Conference to Clinic: Integrating CD38-Based Quadruplet Therapy Into Care of Transplant-Ineligible and Transplant-Eligible NDMM

 

[00:21:44]

 

Myeloma Treatment Paradigm

 

Let us start off with the rationale for adding in CD38 as part of the induction therapy regimen.

 

I would argue that this graph has driven me crazy for about 15 years, because the presumption is that when you get to relapses, that the duration of response ends up getting shorter and shorter and shorter. I think what we have been excited about in terms of many of the recent new adds to our therapeutic armamentarium is that sometimes our immunotherapy approaches can be so good that they may actually even be better than what we saw on the front end with induction and consolidation.

 

If you think about the current paradigm, it really is divided into these 2 groups of treatment approaches. On the top, you see patients who are stem cell eligible, where you give an induction consolidation. At least in the United States, I think we think about the transplant as the consolidation. Then you go on to maintenance therapy. Whereas if you are transplant-ineligible, you get induction followed by continuous therapy, really highlighted with the MAIA study, but other trials that I think Dr Mikhael is going to talk about as well.

 

Now, I will say that I think that this distinction or differentiation is somewhat arbitrary. What I mean by that is the idea that in Europe, if you are over age 65, you are considered transplant-ineligible. If you are in the US up to age 79, you are considered transplant eligible.

 

The story I always like to give is I have said no to 50-year-olds, and I said yes to 77-year-olds. I think there really is a lot of interplay there, ultimately trying to understand how frailty plays into the discussion, and I think Dr Mikhael is going to touch on some of those concepts of frailty in his discussion as well.

 

As we think about treatment approaches overall, again, I said this is what we are going to focus on here in the next 90 minutes, is really this difference between induction therapies for older or frailer patients.

 

[00:23:49]

 

Factors Driving Treatment Decisions in MM

 

Now, as I mentioned, frailty really is 1 of the major determinants of outcomes. As you can see, if you look independently of genetics and tumor mass at the time of presentation, frailty actually is 1 of the most prognostic factors in terms of outcomes for patients. So yes, we have to deal with some of the genetic factors that we know can result in outcomes that are better or worse, as indicated by that low risk, high risk on the left.

 

But frailty in and of itself does limit your ability to deliver intensive therapy. We know that intensive therapy results in deeper responses. Deeper responses ultimately translate into better progression-free survival and often into better overall survival. That balance between frailty and genetic risk and all of those things are part of the process we go through when we are trying to understand how to manage a newly diagnosed myeloma patient.

 

[00:24:48]

 

Defining High-Risk MM and Additional Considerations

 

Now, what I want you to see on the left, in the upper left under cytogenetic risk is the new IMS/IMWG definition of high-risk myeloma. Everybody had their own definition of high-risk, which was great until you tried to compare across different trials. Then what you realized is that some trials define it 1 way, other trials define it another way. It really became very confusing.

 

This new definition, which was just published in JCO about a month ago, actually is a way to define the highest of the high-risk group of patients. These are patients that have both abnormalities of chromosome 14 with amplification of 1q or deletion of 1p, or they have del(17p), or they have p53 mutation. But realize that simply amplification of 1q alone is not considered high-risk anymore.

 

That is really based on data with triplets and quads. It suggests that the marginal negative impact can be overcome by the use of combination therapy. But if you have deletion of 1p and you have amplification of 1q, that is considered a high-risk cohort of patients.

 

We also know that patients with beta-2 greater than 5.5 with normal renal function is an independent prognostic feature. Then again, you can see some of the other functional high-risk groups of patients, particularly patients with functional high-risk, meaning relapse within 18 months. I actually think in the current era of quadruplet-based therapy, patients who relapse within 3 years of diagnosis likely represent that functional high-risk and happy to speak to why I use 3 years as opposed to 18 months during the Q&A as well.

 

[00:26:45]

 

Immune-Based Therapy: Targeting CD38

 

Now, if you think about what is it that allowed us to bring in a fourth drug because many drugs had auditioned to be that fourth drug. RVd, I think all of us would agree has been a standard for a long period of time, and we have tried to add things to it, like an HDAC inhibitor like cyclophosphamide or other new drug targets.

 

At the end of the day, none of them really panned out because the toxicity ended up being too high. But where CD38 came in, that made it such an important change in the paradigm is the idea that CD38 obviously is highly expressed on myeloma cells. It does function as an important part of adhesion molecules and mediates immunosuppression, but also CD38 is a great partner for both the IMiDs and the proteasome inhibitors. So basically you have a 3-way synergy going on when you use an anti-CD38 antibody in combination with a regimen like RVd.

 

We know, for instance, that the lenalidomide and the anti-CD38 are synergistic. We learned this from the POLLUX trial. We learned this from the APOLLO trial and many other trials that combined an anti-CD38 with an IMiD. We also learned from other trials combining an anti-CD38 with either bortezomib or with carfilzomib that we also get synergy in that context as well.

 

This really nicely identifies what the potential upsides of this quadruplet combination could ultimately be.

 

[00:28:23]

 

Rationale for IMiD + CD38 mAb Combinations

 

This is highlighted really nicely here again, where you see some of the immune mechanisms that CD38 antibodies do, such as elimination of Tregs, elimination of MDSCs, and elimination of Bregs. But really to me, it is about the synergy between immunomodulatory agents and proteasome inhibitors that really ultimately make this a much more palatable combination. As we will see in the clinical data, it really makes it a lot more clinically relevant across the board.

 

[00:28:54]

 

Rationale for PI + CD38 mAb Combinations

 

Now, again, here is the rationale in a little bit more detail for the PI plus the anti-CD38, what I showed you before was the IMiD combination. What I think you will see really nicely here is that some of this really does have to do with really in-depth combinations, including induction of immunogenic cell death, and that you get these things like prevention of immune escape and activation of NK-mediated ADCC.

 

Again, these represent the preclinical rationale for combining not only PIs and IMiDs together but also combining each of them with an immunomodulatory drug and a proteasome inhibitor together.

 

[00:29:40]

 

Currently Approved CD38 Antibodies

 

Now as you can see, these are the currently approved anti-CD38 antibodies in both the US and the EU. While this first column is IV daratumumab, which is what we did way back in 2015, all the way up through probably 2017 or 2018, I think is when daratumumab switched to subcutaneous. You can see I think for the most part we are either using subcutaneous daratumumab or we are using isatuximab.

 

In fact, I think we are all very excited about the idea of an on-body isatuximab that would give us a little bit easier mechanism of delivery for another anti-CD38 antibody as well.

 

These give you some indications for where they are approved based on randomized phase III trials.

 

[00:30:26]

 

Newly Diagnosed MM and the Evolving Role of CD38 mAb Therapy

 

Now again when we think about the evolving role of anti-CD38 in combination with induction therapy, what you will see on the left is that CD38-based quad using either RVd or KRd as the backbone transplant and then maintenance therapy that is either single agent lenalidomide or lenalidomide plus an anti-CD38 antibody.

 

Then on the right side of this, you will see the high-risk cohort of patients where again it is the same concept of an anti-CD38 based quad with transplant. At least in our hands right now an IMiD and a PI does remain the standard for the new IMS definition of high-risk patients, where no matter what you do, those double hit patients really seem to have very challenging outcomes across the board. We do actually combine that with an anti-CD38 to try and give them the maximal benefit from combination maintenance therapy.

 

On the right side—and you are going to hear more of this from Dr Mikhael as well—DRd, I think has become a standard of care for the transplant-ineligible, or as I describe the frail patient. But certainly alternatives include modified RVd-lite or Isa plus RVd. Again, that is continued until progression or de-escalation of therapy as indicated in the slide.

 

[00:31:49]

 

Conclusions

 

I think in summary, again, there is good biologic and preclinical rationale for combining anti-CD38 antibodies with both IMiDs and PIs. Fortunately, the combination does not significantly impact toxicity. I think there are a couple of areas where perhaps we see perhaps a little bit more neutropenia in the combination of an IMiD plus an anti-CD38. The infection risk is likely a little bit higher in that quad combination, but I think we have all been using these combinations long enough that we have learned how to mitigate those combinations and risks.

 

Quite honestly, they are not for all patients. Some patients go and tolerate a quad without a significant increase in infections. Others do have more infectious complications. Those are patients where preemptive or prophylactic IVIg may offer significant benefit as well.

