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Joseph Mikhael, MD, MEd: Hello. This is Dr Joseph Mikhael, and welcome to season 2 of the Medscape InDiscussion multiple myeloma podcast series. Today, we have the exciting opportunity to take out a crystal ball and look into the future, as our title today is “What Is the Future of Multiple Myeloma?” I honestly cannot think of anyone more qualified to be prophet-like, looking into the future, than my dear friend and former colleague at Mayo Clinic and still lifelong colleague, Dr Shaji Kumar.
Dr Kumar is a consultant, professor, and researcher in the field of multiple myeloma at Mayo Clinic in Rochester, Minnesota. He leads the whole myeloma program across all of the Mayo Clinic Enterprise. I could spend hours talking about all that Shaji has accomplished. But one key thing I would say about Shaji is that he has brought the whole spectrum of myeloma in his career; he’s worked from bench to bedside. He has worked in frontline therapy and relapse therapy. He’s really worked across the whole spectrum, and that’s why I think he’s particularly qualified today to have this conversation as we think about the future of myeloma. Dr Kumar, welcome to the Medscape InDiscussion multiple myeloma podcast.
Shaji Kumar, MD: Thank you, Dr Mikhael, for having me on this podcast. I look forward to our discussion.
Mikhael: Obviously, I put you in a bit of a tough situation because it’s one thing to talk about a trial that’s already been conducted and how you apply it in the clinic and so on, but I do think that it’s worth looking into the future. When we started in myeloma 20 years ago, sadly, most of our patients didn’t live much more than a year. We had very few diagnostic and therapeutic options for our patients. It really was a dismal disease. One of the reasons why I went into myeloma is that one of my high school classmates developed myeloma in his twenties, and I wanted to take care of the patients who were the sickest of the sick, as it were.
What has happened over the last 25 years? Expected survival is well over a decade. We have over 20 drugs approved. We have radically improved, I would suggest, both the quality and the quantity of life of our patients with myeloma.
But it’s not over yet. We have a lot more to do. So what I was hoping to do with you today, Shaji, was to think about a few different areas and what the future may look like in those areas. You have done a lot of work in the lab. You’ve been very much involved in our diagnostic criteria for the International Myeloma Working Group. The Mayo Clinic has recently moved to a new modality of testing for myeloma compared to the historical serum protein electrophoresis and serum free light chain assay that we use.
Let me ask you about diagnostic tools in myeloma. What do you see in the future? Are we all going to go to spectrometry-based assessment like myeloma, or is the skeletal survey truly dead now, and we really should only be using PET scans or MRIs? Or is it going to be PET-MRI? What do you see as the future of diagnostics in myeloma?
Kumar: You’re so right. It’s amazing the progress that has been made in the past two decades in every aspect of myeloma therapy and diagnostics. You mentioned taking care of the patient as a whole, and I can’t think of it better represented in any cancer than it has been in myeloma. The technology is often ahead of therapy, sometimes, but myeloma may be one place where therapy might be a little bit ahead of diagnostics. That’s not to say that diagnostics haven’t changed.
One of the advantages we have for myeloma is that the cancer cell secretes protein that we can measure in the blood, which many cancers don’t have, where we have to rely entirely on imaging. We have an inbuilt biomarker that has been the cornerstone of myeloma diagnosis for almost six decades since Dr Robert Kyle described many of these conditions.
When you look at myeloma from the diagnosis standpoint and also for monitoring the response to therapy, there are certain things we look for. If we can look at this protein that is secreted by the myeloma cell in the blood or in the urine, we can look for the cells in the bone marrow, bloodstream, or soft tissue, in the form of plasmacytomas, by using imaging. Increasingly, what we are seeing is that we cannot really look for the disease in just one aspect. We have to look at every one of these three sites that we talked about, in order to get a comprehensive understanding. This is important not only for diagnosis and classifying the patient, in terms of where in the spectrum for monoclonal gammopathy of undetermined significance to active myeloma to plasma cell leukemia, they are, but also in terms of prognostication.
