Case: A man in his early 80s with newly diagnosed multiple myeloma (MM) presenting with new anemia and an IgA monoclonal spike

DR CHARI: Hello. Thank you for joining me today to review the myeloma updates from the American Society of Hematology December 2021 meeting.

So in this discussion, we’ll first start with newly diagnosed myeloma. And later, we’ll go to relapsed, CAR T and bispecifics. And within newly diagnosed, we’ll start with the transplant ineligible population looking at the role of frontline versus second line dara. And then, we’ll go into the transplant eligible looking at CD38, VRd and KRd combinations as well as VTd.

So here’s a case to kind of set us up for the first patient example, first group. 80-year-old male with a history of hypertension, diabetes, stable coronary artery disease, renal impairment, clearance of 45. He has new anemia, hemoglobin of 10.5 from a baseline of 12.5. Found to have an IgA monoclonal spike, 2.5 g/dl. Increase in lambda light chains of 200. The marrow shows 40% lambda restricted plasma cell. And as is typical, older patients tend to have less high-risk features. Normal FISH. ISS2, normal LDH. So the question is, how do we treat this patient? And, again, it’s like a math question because if you have 6 different categories of drugs with multiple drugs in each class, what are the possible permutations and combinations? But I think we can distill down to these 5: RVd, RVd-lite, dara/VMP, dara/Rd and ixa/Rd.

So I’m going to walk you through this slide because this slide has a summary of the major components of these studies. And I think one of the challenges is rather than going through one study at a time, especially when there’s so many choices, I’m going to highlight on these slides any updates that we’re getting from ASH 2021. Here, there wasn’t a specific update on these, but it sets up one of the interesting presentations. So what we have here are the pivotal studies for newly diagnosed myeloma. On the left, SWOG 777 which is VRd versus Rd, the randomized Phase III. RVd-lite, a single arm study with 50 patients. The ALCYONE study which is dara/VMP versus VMP. MAIA, DRd versus Rd, dara/len/dex. And TOURMALINE, ixazomib/len/dex versus Rd. And so why do I have it displayed in this format? Well we’re always tempted in medicine to do cross study comparisons and yet we’re always slapped on the wrist for not doing that, but I think here, you can see some salient differences already, first being the median age. And you can see the SWOG 777, while it’s without transplant, it’s really not a fair statement because it’s without the intent to transplant. And you can see it’s almost a decade younger patients than the other studies. And why is that important? Well here, the bortezomib was given twice weekly and this is a younger patient population. So with that, that’s one reason I’ve shown it in this way. And the second reason I’ve shown it this way is you can see even with the same control arm of Rd in the 777 study, MAIA and TOURMALINE, Rd can give you a PFS as short as 22 months to as high as 34 months. And so whenever we’re tempted to do these cross study comparisons, you’re going to be led astray because there’s clearly differences and that’s why we have these randomized studies.

And at the bottom, you can see that unlike the SWOG, which is twice weekly, the other studies typically do not do bortezomib twice weekly because older patients just don’t tolerate it. More neuropathy, more gastrointestinal issues. So we’re always taught if you’re going to look at a study, does it apply to this older patient, our 80-year-old guy sitting in front of us in clinic? And I doubt many of us would give an 80-year-old twice weekly bortezomib. And so then, how do you make some comparative statements? And I think one way is to look at the hazard ratios which are shown at the top. And this tells us that for adding that extra agent, what are you getting in return? And so in the left, SWOG, you have about a 25% improvement in the PFS. With the VMP, you have an almost 60% improvement. MAIA, 50%. And TOURMALINE, only about 20%. And you can see that actually crosses 1 and that is not an approved regimen for frontline myeloma because of inadequate benefit.

So I think this really sets up one other point is, of course, the overall survival. I think a lot of folks want to see that OS benefit. And interestingly, the SWOG at the left did show an OS benefit, hazard ratio of 0.7, however, it did not show statistical significance in the older population. So, again, this goes back to making sure that the patients are representative. The hazard ratio actually crossed 1. So if you have an older patient like the one we have in our case, twice weekly bortezomib in a SWOG will not lead to an OS benefit in that population. In contrast, the dara/VMP and MAIA do show statistical significant benefit with the median age of 71 to 73.

So this is a set up, but I think this is an important set up for the question of, well we know that daratumumab works later as well, do you need to use this upfront? Can you start with, say, RVd-lite shown in the second column which is actually deliverable? This is a 73-year-old population, very encouraging PFS of 35.1 months. And so a lot of people say, well I’m so used to RVd and it’s tried and true. And so okay I get all your comments about the SWOG and the limitations, but why can’t I just use RVd-lite? And I know dara is effective, why not save it for relapse?