 

What we do know about the quad is that the depth and speed of response is really quite impressive, and questions about the relative benefit of anti-CD38 in maintenance. There are randomized trials evaluating lenalidomide vs lenalidomide-daratumumab for patients who either did or did not get an anti-CD38 as part of their initial induction therapy. Those in my mind are going to be critical to establishing the role of dual maintenance as a standard, as opposed to simply lenalidomide alone as the maintenance problem.

 

[00:33:15]

 

Scope of the Problem

 

Okay. Let us talk about newly diagnosed patients, particularly in the context of transplant-eligible patients. What I like to start off with is a little bit of historical math here. In 2025, there are about 36,000 new cases of myeloma. Predominantly or a little more than half are men. A little fewer than half are female. What we do know is that when you go back to like 2008, 2009, that number was somewhere around 16,000 to 17,000 new cases per year.

 

Now, many people look at that and say there is an epidemic of myeloma. The number of cases has doubled in the last decade. But the reality is that what we are seeing is that as patients are living longer, the frequency of plasma cell disorders is becoming higher and higher because we know the prevalence of things like mGUS and smoldering increase with age as well.

 

Also, this is being picked up a lot more frequently as patients are coming to doctors and to medical attention, a lot more frequently now than they were 30 years ago. So we are picking up some of those precursors overall sooner than we would have before.

 

Well, we also know that the average number of deaths is about 12,000 per year. I think a good problem that I think Dr Mikhael and I and many of us who specialize in myeloma are all experiencing is that we have a growing patient population because the incident number of patients is continuing to increase. If you are growing 36,000 per year and fortunately you are losing only a third of them, then you have two thirds that are continuing on year after year after year, and the pool of patients does continue to grow.

 

Now the incident number is about 192,000 in the US overall. Now this 5-year survival of 62.4%, I actually think that that number is pretty dated. If you look at our own center, our 10-year survival is somewhere around 60%. Certainly 1 of those take-home messages is if you want to live longer, come see our group. But I think the reality is that many groups across the country are seeing better overall survival because we have better drugs to use and patients’ outcomes are significantly improving. I think that is really recognized and represented in the next bullet after that.

 

I did see a patient yesterday in clinic who I talked about the fact that the transplant is not likely curative for that patient, but the treatment is highly sensitive and can be put back into remission multiple times with the new treatments that we have. At first, he was a little disappointed by the fact that he could not be cured with initial therapy. But then again, the analogy I always give, and I am curious how Dr Mikhael handles this as well, is if you have hypertension and you take your antihypertensive, are you cured of your hypertension? The answer to that question is no. But you still can live a really long time simply by taking the therapy that controls the problem. In many ways, that is what myeloma has become in 2025.

 

[00:36:30]

 

Risk Stratification: IMS/IMWG Consensus on High-risk Myeloma Definition

 

I mentioned previously the definition of high-risk myeloma. I am not going to belabor that here again. But you saw that these are the new definitions of patients with high-risk. The old standard of either (4;14) or (14;16) or (14;20) alone no longer connotes high-risk disease as defined by the IMS/IMWG criteria.

 

What you do see is that it has to be combined with an abnormality of chromosome 1, and the only non-genetic factor that now characterizes as high-risk disease is beta-2 greater than 5.5, presuming the creatinine is less than 1.2. This is really critical because even as we sought to eliminate non-genomic based definitions of high-risk, beta-2 greater than 5.5 continued to be 1 of the most powerful prognostic indicators that we have. So we could not just throw it out because it really was as good if not better than many of the other genomics defined high-risk categories.

 

[00:37:38]

 

RVD Induction Therapy (N = 1000 Patients)

 

Now, I want to give you a standard before we get into some of the quad data for what we think has been a benchmark for outcomes for patients. This is the RVD 1000 series that we published at our center just a few years ago looking back at 10-year follow up on a cohort of patients who all received RVd induction, most received transplant and then received risk-adapted maintenance.

 

What I think you will see here quite nicely is that the median progression-free survival for the standard risk patients was 80.3 months. When we talk about not using a transplant, remember that is the number you have to beat if you are going to talk about not using a transplant. I am going to show you some data later on where even with an anti-CD38 antibody, where you think you are making non-transplant data look better with a transplant that PFS is now well above 80 months as part of a quad induction for standard risk myeloma.

 

Again, if you look at overall survival on the right, you can see that at 10 years, the median survival for the standard risk has not been reached yet. The high-risk is somewhere around 80 months is the median expected survival. I can tell you with our most recent cut of the data from the Dara-RVD 500, it is well in excess of 80 months now as well. We are certainly seeing significant improvements with the addition of an anti-CD38 antibody.

 

[00:39:05]

 

Induction Regimens in TE Patients With NDMM: Efficacy

 

Now what are the regimens that we know that really have NCCN category 1 based on phase III data level evidence. What you will see here at the top is the previous standard which was RVd plus transplant vs RVd alone. That was then I think upped by the addition of daratumumab to RVD. We then saw the randomized phase III PERSEUS, which was a bigger patient population than GRIFFIN that basically did the same design as GRIFFIN with daratumumab-RVd followed by transplant, followed by DR vs RVd transplant followed by single agent lenalidomide.

 

The IsKia trial is isatuximab-KRd vs KRd with transplant. Then the GMMG-HD7 was Isatuximab-RVd vs RVd. Both got transplants. Then a secondary randomization to either isatuximab-R vs R, which to me is actually going to be a really important end point. Unfortunately, we have to wait a long time to see it, but I think that will answer the question about the relative benefit of CD38 in induction, as well as in maintenance therapy for the same group of patients. I am certainly very excited about that.

 

What you will see here across the board is very high CR rates. MRd rates that are at least 50% higher favoring the Group that got the anti-CD38 antibody and progression-free survival that was significantly better for the group that got the anti-CD38 antibody as well.

 

[00:40:38]

 

PERSEUS: D-VRd vs VRd, Confirmation That Targeting of CD38 Benefits Transplant-Eligible Patients

 

I am going to show you just 1 or 2 examples of this, even though I have it summarized in that table, because I think the data really is very important.

 

This is the schema for PERSEUS, D-RVd transplant, D-RVd consolidation, D-R times 2 years. Then if you are MRd negative, you get single agent R. If you are MRd positive, you continue on D-R. This is until progression.

 

On the bottom, it is basically the same schema but no daratumumab. So no anti-CD38 antibody. Again, this in many ways mimics what was done in the GRIFFIN trial overall.

 

[00:41:12]

 

PERSEUS: PFS and MRD Negativity ≥ CR Rates

 

Now if you look at the progression-free survival, you will see a big difference at 4 years. This is 48-month progression-free survival. 84 vs 67 is often a hard number to remember. So what I am going to tell you is that 67% at 4 years is almost super imposable on determination.

 

It is internally consistent with what we see with RVd transplant, single-agent lenalidomide maintenance. At the same time, that 84% means that at 4 years, only 16% of patients had relapsed. That means you are averaging 4% per year. If you look at the control arm, you are actually averaging 8% per year. You have cut the relapse rate per year in half by adding in an anti-CD38 antibody.

 

What allows you to do that? Well, your MRD negativity goes from 47 to 75. At 10 to the minus 6, you basically double the MRD negativity rate. Those are not unrelated. Those are likely linked, that deepening of MRD negativity at 1 year and sustained MRD negativity being higher for the group that got daratumumab likely is the reason that you have been able to cut the relapse rate per year down significantly.

 

[00:42:42]

 

PERSEUS: PFS by Sustained MRD Negativity ≥ CR Status

 

Now, if you look at sustained MRD negativity, particularly for patients who had a CR or better, if you were sustained for 24 months, you can see those curves are relatively flat. Now, many will argue that whether you got daratumumab or you did not get daratumumab, if you were sustained for 24 months, you did about the same. That is a true statement. The problem is you are not going to know who those people are at the time of diagnosis. You got to make a call. You got to make a decision on who you are going to really optimally treat in order to magnify that group of patients.

 

Again, the percentage of people that have sustained MRD negativity in the daratumumab arm is almost 2- to 3-fold higher than it is in the non-daratumumab arm. If you are playing Vegas odds, you want to play the odds that give you the biggest proportion of people that are going to be sustained MRD negative at 24 months. That clearly includes the addition of daratumumab.

 

Yes, that means you may be over-treating a few patients, but we have accepted that risk in many other treatments where we know that the benefit for the population ends up being greater than for the individual.

