Venetoclax for Multiple Myeloma in the Post-CANOVA Era With Rahul Banerjee, MD, FACP, and Andrew Yee, MD
At the recent International Myeloma Society (IMS) Annual Meeting in Athens, Greece, results were presented of the CANOVA study of venetoclax for patients with relapsed/refractory multiple myeloma. After returning from the meeting, Dr. Rahul Banerjee, Assistant Professor of Medicine at Fred Hutchinson Cancer Center and Oncology Data Advisor Editorial Board Member, and Dr. Andrew Yee, Clinical Director for Multiple Myeloma at Massachusetts General Hospital, sat down to reflect on the surprising results of the trial and its implications for the current and future treatment of patients with t(11;14) multiple myeloma.
Rahul Banerjee, MD, FACP: Welcome back to Oncology Data Advisor. My name is Rahul Banerjee, and I'm one of the Board Members of Oncology Data Advisor. I'm also an Assistant Professor of Medicine at the Fred Hutchinson Cancer Center in Seattle.
Today, it's my pleasure to be joined by Dr. Andrew Yee. Dr. Yee is a Clinical Director for Multiple Myeloma at Massachusetts General Hospital in Boston. He's also an Assistant Professor of Medicine at Harvard Medical School. He specializes in multiple myeloma. Both of us were there at the International Myeloma Society Meeting two months ago in September, in Greece, where the CANOVA study of venetoclax and dexamethasone was presented. Dr. Yee, it's a pleasure to have you joining us back on the program today.
Andrew Yee, MD: Hi, Rahul, thanks for having me. It's always great to be talking about myeloma, especially on a late Friday afternoon. It's always fun. I think the key disclosure is that we were actually talking about this trial before Athens. Before the CANOVA data was presented, all of us were really excited to hear this data, and all of us had assumed it was going to be a slam dunk in favor of the venetoclax arm. When the data was presented, that was a little bit of an eye-opener. It did put some pause on how we think about the efficacy in t(11;14), as well as clinical trial design.
Dr. Banerjee: I completely agree. This was originally going to be part of Blood Cancer Awareness Month, talking about "precision medicine in myeloma—are we there yet?" We talked this big game, with all this cool data that we'll talk about from the BELIINI study. I don't know if you or any listeners are fans of Loki and the Marvel Cinematic Universe, but now we have to time slip backwards. CANOVA changed everything, as we'll talk about, and now we're back to rerecording our podcast.
We were both in Athens that day, and I feel like a hush came over this auditorium of hundreds of people in this ancient opera house in Greece, when the study was presented. So, let's get into it then. As we've set this big stage about how the study was a surprise to us, let's talk about t(11;14). What does it refer to in myeloma when you hear that someone's myeloma cells on their bone marrow biopsy have t(11;14)? What do you think about?
Dr. Yee: When we think about multiple myeloma, we think about some characteristics and molecular subtypes, and immunoglobulin heavy chain (IGH) translocation is one of the characteristic subtypes. About half of myeloma patients will have an IGH translocation, and this includes t(11;14), t(14;16), et cetera. These translocations are felt to be there from the beginning. These are presumably involved in one of the early stages of the transition from being a benign plasma cell to a myeloma cell. In t(11;14), you have the IGH locus connected to chromosome 11, which we think of as cyclin D1. About 15% of patients, roughly, will have t(11;14). The other interesting thing is that it's not necessarily related to cyclin D1 per se, in and of itself, and it has to do with the Bcl-2 pathways, et cetera.
Then a couple other things to point out—number one is that t(11;14) really requires fluorescence in situ hybridization (FISH) to detect it. You can't just do conventional cytogenetics to pick up t(11;14). This applies to other translocations, like (4;14), for example. It really emphasizes that if you have a clinical concern from myeloma, clinicians should be doing a myeloma-specific FISH panel so that you can pick up these specific translocations. The other thing about t(11;14) that's interesting is that it can be associated with certain phenotypes like non-secretory disease, for example, and it tends to be more prevalent in conditions like amyloidosis or plasma cell leukemia. There are all kinds of unique clinical characteristics with t(11;14). Then this will probably segue into our discussion of venetoclax, since another interesting feature about t(11;14) is that sensitivity to inhibition of Bcl-2.
Dr. Banerjee: Absolutely. Yes, it's an excellent segue. Going back to FISH, I think most physicians look at patient diagnosis as standard-risk versus high-risk, and then people think it doesn't really matter after that. This is a scenario where in the real relapse/refractory setting, if you know someone has t(11;14), it might actually change your management. Maybe we can get into it with the BELLINI study, because that's what first paved the way for this paradigm. Can you tell us a bit more about that study?