And so some of the issues with doing that is these concepts of attrition and diminishing returns. On the left, if you start off with 100% of patients, with each successive relapse, we lose patients. And on the right side, if your first duration of therapy is the longest, with each successive relapse, you’re going to have diminishing returns. And so the point of this slide is, generally, we feel that high-risk, frail elderly aren’t going to get to the nth relapse. So this kind of saving my drugs for later really has not been borne out. And in attempt to get at that is this next study which was presented by Dr Fonseca at ASH 2021.

And so what they did is looked at different regimens looking at DRd, VRd and Rd. And on the right, you can see that they did some best case scenarios and some sensitivity analyses. And so the first column is, what if you use DRd in your frontline and in your second line, you use a pomalidomide or carfilzomib-based regimen? The second column is, what if you use VRd in your frontline and then save dara for the second line? And the third column is Rd in the frontline and then dara in the second or later. And what you see in the row is that the incremental overall survival benefit in the middle column if you use dara as frontline in that first column is 2.5 years more than if you use VRd. And compared to Rd, it’s 3.5 years. And that was borne out with sensitivity analyses as well. So what this tells us is that kind of what the previous slides supported, you want to use your best drugs early and the presumption that you’re going to be able to keep this patient for relapse is really not always substantiated and the tremendous benefit, the first remission is the longest. So why not use your best drug? So I think between the MAIA compelling data and these dataset, it really does cement the front-line CD38/Rd combination as the gold standard.

And just to go back for a second, I want to emphasize something which is that with the median follow-up of 56 months on MAIA, the median PFS was not reached with the DRd arm and that’s in that fourth column. So that’s pretty impressive. We’re rivaling outcomes of transplants. So this is approaching 5 years and longer without a median. So I think these are really exciting data for our older patients.

DR LOVE: The data presented by Dr Fonseca, was that a trial or sort of an analysis of data?

DR CHARI: It was an analysis. It wasn’t a trial.

DR LOVE: So it was a theoretical construct?

DR CHARI: Correct. Yeah.

DR LOVE: That’s really interesting.

Case: A woman in her early 60s with newly diagnosed MM presenting with hypercalcemia and FDG avid lytic lesions

DR CHARI: So now let’s move to a younger patient. 60-year-old female, hypercalcemia, FDG avid lytic lesions, monoclonal spike of 2.4 g/dl. It’s an IgG kappa with a kappa free light chain of 750. The marrow shows 25% kappa restricted plasma cell. She does have amplification of chromosome 1q, ISS Stage II, and an increased LDH. And so this case brings up a lot of questions. What do we use for induction in this transplant eligible patient? Should we do VRd, KRd, the inclusion of dara to the VRd or dara to the KRd? And then there’s also, not yet approved, but isatuximab studies. Should we transplant her or not if these regimens are getting so good? Should we do consolidation after transplant if the regimens are so good? And finally, what do we do for maintenance? Is len enough? Because that’s been our tried and true. Should we do doublet therapy with len adding dara, ixa, bortezomib, carfilzomib? So a lot of questions. Let’s see how the data pan out from ASH 2021.

So, again, you’re used to now the content of this slide and so I’m just going to walk you through, from left to right, the studies. IFM 2009 was the study that compared RVd to RVd with transplant. So the control arm did not get a transplant. And this is an important distinction in some of these regimens because not every study has transplant as the investigational question. FORTE also had the transplant as a question because they compared KRd with or without transplant. CASSIOPEIA differs. And actually, all of the subsequent studies differ from the first 2 because in this, all patients got transplanted. And the questions being asked are more different and they’re about the induction and consolidation. So in CASSIOPEIA, it’s dara/VTd versus VTd. In GRIFFIN, dara/VRd versus VRd. So CASSIOPEIA being from Europe, GRIFFIN being from US. Important distinction is that so far, all of these studies are Phase III, GRIFFIN is actually a randomized Phase II with only about 100 patients in each arm. So keep that in mind when we look at the outcomes. The MASTER study is a single arm study, dara/KRd with transplant. And the GMMG HD7 is, again, everybody got transplant, but this is VRd plus or minus isatuximab, another CD38 monoclonal antibody.

