Activity Transcript

Sagar Lonial, MD, FACP: Hello, I'm Dr Sagar Lonial from the Winship Cancer Institute of Emory University in Atlanta, Georgia. And I'm going to spend the next few moments really talking about some practical management issues for patients with early relapse of multiple myeloma. So let's go ahead and get started. Again, this is my affiliation and where I'm from. And I want to start off setting the stage, and I want to start off setting the stage showing you where the current state of the art in myeloma is. And this is a series of a thousand consecutively treated patients at our institution, called the RVD 1000 series. And what we know in this is that patients all received lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy. Almost all of them went on to high-dose therapy and autologous stem cell transplant. And then they received risk-adapted maintenance. And what I mean by risk-adapted maintenance, is single agent lenalidomide for standard-risk and RVD consolidation for 3 years, followed by lenalidomide alone for high-risk myeloma.

And what I want to identify as our current standards of care or benchmarks if you will, is that patients with symptomatic myeloma can expect to have a median progression-free survival of about 65 months on average. That number jumps to 80 months if you start to include standard-risk myeloma patients. And in fact, the median expected overall survival is 10 years or more for all patients. And again, if you look at the standard-risk patients, the median has not yet been reached with 14-year follow up. And so what I think this really does is establish a new benchmark for what we should expect for patients with the diagnosis of multiple myeloma who are younger and fitter in general, but certainly are well enough to go through high-dose therapy and transplant.

Now, one of the things that you'll notice from this series of curves here is that it does not appear, at least as yet, that there's a plateau on that curve. And so obviously, we need to begin to understand how to deal with patients with early relapse. And in many ways, I would argue that early relapse is the new newly-diagnosed myeloma because patients can often have as long if not a longer duration of remission in first relapse given how effective our tools are for treating them in 2023.

And so what you see listed on this slide is a number of different factors that go into making those decisions. There are things such as frailty, morbidity, risk assessment, treatment history, and lifestyle that all go into how you may think about choosing regimen A or choosing regimen B in the management of a patient with early relapsed multiple myeloma. But at the end of the day, we as providers and physicians, should probably choose the regimen that is the most effective, is the safest, and maintains the highest quality of life. Because again, our goal is to get a really long second remission out of whatever we're choosing as part of our initial salvage therapy.

Now, historically, we've always talked about proteasome inhibitor backbones or immunomodulatory inhibitor backbones. And in the last 5 years, what's really come to the forefront is that we have a third backbone, and that third backbone is anti-CD38 monoclonal antibodies. And I would argue for a patient who is not resistant to an anti-CD38 antibody, that now becomes the major backbone to which we either add a proteasome inhibitor (PI) or we add an immunomodulatory agent. And which one of those is something we're going to spend the next few moments really talking about.

So let's talk about the randomized phase 3 trials that used lenalidomide (LEN) and dexamethasone (DEX) as control arms. And as you'll see from the left all the way to the right, there's ixazomib (IXA) plus LEN/DEX, there's elotuzumab (ELO) plus LEN/DEX, there's carfilzomib plus LEN/DEX, and there's daratumumab (DARA) plus LEN/DEX. And I think that one of the real challenges, and it really hurts me to say this in 2023, is that LEN/DEX is no longer considered a standard control arm because almost all patients are going to be progressing on single-agent lenalidomide in the context of first relapse, whether they are transplant eligible, where they're likely going to be progressing on LEN maintenance or, at least at our center, an immunomodulatory drug (IMiD) plus a PI in combination as maintenance therapy if they're high risk. Or if they're transplant ineligible, they're going to be likely progressing on continuous lenalidomide therapy.

Based on this, these 4 regimens, to me, are not reasonable to consider in the context of first relapse. And that to me is really important because while we did certainly enroll lots and lots of patients in these trials, the use of LEN/DEX in a LEN/DEX refractory patient really doesn't offer significant clinical benefit.

So then we start to think about trials that use bortezomib and dexamethasone as a control arm. And what you see here are a number of them including pomalidomide with bortezomib/DEX, daratumumab with bortezomib/DEX, carfilzomib (CAR) single agent, or CAR/DEX, vs bortezomib/DEX, selinexor in combination with bortezomib-DEX, and finally venetoclax (VEN). And we're going to touch on the last 2 in a couple of specialized circumstances, but recognize again that many of these are not typically used. And I'm going to show you data why we've likely shifted towards a different PI in the context of early relapse.