 

[00:44:00]

 

GMMG-HD7: Isa-VRd vs VRd for Transplant-Eligible NDMM (Part 1)

 

Now, if you look at the GMMG-HD7, this is basically the same trial as PERSEUS. Only it used Isa-VRd vs VRd. Then as I mentioned before, there was a secondary randomization. I think it was in this trial, the secondary randomization to either Isa-R vs R. Again what you are seeing is that same separation of progression-free survival curves. The relapse rates at 48 months are very similar between those 2 treatments.

 

IsKia: Isa-KRd vs KRd for Transplant-Eligible NDMM

 

Again, if you look at MRD, you can see MRD was tested at a number of different time points.

 

[00:44:38]

 

IsKia: MRD Negativity

 

You can see that the MRD negativity and sustained MRD negativity at 10 to the minus 5 and 10 to the minus 6 is in fact substantially higher for the group that got isatuximab compared to the group that did not get isatuximab.

 

This is again really further demonstration that the anti-CD38 antibody, isatuximab can do the same thing.

 

[00:45:03]

 

IsKia: 1-Yr MRD Negativity by Subgroup and HRCA

 

Now again if you look at IsKia, which is another trial and we have only seen early data on this, what I think is really quite interesting is they are looking at patients with 1 and 2 year, they are looking at patients specifically who have high-risk disease, standard risk disease, or RISS 2 and 3 or higher. You can see that the benefit for the isatuximab arm, along with KRd is significantly better. Again, almost 3-fold higher when you look at MRD at 10 to the minus 6 compared to the group. So really substantial benefit for the addition of the anti-CD38 antibody.

 

[00:45:46]

 

MIDAS: MRD-Driven Strategy Following Isa-KRd Induction

 

Now the most recent trial that entered this discussion was the MIDAS study. MIDAS is using an MRD-driven strategy following Isa-KRd induction. What you will see here is they did not use genetics to define high or standard risk. What they really used was depth of response.

 

If you did not achieve MRD negativity at 10 to the minus 5 after 6 cycles of Isa-KRd, you were considered high-risk. If you were in high-risk, you were on that bottom arm of the trial and you got randomized to either 1 transplant with consolidation or 2 transplants.

 

On the other hand, if you were MRD negative at 10 to the minus fifth, you were considered standard risk and were randomized to 1 transplant vs no transplant.

 

[00:46:34]

 

MIDAS: MRD Negativity

 

What we saw at least recently is really 2 sets of data. The first is that if you were not MRD negative, you were more likely to have (11;14) translocation, than you were not to have (11;14). At the same time, if you were MRD negative, you were more likely to have the (4;14) translocation. That is certainly to me, a de-escalation question in that context is very concerning.

 

But what they showed us is post consolidation, that whether you were MRD positive or negative, the cumulative difference in MRD negativity was no different. In my mind, and many are debating what this really means. Many would argue that it means if you are MRD negative, you do not benefit from a transplant. I actually think it is too early to make that conclusion, but I do think it is certainly going to make it harder for a transplant to demonstrate benefit.

 

At the same time, if you were MRD positive, the benefit of a tandem transplant is less clear as well. Again, I think we are going to need to see progression-free survival ultimately to make those decisions overall.

 

[00:47:44]

 

MIDAS: Changes in MRD Status

 

Here is just an example of some of the changes in MRD that we are seeing post induction vs post consolidation, particularly looking at the (11;14) subset of patients where we know their responses are slower. (11;14) does not always convey a poor risk factor as it was treated in this trial. It is not surprising to me that they did not necessarily benefit from a tandem auto. But I think the (11;14) clearly do benefit from a single auto, even if they do not achieve MRD negativity.

 

[00:48:19]

 

Updated D-RVD 500 Series

 

Now I am going to finish updating you with the daratumumab-RVD 500 series. This is a series from our group again looking at real-world data comparing progression-free survival for daratumumab-RVD in blue as opposed to RVD in red. What you are seeing is that the curves are separating relatively early that the 2-year progression-free survival mimics almost identical to what I showed you in PERSEUS, 93% vs 82% in the RVD 1000 series.

 

What I think is really different from PERSEUS is that the overall survival is different now in R series as well. I think that likely is because in our real-world series, we are including more patients who have high-risk disease that were likely excluded from PERSEUS, and in fact, the early edition of an anti-CD38, while alone may not be sufficient in combination with a regimen like RVD may be salvaging some of those people that we lose very early in the course, and allowing them to have a better overall survival than the historical reference of RVD alone.

 

[00:49:26]

 

Significantly Longer Estimated PFS Projections With DVRd vs VRd for the Best-fit Distribution

 

Now, I am going to wrap up really making the case here that I think that while we are talking about the potential benefit or utility of transplant based on MRD negativity as seen in the MIDAS trial, this is an analysis that was presented by Dr Sonnenfeld in the EMN Group, looking at an estimate of progression-free survival over time for the many trials that and the many arms of both PERSEUS and CEPHEUS.

 

You are going to hear more about CEPHEUS from Dr Mikhael in just a moment. But CEPHEUS is basically PERSEUS, except no transplant. It is basically looking at daratumumab-RVd without a transplant and their PFS looks quite impressive and is clearly better than RVd alone. But if you look at the estimated progression-free survival for PERSEUS vs CEPHEUS, it is basically double.

 

Now, do I believe that it is really 20 years for PERSEUS? I do not know that I believe it is really 20 years for PERSEUS, but I think that the magnitude of benefit for the transplant is likely double than it is in the CEPHEUS trial, where there is no transplant. This, to me, is a reason not to stop referring patients for high-dose therapy, because I think there continues to be a significant benefit of giving patients the longest first progression-free survival they can get as part of their initial induction therapy.

 

[00:50:53]

 

Conclusions

 

I have my conclusion study. I think we do have a uniform definition of high risk. I showed that to you in a couple of places now. Quad induction is clearly important and drives higher rates of depth and response pre-consolidation. I do think the role of high-dose therapy continues to be important with projected PFS of greater than 14 years. Risk adaptive maintenance is important. I did not touch on that but happy to talk about that during Q&A.

 

Finally, data on early depth of response predicting long-term outcomes. I think MIDAS is really interesting. It is hypothesis generating, but I do not think it is quite ready until we see PFS benefit, to make us change our practice about delaying transplant for patients that achieve MRD negativity.

 

[00:51:40]

 

Optimizing Clinical Outcomes With CD38 Antibodies for Transplant-Ineligible Patients With NDMM

 

With that, I will hand things over to Dr Mikhael and let him take it from here.

 

Dr Joseph Mikhael (HonorHealth Research Institute): Wonderful. Thank you, Sagar. Well presented, as always. He is the master, and he does it well. I will challenge some of the statements that he made when we get to the Q&A to think a little bit about it. I actually about 99% agree anyways, Sagar. But there is always a few things.

 

I might comment that, although I think it is still appropriate to refer for transplant and we do need more time to decide on that, I would not be buying transplant stock right now, because I am not sure how much longer we will be doing that, but time will tell.

 

Let us shift our focus a little bit. I actually really enjoyed the way Dr Lonial described the notion that we are challenging this historical division of transplant eligible and ineligible. Sometimes it is just mitigated for those of you who are here from Europe, for example, it may be mitigated by sheer age, or in my home country in Canada, where there are certain provinces that say if you are 65 years old and 1 day that is it, you are too old for transplant.

 

But I think we are shifting and are thinking a little bit also about whether or not someone is quad eligible because there are patients who you might initially see who are in your mind, not transplant-eligible, but with the rapidity and the benefit of initial treatment, sometimes the frailty is guided by the disease. As we control their disease, we have had patients who at first I think, oh, I do not know if I could ever take it to transplant, but then they start a round or 2 of quadruplets and all of a sudden now they seem to be eligible.

 

For the sake of this talk, we are still, as you can see from the title, distinguishing transplant eligible and ineligible. But it is fascinating how those 2 areas have really had a very similar, at least initial treatment prior to a stem cell transplant.

 

[00:53:39]

 

Objectives

 

What are my objectives in this section? Here I have 2 sections, just like Dr Lonial did. Well, we will speak primarily about transplant-ineligibility, or patients who are ineligible for transplant. Then we will talk a bit more about aspects of health equity.

 

In this first section, we will talk a little bit more about the depth of response. I mean, you cannot go to a myeloma meeting now and not hear the phrase MRD. You just heard Dr Lonial beautifully describe the MIDAS trial. It is not just the MIDAS trials. So many of those trials he has mentioned, whether it is a primary or secondary endpoint of the study, we are using MRD negativity so much more and will likely be guiding more of our therapy. We will talk a little bit about MRD. We will look at those quadruplets that we are using now in transplant-ineligible patients, although I agree with what Dr Lonial said, not everybody. You do not want to go see your patient tomorrow and say you will take a quad and you will like it. Not every patient should be treated with a quad, and we will talk a little bit about that.