Dr. Yee: I think even before BELLINI, there was the appreciation that cell lines with t(11;14) were very sensitive to venetoclax. That led to some initial studies where they were seeing response rates of 40% with venetoclax as a single agent. Then that paved the path for BELLINI, which was a phase 3 randomized study that compared the addition of venetoclax to bortezomib/dexamethasone versus bortezomib/dexamethasone in relapsed/refractory patients. This was across all patients, irrespective of translocations.
The study was moving forward, but then there was a "Dear Investigator" letter in 2019 that showed that the road was getting bumpier, because there was a concern for increased mortality with the venetoclax arm, and that led to a clinical hold. This speaks to the importance of doing randomized studies. We kind of assume that this drug's going to work great, but then you need a phase 3 study to really see what the difference is. You can't just rely on single-arm studies. It turns out that, yes, across all comers, there was a concern for increased mortality, and that could perhaps relate to infection.
But in the small subset of patients that had t(11;14), you saw a whopping benefit in terms of efficacy—a hazard ratio of 0.12, and the overall survival was maintained. This suggests that because of the degree of efficacy, it sort of overshadows any potential decrement related to infection. I think that was just a tiny number of patients, maybe 20 patients, a small proportion. But based on those findings, it did motivate using venetoclax off-label, especially in patients who've exhausted all options. Having this as an option was helpful. I think this motivated the CANOVA study, because you need a confirmatory study. Again, it was a post-hoc analysis. There are examples of where post-hoc analyses have led people down unintended paths. The CANOVA study is meant to be a definitive study to really answer the question, can we use venetoclax in t(11;14)?
Dr. Banerjee: Very, very well-stated. I remember that letter, just as you do. The FDA was so rushed to un-pave that road that you could actually see the little red squiggles in the Kaplan-Meier curve from the spell check, because they took a screenshot so quickly to get the data out here. But you're right—the idea is that, as you're alluding to, venetoclax does have risks in these patients like infections. So, who are these patients for whom the benefits dramatically outweigh the risks? BELLINI couldn't directly answer that question because it wasn't powered or designed to. Let's pivot to CANOVA. How was CANOVA designed, with that in mind?
Dr. Yee: CANOVA is focused on patients with t(11;14). It was a randomized study comparing venetoclax/dexamethasone (dex) versus a standard control of pomalidomide/dex, which the audience has heard before because there are two other randomized studies that use pomalidomide/dex. It was a standard pomalidomide/dex regimen: 4 mg of pomalidomide, 40 mg of dex. I think the thing to appreciate with CANOVA is that they used 800 mg of venetoclax with 40 mg of dex, and they randomized about 130 patients to each arm. Rahul, thinking about this further, we were waiting for CANOVA for a long time, right?
Dr. Banerjee: Many years, indeed.
Dr. Yee: A long time. I was thinking going into this, based on BELLINI, based on the hazard ratio, this was going to be a slam dunk. It's going to blow it out of the park. That was my initial thought, but then I was thinking, it's been taking such a long time to read out. Of course, some of it had to do with COVID, which was affecting the accrual. But generally speaking, if something works really well, you hear about it. It reaches its end point pretty quickly, and then usually there's a press release. I'm just thinking about, for example, some of those daratumumab-based studies. With daratumumab for newly diagnosed or relapsed myeloma, they'd accrue, then there'd be a press release pretty quickly. For example, I think about daratumumab/lenalidomide/dex, how that study started after inotuzumab and after ixazomib, but they presented their data before because the hazard ratio was so effective. Anyway, my assumption was, "Oh, CANOVA has a great hazard ratio." The longer and longer we waited, I was getting a little bit concerned, but I was still really hopeful.
Dr. Banerjee: Especially because, as we talked about in the first iteration of this podcast, it was precision medicine against generic medicine. These are not cookie cutter, precision pills that block 11;14. I think BELLINI was a triplet versus doublet, and this is a doublet-to-doublet trial, right? They were a little more ambitious.
Dr. Yee: It's focused, it's not all comers, but it didn't meet its primary end point. The progression-free survival (PFS) was not statistically significant. Referring to my notes here, it was 9.9 versus 5.8 months. The hazard ratio was 0.823, and the P value was 0.237. It didn't meet its primary end point. Initially I thought, "0.823, that's not even that dramatic." And it's not the 0.12 that we saw in that tiny subset of BELLINI. We're trying to unpack why this is the case. How did it play out this way? One of the explanations was that this has to do with how we think about International Myeloma Working Group (IMWG) confirmed responses and how we define progression events. For IMWG, you need a confirmed progression event, as in you can have an M-spike go from 0.5 to 1, but it has to be confirmed on the subsequent blood test to say this is confirmed progression.