Finally, pomalidomide (POM)-based salvages become a third option for many of these patients. And as you'll see, we have data with POM/DEX, with bortezomib POM/DEX, carfilzomib/POM/DEX, DARA/POM-DEX, IXA/POM/DEX, ELO/POM/DEX, and isatuximab (ISA)/POM/DEX. And I think one of the real challenges when you compare POM/DEX-based approaches in salvage vs say carfilzomib/DEX or bortezomib/DEX, is the lines of therapy confounding variable.

And what I mean by that is that most trials that use POM/DEX as a control arm are third-line salvage therapy, whereas most trials that use either bortezomib or carfilzomib as the control arm are second-line salvage therapy. So there may not be an absolute difference between the efficacy of say, an anti-CD38 paired with POM vs an anti-CD38 paired with carfilzomib, but at the end of the day, they are separated by lines of therapy, and that may give you a false sense of efficacy that one is potentially better than the other.

Let's talk a little bit about a standard regimen for early relapse. And these are data from our center published several years ago now looking at DARA/POM/DEX in first relapse, both looking at progression-free and overall survival. This is from a paper we published in Cancer looking at our experiences with DARA/POM/DEX in either DARA-resistant, DARA- and POM-resistant, or DARA- and POM-naive patients.

And what I think you'll see is that the median progression-free survival (PFS) has not been reached with about 41-month follow up, suggesting that this could in fact be a very effective regimen, and for a number of years has been our standard go-to for patients with first relapse standard-risk myeloma. Now, if you then look at the randomized phase 3 trial, the APOLLO trial that tested DARA/POM/DEX vs pomalidomide and dexamethasone, what you'll see is a median PFS of about 12 months for the DARA/POM/DEX (DPD) arm compared with only 6 months for the group that got pomalidomide and dexamethasone. Now, as a skeptic you might say, "Well, that previous slide looked a lot better than this one. What's the difference?" The lines of therapy. A majority of these patients were second- or third-line therapy, not first salvage. And for that reason, I think we're seeing a reduction in the PFS for DARA/POM/DEX in this randomized phase 3 trial. And I'm going to show you some additional data that really speaks to which patients may benefit from a pom-based approach vs a carfilzomib-based approach in just a few moments.

On the other hand, in the CANDOR trial, what you see with DARA, carfilzomib, and dexamethasone vs carfilzomib and dexamethasone really does reflect that first-relapse patient population. And what you see is a very high overall response rate of 84% compared with only 75% in the CAR/DEX arm, much higher complete response (CR) rate, much higher minimum residual disease (MRD)-negative rate. And that translated into an improved progression-free survival, favoring the group that got DARA in combination with carfilzomib and dexamethasone. Remember the shapes of these curves because I think you're going to see similar shapes as we go on to other anti-CD38 antibodies as well.

Now what about isatuximab plus POM/DEX? This is the ICARIA trial. Again, what you're seeing here is a median PFS of about a little over 11 months compared with 6 months for pomalidomide and dexamethasone. Again, looks similar to what I showed you for APOLLO just a few moments ago. And most of these patients were third-line therapy, not second-line therapy, which I think reflects why the PFS is shorter than what we're seeing in carfilzomib combinations. Nonetheless, there may be patients who are better suited to a POM-based combination vs a carfilzomib-based combination when you're partnering it with an anti-CD38 in the context of first relapse.

And finally, what you'll see here is isatuximab in combination with carfilzomib and dexamethasone. Again, what you're seeing is very high overall response rates, very high CR rates, and a much higher rate of MRD-negativity with a long follow-up now of over 20 months. And in fact, if you begin to look at progression-free survival, again the shapes of these curves look similar to what I showed you for the CANDOR trial before, combining carfilzomib with daratumumab and DEX. This one is combining isatuximab with carfilzomib and dexamethasone vs CAR/DEX. And in fact, I would just note that the CAR/DEX control arm down here at the bottom is very similar to what we see in the ENDEAVOR trials, suggesting that this control arm was behaving as you would expect. The ISA/CAR/DEX arm is simply superior in this randomized phase 3 trial.