So, looking at the blood and the urine for the protein. We did protein electrophoresis for the longest time. We did immunofixation electrophoresis for the longest time in order to perform quantitative and qualitative assessment of the monoclonal protein. As you mentioned, we have now switched to mass spectrometry-based assessment, which is not only more sensitive but a lot more sensitive. It is also more specific or accurate. You can clearly know what you are looking at, even in very small amounts. Importantly, it is much easier to do.
For example, you also said Mayo switched the methodology. We went from a huge lab to basically 10 tabletop machines with four or five people who run the lab now. The footprint has gotten to be substantially smaller, with the number of people needed to do the test being much, much less, and the turnaround time is quite fast.
Mikhael: Let me ask you about that for a moment. You’ve gone to spectrometry-based assessment now, so you’re not doing the old school serum protein electrophoresis, and I’m sure we both have a little PTSD from doing that as fellows in the lab. How quick is that turnaround time now with the spectrometry-based assessment?
We have sometimes structured our whole clinics around having a patient come in a week before they see us so that we can get those blood tests done and have the results back. When I think about the future of myeloma, could it be that someone comes into the clinic and, half an hour later, you have the result of the spectrometry-based assessment? How quick is your turnaround?
Kumar: Well, we’re not yet at half an hour, but within 24 hours, we have it. If they get the blood drawn before 10:00 AM, we can have it before 5:00 PM.
Mikhael: Wow. Logistically, that would really speed things up. When I worked at Mayo here in Arizona, and for you in Rochester, sometimes you have people traveling from quite a distance. So they would have to have an extra 3 days at the hotel right there in beautiful downtown Rochester, so that they could get the testing done. I think it has a pragmatic point of timing.
The other point that I thought was very good that you made was that it’s more accurate not only in quantifying but also in differentiating different kinds of proteins. Right now, a lot of our labs don’t discriminate the IgG kappa if it’s coming from a drug like daratumumab or isatuximab. And so we have a lot of patients saying, Oh no, I still have this M spike of 0.2, when in fact we can say, no, actually that’s the daratumumab. That’s the isatuximab when it’s done by mass spectrometry-based assessment.
Kumar: Exactly. And that is quite timely when you’re thinking about the monoclonal antibodies becoming mainstream. I think it’s quite timely that we went to a mass spectrometry-based assessment.
Mikhael: Before we leave the diagnostics, let me ask you two quick questions about diagnostics. One, do you think that we can do less bone marrow [biopsies] in the future? Are we going to have the technologies, as you said, whether we look for the protein or the cells in the blood?
The second question is, what do you see about the future of imaging? I would love to do fewer bone marrows on our patients. Do you think that’s going to happen?
Kumar: Absolutely. I think it’s only a matter of time. The first step that I think is going to happen is that we are going to do less bone marrows because we will know the right time to do a bone marrow, based on the mass spectrometry testing. If you were to wait until the mass spec becomes negative to do the bone marrow, you can be assured that they at least have less than 5% plasma cells, and obviously, more likely to be minimal residual disease (MRD) negative if you’re trying to use that for your response assessment and MRD testing. At baseline, I think everybody will need a bone marrow, but the subsequent bone marrows during the disease therapy is going to be less often.
Fast-forwarding a little bit more, I think it’s only a matter of time before we can get the blood assay sensitive enough that it actually picks up everything that’s in the bone marrow. Right now, all the testing that we have in the peripheral blood, whether we are looking for intact cells or looking for the DNA from the tumor cells, seems to be at least a lot less sensitive than what it has been in the bone marrow itself. But I think that is going to change for two different reasons.
One, I think as patients are living longer, many of these patients tend to have disease outside the bone marrow, and that may not be picked up by a bone marrow biopsy. And two, I think the sensitivity of those peripheral blood tests is going to increase, and we can actually sequence an extremely small amount of DNA out of the blood in the future, which will be, I think, much more globally representative of the tumor everywhere in the body.