So first thing that I’m going to call your attention to is the amount of chemotherapy given. People make all of these blanket statements that, you know, this regimen is better than that one. And I think we need to drill down a little bit into the amount of chemotherapy people are getting because you may think it’s just everybody is getting X number of cycles of chemo and that is not true. What I’ve done here is summarize the number of days of chemotherapy, but for the sake of simplicity, let’s look in red as to the number of 28-day cycles. So in the IFM, 3.75 versus 6. In the FORTE, 8 versus 12. So just keep in mind, the nontransplant arm got an entire year of KRd which, I think, is commendable that they did it, but it’s really hard to do that in the real-world, especially with twice weekly carfilzomib. CASSIOPEIA gave 6 months. GRIFFIN, 4.5. MASTER, anywhere from 4 to 12.

This was a unique risk adapted study. We’ll do a deeper dive. And finally, the GMMG study, 4.5, but what’s unique about this one is this is just — this is very early cut off and so this is just prior to transplant. You can also see that the mobilization for stem cells differs. In Europe, they tend to use a lot more cyclophosphamide mobilization. In the US, more plerixafor. And the MASTER and GMMG did not report their mobilization. And because there’s so much variability in the amount of chemo, the timepoints, you know, I’m not going to spend too much time on the differences. They’re all very effective. We’re looking at response rates of 90+%. Very good partial response in higher of anywhere from 77 to 95%. I think it is interestingly that with the GMMG study, relatively short follow-up, but they’re getting deep responses which is great. CR rates are also as shown here with a very impressive stringent CR rate of MASTER of 84% which is amongst the highest we’ve seen so far. And the follow-up, of course, differs.

And at the top, you can see the PFS that is really, you know, all of these depths are great, but they’re surrogates for PFS which ultimately, would be a surrogate for OS. But in the PFS, we can see that in the IFM, and so one of our questions was, should you transplant or not? We have 2 studies that answer that question. It was the first 2, RVd with or without transplant, KRd with or without transplant. And both showed that the experimental arm with transplant did better than the control arm. And you can see that at the top with the hazard ratio of 0.65 and 0.64. So nearly identical and so we’re seeing almost a 35% benefit of PFS with the role of transplant. So, to me, I think that cements that transplant still cannot be eliminated. And then when we look at CASSIOPEIA, this was a different question. Everybody got transplanted, hazard ratio of 0.58. And GRIFFIN, 0.46.

And in the red box here, is I’ve shown you what’s new updates from the various studies.

So in CASSIOPEIA, the daratumumab could be either in induction and consolidation or in maintenance or in both or in none. So it’s a different study design than GRIFFIN. And what we see here is the update from Dr Avet Loiseau at ASH, was the rates of CR and MRD negativity. And you can see, here are those 4 arms that we mentioned, VTd observation, VTd with dara and maintenance, dara/VTd with observation and dara/VTd with dara maintenance. And I think what this tells us is, on the left, MRD negativity highest at the very top, lowest at the very bottom as you might guess. More dara, more MRD negativity. And the statistical comparisons done that show significance are in the top 2. So the addition of dara in the induction and maintenance was not statistically significant in terms of MRD negativity, however, the bottom 2 were significant.

Dara and maintenance did overcome not having dara in the observation arm. So this is an important other distinction that the control arm, because this study was designed a while ago, was not with len maintenance. So it was just observation. So it's a little bit easier to do better than nothing than it is to do better than len maintenance.

Then when we look at 1-year MRD negativity, this is super important. One of my pet peeves is that MRD negativity, people put into this mystical box for myeloma. MRD negativity in myeloma is not the same as PCR negativity in CML. It’s just a surrogate endpoint. And so we need to put a caveat that MRD negativity must be sustained and eventually does not supersede the need for PFS and OS follow-up. With those caveats, let’s look at sustained MRD negativity. One-year, you can see, again, the same trend, highest to lowest, 48% down to 21%. And when you look at the pairwise comparisons, again, only the bottom 2 were significant. And finally, at the 2-year sustained MRD negativity, again, same trend, nothing different. And so my interpretation of this is that the MRD negativity is the best when you use it upfront and in maintenance. And so the study does not answer the question of if you use dara with len maintenance.

About the synergy. Because we know that len maintenance from several studies not only extends your PFS, but extends your OS. In the US, we routinely have been using len. And actually, it’s also now approved in Europe. So we’ll look at the GRIFFIN study coming up, but I think this does say that if you use dara upfront, some of the people have been interpreting it as you don’t need it in maintenance if you got it upfront. But if you didn’t get it upfront, then you should get it in maintenance. The only caveat I would put on that is I think we need longer follow-up. If you believe in MRD negativity as a surrogate, the regimen that has the most MRD negativity should eventually get better PFS and it’s just we need longer follow-up because keep in mind, these patients are doing very well because they’re getting effective therapy.