The other point that I'll make for the carfilzomib combinations is that they are using 56 milligrams per meter squared twice a week. And so I know that many groups have switched now to 56 once a week or once a week dosing of carfilzomib. It's not clear that you're necessarily going to get exactly the same PFS benefit by partnering an anti-CD38 with a once-a-week dosing of carfilzomib as we're seeing in these 2 large, randomized phase 3 trials where you're using a much higher effective dose of carfilzomib. So just something to keep in mind. And certainly at our center, I will start people on the twice-a-week dosing schedule, and then when they are ready to see us less frequently, will back down to the once-a-week dosing schedule just from a practical perspective.

The other trial that I think is important to look at in the context of phase 3 data is the ELOQUENT-3 trial. This is ELO in combination with pomalidomide and dexamethasone vs POM/DEX. And again, what you're seeing here is about 11 months vs 6 months, again, a later line of therapy. So 3 or more, for the most part, lines of prior therapy when patients were enrolled onto this trial. So a later relapse experience. But what you're seeing is a higher overall response rate, you're seeing a higher CR rate, and that does in fact translate into an improvement in progression-free survival.

How do we, at our center, begin to tease out who we might consider DARA/POM/DEX for first relapse vs who we might consider it for later relapse? And what I want to show you is an analysis that we did looking, really, by risk. And the risk that we identified was people who relapsed within 30 months of diagnosis. And that's on the right side of the curve. If you relapse after 30 months from diagnosis, then this is the curve of DARA/POM/DEX with a median PFS that has not been reached now with long follow-up. On the other hand, if you relapse within 30 months, the median PFS is very short at only 8.9 months, suggesting these are patients that perhaps need an alternative treatment approach.

And so at our center, based on time from diagnosis to relapse, if you relapse early, if you have functional high-risk myeloma, then we typically will go with DARA/carfilzomib/dexamethasone. If you relapse later, we'll go with DARA/POM/DEX as our first salvage based on this algorithm that I think gives us a sense beyond just genetics in terms of who's going to do well vs who isn't.

Let's look at other agents in the context of early relapse. This is the STORM trial, which was selinexor plus dexamethasone. And while this trial was not an early relapse, this led to the FDA approval of selinexor in the refractory relapse setting where you're giving selinexor 80 milligrams twice a week in combination with dexamethasone, with about a 26% overall response rate. Now, that subsequently led to a randomized phase 3 trial called the BOSTON trial where selinexor/bortezomib/DEX with selinexor being given once a week along with bortezomib once a week in the yellow curve compared with twice a week dosing of bortezomib-dexamethasone and demonstrating superiority of the triplet over the doublet in this context. And what I think you'll see here again is that this certainly is a reasonable thing to consider in the context of early relapse based on this randomized phase 3 trial.

The other drug that I like to think about early in the context of relapse is venetoclax, but I only really think about venetoclax in the context of the 11;14 translocated patients. And as you'll see from this phase 1 trial, if you look at single-agent venetoclax in 11;14, the response rate's about 40%. If you then look at VEN/DEX in a phase 2 trial for only the 11;14 subset, what I think you'll see is a 60% overall response rate in the context of the phase 1 portion of this trial. And you'll see about a 48% response rate in the context of the phase 2 portion of VEN/DEX in this as well. And what you'll see down at the bottom is the median lines of prior therapy. So venetoclax clearly has activity. Probably the most synergistic partner with venetoclax in myeloma is dexamethasone. And so VEN/DEX is a go-to that I will often use in this context for management of early relapse multiple myeloma.

The challenge with venetoclax is that there was a randomized phase 3 trial of venetoclax/bortezomib/DEX vs bortezomib/DEX. And this trial design, I will tell you ahead of time, was a flawed trial design because it didn't just take the 11;14. It took everybody, and it randomized them 2:1 to venetoclax/bortezomib/DEX vs bortezomib/DEX with the primary endpoint being progression-free survival. And what you'll see here is that PFS clearly was better for the venetoclax arm compared with the non-venetoclax arm, but the overall survival was worse. And this likely had a lot to do with the fact that many high-risk patients who were not 11;14 were getting randomized to really suboptimal therapy with either bortezomib/DEX or venetoclax/bortezomib/DEX. And in the non-11;14, venetoclax was not offering benefit. And so this trial ended up being read out as a negative trial.