Mikhael: That’s fascinating. I work at a translational genomics research institute where we’ve developed a test now — with just the peripheral blood, we can literally fully sequence someone’s myeloma. It’s remarkable.
Kumar: It’s remarkable what we can do. Certainly, there’s a lot more we need to understand, because it may not show all the abnormalities that may be present in the bone marrow. So we need to get to a point where the sensitivity is good enough that it captures everything.
Mikhael: Absolutely. And then my last question on diagnosis, because I know we have to talk about therapy. It’s amazing there’s so much to talk about in myeloma. Do you think we’re going to have much of a change in imaging? Or do you think now that just PET and whole-body low-dose CT will rule the day?
Kumar: I think we are moving to a place where the skeletal survey should no longer be considered standard of care. Certainly in resource-restrained environments, I think it’s reasonable to at least do that. But I think the basic minimum should be a whole-body low-dose skeletal survey. Ideally, every patient with myeloma should have either PET-CT at baseline or functional whole-body MRI at baseline. Because what we are seeing is, one, if you have extramedullary disease in a diagnosis or a relapse, it’s a poor prognostic indicator, but we can also follow that lesion using a functional imaging study. But on top of the soft-tissue disease, what we are seeing is the changes in the bone marrow itself. In terms of the activity, it has an additional value in terms of predicting the depth of response. So I think in the future we are going to have, ideally, everybody get a baseline MRI or a PET-CT, which then will be followed up once they get to be MRD negative and mass spec negative, as the imaging also becomes negative.
Mikhael: Perfect. Well, you heard it here first on the Medscape InDiscussion multiple myeloma podcast from the world-famous Dr Shaji Kumar, that’s how we’re going to be looking at patients in the future.
Let’s shift our focus for a minute, Shaji, and talk about therapy. We often get so excited about relapse therapies, and we always have new, exciting modalities, which we’ll come to in a moment. Let’s talk a little bit about frontline therapy and maintenance, and then we can talk later about relapse.
There really has been a lot of change in frontline therapy. We had a great discussion with Dr Saad Usmani about quadruplets and how they’ve really, for the vast majority of patients, now become the standard of care. But if you look into your crystal ball 5 and 10 years from now, what do you see as major themes for frontline therapy? Are we going to still be doing quadruplets? Are we going to be transplanting patients? Are we going to chimeric antigen receptor (CAR) T-cell therapy? Are we going to be doing bispecifics upfront? All of the above? What do you think?
Kumar: It’s amazing how much it has changed, especially in the past 5 years, in terms of frontline therapy. It took forever to go from just dexamethasone to a doublet. Then it took a long time to go to a triplet. It really did not take a long time to go from a triplet to a quadruplet because of the efficacy of the new therapies. The data from the PERSEUS trial are amazing when you’re talking about a dexamethasone injection and a single transplant and no maintenance at 3-year progression-free survival (PFS). And now we are talking about a quadruplet injection therapy, single transplant, and two-drug maintenance, giving you maybe a 15-year PFS. That is a fivefold improvement in just the first line of therapy. If you’re talking about somebody who is 65, that person is 80 already, and if you can get them one more therapy, that will give them 15 more years; they’re not going to be talking about myeloma for that particular person. So you are really looking at a paradigm where the average patient with myeloma might need no more than three lines of therapy to get them through their lifespan.
Where can we go from here? That’s going to be the interesting thing. The first question that always comes up is, is transplant going to be there? If I were to predict, I would say transplant is going to go away. The question is, what is going to replace the transplant? I think the quadruplet regimen with a doublet maintenance without transplant might still give us a long enough PFS that we could think about transplant in a more selective manner. People who don’t get the long PFS then might be getting a transplant, or may be getting a CAR-T. Clinical trials will tell us. But the people who do very well with the quadruplet and not transplant might go 15 years, and they might get immunotherapy at that point in time.