One of the issues going on was that patients were being switched to a new line of therapy even before it was formally confirmed as progression. As a result, those events were censored. Now, if you reanalyzed the data post hoc and say, "Okay, anybody that changed to a new line of therapy, we're going to call it progression," well, then you do see the hazard ratio of 0.6651 and the P value of 0.003. That was the post hoc analysis, so that was one aspect of it. The second aspect of it was the overall survival. There was that concern about worse overall survival, but actually, the overall survival improved. The hazard ratio was 0.697.
Normally, I tend to be really enthusiastic when we're talking about stuff, but I think something to point out is that there were some concerns with infection. There were seven treatment-related adverse event deaths that were attributed to venetoclax. That's something to be mindful of as we're using this drug. Now, how do I think about that in clinical practice? What does this mean? The dosing of venetoclax is 800 mg, and in clinical practice, I think 400 or even 200 mg can work very well. Part of me wonders, with a lower dose, maybe that risk of infection and other side effects would be much less. Some of the other side effects are gastrointestinal (GI)–related, such as diarrhea. Venetoclax comes in 100 mg pills, which makes it easier.
Dr. Banerjee: Completely agree. We'll come back to that at the end; we'll come back to how we approach it now in terms of dosing in the real-world setting, not even retrospectively, with our own patients today. You're right—I think one of the biggest takeaways from the study for me was not really anything to do with venetoclax or pomalidomide, but all of a sudden, clinical trial design. How do you define censoring? Is it informative or non-informative? Normally, someone coming off study early should really be completely random, non-informative. Here, clearly, patients who were on pomalidomide were being taken off at higher rates and moving to something different, so they weren't really counting towards this PFS advantage.
Dr. Yee: Just to point out, Rahul, I wonder what would have happened if they had put more patients on too. If they had put maybe 50 or 100 on—I don't know the statistics behind this—but maybe if they had more patients, maybe the hazard ratio would have been statistically significant.
Dr. Banerjee: Agreed. But like you alluded to is, there have been other studies with pomalidomide where you see better, deeper responses, but increased mortality. Here, the overall survival was not statistically significant. What we saw is more of a function of the quirks of clinical trial design and how the end point was defined more than anything.
Dr. Yee: Exactly, or just maybe you need to have more patients. Of course, these trials are cumbersome; they require resources and money, et cetera, in terms of the dosing. In these studies, all the patients started at the assigned dose from day one. There was no loading dose. There's not the concern for tumor lysis syndrome that you would see with chronic lymphocytic leukemia, so all these patients started full dose from day one. But I think in practice, in some patients, they do start at 200, some patients at 400.
The other part, too, is that CANOVA used a doublet, but I think we should also think about triplet combinations. I'm just thinking, for example, somebody who has myeloma with (11;14), they're on daratumumab, and they're progressing. I think that would be a perfect opportunity. They've never seen a proteasome inhibitor, and they have t(11;14). Even with the results of the CANOVA study not being positive, I'd feel totally comfortable using venetoclax or pomalidomide in that patient population.
Dr. Banerjee: Agreed—even venetoclax with bortezomib, what the BELLINI study did—you have to wonder, if CANOVA did the same as BELLINI but with t(11;14), if things would have been different.
Dr. Yee: Exactly. If it was a repeat BELLINI, then it could have been a slam dunk with a tiny number of patients.
Dr. Banerjee: So, maybe we can pivot to that now that we've done this time slip. Basically, for the audience listening, we did this entire podcast and were so excited about CANOVA coming out, and then it changed in the last second. We were like, "Let's time slip backwards and start over again." There were some other research abstracts presented at IMS with venetoclax in t(11;14) that didn't involve CANOVA. Can you talk a little bit about those and whether you would lean towards those instead in real-world practice today?
Dr. Yee: Right, there were other randomized studies that were presented as well. Dr. Kaufman presented two studies. One looked at daratumumab with venetoclax and dex, and the other one looked at carfilzomib with venetoclax and dex. Granted, these studies were relatively small; each of these arms had around 15 to 20 patients. But consistently, you saw that there was a numerically significant improvement with the addition of venetoclax. For venetoclax/carfilzomib with dex, there was a doubling of the PFS—32 versus 14 months when you added venetoclax to carfilzomib and dex. Then the next question, was it statistically significant? I think it didn't show statistical significance because the numbers were so small. In my mind, these are just more proof of concept, by extension, that venetoclax can add significant benefit in t(11;14) with the choice of partner. It just means that you have just more opportunities to partner with venetoclax.