 

I think part of the application of quads is these last 2 objectives, which is making sure that we assess our patients appropriately when it comes to frailty. When we select transplant eligibility. But also, I will share a little bit of my experience, and I want to be careful not to get too much into anecdotal treatment, although there is a lot of work now looking at how we dose-modify those quadruplets.

 

Dr Lonial had mentioned maybe sometimes we have to give prophylactic therapies like IVIg or others, but there are things that we can also do with the quads themselves, the dosing of the drugs that in certain patients in particular, might either allow us to give the quad or allow for fewer side effects. I will share a little bit about common practice.

 

[00:55:26]

 

Relapsing Nature of Multiple Myeloma: Clones Change Over Time

 

You saw a relatively similar slide to this earlier, so I would not spend a lot of time on it. This one emphasizes the fact that we have to remember that myeloma does mutate and change over time. The patient is getting older, they are acquiring more comorbidities as well as the disease is acquiring new mutations.

 

We are defining some of the relapse results in a shorter period of remission by virtue of the therapies that Dr Lonial had mentioned. But I would like to re-emphasize the point that he made, that what we do front line makes a big difference in the long term. No matter what great options we have later, we still want to give patients the longest first remission possible because that contributes not only to their quantity, but their quality of life as we go forward. That is why these therapies are so important.

 

[00:56:15]

 

Depth of Response Matters!

 

We are learning. And it goes without saying that that depth of response matters. In this initial slide here, you see how we measure MRD negativity by different levels. You can just imagine the more precise we become, the fewer and fewer cells that we detect, the likelihood that the patient will remain in remission longer. There are always exceptions to the rule. The biology of myeloma is complicated. It humbles us on a regular basis. We have some patients, and I know Dr Lonial has patients in his practice where they have never achieved a VGPR, let alone an MRD negativity. They live a very, very long time. But that is a small fraction of patients. In general, the depth of response matters. The deeper the remission typically will translate into a longer period of time in remission.

 

[00:57:08]

 

Transplant-Ineligible Patients

 

Our Spanish colleagues have helped us understand this. I find these studies fascinating because this looked at both progression-free and overall survival. There is a lot of data here, but I will simplify it. Basically, if you are on the red line, then patients did not respond. So no surprise they do not do well. If you are in the green line, you are MRD negative, they did the best. No surprise.

 

What was surprising here is that all the categories of response otherwise are pretty much merged together. Whether someone had a 51% drop in their monoclonal protein, or 99% drop in their monoclonal protein, or even 100% without MRD negativity, their outcomes were quite similar. There is something unique about getting into true MRD negativity, and that is 1 of the reasons why we talk about it so much.

 

[00:57:57]

 

Transplant-Ineligible Patients

 

As we think about transplant ineligible patients, there are just 3 trials I get to quickly summarize, and I know we are giving a lot of data tonight. I will reiterate again, if you have questions, please put them into the Q&A box. We will have plenty of time at the end because we still have about 45 minutes, and I am clearly not going to be babbling for that long. Please enter your questions as you wish.

 

There are 3 important studies that I want to review that you can see are all large studies with a pretty much huge number of patients, almost over a 1,000 patients here in total, where we will look at as Dr Lonial has already primed us to quadruple therapies of using a CD38 with bortezomib and lenalidomide and dexamethasone vs VRd, either with isatuximab or with daratumumab. Let us walk through them a little bit so that we can understand.

 

[00:58:48]

 

Tips for Assessing Frailty

 

As we come to the studies, let me just preamble that when we are assessing frailty, it really is not just about age. Now there are some age cutoffs. We have a controversial case that we shared with you where we had the 80-year-old individual. I hope that gets you thinking a little bit, but age is not by itself that important a factor in general with the exception of maybe sheer extremes. There is a lot more to do with frailty.

 

As I commented earlier, disease burden may play a role in frailty and that may improve. Certain aspects of frailty can improve with treatment. Others that do not improve or even perhaps worsen by virtue of the treatment that we give.

 

There should be some kind of appropriate geriatric assessment. Obviously, it is a whole other talk to give to that. But there is an IMWG frailty score. There are other scores that are available to them. Obviously, some of the larger centers that have big multidisciplinary clinics with the geriatric experts can really help. But in general, we want to have a standardized system of doing this. You do not just look at the patient, say, they walked in, they look pretty good. Therefore they are not frail. We want a more rigorous method of doing so, and there are many methods.

 

That being said, as we treat patients, we want to give them that benefit of the greatest therapy possible to give them that depth of response. But there are aspects of frailty that will cause us to have to dose adjust, whether it is going down to a triplet or a potentially even dose reductions within the triplet or quadruplet.

 

[01:00:24]

 

Phase III IMROZ: Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone
(Isa-VRd) vs VRd for Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma

 

The first of these studies I mentioned was the IMROZ study.

 

[01:00:28]

 

IMROZ: Isa-VRd vs VRd in transplant-ineligible NDMM

 

The IMROZ study was a particularly important study because it led to the approval of isatuximab-VRd or bortezomib, lenalidomide and dexamethasone here in the United States last year in 2024. As you can see here, the design of the study pretty straightforward, Isa-VRd vs pretty much standard VRd. This was given with the traditional dosing of bortezomib given twice weekly on this regimen that you see here.

 

What was quite impressive out of this study really was the primary endpoint of progression-free survival.

 

[01:01:00]

 

Primary Endpoint Met: Interim PFS Analysis (IRC Assessment in ITT Population)

 

Let us just look at this. At 5 years, you have 63% of people still in remission in the quadruplet vs the triplet arm were about 45%. This is quite striking to us because this is about—and I hate to cross trial compare—but the MAIA study that Dr Lonial referenced, which has really been our standard up until now of using DRd. So not having added the bortezomib to that combination gave us about a 5-year PFS of 53% roughly.

 

You have about 10% improvement, again, with all the challenges of cross trial comparisons. But we will give you another study to help demonstrate the difference.

 

[01:01:46]

 

Phase III BENEFIT (IFM2020-05): Isatuximab + Lenalidomide and Dexamethasone With Weekly Bortezomib vs Isatuximab + Lenalidomide and Dexamethasone in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma

 

That is the BENEFIT study. In the BENEFIT study, they took a similar quadruple, isatuximab plus VRd.

 

[01:01:51]

 

BENEFIT: Study Design

 

But here compared it instead of VRd compared it Isa-Rd, if you will. A similar approach to the historical MAIA study of a CD38 lenalidomide and dexamethasone.

 

The second differentiating feature of this study was that the bortezomib was given once weekly, and you can see it was planned to give to about 18 months. Now, by the author's own description, they figure that most of the benefit of the bortezomib was had by 1 year, and that extra half year likely contributed to more toxicity and not so much to further depth of response. Again, I always want to be careful, but I will be coming back to this point that I typically try not to use more than a year of bortezomib in older, more frail patients who are not going to transplant because you are kind of asking for neuropathy. I want to be particularly cautious. As we all know, sometimes neuropathy can be irreversible. We have to be very careful in detecting it and talking to our patients about it and intervening typically with less frequent dosing.

 

In fact, some of my patients, as I will show you in a moment, at the 6-month mark, I reduced the bortezomib every other week, but we will come back to that as we think a little bit about how we approach a dose modifying these.

 

[01:03:07]

 

Primary Endpoint: MRD- Rate at 18 Mo (ITT Population)

 

Nonetheless, in the BENEFIT study, which is a little bit earlier on, but its primary endpoint was MRD. That is why we do not have a lot of PFS data. You can see a rather dramatic difference in that primary endpoint in the fraction of patients around 50% with the quadruplets, vs more like a 25% in those patients that just had the triplet.

 

We had this great case that Dr Lonial made of adding a CD38 to the standard VRd. I think now we also have a similar case of the ongoing value of bortezomib, as we have seen in the studies he presented for transplant eligible and now here for transplant ineligible patients or these patients are not going to transplant.

 

[01:03:48]

 

CEPHEUS: Study Design

 

Then lastly, the CEPHEUS study, which he also referenced very clearly, was much like the PERSEUS study. But now in patients that are either transplant ineligible or, if you will, deferred those who did not want to go immediately to transplant. You can see this is now daratumumab the other CD3 antibody given with VRd.