But what I want to point your attention to was the 11;14 subset here, and what you see is a huge difference in progression-free survival favoring the group with 11;14 translocation, and there was in fact no survival decrement in those patients. And so I still don't have any hesitation or reservation enrolling patients with 11;14 myeloma into the context of venetoclax-based therapy. And I do believe that bringing this earlier and earlier ultimately is better for patients because this is such a precision medicine approach in multiple myeloma.

Now, again, the final survival analysis, one of the things I want to highlight for you here is that if you're 11;14 positive, the hazard ratio was 0.12, favoring the use of venetoclax. And in fact, the hazard ratio for overall survival if you were 11;14 was 0.61, also favoring the use of venetoclax early on. And so I don't consider this as an agent for non-11;14 patients. I only consider this as a salvage in the 11;14 subset of patients.

Let's talk about a couple of clinical pearls or practical areas just as we begin to wrap this up. And so I think that the determination of refractoriness at first relapse is really important. For instance, we know that many patients nowadays are receiving daratumumab or anti-CD38 as part of their initial therapy. If they don't continue on that approach in the context of maintenance, then I do not consider them resistant to an anti-CD38 antibody. On the other hand, many patients who are receiving lenalidomide as part of their initial regimen and then receive lenalidomide as part of their continuous maintenance, I will consider them resistant to lenalidomide in that context, and so will not revisit a lenalidomide-based triplet in the context of first relapse. We talked about this early on, and I think that if a patient is progressing on LEN, the marginal benefit from a LEN-based combination is pretty minimal.

The second thing I want to touch on a little bit is dexamethasone. I think it is important, particularly in the context of continuous therapy, that we don't need dexamethasone or steroids forever. And in fact, we'll typically use it for the first couple cycles of therapy, then begin to taper down and potentially try and get patients off steroids by the first 6 months of their first salvage. What that functionally means is that they may be receiving an anti-CD38 antibody and have no steroids on board any longer as a pre-med. That is okay as long as they've done well with their first few months of therapy and they're tolerating their current regimen pretty well.

And by the same token, many of the pre-meds that are used as part of an anti-CD38 regimen, such as diphenhydramine or acetaminophen or other pre-meds used to reduce the rate of reactions, those can likely be discontinued after 1 to 2 cycles of therapy as well. So that when I have a patient who's getting, for instance, long-term POM/DARA, the DEX is likely gone, the diphenhydramine is likely gone, as is the acetaminophen. So patients are really just receiving 2-drug therapy and it makes their experience and their quality of life significantly better to not necessarily be on these treatments over a longer period of time.

And I do think it's appropriate to recognize that dose adjustments to maintain patients on therapy are perfectly reasonable and appropriate. I will often dial down the dose of pomalidomide based on how patients are doing, particularly when you stop the dexamethasone, as this does become a really important practical pearl in the management of their myeloma. So again, I think just to wrap up, in early relapse the backbone is likely a CD38 antibody, and then you partner with it either an IMiD or a PI. I showed you one way that we make that decision based on how long that first remission lasts.

If you now get through second-line therapy and are now thinking about third-line therapy, you can switch classes. So if you got an IMiD and an anti-CD38 as first salvage, switching to a PI like carfilzomib in the next salvage certainly is one relevant way to think about it. Precision medicine, I think, is here for the 11;14 subset. I like to use venetoclax early in the relapse setting so that I can maximize its benefit in a more sensitive patient population.

And finally, the next set of trials evaluating this, really, you're going to come down to B-cell maturation antigen (BCMA)-directed targets, whether they're chimeric antigen receptor (CAR) T-cells, bispecifics, or we hope that the antibody-drug conjugates will also come back. Those will be important questions for us to ask as we begin to think about cycling drugs, combining drugs, and ultimately, hopefully getting patients who relapse early in the course of their disease back in long-term remission. Thank you again for your attention, and have a good rest of the afternoon.

This transcript has been edited for style and clarity.