2-Minute Drill: Experts Highlight Latest Blood Cancer Research Following 2022 ASH

Video

Following the 2022 ASH Annual Meeting and Exposition, Peter Voorhees, MD; Amrita Krishnan, MD; and Josh Richter, MD, participated in a rapid-fire question-and-answer 2-Minute Drill program, hosted by CancerNetwork®. Topics ranged from most exciting data in blood cancer, as well as what research needs more follow-up.

Transcript

Ryan McDonald: Hello, and welcome to 2-Minute Drill, a video series where no subject is off topic. We'll talk about the latest clinical research—whether it's good, bad or ugly—from the most recent cancer conferences. Either way, we'll get to the point, but we're going to do it fast. Bringing together some of the leading and most engaging voices in cancer care, CancerNetwork®, home of the journal ONCOLOGY®, will offer unbiased, unscripted thoughts and opinions from our panel about the 2022 ASH Annual Meeting and Exposition.

I'm your host, Ryan McDonald, associate editorial director of CancerNetwork®. And today I am joined by Dr. Peter Voorhees, director of outreach for hematologic malignancies at Atrium Health’s Levine Cancer Institute; Dr. Amrita Krishnan, director of the Judy and Bernard Briskin Multiple Myeloma Center at City of Hope; and last, but certainly not least, Dr. Josh Richter, director of Multiple Myeloma at the Blavatnik Family- Chelsea Medical Center at Mount Sinai.

Before we jump into today's topics, I’m going to go over some ground rules. First and foremost, while many shy away from talking about themselves, on this show we really want you to. If you have a trial you presented, we want to hear about it. Do you have a drug you're investigating? If so, please tell me the name because if it has more than 3 syllables, I’m not sure how to pronounce it. Two, we don't want or need your financial disclosures. We're limited on time, and we all know that some of those disclosure slides could take upwards of 20 minutes alone, so just skip it. Three, this is meant to be fun. Obviously, the bullies are not welcome here. But we agree to disagree. So speak up and tell us your thoughts. But again, let's do it fast.

With that, please be mindful of the clock. The last thing I want to do is cut you off, but I will [with] an annoying buzzing sound. Each question will be allotted a certain amount of time to be answered. So please keep your eye on the timer. Let's jump right into it.

So the first topic; each of you will get just 1 minute to tell us what was the biggest surprise that came out of ASH. Dr. Richter, let us know what you think was the biggest surprise.

Josh Richter, MD: One of the biggest surprises was, we've seen a lot of trials for things like the MAIA [NCT02252172] study and the GRIFFIN [NCT02874742] study, of which I have to admit Dr. Voorhees is one of the leads on, and we've known that these have improved outcomes. But in the back of our mind, we're always kind of wondering, are we trading off improved efficacy for some type of toxicity or decreased quality of life. And both the MAIA study and the GRIFFIN study showed that when you add daratumumab to the upfront regimen, not only do we improve outcomes, but quality of life is actually not only maintained, but in many ways improved. So in my mind, I think that not only did this solidify dara/rev/dex as an upfront standard, but with Dara VRD being so good. Even in my session, I asked the person who presented it is VRD dead upfront. And I think we all know what the answer is.

McDonald: Dr. Krishnan, we will move down to you. Same question. What do you think was the biggest surprise that came out of ASH?

Amrita Krishnan, MD: I don't know that there were surprises. I think the biggest surprises, we still don't know how long to give therapy for and when to discontinue therapy and that's in the upfront setting and in the relapsed setting. In terms of that, I mean, maintenance therapy, Myeloma XI; ... When do we stop maintenance, and also in the relapsed setting with the bispecifics, because they are incredibly exciting. But they also, you know, confer a fairly high infectious risk. And again, most of them are given until progression. So we don't know when we can safely stop them.

McDonald: Dr. Voorhees, I'll round things out with you. What was the biggest surprise that came out of ASH?

Peter Voorhees, MD: I think the biggest surprise for me was results from one of the cohorts in the KarMMa-2 trial. And this was specifically patients in early relapse. So this is second line therapy for ide-cel. We all have been very optimistic that moving CAR T-cell therapy into the earlier treatment continuum, is going to lead to more durable responses. You've got better T-cell fitness in that situation; you should get a better product; you should get more durable responses. But in this particular cohort of patients, the median progression-free survival was approximately 11.5 months, which, you know, in my mind was a bit disappointing. Now in defense of the study, these were high-risk patients, functionally high risk with early relapse. So, how would the comparators [do]? But there was a subgroup analysis that showed that the median progression-free survival for early relapses ... was over 20 months.