 

[01:04:10]

 

CEPHEUS: Primary Endpoint of Overall MRD-negativity ≥CR (10^–5 and 10^–6) Rates and PFS

 

Again, quite impressive results with these patients where at 54 months here we are not quite out at the 60-month mark, you have 68% of patients still in remission vs about half with VRd. That depth of response specifically by virtue of MRD negativity, if we look at it, MRD at least 10 to the minus 5 in 61% vs 39, or 10 to the minus 6 of 50, 46% vs 27. Again, a really significant difference by adding that daratumumab to the historical VRd backbone.

 

[01:04:44]

 

Phase III CEPHEUS: Subgroup Analysis of Daratumumab + Bortezomib, Lenalidomide,
and Dexamethasone (DVRd) in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma

 

Then lastly, we have a recent update to that study, the CEPHEUS study, where they selected out those that were truly transplant ineligible. Remember, it was a combination of those who were deferred and those who were ineligible.

 

[01:04:58]

 

CEPHEUS TIE Subgroup: Overall and Sustained MRD Negativity ≥ CR Rates

 

Herewith we look more specifically at the ineligible. They looked at both MRD negativity and sustained MRD negativity. I am glad that Sagar made comment about the fact that MRD is a very powerful tool, but it is particularly powerful when it is measured on a repeated basis because, paradoxically, we have some patients in myeloma that get this great deep response, but then they relapse very quickly. We want patients to get into a response and stay in a response.

 

At every turn hear that, when we look at whether it is overall MRD negativity or sustained MRD negativity at 1 year and 2 years, it clearly favors the quadruplet over the triplet for those patients who are transplant-ineligible.

 

[01:05:41]

 

CEPHEUS TIE Subgroup: Progression-Free Survival

 

Indeed, we can see almost identical PFS, 69% vs 48% that we saw in the whole cohort. This really did apply across the board, even those who were transplant-ineligible.

 

[01:05:55]

 

Important Lessons in Transplant-Ineligible Patients

 

What are maybe some of the key lessons as we try to wrap up this section? Again, this is where we will have a bit of a discussion. It all depends on how you define the word most. But I do think that it is feasible to give quadruplets to the majority of our patients.

 

Now there are some patients that it is clearer that you would not do that. I did not note specifically in the IMROZ study that if you are 80 years or older, you were not eligible for the study. But as we commented before, frailty is the better measure than just age.

 

The concept, I think, of combining these multiple mechanisms of action is clearly validated that there is that synergy that Dr Lonial started this talk with, describing using these different mechanisms of action together. I think we still need to get better at assessing frailty, because it is still done very differently in different places. We are working at the International Myeloma Working Group to standardize that more clearly.

 

Now, again, this is a little bit now softer evidence than what I have shared with you in terms of phase III. But to give some guidance and some help as we use it pragmatically, that there are patients in whom we can dose modify. I am particularly concerned in an older, more frail patient about neuropathy because it can be so life incapacitating. Of course, it can incapacitate anyone, but so I will typically use the weekly bortezomib by virtue of the BENEFIT study.

 

In Dr Lonial group, they do continue to use it twice weekly in certain patients. I think that is valid by virtue of the studies the way they were done. But I think in particular in the older, more frail patient, I would look to that and I would look to pretty much stopping it at 1 year, obviously, based on how the patient is doing and even sometimes at 6 months based on their depth of response. A lot of these patients have a great response. I may consider dropping it to every other week.

 

Often, I have to say, do not always use that full 25 mg of lenalidomide in the older, more frail patient that there are times we can go down to 15 or 10. Lenalidomide is such an interesting drug is that I was just telling a patient yesterday in clinic, okay, giving you 10 mg, it sounds like it is less than a half of the 25 mg. But the effect of this drug is not so easily dose-dependent in the way that that it works. Some of these patients can really do well with lower doses.

 

Then, I know that Sagar and I battle over this notion of Down With Dex. I will share with you something about that in just a moment. But I do think that now we have this powerful synergy of these 3 major classes of drugs. The role of dexamethasone, which we do love. Dexamethasone helps with antimyeloma effect. Dexamethasone reduces infusion or administration reactions. Dexamethasone can help with pain. Dexamethasone can even help with nausea to some degree.

 

I do think that its greatest benefit is within the first few months. With time, as dexamethasone causes more side effects, I am more prone to tapering it over time.

 

Risk status may also influence your thinking around a triplet vs a quadruplet, where we know based on the new classification that Dr Lonial shared with us, that if I have that older, more frail patient, I am wrestling between a triplet and a quadruplet, and I think triplets are still valid in that context. If I know that patient is higher risk, I may be more concerned and more interested in adding the bortezomib to the triplet combination.

 

[01:09:15]

 

Down With Dex!

 

This Down With Dex, as I was sharing with you that we just had a wonderful nurse practitioner I have the privilege of working with, and I just wrote a cute little editorial called Down With Dex. I am not saying it is the gold standard.

 

What we have done is be careful off the start to not start everybody on 40. Thankfully, a lot of our protocols now ensure that that is not the case, especially in older, more frail patients. Our French colleagues are even creating protocols where dexamethasone is only given for 2 months. But what we are suggesting here is choose that starting dose, give it for 2 to 3 months, and then begin a taper over time with very careful watch, obviously, of their response and their toxicity as we go forward. We had that big drop from high dose dexamethasone to low dose dexamethasone years ago, and I do think now we are likely moving to lower dose dexamethasone exactly amount to be defined.

 

[01:10:04]

 

Frontline Therapy: Conclusions

 

To close this section, a few conclusions. I think we can argue that we have already transitioned to quadruplets, especially patients eligible for frontline treatment, those who are eligible for transplant. I think a significant proportion of patients who are so-called transplant ineligible. As we have noted, we need to maybe start thinking in terms of quad eligible as opposed to just transplant eligible, not eligible. I think we still have some questions about the optimal length of quadruplets in both groups.

 

Dr Lonial mentioned that we need to wait a little bit longer for some of the maintenance studies to guide us through dual maintenance vs single maintenance, which may also be adjusted by virtue of risk. But nonetheless, getting that synergy off the start is quite clear.

 

I think MRD is becoming an increasingly important factor in what we are doing, whether or not it massively changes our treatment, we need good data going forward because above all, do no harm. I do not want to over-treat nor under treat my patients. Paradoxically, for some of these patients who we may be able to discontinue therapy with time, giving more upfront may actually give them a shorter time total on therapy.

 

It is not always more and more and more by the myeloma doctor. There may be an opportunity to actually shorten therapy overall.

 

[01:11:22]

 

The Evolution of Myeloma Therapy

 

I just like to always show this slide because it is amazing how far we have come. In the early days when Dr Lonial and I were myeloma newbies, this was a really easy slide to present because it had 1 or 2 drugs on it. Now the list continues to grow and quite likely will grow in the next week.

 

[01:11:46]

 

Strategies for Supportive and Equitable Care in NDMM

 

At this point, let us just shift focus for our final talk before we open up for Q&A, where we have strategies, as we have described it here, for supportive and equitable care in myeloma.

 

I know sometimes we will get to a topic like this, and people turn off. We really encourage you not to turn off because this is so important. I say it all the time not to sound cheesy, but to be honest, we do not treat myeloma. We treat people.

 

Now people with myeloma are living longer than ever. Sagar, to reassure you, I absolutely use the same example of hypertension in the clinic. People say, when is myeloma going to be cured? Well, we have not cured high blood pressure. We have not cured diabetes, but we control it for long periods of time. This now is even more important than ever that we pay attention to someone's quality of life.

 

Furthermore, there are dramatic health inequities in myeloma. In fact, I could argue that myeloma is the most disparate cancer within the African American community. Being African American myself, this is personal and professional, but we need to ensure that as we care for our patients, we are sensitive to the fact that those inequities exist.

 

[01:12:58]

 

Objectives

 

For these last few minutes, I will talk a bit about the importance of support of supportive care and give you a bit of an approach to some of the ancillary therapies. I am not going to go through every single 1 of them. We have put some of them in chart format so that you can have them after.

 

Kendall nicely noted at the start that you can get these slides thereafter. We will talk about the health disparities and maybe hopefully give you some very practical tips, even just in the clinic on a daily basis that can help you provide more equitable care to your patients.

 

[01:13:27]

 

Supportive Care in Frontline Therapy

 

As we think about patients now receiving these quadruplets that we have just discussed, we have to think about the rest of them as well. Inevitably when you are giving someone a quadruplet, you are also giving them an antiviral prophylaxis. That is particularly important. We use it for CD38 antibodies as well as proteasome inhibitors.