The GRIFFIN was dara/VRd versus VRd. Keep in mind that the primary endpoint was just the depth of response, stringent CR, but what was interesting is with now about 39-month follow-up, the PFS curves, again, the medians are not reached and that’s what the arrows show, but the PFS hazard ratio was 0.46, confidence interval of 0.21 to 1.02. So, again, technically crosses 1, so we can’t say with rigor that this is significant. However, for a Phase II study that was randomized, I think this bodes well. And so personally for me, these 2 studies support the use of frontline CD38 quad-based regimens. It’s interesting that there are some skeptics and naysayers, the later adopters, but we started using VRd as a backbone in the US for induction for almost a decade on the basis of a single arm Phase II study and now we have several studies, both the CASSIOPEIA and GRIFFIN, supporting frontline dara, but I think everybody has got to make their own decisions. But I think these data are very encouraging. And, of course, the randomized Phase III of dara/VRd versus VRd is ongoing.

So moving now to the MASTER study. This is a study looking at dara with the carfilzomib, lenalidomide and dex followed by transplant. And what they did that was very unique and commendable is they used MRD guided consolidation. So based on how sustained your MRD negativity was, you either got no more consolidation, you got 2 or 4 cycles of dara/KRd. And so on the left, we look at MRD negativity in all patients, those with no high-risk features in the middle, 1 high-risk and 2 or more high-risk. And basically, you can see that the trend is that as you go from post-induction, which is the first set of bars within each group, to post-transplant to then the KRd directed consolidation, of course, regardless of whether you’re looking at 10-5 in red or 10-6 in blue, both are improving with time. But what’s interesting about this particular graph is that as you get more high-risk features, you see that those rates are lower. And you could ask, well what does that mean? The curve on the right translates that into PFS. And you can see that if you’re doing — if you have 0 or 1 high-risk feature, your PFS and OS are quite excellent, but the high-risk patients, these are really the ultra-high-risk, their PFS and OS is falling. And those are statistically significant.

So what that tells us is that number one, high-risk still remains an unmet need in 2022. Even with very potent dara, carfilzomib, lenalidomide and dex, we’re still not able to overcome high-risk. This is where we need novel approaches. We’ll see some really exciting data for T-cell redirection. Love to see that move upfront to see if this can be overcome. But the second thing I would say is it goes back to my earlier statement, I don’t think MRD negativity is this mystical cure that we are looking for. Of course, we should all be striving for cure, but MRD negativity, to me, is just a deeper response. And in the same way, you know that patients who have a VGPR are going to do better than a PR, you know that MRD negativity is going to do better than those who are positive, but the fact that the curves are separating tells us that these are still a surrogate endpoint. I think we need biological-based cure to really determine if we’re making a dent.

And I would predict, and this will happen with FORTE as well with additional follow-up, I think we will likely see even those standard-risk patients start to relapse. And we saw that actually in a recent study that was also at ASH which was called the CEASAR study, KRd transplant followed by consolidation and maintenance. This was for smoldering myeloma. Initially, they look good, but even though smolderings are relapsing. So, to me, MRD negativity really is just a surrogate endpoint. It belongs in clinical trials. It belongs in the use of regulatory approvals for earlier readout, but I don’t think it is quite yet a cure that tells us that we can stop therapies reliably. But stay tuned.

And the final study in this newly diagnosed segment with transplant is the CD38 monoclonal antibody known as isatuximab with VRd versus VRd. The primary endpoint here was MRD negativity. And so pretty standard design, 1:1, quad versus triplet. And here, the data cut off is just after this induction. So they have not yet been transplanted. And what they showed was that the 50.1% versus 35.6%, odds ratio of 1.83, statistically significant indicating that more MRD negativity with the addition of isatuximab. I think this is great. And they claim that this is the first study that’s showing this benefit of MRD negativity after induction. But to be fair, I don’t think we’ve had a readout in a lot of these other studies. I think we’ll have to stay tuned to see what happens after transplant. And as I showed you on that initial table, there’s tremendous variability. And so, for example, when you look at GRIFFIN, there were only 4.5 cycles of chemotherapy given in GRIFFIN and that includes induction and consolidation. Here, you’re looking at 4.5 months of chemotherapy just prior to transplant. So, again, I really caution from doing these cross study comparisons. I think each study has its own merit. And clearly, they have their control arm. But I don’t think we should be doing these comparative statements that one quad is better than another quad because we don’t have any data to support that. And keeping in mind also, of course, that daratumumab is subcutaneous, isatuximab, IV. But very encouraging data and we’ll have to see how all of these pan out.

