Andrew Spencer, MD, MBBS, FRACP, FRCPA discusses the significance of the PANORAMA 3 study in multiple myeloma.
The addition of oral panobinostat (Farydak) to subcutaneous bortezomib (Velcade) and dexamethasone demonstrated favorable outcomes in patients with relapsed/refractory multiple myeloma in the phase 2 PANORAMA 3 trial, suggesting that with proper toxicity management and a subcutaneously delivered proteasome inhibitor (PI), the regimen is safe and effective, according to Andrew Spencer, MD, MBBS, FRACP, FRCPA.
“The fact that the regimen is [more easily delivered than in the PANORAMA 1 and 2 trials] is probably the most important takeaway [from the study]. Because this activity [was seen] in adverse biology myeloma, this combination is worth revisiting, and the bad press that was generated from the prior randomized study has been put to bed,” said Spencer.
In the study, the addition of the histone deacetylase (HDAC) inhibitor led to 8-week
objective response rates (ORRs) of 62.2%, 65.1%, and 50.6% in patients who received the triplet at the 20-mg 3-times-weekly dose, 20-mg twice-weekly dose, and 10-mg 3-times-weekly dose of panobinostat, respectively. The median duration of response was 22 months, 12 months, and 11 months, respectively.
In an interview with OncLive®, Spencer, head of the Malignant Haematology and Stem Cell Transplantation Service at The Alfred Hospital, professor of Haematology at Monash University, head of the Myeloma Research Group and co-director of the ACRF Blood Cancer Therapeutics Centre at the Australian Centre for Blood Diseases, discussed the significance of the PANORAMA 3 study in multiple myeloma.
Spencer: For the past 2 decades, treatment for myeloma has been predicated on the use of immunomodulatory drugs [IMiDs] and PIs, and they’ve undoubtedly resulted in remarkable improvement in disease control and survival in patients with myeloma. However, there has really been a requirement for drugs with alternative mechanisms of action. Work [spanning at least] the past decade has shown that HDAC inhibitors have activity in cancer and have a very pleiotropic mode of action. We and other groups have looked at these agents in myeloma in various contexts. There’s a strong rationale to look at these agents in myeloma. There is also preclinical data showing that through a variety of mechanisms, you get synergistic cell kill when you combine HDAC inhibitors with PIs.
These drugs were explored in the clinic in a variety of contexts, largely with panobinostat, but also work was done early on with vorinostat [Zolinza], which is a far less potent agent than panobinostat. The pivotal vorinostat study really wasn’t positive, so it fell out of favor even though it’s approved for use. A lot of this work culminated in the early PANORAMA 1 and 2 trials, which confirmed the ability of panobinostat to re-sensitize patients who were bortezomib [Velcade] refractory. This was a very important observation that you could re-sensitize these tumor cells. The randomized study with IV [intravenous] bortezomib clearly showed a progression-free survival benefit [PFS] with the addition of panobinostat to bortezomib. The intriguing observation in that study was that the median PFS in the intention-to-treat population with panobinostat and bortezomib was around 12 months versus 8 months with the control. When you looked at the more refractory or advanced patients, that median PFS was preserved; the median PFS in the panobinostat group was still around 12 months but had fallen to 4 months in the control group, which paradoxically suggested that panobinostat might have activity in patients with adverse biology.
Certainly, in our experiences since then, and in some jurisdictions, particularly in Japan, panobinostat clearly has activity in patients with extramedullary disease and other advanced disease manifestations. Therefore, it’s a very interesting drug, undoubtedly, because of that pleiotropic mechanism of action and the different mechanisms of action compared with the other agents available.
There were 2 issues with the original randomized study of panobinostat and bortezomib versus bortezomib alone. One was that the twice weekly IV bortezomib dosing schedule was used, which was mandated by the FDA approval for bortezomib in that schedule and route of administration. The second issue was that the study was undertaken at 350 or more sites around the world, and I suspect many of these sites weren’t all that experienced in clinical research, and certainly very few of them would have had experience with panobinostat.
We knew from our involvement in the phase 1 trials with panobinostat that you had to get used to using it [because it has a] different spectrum of toxicities. In that randomized trial, there were issues predominantly with gastrointestinal [GI] toxicity. If you look at concomitant medications, [you could see that the adverse effects (AEs)] weren’t managed appropriately. A lot of these patients never received anti-diarrheals, for example. Therefore, in that original study, there were issues around familiarity and toxicity management.
