials—is that you may not have had the same exposure to lenalidomide before you came into those trials. The hazard ratio and how the control arm performs in each of those trials are really important because the absolute numbers may not be the same, but the magnitude may be different.

Medscape: There were also studies just presented on carfilzomib and panobinostat—one in patients with relapsed and refractory disease, and one in patients with newly diagnosed disease. Let's start with the results in the relapsed and refractory setting.

Dr Lonial: Jonathan Kaufman from our group presented our phase 1 data combining carfilzomib with panobinostat. Panobinostat is a pan-histone deacetylase (HDAC) inhibitor. It's a new class of treatment for myeloma.

The PANORAMA-1 study[4] was a randomized trial of panobinostat plus bortezomib/dexamethasone vs bortezomib/dexamethasone. One of the challenges in that study was the adverse events—nausea, vomiting, diarrhea, and fatigue. A lot of that was thought to be associated with the use of intravenous bortezomib rather than subcutaneous and a bit of a learning curve with panobinostat for a number of investigators.

This trial[5] that Dr Kaufman presented was a phase 1 study looking for the right dose and schedule for panobinostat with carfilzomib. What we found was that the maximum tolerated dose was 20/36 mg/m2 of carfilzomib, with 20 mg, three times a week, weeks 1, 2, 3 of a 4-week schedule. We didn't use a lot of dexamethasone in this trial. We only used 8 mg/wk of dexamethasone.

Our response rate was almost 50%, and our median PFS was 11 months. If you look at patients who were sensitive or resistant to bortezomib, it didn't appear to affect the response rate. Both sets of patients seemed to benefit, speaking to the idea that the HDAC class can help overcome bortezomib resistance, but it also may be active even in patients who are not resistant to a proteasome inhibitor as well.

Medscape: Could you comment on patients' ability to stay on both of the drugs, which the investigators mentioned? Peripheral neuropathy sounded like a particular focus of the investigators when they were thinking about this combination.

Dr Lonial: One of the important questions that came out of PANORAMA-1 was dose intensity. Were you able to maintain the dose and schedule that you wanted, or did patients have to take less of the drug because of toxicity?

What I think Dr Kaufman showed nicely is that at the maximum tolerated dose, the dose intensity was well over 90% for both carfilzomib and panobinostat, suggesting it wasn't that you gave a lot of drug and then people had to come off. You were able to keep them on drug and maintain 90% of the planned delivered dose throughout the course of therapy. That's an important piece, because it's not just a matter of getting to the right dose, but also a matter of maintaining that right dose over time to maximize the duration of benefit.

The neuropathy signal on this trial was almost nonexistent. That's sort of a nice hallmark of carfilzomib-based combinations. You just don't see a lot of peripheral neuropathy with carfilzomib.

Medscape: Moving on to ASH abstract 33, the trial of panobinostat plus lenalidomide/bortezomib/dexamethasone (RVD) in patients with newly diagnosed disease[6]: It seemed to me that there was a very high overall response rate in this trial.

Dr Lonial: That trialwas really building, again, on the PANORAMA-1 experience, as well as a trial we did with Dr Shah where we combined an older HDAC inhibitor called vorinostat with RVD.[7] The principle is not just to look at response rate, because RVD alone has a response rate of 100%. What I think Dr Shah and many of us have been trying to do is increase the proportion of patients who achieve complete remission (CR) within four cycles.

If you look at CRd, which is an alternative to RVD, the CR rate at four cycles is almost the same as RVD. What Dr Shah was trying to do was to say that if you add in a fourth drug, and that drug is an HDAC inhibitor—which can be synergistic both with the immunomodulatory drugs and the proteasome inhibitors—can you increase the CR rate?

What he found in his dose escalation study was that he couldn't get above 10 mg of panobinostat, which is about one half the typical dose that we use. Even at that lower dose of panobinostat, he was able to show in a small phase 2 experience that about 50% of patients achieved a CR within four cycles. The speed and depth of the response were higher than what you might expect for RVD, or even CRd, that early in the course. So, I think in many ways, he achieved his goal. He was able to increase the complete response rate.

I think it remains unknown whether panobinostat is the best HDAC inhibitor to use in combination with RVD, or whether there may be other, newer HDAC inhibitors, such as rocilinostat, that may have less of a heme profile and less of a gastrointestinal toxicity profile that may allow you to get to higher doses.

Medscape: One question from the audience touched on the issue of having a lot of drugs in the mix, and using a four-drug combination vs using a triplet for a longer number of cycles. That was an argument that was raised. It seems to run counter to what you're saying about getting a very early response.

Dr Lonial: One of the things that we're beginning to understand is that even within a given patient, all of the plasma cells are not the same. I think Dr Shah and many of us believe that you want to hit those cells from many different angles at once, early, if you're going to suppress what we call "clonal evolution." Treating with fewer drugs for longer doesn't necessarily get you that same goal. It may drop the protein by the same effect, but it doesn't necessarily address that clonal evolution concept. I think what Dr Shah is trying to do is figure out ways to get rid of more of those clones or prevent emergence of drug-resistant clones by hitting those cells with multiple mechanisms.

Medscape: There seems to be some question about the role of panobinostat before and after transplant. Can you talk a little bit about research issues moving forward?

Dr Lonial: There are drugs that fit in the how-do-you-kill-plasma-cells class, and those are proteasome inhibitors, immunomodulatory drugs, corticosteroids, and monoclonal antibodies. Then there are other drugs that may fit in subsets of myeloma.

I think the real challenge to the HDACs is which subset is the best for them. We've had good experience with panobinostat plus carfilzomib in patients who appear to have high-risk or aggressive myeloma, but you don't want to pigeonhole the drug just for those patients. Are there other subsets of patients who may benefit in the induction or the maintenance setting? We don't know that, but I think that's what his study is trying to explore.


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