Next, I’d like to move to the relapsed myeloma and we’ll cover a couple of abstracts, the use of selinexor post-dara, BELLINI as well and a little bit about belantamab.

So here, there’s a study looking at the use of selinexor treatment in daratumumab refractory patients. And this is an ex vivo drug sensitivity in an RNA-Seq analysis. And I think one of the reasons this is important is, again, the whole sequencing question because if we now agree that both for transplant eligible and ineligible, CD38 frontline is really here to stay, with the caveat being, of course, that in the transplant eligible patients, we know that len maintenance is going to be used until progression, dara and if isa pans out, the GRIFFIN study, for example, only did fixed duration.

So there’s a slight distinction and I bring that up because a lot of people talk about relapsed myeloma. Not all relapsed myeloma will necessarily be CD38 refractory, but let’s just take the example that they are and what you can see here is different populations of cells. And so in panel A, the ex vivo drug sensitivity is relapsed in the immediate prior line is in blue, earlier prior line is green and in dara naïve is red. And there’s more sensitivity actually in the dara and the immediate prior line. That’s also shown in the expression profiling in panel B in the middle. And then the pathway analysis shows that there’s different genes that are upregulated in daratumumab resistant versus selinexor responding patients. And so basically, I think this slide shows, and this study, that selinexor which is a novel MOA may be particularly beneficial in patients who are CD38 refractory. Again, of course, these are laboratory translational studies and we need to validate them in prospective clinical trials as well.

So you’re used to this display but now, we’re going to move to the relapsed disease and to set up the BELLINI study. So what are we showing here? These are bortezomib/dex backbone studies. In myeloma, we’re fortunate to have a lot of pivotal Phase III studies, all in high-impact journals, all FDA approved. So we have the OPTIMISMM study which is Vd control arm versus the addition of pomalidomide. BOSTON study which adds selinexor. CASTOR adding dara. ENDEAVOR, carfilzomib at high 56 mg/m2 twice weekly. And BELLINI, venetoclax. So all Phase III studies, randomized. And, again, in pink, you see that the Vd control arm itself can have a PFS as short as 7.1 months to as high as 11.4. So, again, we should avoid cross study comparisons. And I would just add one caveat that CASTOR is the only one that was fixed duration Vd. All of the other ones were until progression. But it tells us that whether you intend to give Vd for fixed or until progression, it’s hard to give this drug twice weekly until progression because of the neuropathy and side effects. Lines of therapy, anywhere from 1 to 2. And then prior len refractory which is important because that confers the worse outcome. Other than the pom study, they tend to be around 25%, median follow-ups. BELLINI was updated at this ASH of 45.6 months. The CRs are as indicated.

And then the hazard ratios, here’s the experimental arm PFS. And you can see that they stack up from 11.2 to 23.4 months. But the hazard ratios fall into the range of 0.31, a low for CASTOR to as high as 0.7. What’s unique about this BELLINI study which is venetoclax/bortezomib/dex that was updated by Dr Kumar at this year’s ASH is it does have a PFS benefit. You can see, and the median is 23.4 versus 11.4. Hazard ratio of 0.58. But cautionary tale that even PFS is a surrogate. We talked about MRD being a surrogate but look what happens in the bottom row for overall survival. Not everything’s been reached. Some of the follow-up is shorter. But in the ENDEAVOR study, the hazard ratio was significant, but in BELLINI, the hazard ratio was actually in the wrong direction. There were more deaths in the venetoclax/bortezomib/dex arm than the Vd arm and that was 1.19. And so the question is, what’s going on?