 

Often, we may be using antibacterial agents. We may not routinely do this in all patients up front. We use PJP prophylaxis more and relapse myeloma with CAR T-cell therapy and bispecifics, but there are certain patients in whom that may be necessary.

 

We absolutely need some form of anticoagulant therapy when we are treating patients with an immunomodulatory drug. Some patients may be able to just have aspirin. But if there are other risk factors, as I will show you, we may have to use something more intense. Let us not forget, we still have, sadly, a disease that affects the bone. Now we have very potent bone strengthening drugs. We typically use either zoledronic acid or denosumab. That becomes very important to help reestablish bone health and reduce the risk of further fractures or bone pain.

 

[01:14:36]

 

Steroids: The Drug We Love and Hate

 

I have already spent a fair amount of time talking about dexamethasone, so I am not going to get into it in great detail. We know that there can be a lot of side effects from it. I have already outlined part of a plan to help with tapering it.

 

But having patients take it a consistent time. I can tell you, after many years of doing this, we track this a little bit. When I was at Mayo Clinic the majority of patients found that taking dexamethasone in the morning was beneficial to them because the energy they got out of it was during the day and maybe kept them up a little bit at night. But for the majority of patients that happens.

 

But I must say up to about a quarter of patients do not get the kick in of energy from dexamethasone for several hours. In patients like that, I may suggest taking it in the evening, in fact, where it affects their energy the next day and they are able to sleep that night. Just another small tip with regards to dexamethasone.

 

[01:15:36]

 

Peripheral Neuropathy

 

Neuropathy is a very significant challenge. Neuropathy, of course, has multiple sources. It can be the disease itself. It can be the treatments, of course, that we give. Typically, it is bilateral, presents with numbness, tingling in the tips of the fingers and the toes and can ascend through the palms and the soles of the feet, right through the ankles and up.

 

Typically, as we commented before, using bortezomib less frequently, using it subcutaneously and at times having to discontinue it even or dose adjusting it are the only ways we can handle it. There are some other things that we want to make sure some patients have benefited from neuroprotective supplements, as you see here, like B complex vitamins. Always want to make sure that if patients really are not sensing and feeling things, that they wear shoes or have some protection so that they are not walking into sharp objects in their home. So we really want to do as much as we can to support the patient through this.

 

[01:16:32]

 

Thrombosis: Managing DVT and PE Risk

 

Then thrombosis. I noted already that myeloma itself is a risk factor for thrombosis. Add to it that we are giving almost universally immunomodulatory drugs. Now we have a lot greater comfort level of using these agents where typically, at minimum with little other risk factors, we would use aspirin, but we are very comfortable now using the DOACs, using the oral agents, and finding that we are having to use warfarin and heparin much less now than before.

 

There are some other non-pharmacological features that listed here like exercise. In certain cases, there may be benefit of using stockings. Then of course modifying risk factors of which some of these can be modified primarily, smoking, obesity, and immobility.

 

[01:17:19]

 

Infections

 

Now again this is a bit of a list slide. So I am not going to go through it in a lot of detail. But depending on the kind of risk, we have commented that almost all of our patients receive viral prophylaxis for herpes simplex and CMV. But there are certain situations where we may consider bacterial, PJP, or fungal infections.

 

COVID, we hope continues to wane, but nonetheless, we do want to have our patients protected as much as possible. Not so much in the frontline setting, although can happen much more so in the relapse setting when patients have a very low IgG level with significant risk of infections, we provide IVIg as well.

 

[01:17:57]

 

Additional Considerations – We Treat People, not Myeloma...

 

Then a couple of other things I noted. We treat people not myeloma. We have to look at the whole of a patient. With all of these new agents, there can be very considerable financial toxicity, and there are a lot of ways to mitigate that and opportunities providing our patients. We know that both patients and their partners, somewhere in the realm of 30% to 50% of them will experience very significant psychological and psychiatric challenges, including PTSD. So making sure that we care about their full needs is necessary.

 

I think patients, when they are educated, I am biased because of the role I play at the International Myeloma Foundation, Dr Lonial sits on our Board. If you want patient education and even other education, we encourage our patients to go to myeloma.org. We know that patients who have support and psychosocial support actually have better outcomes, and we need to care for those patients that are caring for those people who are caring for the patients, the care partners, the caregivers require support. Not to mention nutrition services, sleep support, sexual and reproductive information. There really is so much more, and we do not overwhelm people.

 

But I like to include this in the slide to remind people that there is so much more to myeloma.

 

[01:19:06]

 

What are Health Disparities?

 

Lastly, there is the issue of health disparities. I like the definition given to us by the CDC, and I have highlighted 2 words here that they are preventable differences and the burden of disease, injury, violence or opportunities to achieve optimal health. These things can be fixed. If anything, we are coming to appreciate that. We have a very poor outcomes in certain populations within the country. It is not because of the biology of the disease per se. It is really because of late diagnosis and access to therapies.

 

Health equity refers to when we can allow patients to live to their highest level of health. You are caring for your myeloma patient. You want them to live to their highest level of health.

 

[01:19:49]

 

What Are the DRIVERS of Disparities in MM?

 

What drives this? This is a whole talk in and of itself, because there are systemic features that affect everyone's health. Racism, the way the healthcare system is employed and the social determinants of health.

 

Sometimes we skim over these things, but these are important. I was just telling 1 of our fellows the other day, your patient is not going to listen to your beautiful description of CAR T cell therapy if they are hungry. Sometimes we need to ensure that their security and their home security of their diet, these are the kinds of things that we need to pay attention to.

 

In red, I have highlighted more of the things that are specific to myeloma, which really the 2 major features here are the delayed diagnosis and access to care.

 

One of the great mimics of myeloma, of course, is diabetes. How many patients ultimately get diagnosed with myeloma? When we look back and say, they had a little bit of proteinuria, they had a little bit of anemia, they had a bit of renal insufficiency, and it was all attributed to diabetes. Diabetes is considerably more common in the African American and Latino American populations. Just keeping that in mind, and we do a lot of education to primary care doctors to help facilitate that diagnosis.

 

Then, as you heard from Dr Lonial, if we think over the years what has improved the survival of myeloma? Triplets, transplants, clinical trials, more recently, CAR T-cell therapy, the 4 Ts, as I call them. Unfortunately, we have demonstrated that there can be reduced access to those 4 kinds of treatments, specifically within the African American and Latino American populations.

 

[01:21:15]

 

A Call to Action – Facts About Black Patients and Myeloma

 

I try to summarize facts into these top 7, and they are relatively easy to read here, so would not go through in a lot of detail, but there is a longer time for the diagnosis. We know that African American patients are typically younger but also have twice the risk of developing multiple myeloma. I actually prefer the word African American here than Black. This changed on my slide, because remember African American refers to a more genetic, geographical position. I give myself as the example. I am African American, but I'm not Black.

 

Socially speaking, when we look at access of therapies, that tends to reflect the Black population. It is not an exact overlap but obviously very strong overlap. As I have noted, Black patients are less likely to receive the 4 Ts. Interestingly, Black patients and African American patients are less likely to have high-risk multiple myeloma in historical cohorts, and yet survival outcomes.

 

A Black man or a Black woman diagnosed with myeloma today is expected overall to live half as long as the same aged white men and white women. Now, I maybe should not use the word today because that is based on historical numbers. Those numbers are actually proving. We have even had just very recent data that is telling us that it is improving. But we know when patients are given equal access to the same diagnostic and therapeutic algorithm. Let us say, for example, in the VA system, or at least theoretically, everyone independent of race or ethnicity are given the same access to diagnosis and to therapy that in fact Black patients do just as well, if not better, than white patients with myeloma.

 

That sets the standard to help us realize that this disparity is preventable. This disparity can be overcome by ensuring we have better care for our patients.

 

[01:23:02]

 

Key Tips in Providing Equitable Care

 

Final tips around equitable care. Some of this is straightforward. Some of this is more involved, which is being aware of the causes and the severity of that disparity. Sometimes we are a little bit ignorant. We may be spoiled in our personal lives and not realize the impact of socioeconomic status, for example.

 

To understand unconscious bias that sometimes we can unconsciously, that is why it is called unconscious bias. I want you to be conscious of what you may be unconscious of to overcome what you may be thinking when you are in clinic that we support community engagement. This is a bigger and greater topic, but 1 that is very dear to me, which is this notion that as a healthcare community, we do not just think come to us when you are sick. We should be going out to the community to promote health and to promote wellness in general. That is what builds trust.