McDonald: Next topic. You'll each get 2 minutes; so we're going to spice it up a little bit, give you a little bit more time. What trial do you think will be the most practice changing that you heard out of ASH? So Dr. Krishnan, I'm going to start with you.

Krishnan: I think, and I'm not saying this just to butter up Dr. Vorhees, but I think GRIFFIN is still very practice changing to me. With longer follow up, it cements the role now of quadruplet induction therapy and also dara-based maintenance regimen in regards to MRD, in regards to quality of life that Dr. Richter showed, in regards to progression-free survival, I don't need to see overall survival because obviously that is going to take a while, but I think there's enough in that body of evidence to support quadruplet induction.

McDonald: Dr. Voorhees, you’re up next.

Voorhees: As far as practice changing, I think that there's a lot on the horizon. But as far as here and now practice changing, I would agree with Dr. Krishnan on that the quadruplets in the newly diagnosed space continue to impress. She alluded to the GRIFFIN trial, but there was also interesting data with isatuximab and KRd [SKylaRk; NCT04430894], both out of MGH and Betsy O'Donnell's work, which looked really interesting. And then ... that regimen in a high-risk patient population, and really quite impressive, overall response rates and depth of response, which I think is incredibly encouraging. And at least in the early days, very impressive progression-free survival. The other thing that was interesting, and it gets to Dr. Krishnan's point about when do you stop therapy. We did an analysis of the GRIFFIN trial and MASTER [NCT03224507] together looking at cytogenetic risk, and what you saw on both studies is that if you had 0 or 1 high-risk cytogenetic feature, you did incredibly well with regards to progression-free survival, and there was really no difference. When you went to 2 cytogenetic high-risk features, then you start to see inferior progression-free survival, which I think is very important. But the other thing that's kind of interesting about this, and, these are relatively small studies, and perhaps the MASTER trial needs a longer follow up, but the PFS curves, based on cytogenetic risk, are virtually superimposable. And in the MASTER trial, they stopped therapy after two consecutive MRD negative reads. It'll be interesting to see how that study reads out in longer follow up for those with 0 or 1 high-risk feature.

McDonald: 3 seconds on the shot clock, Dr. Vorhees. Dr. Richter, I'm going to pass the ball to you give you the opportunity to posterize your opponents and take us home.

Richter: These guys are talking about an area upfront where the response rates are already 100%. And they're going for 101%. So what was most game changing to me was in the relapsed setting, the cevostamab trial [GO39775; NCT03275103] and there were two presentations. One was an oral presentation by Suzanne Shudel ... where prophylactic tocilizumab was given. The other was a poster with Dr. Alexander Lesokhin, of [Memorial Sloan Kettering Cancer Center] being the lead author, I was second; so I was No. 2 on that one.

And I think these two together actually formulate the way we're going to consider approaching bispecifics in the future, as Dr. Krishnan pointed out, right now, we're just giving these drugs and we don't know when to stop. And what the poster that Alexander presented was that we're looking at patients who we treated for 17 cycles, so one year and then stopped, and then monitor them. And we have a number of patients who are 6 months and couple patients more than 12 months out after stopping therapy with bispecifics, still in remission. So that's getting to be really exciting. Now, this wasn't a biologically determined amount of time, the next generation of trials are probably going to pick something like consecutive MRD, or depth of response before stopping, but we're getting there. And what Dr. Shudel presented was prophylactic tocilizumab, which in this trial and cohort, compared to a control, reduced the incidence of CRS from over 90% to the 38% range. So I think what we're likely to see with bispecifics going forward and efforts to get them out to the community is things like prophylactic tocilizumab and fixed-duration therapy.

McDonald: What trial is going to lead to the next FDA approval the soonest following ASH? Dr. Voorhees, I'll give you 1 minute.

Voorhees: I suspect that we're all going to answer the same here. So talquetamab, the GPRC5D bispecific antibody, looks awfully good. Ajai Chari from Mount Sinai looked at two different dosing schedules of talquetamab in patients with relapsed refractory multiple myeloma either weekly or every other week dosing. Median prior lines of therapy were 5, the majority of patients had triple class refractory disease. And in spite of this, the overall response rate, you know, was 70 to 75%. You know, and median progression free survival and duration of response, also look very impressive. Interestingly, the rates of grade three and higher infection seems to be less than with the BCMA bispecifics, and that may be due to the fact that there is less GPRC5D on normal plasma cells and less IVIG was needed as well.

McDonald: Dr. Richter, are you in the same boat as Dr. Voorhees?