And here is the breakdown of the patient populations to help elucidate that. And this has been published before, but this is the final update looking at overall survival because previously we had interim. And actually to be fair, that hazard ratio for death was diminishing with further follow-up. So what we see here is that the median PFS hazard ratio is 0.58 in the first row. Median OS hazard ratio of 1.19 which is what you saw in the table. But look at what happens in the second row of each of these tables. 11;14 myeloma, hazard ratio of 0.12 which is a 90% improvement in the likelihood of progression, 36.8 months versus 9.3 months. Admittedly, a small sample size, but this is our first example of myeloma of personalized medicine. If you don’t have these, the hazard ratio is not significant for PFS. And similarly, for overall survival, the hazard ratio for 11;14 is 0.61. Again, wide confidence interval, but definitely trending in the right direction. If you don’t have 11;14 and you don’t have BCL2 overexpression, and I caution, this is not by immunohistochemistry, but by PCR. So it’s not available at the bedside, but it is done in the study. If you have non 11;14 and non BCL2 overexpression and, of course, venetoclax targeting BCL2, the overall survival hazard ratio was in the wrong direction. So I think BELLINI is a very important cautionary tale. Let’s look at MRD negativity. Let’s look at response rates and PFS, but don’t forget the OS readout because you may be harming patients. But I believe these data really support venetoclax. I personally am using venetoclax admittedly off label in relapsed myeloma as early as I can get it for my patients because a hazard ratio of 0.12, if you look on the other Vd studies, it really even beats out the DVd. So it’s really a gamechanger and we really look forward to larger randomized studies with enrichment of this population to validate that.

Now let’s talk about the BCMA antibody drug conjugate known as belantamab. This is — these are the studies that have been done with this agent. DREAMM-2 is what led to its approval which was 196 patients, triple class refractory. The only update we got at ASH was this ALGONQUIN study which combined this belantamab with pomalidomide and dexamethasone. The dosing that was studied varied, but the group that had the largest was with q4wk dosing. And importantly, all of these patients were pom naïve.

And the take home message from this combination is very encouraging efficacy data, 25.3 months PFS compared to the triple class refractory monotherapy which, of course, is a difficult population and very different with a PFS of 2.8 months with the approved dosing of 2.5 mg/kg. But the keratopathy remains a problem. 75% of patients had Grade 3 and higher keratopathy and 100% had keratopathy. So I think we would all like to see this drug get more investigation into the right dose and schedule to mitigate that keratopathy. There is a REMS program for this drug. But I think the data are very encouraging for this efficacy perspective.

Updates from ASH 2021 on CAR (chimeric antigen receptor) T-cell therapy for MM

DR CHARI: Now let’s switch gears to T-cell redirection CAR T. And to just set the stage, and it goes back to what I was alluding to with the belantamab, there was an interesting study in myeloma that looked at many drugs and many studies and found that to get a drug approved in advanced myeloma, you basically need a target of 20% response rate. But obtaining a 20% response rate is challenging. You can see that when you’re not triple class refractory, which is PI, IMiD and CD38, the median OS is 11.2 months. But then as you go to quad, triple and then when you get to penta-refractory, the OS is only 5.6 months. And many might say these patients could even go to hospice. So 20% response rate in the heavily treated population seems like a pretty low benchmark, but that’s what a lot of agents like selinexor, belantamab are proved on the basis of that for accelerated approval.

And so, of course, there’s a lot of interest in oncology of T-cell redirection. In advanced myeloma, we know that T-cell health is impaired. You have less memory T-cells, you have a lower CD4:8 ratio. You can see all of these perturbations in normal immune function. And yet, I ask the question in Phase I studies of relapsed refractory myeloma with median of 6 lines of therapy, T-cell engagers are giving response rates of 60 to 100%. Keeping in mind that the benchmark was pretty low at 20%. And the PFS usually would be 3 to 4 months and now, we’re seeing 9+ months. So it’s kind of a dramatic paradigm shifting change. The targets that are getting the most attention are BCMA on the left, GPRC in the middle oval and FCRH5 and we’ll talk about these 3 targets.

Why study BCMA, B-cell maturation antigen? This is a receptor for some B-cell transcription factors, BAFF and APRIL. When you knock these out in mice, B-cell survival is normal, but there’s impaired plasma cell survival and as a result, you do have decreased antibody production which is an important feature of BCMA targeting drugs, particularly in the era of COVID which we’ll get to in a second. But you can see that BCMA expression primarily shows up later in B-cell ontogeny.

And when we look at CAR T therapeutics, and shown in the red boxes are the updates from ASH to put it into context, but basically, of CARTITUDE-1 which is cilta-cel and then this CRB-401, ide-cel, 21217 and then CT103A. These are different CAR Ts. You can see that they range in the sample size. And I should add that the CARTITUDE-1 also got an update. So they have median very heavily treated 5 to 8 lines of prior therapy, triple class refractory. Primarily, US-based regimens and Western Europe will have very high percentages. Those coming from China, a little bit less, 17%. CAR T doses vary across these constructs, as little as 0.75 x 106 to as many as 800. And so you can’t do cross study comparisons. Each constructs are different. Most of these are lentivirus, but there is a transposome and then some of these are murine, some are human and some are llama. And the response rates, amazing across the board, we’re looking at 70 to 100%. CRs ranging from 33 to 83%. We did get updates from the CARTITUDE-1 with additional follow-up.