Dr. Banerjee: Absolutely. It was interesting that one of Dr. Kaufman's abstracts had venetoclax 400 mg and venetoclax 800 mg, and you could see that 400 probably worked as well. Again, we're not able to tell for sure; but it was non-inferior, so to speak, in terms of maybe fewer toxicities and working just as well. Then maybe I'll close by asking you, so now that we've time-slipped all over the place and we're in our current multiverse, now in our sacred timeline, we are where we are now, how will you use venetoclax for your patient with t(11;14) who comes into clinic tomorrow. Let's say they've received two prior lines. How would you approach venetoclax or not approach venetoclax there?
Dr. Yee: I think CANOVA doesn't change my usage of venetoclax; I'll continue using it the same way. If anything, Dr. Kaufman's data from Athens further reinforces usage of venetoclax, especially in a three-drug combination. If I saw a patient who has t(11;14) and relapsed disease, I think that would be a perfectly fine opportunity to use venetoclax. Sometimes I do use it as a doublet with dexamethasone, and sometimes I use it as a triplet. Then I should acknowledge that there are other trials looking at Bcl-2 inhibition. BeiGene, for example—just a disclosure, we're involved in the clinical trial using BeiGene's, sonrotoclax, which is another Bcl-2 inhibitor—it has some characteristics where it's more potent than venetoclax. I think there will be opportunities for other clinical trials to look at Bcl-2 inhibition and further round out where Bcl-2 inhibition plays in myeloma care.
Dr. Banerjee: Absolutely. I'm looking forward to the next iteration of this talk next year, hopefully with fewer surprises, and we can do the podcast on the first time around and not the second time around. With that in mind, thank you again, Andrew, for your time and expertise on this matter. For everyone listening, thank you for humoring me in my Marvel Cinematic Universe multiverse references, and thank you all for your time. Have a good day.
Dr. Yee: Thank you, Rahul, I appreciate it.
About Dr. Banerjee and Dr. Yee
Rahul Banerjee, MD, FACP, is an Assistant Professor in the Division of Medical Oncology at the University of Washington. He also holds a faculty appointment at the Fred Hutchinson Cancer Center. Dr. Banerjee previously completed his Hematology/Oncology Fellowship and Advanced BMT/CAR-T Fellowship at the University of California, San Francisco. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR-T therapy. His research interests are in toxicity management, digital health, and the patient experience.
Andrew Yee, MD, is the Clinical Director of the Center for Multiple Myeloma at Massachusetts General Hospital and an Assistant Professor of Medicine at Harvard Medical School. He specializes in the treatment of multiple myeloma and plasma cell dyscrasias, including monoclonal gammopathy or unknown significance, AL amyloidosis, and Waldenstrom macroglobulinemia. Dr. Yee has served as the principal investigator of numerous clinical trials.
For More Information
Mateos MV (2023). Results from the randomized, open-label phase 3 CANOVA study of venetoclax-dexamethasone versus pomalidomide-dexamethasone in patients with t(11:14)-positive relapsed/refractory multiple myeloma. Presented: 2023 International Myeloma Society Annual Meeting. Abstract OA-52. Available at: https://imsannual2023.eventscribe.net/fsPopup.asp?PresentationID=1306640&mode=presInfo&embedded=false
International Myeloma Foundation (2023). AbbVie announces results from phase III CANOVA trial of venetoclax. Available at: https://www.myeloma.org/news-events/multiple-myeloma-news/phase-3-canova-study-results
US Food & Drug Administration (2019). FDA warns about the risks associated with the investigational use of Venclexta in multiple myeloma. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-risks-associated-investigational-use-venclexta-multiple-myeloma
Kaufman JL, Quach H, Baz RC, et al (2022). An updated safety and efficacy analysis of venetoclax plus daratumumab and dexamethasone in an expansion cohort of a phase 1/2 study of patients with t(11;14) relapsed/refractory multiple myeloma. Blood, 40 (suppl_1):7261-7263. DOI:10.1182/blood-2022-163809
Kaufman JL (2023). First results from the randomized portion of a phase 2 study of venetoclax plus carfilzomib-dexamethasone vs carfilzomib-dexamethasone in patients with t(11;14) relapsed/refractory multiple myeloma. Presented at: 2023 International Myeloma Society Annual Meeting. Abstract OA-29. Available at: https://imsannual2023.eventscribe.net/fsPopup.asp?PresentationID=1302336&mode=presInfo
Transcript edited for clarity. Any views expressed above are the speakers' own and do not necessarily reflect those of Oncology Data Advisor.