Richter: Absolutely. And it was probably not by accident, but not only did the New England Journal of Medicine article—of which Dr. Chari was first author—come out during ASH, but Janssen, the company that makes it, filed the drug with the FDA right at the beginning of ASH. So we know this is coming on the horizon. And the fact that right now we have two FDA approved BCMA CAR Ts—we have one FDA approved BCMA bispecific antibody, we'll have to pour out a little liquor for our failed BCMA targeted ADC. But we have a number of patients now entering heavily relapsed that are BCMA-refractory or progressing beyond BCMA therapies and really exciting to now have a non-BCMA-based T-cell engaging antibody. And as Dr. Voorhees expertly pointed out, the risk of infections in the non-BCMA assets seems to be lower. So really excited about that.

McDonald: Dr. Krishnan?

Krishnan: I'm even more biased because I'm on the talquetamab trial as well, and the New England Journal [of Medicine] papers. So I completely agree with that. I did want to point out a couple of things. So there were a couple of presentations in terms of sequencing. So Kevin Reyes, from UCSF, looking at when you relapse [after] 1 T-cell engaging type of therapy, what is your response to another T-cell-directed therapy? It does seem to be lower in terms of response rates—around 40%. And we saw that also in, for example, the elranatamab [trial] where they have a prior BCMA-treated cohort. So elranatamab, BCMA, bispecific, 70% response rate, but in a prior BCMA-treated cohort, response rate drops down to between 40 to 50%. So I think sequencing [is] important, we also saw some really interesting data ... looking at mechanisms of resistance, and we do see evidence of BCMA-directed mutations that may influence our use of sequential BCMA-directed therapies. Interestingly, even more is, we also see GPRC5D mutations in patients treated with prior BCMA-directed therapy. So I think sequencing of these agents remains the next year's ASH question.

McDonald: Each of you will have 1 minute. We’ve talked about approvals, potential approvals and most practice-changing data. But let’s be honest, no everything is as positive. Some things leave us scratching our heads. What trial requires the most follow-up as a next step? Dr. Richter, I’ll start with you.

Richter: Besides all the therapeutic trials that everyone gets really excited about, there's been a bunch of these diagnostic intervention trials, and one that I found to be very interesting, was ... about the role of evaluating circulating clonal plasma cells in newly diagnosed patients to kind of figure out the course of therapy. And one of the things that patients are begging for is that bone marrows are a literal and figurative pain in the behind. And if we're able to kind of come up with a way to better quantify and stratify patients by peripheral blood testing, you know, that will be very applicable to a wide group of patients. So they're already showing that circulating clonal plasma cells may be predictive if you have them or don't have them at different time points in terms of peripheral MRD analysis. I don't know that it's quite ready for primetime and [to be] utilized everywhere, but this is something that once it gets up and running, and we don't have to stick giant needles in everyone, I would be really excited for it.

McDonald: Dr. Krishnan, same question.

Krishnan: I think that really the most controversial area now in myeloma is smoldering myeloma. So I did want to highlight when you say we need more data, I think this is extremely the case in smoldering myeloma. And so the ASCENT [NCT03289299] trial, which was, I think Dr. Vorhees knows it well, is, but in regards to first high risk, smoldering myeloma, using daratumumab, carfilzomib, and lenalidomide and dexamethasone for two years, they certainly showed high responses, they had a PFS of 90% at three years. But I still, what we really need to know is, are you changing the natural history of the disease, and so that's where we need much longer follow up on these kinds of progressive interventions earlier in smoldering myeloma.

McDonald: Dr. Voorhees, I’ll come to you.

Voorhees: I think that there was very interesting data presented on the combination of daratumumab, lenalidomide and teclistamab in early relapsed multiple myeloma. It was a relatively small cohort of patients, but not surprisingly, the overall response rate was very good. And the overwhelming majority of those responses were very good partial responses or complete responses. But you know, we need longer-term follow up to determine; we all know that these are going to be very effective. The question is, what is the safety? Getting to the point of continuous teclistamab dosing with better prophylaxis earlier in the disease continuum, perhaps the infection signal will be less severe. But Janssen is gearing up to do a phase 3 study in newly diagnosed transplant-ineligible patients, so this safety signal is going to be very important going forward.

McDonald: Studies aside, this next topic could be anything out of ASH—trials, data, certain drug, presenter, the meeting itself even, you name it, 30 seconds each. Who, or what, was the biggest winner out of ASH? Dr. Krishnan, I'll turn to you.

Krishnan: I think we all were, actually. Because it was just to be able to get together again, see our colleagues; I think they said 27,000 people, so ASH is back, and it was great to be there.

McDonald: Dr. Voorhees, biggest winner out of ASH?