 

Part of the historical challenge of outcomes within, in particular, the Black population has been a lack of trust. Part of that trust can be rebuilt over time.

 

Participating in primary care education to ensure most of us, as myeloma doctors or hematologists or oncologists, we have that primary care network that we work with. They are the ones that call and say, “Hey, what test should I be doing? How should I be doing this?” We want to help in their education to facilitate that early and accurate diagnosis.

 

Within ourselves, we want to practice greater cultural, what is sometimes been called competence, to make sure that we are listening, that we understand how someone's cultural background may influence their decision making to choose to go on to a trial or to go to a therapy or not, and be particularly aware of that lack of trust within the healthcare system when it relates to trials and ways that we can overcome that.

 

Then lastly, support programs that are designed and obviously I am going to have a little bit of a commercial here. But I figured Sagar is with me and he is on our Board.

 

[01:24:55]

 

M-Power = Myeloma Power

 

That we have created a program at the International Myeloma Foundation that you can read about at myeloma.org called the M-Power program. I am only going to show you 1 slide on it. But our whole concept here was to improve the short and long-term outcomes of Black patients with multiple myeloma. That is a bit of a play on words. M-Power, myeloma power to empower patients to change the course of myeloma.

 

It is built on 3 principles:

 

• To engage the community, as I have described;
• To educate the primary care world; and then,
• To enhance the direct care of our patients, primarily through our providers, that we provide better care to our patients.

 

You can learn more, as I show you there on the website.

 

[01:25:35]

 

Let's Revisit Our Questions

 

With that, I will stop. Kendall, perhaps I will turn it back to you to revisit these questions. I see that other questions are coming into the Q&A box that makes me happy. But maybe we will get you because you read them off at the start to take us back to the post-test questions.

 

[01:25:51]

 

Pretest 1

 

Kendall Schick: Sounds great. Thanks so much, Dr Mikhael. Well, thank you once again for such a great presentation to both of our presenters. That was great to get your perspectives and everything. We are going to start with our post-test question here 1.

 

An 80-year-old man presents with progressive fatigue, weight loss and new-onset back pain. Laboratory evaluation reveals hemoglobin at 9.5, serum creatinine of 1.3, serum M-protein of 3.8. Bone marrow biopsy confirms 50% clonal plasma cells. He is diagnosed with multiple myeloma. He has controlled hypertension. He has an ECOG performance score of 1. He is considered transplant-ineligible. Which of the following treatment regimens would be most appropriate? Is it:

 

1. VRd;
2. DRd;
3. Isa-VRd; or
4. Rd.

 

Please submit your answers.

 

Dr Mikhael: I am on the edge of my seat here, Kendall.

 

Kendall Schick: I do not know if we get the responses in real time here. Unfortunately, I do not know if we have that capability, Marcus.

 

Dr Mikhael: We do.

 

Kendall Schick: There we go.

 

Dr Mikhael: We have 63% for Isa-VRd. Is now a good time to have a quick conversation about it?

 

Kendall Schick: Yeah, absolutely. Go ahead.

 

Dr Mikhael: I built this question with a bit of a trick to it, because I had commented that IMROZ, patients 80 and above were not eligible, but tried to give you the sense that this was a relatively fit person. I am not sure there is a right answer here. I mean, I think you would have to have a conversation with the patient. I think between answer 2 and 3, I would agree. I would give this patient likely either DRd or Isa-VRd with some of the dose modifications that I have mentioned.

 

Sagar, I know you have thoughts on this too. I wonder how you would approach this patient.

 

Dr Lonial: Yeah. I mean, I think if somebody is clearly fit, the idea of using weekly bortezomib and an anti-CD38 as part of a quad makes sense. I think if they are standard risk genetics, the additive benefit of the bortezomib is to deepen the response. But the DRd PFS is pretty good. Five years as a median is pretty respectable, I think.

 

To me, that is really the question is how fit is fit? Yes, I am sure you can do it. But what is the additive benefit in a truly frail patient population?

 

Dr Mikhael: Yeah. Great point. That obviously reminds us of the importance of being able to help assess that and have the conversation with the patient to see. I mean, there are some patients who are really on the fence. We may just start with a triplet and potentially add a fourth drug. I know we do not have great evidence for that, but if there is a response, not as quickly as we wish , I mean, that could always be an option as well.

 

Great question.

 

[01:28:52]

 

Posttest 2

 

Kendall Schick: Question 2 here. In your practice, which of the following infections do you routinely provide infection prophylaxis in patients receiving anti-CD38 antibodies? Please submit your answers.

 

Let us close the poll.

 

[01:29:23]

 

Posttest 2: Rationale

 

Dr Mikhael: Sweet. People were listening to what we had said about the concern for varicella is typically what we look for. There may be some situations where we do use CMV prophylaxis, but not typically patients receiving an anti-CD38. Great. Well done.

 

[01:29:43]

 

Posttest 3

 

Kendall Schick: Third question here. How confident are you to implement strategies supporting equitable access to novel therapies and supportive care in Black and underserved patients with multiple myeloma? Please submit your answers.

 

We can close poll.

 

Dr Mikhael: Okay. Well done. Hopefully we have moved the needle a little bit here, but I see that together, modest and confident is the majority. That is great. Hopefully these tips will further deepen your confidence.

 

[01:30:32]

 

Poll 4

 

We just got a couple more poll questions before we get to the Q&A session here. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

1. Yes;
2. No; or
3. Uncertain.

 

Close poll.

 

[01:31:10]

 

Poll 5

 

Our last question. Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education. You can enter your response in the text box there in front of you. While people are doing that, we are going to leave the poll open. But we can go ahead and move on to the audience Q&A.

 

[01:31:31]

 

Q&A

 

Dr Lonial: Thanks, Kendall. Joe, I have had a chance to go through these already. The first 1 I am going to punt to you. Can you briefly expand and comment about on-body isatuximab? I think you probably had more experience with that than I have.

 

Dr Mikhael: Sure. As Dr Lonial mentioned in his talk, we typically historically gave daratumumab IV. We switched it to a more standard subcutaneous injection. Although it is pretty incredible science how they put those together. Now we have been using isatuximab IV, they have created this small device. I love how the French call it the escargot, a little snail.

 

It is a small device that sticks to the skin, has a tiny 30-gauge needle inside, and just a button is pressed, and then it infuses the drug typically over 12 to 14 minutes. This was presented with new data just at ASCO and EHA. It is not yet commercially available. We anticipate it probably will be in 2026, and I think it is going to facilitate the use of the drug given over a much shorter period of time.

 

I would not get too far ahead of myself, but even potentially has down the line the opportunity to perhaps give it even outside of a classic healthcare context, because it does not necessarily need a nurse to administer it like we do with some subcutaneous injection. You will hear more about what was the artist formerly known as the on-body device, now known as the on-body injector or the OBI?

 

Dr Lonial: Great. Thanks, Joe. The next one is, do you think we will eliminate age altogether as a determinant of therapy? My guess is the answer will be yes. I think we just need to get more attuned to what that frailty scale really looks like in order to get to that. I mean, I think we are already recognizing that we are giving CAR T cells to patients in their 80s. I think I have heard of one patient in their 90s getting a CAR T-cell.

 

I think we are on our way to doing it, but the instruments are not quite ready yet. I am sure you want to add. Go ahead.

 

Dr Mikhael: No, I agree. I agree with the above.

 

Dr Lonial: Okay. In your practices, which frail patients would you consider for quad? Can you put some more description to your picture of these patients? Joe, you go first.

 

Dr Mikhael: Yeah. I mean that is a great question, Timothy[?]. Thank you for asking that. A couple of things. There are different indices that can be used in different features. I put a fair amount of emphasis on asking them what they are doing in a typical day.

 

I have patients, are they walking independently by themselves, doing all of their usual self-care, cooking for themselves.

 

I mean, I was talking to a patient this week who was 84 years old, and he walks 2 miles a day. I mean, that is a fit person, right? When I worry more about frailty is obviously to the extreme, are you spending more than half the day in bed? I mean, that is a performance status phenomenon at one extreme, but it is the in-between that becomes challenging. The one who says, no, I am not walking miles a day or walking independently. Yeah, I get up and move around. I do cook for myself. That is where the bubble is more challenging to make that more careful frailty assessment.

 

The second thing I add to so typically what they are doing in a day. Then secondly, are there other comorbidities that influence that frailty. I mean, how significant might they have of diabetes or of renal insufficiency or of other medical conditions? Have they had a heart attack that has impaired their function? Do they have atrial fibrillation that might be limiting their activity? Those things then add a dimension.