With about 24-month follow-up, the PFS was not reached, 61% in comparison to 8.6 months with ide-cel, 25.3 for the CT103. So stay tuned for more mature data, but that’s really encouraging keeping in mind the heavily pretreated nature. We were just looking for a PFS of 3 to 4 months and now we’re getting over 24 months. OS, very encouraging, 74%. Striking about ide-cel, 8.6 months PFS, but 24.8 months OS which is important because it tells us that the CAR T is resetting these patients in some way. It’s not that these patients are going from CAR T to dying, they’re able to be salvaged which is amazing for these patients. CRS is obviously common to CAR Ts. The rates range from very low for the LUMMICAR and the BCMA-101 that were presented at prior national meetings to as high as 95%, but high-grade CRS tends to be low on the order of less than 5%. Neurotoxicity ranging from 1 to 20%, but high-grade typically on the less than 10% side.

So there were a couple of updates of how do you interpret this data compared to real-world therapies for these heavily treated patients? There’s the so-called LocoMMOTION study that was studied by Dr Mateos. This is not an interventional study, but rather a real-world comparator study. And you can see that when they compared cilta-cel to real-world patients, these were form clinical practice, the hazard ratio was three-fold better for the cilta-cel even with adjusted 4.43. You can see that the PFS hazard ratio is 0.15 after adjustment which is quite impressive. And for OS, 0.38. When you restrict it, because one of the challenges with CAR T is not everybody who signed consent was actually able to get to infusion. So in the bottom part of the table, for this cilta-cel patients who actually got infused, you can see that the overall response rate still remains favorable and, of course, the PFS and OS hazard ratios are even better.

And, of course, the purpose of these is that the accelerated approval studies that are done don’t have a comparator arm and it’s to put these into context and the preliminary data, of course, being very encouraging. It will have to be confirmed by actual prospective randomized controlled studies.

And just an update on CARTITUDE-2 from ASH. And the difference between CARTITUDE-1 and 2 is shown here. Smaller study, 20 patients. This is a Phase II unlike the previous one which was Phase I. Much less heavily pretreated, only 2 lines of prior therapy. Much less triple class refractory. Same dose. Same construct. Follow-up is much shorter, only 9.7 months versus 24 months for the cilta-cel that we heard about. Same great response rate. Same CR rates. PFS, very encouraging, but fairly limited follow-up. Encouraging OS. But I think the biggest take home from the CARTITUDE-2 is not so much the efficacy, it’s the toxicity profile because these patients being less heavily treated, we talked about the impairment in T-cell profile and immune health of advanced myeloma, the question, of course, is if you move T-cells earlier, what’s going to happen to the toxicity profile? Are you going to see more toxicity? CRS remains the same. The Grade 3 and higher, 10% of 20 patients, so we’ll need to see larger numbers. But it’s not whoppingly high. Neurotoxicity, in contrast, none of these patients had high-grade neurotox. So I think this bodes well for the movement of T-cell redirection in earlier lines of therapy.

Data on bispecific antibodies at ASH 2021

DR CHARI: And to conclude our discussion today, let’s move to bispecifics because not everybody can wait to get to CAR T. So fortunately we have a lot of bispecifics in myeloma. And, again, for simplicity, I’ve summarized them in tabular format. The ones that have been updated at ASH are shown in the red box here. But in prior meetings, we’ve heard about AMG-701, CC-93269 and we are hearing now about erlantamab, REGN5458, teclistamab and TNB-383B. So the treatments typically, they’re all IV. The notable subQs are elranatamab and teclistamab. Sample size ranged from 20 to almost 165. All heavily treated, 5 to 6 lines of therapy. Many triple class refractory, anywhere from 20 to 80%. The response rates are, again, those days of 20 to 30% are really behind us because the vast majority of these are showing response rates on the order of 60 to 80% at the therapeutic doses. And then the duration of response is not reached. At 6 to 8 months, the vast majority of patients are maintaining their responses.