Voorhees: Well, I do want to give a shout out to one of the bispecifics that we've been working on at LCI. ABBV-383, it was just a poster, but it was a plenary session at [International Myeloma Society] in Los Angeles. And it's got very unique features for BCMA bispecific, it's just once every 3 weeks. We're now looking at every 4-week dosing; there's only one hospitalization for 48 hours, and there's no step up dosing, so a lot of attractive features to allow it to go to the community.

McDonald: Dr. Richter, 30 seconds.

Richter: Well, if Dr. Voorhees is going to give a shameless plug, I'm going to give a shameless plug. We've been doing a lot of work with linvoseltamab, formerly known as REGN5458. And although for the bispecifics, we haven't found any really differentiators in terms of efficacy, they all seem to be in the 60 to 80%. Linvoseltamab has probably the lowest CRS rate—[in] the 30 to 40% [range]. So I think of drugs that we're going to get them into the community, this one may even have a higher potential.

McDonald: As I mentioned earlier, we encourage you to talk about yourself. So, I’m going to give you more time anyway before we close out the day. One minute each, I’m going to let you continue plugging yourselves from the meeting. Dr. Voorhees, is there something you’d like to plug?

Voorhees: I guess the only thing that I would plug you know is the increasing use of quadruplets in the frontline space. And I think you know, daratumumab-RVD continues to impress. You know, we originally showed increased depth of response with the addition of daratumumab to the RVD backbone that eventually translated into improvement in progression free survival. You know, some folks, you know, criticized, you know about the concern for toxicity. But really, that was actually very manageable. And when it comes to patient reported outcomes, you know, in fact, if anything, PROs were superior in the quadruplet arm relative to the triplets. So I think you can make a very compelling case in the United States that for transplant eligible patients, Dara-RVD is the new standard of care in this country.

McDonald: Dr. Richter, I’ll turn things over to you.

Richter: So, the one thing I'm going to talk about is, we've been talking a lot about bispecific antibodies. And so far, every bispecific that we've talked about has CD3 as targeting the effector cell to get the T cells to fight myeloma. We had a poster, again, it's a trial and progress. So we're just getting it off the ground. But it's a non-T-cell engaging bispecific, so it has CD38 to engage the myeloma cell. But instead of CD38 [and] CD3, it's CD38 [and] CD 47. CD47 has the "don't eat me signal." It doesn't have a name yet, it's just ISB1442—is the name of the drug. But the hope is that we can start getting [this] type of bispecific level efficacy rates, but hopefully moving beyond some of the risk of things like CRS, so we have a lot of preclinical data we're about to enter into the clinic, and really excited about it.

McDonald: Dr. Krishnan, I’ll let you take the floor and give some shameless plugs.

Krishnan: I got so many plugs. I don't know where to begin. I'm going to start with the SWOG-S1803-the DRAMMATIC [NCT04071457] study, which gives patients posttransplant len-dara or len alone and at 2 years MRD is checked and patients who are MRD negative are randomized to either continuing or stopping therapy. It's a prospective, randomized trial to answer the most important question, can you stop therapy in patients with a deep sustained response?

My second plug is in regards to CD38. Mechanisms such as CD38 resistance, suggesting that it's not related to CD38 expression, primarily, but also in part to the immune microenvironment. And because of that, we have a trial ongoing using actinium labeled CD38. While not our trial, it is proof of principle. The Takeda drug, whose name is a challenge to pronounce ... with interferon responses and dara-refractory patients. So again, showing the immune system is as important as the target.

McDonald: I want to thank you all so much for joining us. Before we close, I want to give everyone a short 15 seconds each to give us our closing thoughts. Dr. Voorhees I'll start with you.

Voorhees: We’re just at the beginning of immunotherapy in multiple myeloma. We're all excited about the bispecifics and CAR Ts. But there's a whole host of IO agents [on] the horizon. We just need to learn how to combine them in the right way.

McDonald: Dr. Krishnan.

Krishnan: So we have exciting new therapies for patients with myeloma, our issues are access to care for many patients. And I am encouraged to see a huge push in terms of diversity and equity inclusion of patients and clinical trials and we need more of that ...

McDonald: Dr. Richter, 15 seconds.

Richter: So when I started treating myeloma, I would tell everyone, this is an incurable disease. Today we cure a small number of people mostly by accident, but thanks to great work by my colleagues, Dr. Vorhees and Dr. Krishnan. We will hopefully one day soon have a cure for everyone.

McDonald: Thank you again, to all of our panelists. Well, that is all we have time for today. But I want to thank you all for joining CancerNetwork® for the 2-Minute Drill where we offer unscripted, rapid insight on the most recent cancer conferences. I'm Ryan McDonald, have a great day.

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