 

Sagar, I am sure you can add to that.

 

Dr Lonial: Yeah. I think function is a really important part of it. I find when I am seeing a patient, particularly, after the fellow has been in before me, I spend a majority of my time asking them what they do during a regular day, and I think they are a little caught off guard because they do not know why I am asking that. Then I come around to why I am asking it, which is I am trying to make the determination of really how functional are you, and how the disease is impacted, that because we know sometimes we will say, until I had this compression fracture in my spine, I could do anything.

 

The question is, what is the impact of that overall. But I think understanding function is really important. Then just having the discussion with them about, quite honestly, how often do they want to be in clinic to get treatment. Some people, particularly that live far away, say, I want to come as infrequently as I can. That may drive a decision more so again than age in terms of what is going on.

 

Next question is, what about ixazomib vs bortezomib if preexisting neuropathy? I can start with that.

 

I mean, I think we all have recognized that ixazomib does have less neuropathy, but it also likely has less potency. I think it is really a matter of where you are going to potentially give. If they are a fit patient and I want to debulk, I will probably think about carfilzomib as a way to spare the risk of neuropathy.

 

I know my colleague Jonathan Kaufman had a concert pianist that he did carfilzomib as part of his induction. But you could think about ixazomib potentially in the maintenance setting if that were something that were of interest. Joe?

 

Dr Mikhael: Yeah. No, I completely agree with you. I have the same approach. I actually think that we can use carfilzomib. It actually fascinates me in the studies that you presented and that I presented. There is more use of carfilzomib than ever in the frontline setting, even in some patients who may not be transplant eligible. I do not dismiss it.

 

If I have someone who has pre-existing neuropathy. I really do not want to give them bortezomib, because I think you are asking for worsening of that neuropathy. I tend to favor trying to use carfilzomib or question do I really need a proteasome inhibitor? But I tend to if I am going to use ixazomib, I use it when there is less burden of disease like yourself.

 

Dr Lonial: Okay. Is there any adjustment to give the DRd regimen in ineligible patients? I think they are thinking. They said haloperidol. I think they mean the Halozyme maybe, the diluent that you use for the subcutaneous injection, giving it over the long term.

 

I am not aware that there is a long-term complication of giving that. I think I have got somebody on study from MAIA that is now in 8 years and have not seen any issues, but I do not know if you have.

 

Dr Mikhael: No, I have not had any issues as well, so I would not see an issue. If the person is asking about haloperidol, which someone may be receiving separately, I do not see an interaction either. I have had some patients on both.

 

Dr Lonial: Okay.

 

Dr Mikhael: Both aspects.

 

Dr Lonial: What was that?

 

Dr Mikhael: I said we covered both aspects of that.

 

Dr Lonial: Yeah, there we go. What do you think are the key ideas to educate primary care providers about to help with earlier diagnosis or referral?

 

Dr Mikhael: Yeah, that is a great question. We have a whole curriculum for it. But let me narrow it down and say that it is primarily when to think about myeloma, which of course is challenging because there are so many. We think of the classic CRAB criteria, but we really want primary care doctors to think a little bit more about myeloma, especially in high-risk populations like those who have pre-existing diabetes, African Americans and Latino Americans. Obviously, patients as they are aging.

 

Then maybe the second and really important piece is, in fact, we were just reviewing some data yesterday for a study that we are looking to publish, which was when a primary care provider thinks about myeloma, what do they order? The vast majority just orders serum protein electrophoresis. It is not enough. They need to order serum protein electrophoresis and a free light chain assay, because about almost 20% of patients will have light chain only disease and they are going to miss 1 in 5 diagnoses.

 

The strategies that we have are raising awareness in general about when to test for myeloma and then specifically what to test with.

 

Dr Lonial: Okay. What are the strategic approaches IMWG is making to involve myeloma researchers in low-income countries of sub-Saharan Africa in clinical trials experimental researches in myeloma? I know you have done a lot with 2 networks globally. Just curious if you wanted to address that with what the IMF is doing.

 

Dr Mikhael: Yeah, for sure. I mean, the IMF is international, and so we want to cover the planet. We want to do it systematically, but we also want to do it ultimately exhaustively. We have created an Asian Myeloma Network where we have done really tremendous work in Asia. We have created the Latin American Myeloma network.

 

We have in our sights absolutely to include an African network over time. We just had, a few weeks ago, what we call GMAN, our Global Myeloma Action Network. This is the support organizations in different countries, and we are now including Africa. We had a wonderful representation from our friends in Kenya. We provided a grant to support their work and research there.

 

We have just recently been in touch with a group from Nigeria as well. I know that it is still slim amounts of work that we are doing in that region, but it continues to grow year upon year. We actually have a number of people from Africa reach out to us through our info line, electronically or through the phone.

 

I really do think that there is a great opportunity to do much more there, especially as we know with the higher incidence of myeloma, which is clearly underdiagnosed throughout the whole continent.

 

Dr Lonial: There is a question here about palliative care or in the palliative care, what stage do you consider thromboprophylaxis? I will answer that. Anybody getting an IMiD needs to be at the minimum on an aspirin. I do not care whether it is a baby aspirin or a full aspirin, but at least some aspirin prophylaxis.

 

If they are limited in their mobility, they likely need more. I just saw a newly diagnosed patient who has a sacral fracture and is walking, but walks with a walker, so probably less. That is somebody we are actually going to put on a DOAC as part of their primary prophylaxis until we debulk them a little bit more and get them a little bit more functional.

 

I think unless they are not an IMiD sparing approach where they have normal function, normal mobility, they are going to be on some form of prophylaxis. Okay?

 

Do you prefer a DOAC over heparin in the management? I am guessing a prophylaxis, but maybe treatment as well. Joe, do you want to take that one?

 

Dr Mikhael: Yeah. I mean, generally, yes. I think it was a while that we still had to get greater comfort with the DOACs. I just think by virtue of the ease of administration and the monitoring, I do not know what you are doing at Emory, but we are hardly using heparin anymore.

 

Dr Lonial: Yeah. Plus, it is a pain to take those shots. I briefly had to do that a few years ago after surgery, and it is not a lot of fun. If you can get away without it, it is probably better.

 

The last question is ixazomib-lenalidomide maintenance for transplant-ineligible, high-risk patient. What do you think about that?

 

Dr Mikhael: I just do not think we have great evidence for it. Respectfully, the evidence we have for ixazomib maintenance has not borne out as much as we would hope it. I think as you demonstrated and Emory has been a world leader in this, in patients who have high-risk disease, we want to maintain that remission for as long as possible. I do like to add something to the lenalidomide.

 

If they are not able to have a proteasome inhibitor, then I would consider daratumumab. I think the emerging evidence for daratumumab and lenalidomide in that population, in fact most of those patients, if they are transplant ineligible, so they have received either a D-VRd or Isa-VRd or even just DRd regimen, I would plan to keep them on the CD38 and the lenalidomide.

 

Dr Lonial: Yeah, I completely agree. I think the one area that may be different is to consider BCMA-directed therapy in combination with an IMiD. We have a very interesting study looking at belantamab in combination with pomalidomide for high-risk myeloma post-transplant. The data looks really, really good.

 

Remember, we have done KPD, we have done RVd, we have done KRd. This to me looks, among some of the better data that we have seen so far. Hopefully we will have another potential way to think about this.

 

[01:44:57]

 

Go Online for More CCO Coverage of Multiple Myeloma!

 

Okay. I think we are wrapping things up. Again, appreciate the questions. appreciate everybody's joining us this evening. Again, you can go online for more CC0 coverage of myeloma. The slides will be available. There is an on-demand webcast. I like that it is certified. That makes me feel better.

 

I think this is really exciting. You can claim CME credit by going to the URL listed here. Or you can claim credit by clicking a button somewhere on the bottom, and then print your certificate upon completion of the online evaluation.

 

Thank you again for joining us this evening. Joe, as always, a great presentation. I think great education. Hopefully people gained a lot of benefit from this evening.

 

Dr Mikhael: Always a pleasure to join you, my friend. Thank you. Thank you to CCO.

 

Kendall Schick: Thank you so much. We will wrap that up. For those of you still with us, I understand there may be a small hiccup with the link. But rest assured that we will contact you via email, and we will be able to provide you with a link to claim credit. Thank you so much and have a wonderful evening.

 

Dr Mikhael: Thank you.

 

[END OF TRANSCRIPT]