And the toxicity profile, we’re seeing CRS in all of these patients, 50 to 90%. But high-grade CRS is typically single digit which is great. One unique thing we are seeing across the board with BCMA targeting is infection profile. So we’re seeing that infections Grade 3 and higher can be as high as 20 to 35%. And, in fact, there are COVID-related deaths, and you can see this in the teclistamab which has a little bit larger sample size, 7 COVID-related deaths. So we talked about knocking out BCMA can impair antibody production, these patients we now know form multiple datasets are not getting good vaccine responses. So I really encourage anybody giving BCMA directed therapy to take use of those COVID therapeutics that have been approved whether it’s the pills, the IV treatments of the injections to prevent because these are the patients that need them. And then the cytopenias are also part of this target with this MOA. And you can see neutropenia ranging from Grade 3 and higher can be as high as 60%. And anemia and thrombocytopenia, a little bit less.

Two other targets that are getting interest, GPRC5d, which stands for G-protein-coupled-receptor classified member D. It’s a transmembrane protein unlike BCMA which can be shed and that’s why there’s actually agents that are looking to block the shedding. This does not have any known shed peptides or extracellular domain shedding which also makes less of a sink effect. Primarily expressed in plasma cells. And higher expression correlates with worse prognosis as you can see on the right. And there seems to be an overexpression, you know, relative to normal in all of the myeloma and precursor conditions as shown in the bottom panel.

Another exciting target is FcRH5 which stands for Fc receptor homolog 5. And this is a surface protein of the immunoglobulin family. It’s related to Fc receptors. We don’t know much about the ligand or the signaling pathway, but you can see protein expression in both the left and middle panel is higher in myeloma cells relative to normal and also, mRNA is higher in myeloma.

So with that preclinical data, when we look at the clinical studies that were presented, there were 3 relevant studies to be discussed. One is the GPRC5d single agent study known as talquetamab Phase I MonumenTAL study. I had the pleasure of presenting the combination study of talquetamab and dara known as the TRIMM-2. And then also, the FcRH5 cevostamab study was presented by Dr Trudel. The single agent study, there were 2 doses, 405 and 800. These are heavily treated, again, across the board in all of these studies, 5 to 6 lines of therapy. The sample size ranges in the various studies as indicated. Interestingly, these studies do include prior BCMA. We’re using a different target and I would submit that our next unmet need, we already said is triple class refractory, but it’ll probably be quad refractory. So what happens when you fail PIs, IMiDs, CD38 and BCMA? So it’s nice to have some representation of these patients here to show for the future. A lot of refractory, penta-refractory as you can see, almost 70 to 80%. And really encouraging response rates, 67, 70% as monotherapy.

And importantly, in the study that we presented, over half the patients had prior BCMA and yet, we’re still getting these impressive responses at 81%. And FCRH5, also very encouraging at nearly 60%. Same story with bispecifics. CRS, this is common, but no high-grade. Infections, what’s unique about GPRC5d is only 5% Grade 3 and higher infection. So I think this is a really different paradigm. Obviously, when you include daratumumab, you can increase the infection profile to the baseline 10% we see. And cevostamab, 19% Grade 3 and higher. The cytopenias with talquetamab seem to be less, at least with the 800 mcg q2wk than we saw with the monotherapies with the BCMA. And comparable also, low rates for the cevostamab. There are some skin and nail related changes with the talquetamab that are important to keep track of and use supportive care. That was actually the basis of one of our presentations at ASH that these are typically manageable with topical steroids and emollients and also hydrating solutions.

So my conclusion for these advanced treatments, advanced myeloma patients for penta-refractory, obviously, keep in mind what these patients want. What are their prior therapies? What’s their organ function? Are they study eligible, interested and have measurable disease? If so, if they have rapid progression and are close to an academic center, bispecifics are great. If they’re more indolently progressing and you have time to collect the T-cells and manufacture and wait that 4 to 6 weeks for the auto CARs to be made, if they can tolerate high-grade CRS, neurotox and if they live far from an academic center, the one and done CAR T really is hard to beat. Also, encouraging data with CELMoDs. If they’re not eligible, there is ide-cel which is a commercially available CAR T. And also, if they have low blood counts or are not eligible for these studies at this time, you can consider salvage auto or 96-hour infusional chemo. And finally, if they have 11;14, venetoclax-based regimen, if they’re not cachectic, because that is one of the side effects of selinexor is weight loss, perhaps 17p deletion, we saw increased retention and borderline renal function, a selinexor-based triplet. And if they’re willing and able to do ocular monitoring, belantamab.