There was also the combination with the IV bortezomib, and from the phase 1b studies, there was clearly a signal for GI toxicity if the dose of the IV bortezomib was escalated. Therefore, the PANORAMA 3 study was mandated to explore ways to try and mitigate this sort of toxicity. It was decided to explore different schedules and doses of panobinostat, such as 20 mg 3-times-weekly, 20 mg twice-weekly, or 10 mg 3-times-weekly, but in combination with subcutaneous bortezomib, which had really become the standard of care in the utilization of bortezomib between that original randomized study and the opening of PANORAMA 3.
PANORAMA 3 is essentially a way of looking at alternative ways of delivering the combination to mitigate that toxicity and also try and reaffirm the evidence of efficacy. Having been involved early on in this particular study, the goal here wasn’t to compare these 3 arms, it was really to look at the deliverability of this combination and look at the different panobinostat schedules with the subcutaneous bortezomib. The end point is ORR, but we really had a very deep level of interest in looking at the toxicity profiles and the ease of delivery in the 3 arms.
The primary end point was ORR after 8 cycles, and not surprisingly, the higher dose of panobinostat is associated with a high response rate. If you give the 20-mg dose of panobinostat, you get a higher response rate. It’s important to remember that almost three quarters of these patients had been exposed to prior PIs, so these were not PI-naïve patients. This was more like a retreatment, adding panobinostat to a PI. The [8-week response rate] was very encouraging. Importantly, we and others have shown that with continued administration of panobinostat, you get deepening of response.
The most important observation from this study was the evaluation of the GI toxicity. Importantly, in all 3 arms, there was far less GI toxicity than had been observed in the prior study with IV bortezomib. There was virtually no grade 3/4 diarrhea or grade 3/4 vomiting, so it really was a more manageable profile. The fact that this is a lot more deliverable is probably the most important takeaway. Because this activity [was seen] in adverse biology myeloma, this combination is worth revisiting. The sort of bad press that was generated from the prior randomized study has been put to bed. This is now a deliverable combination and a very valid option.
One could argue perhaps that one would initiate treatment with 20 mg and then in patients who achieve disease control, perhaps de-escalate to 10 mg as a maintenance strategy with lower toxicity and therefore less of an impact on quality of life. Keeping patients on therapy, in the relapsed setting with the continuous treatment model is incredibly important because we know once you stop therapy, the clock’s ticking and relapse is almost inevitable. It gives some grounding to the notion that you can maintain patients on a lower dose of panobinostat. We recently published some work showing that you can do that, and some patients can have very long-term disease control with lower doses of panobinostat as a single agent. Therefore, you could invoke the idea of initial induction with the combination, and then perhaps winding back to a lower dose of panobinostat maintenance to maintain that response.
Single-agent and combination panobinostat can induce thrombocytopenia. The most common AE [in the study] was thrombocytopenia. Thankfully, as hematologists, we’re reasonably comfortable with managing that, and it’s not something which is really a game changer in terms of deliverability because we know it’s reversible, that platelet counts will quickly recover. Therefore, perhaps, dose interruption or dose reduction can mitigate that. Certainly, once you’ve transitioned over to single-agent panobinostat, that becomes far less of an issue. [Thrombocytopenia] was an expected toxicity, but a manageable one––one that hematologists are far more adept at managing than GI issues, for example.
I would certainly like to see some longer-term follow-up. I’d love to see some survival data, both more mature [PFS] and overall survival data. Having been involved in the steering committee, I know there are some intriguing PFS data already, which [will probably] support the 20-mg dose, 3 times weekly to start with.
Several studies are planned, combining panobinostat with more contemporary PIs and IMiDs, which treating clinicians might find more valuable for managing their patients. There’s certainly data already with agents, such as carfilzomib [Kyprolis], showing a very high level of activity. These data need to be confirmed in other studies, which I think are shortly going to be underway.
There are studies planned, sort of recapitulating what we did, looking at panobinostat posttransplant as a sort of consolidation maintenance strategy. Because of its oral mode of delivery, it lends itself to that sort of long-term maintenance approach. If you have the right dose, it can be given for a long time. There’s a range of different studies kicking off at the moment, exploring different combinations in different scenarios with the drug, which is very important because to let it sort of slip by the wayside was a terrible shame for patients with myeloma.