This assumes that the quadruplet remains a standard. We are already starting to see the immunotherapy agents, the bispecific antibodies, combine that with daratumumab and lenalidomide, and we are seeing very, very deep responses. So if they truly tend to become an improvement over quadruplets, we could be talking about a bispecific antibody an immunomodulatory drug and an anti-CD38 monoclonal antibody used together for a limited period of time, which then gives people 10-15 years of treatment-free interval. I think that’s the key to the next improvement.
Mikhael: I think you’ve hit the nail on the head. Not that we can definitely know what’s coming in the future, but what I really liked about what you said was that it’s not just that more is better. Because we’re hitting the edge of that, going from singlets to doublets to triplets to quadruplets. I love the fact that you didn’t say, Oh yeah, next thing we’re going to do is to have five drugs. And then six to seven. At some point, it’s a bit ridiculous. You’ve commented that paradoxically, it might actually mean a shorter time on therapy. What I’ve learned, even through the quadruplets, is this concept that if we can combine these multimodalities with very effective therapies that can be overlapped, because the toxicities are not overlapping, we have that possibility to actually get people into deep, durable remission and then take them off therapy so that they can get onto my favorite drug, as I say all the time: nada, nothing. Everybody loves to be on nothing.
Do you think MRD is going to be a part of that and risk status? Is that going to help us determine, as you sort of noted, that some people may not ever need a transplant, others might, but some people can stop therapy earlier on?
Kumar: Absolutely, and I think we have two tools. One is obviously the risk status, and I think that is going to be a key element. The second is the depth of response.
To me, treatment of myeloma is going to get individualized primarily based on three factors. One is the frailty at baseline, which will tell you how much of the treatment you can give; the risk status, which tells you how much of the treatment you need to give; and the depth of response, which tells you how long you need to give the treatment. The patients who are MRD negative, at some point, we should be able to discontinue the therapy, and I think we are already starting to see some of that. We saw the MIDAS trial, where the transplant was dependent on the MRD status. We have the data from the PERSEUS trial showing that lenalidomide could be discontinued in people who are MRD negative after 2 years of dual drug maintenance. And hopefully we will see similar data from this SWOG trial that is looking at daratumumab-lenalidomide maintenance. So increasingly, the trials are going to look at the sum total of the risk and the depth of response to determine how long and how much therapy we need to give to an individual patient.
Mikhael: I think that’s a fantastic prediction, and I think that reflects the biology of the disease. We have some patients who need treatment for longer, but overall, if I think of all the patients I’ve just treated, let’s say for the last year, there’s no doubt that I’ve had people on maintenance therapy who probably could be off of it if I could just better predict what would happen with them. I think what I’m hearing from you, as we look to the future of multiple myeloma on this podcast, is that we are going to be able, with those three factors that you noted — baseline frailty, risk status, and depth of response — we’ll be able to have a more individualized pattern of determining what you need and how long you need it. Always with the goal of getting people off therapy. That might be one of the greatest benefits of CAR T-cell therapy is that on the whole, we’ve been able to stop therapy in patients.
I know it’s tough to make you answer this, but do you think we’ll be doing a lot of CAR-T up front?
Kumar: I think we’ll be doing a fair amount of CAR-T, maybe not right away today. But I think in the next five years, as the CAR-Ts are becoming safer, we are already seeing the signs of that, that we can develop CAR-Ts without the lentiviral vector. We can actually give CAR-Ts without the high rate of and neurologic toxicity. So I think the next generation, maybe the generation after that, of CAR-T is going to be a lot safer than what it is today, and that is what it’s going to take for CAR-T to become part of the frontline therapy.
Mikhael: That’s a perfect segue into our final chapter, which is to think about really what excites Shaji Kumar about the future of myeloma in relapse multiple myeloma. I think of so many molecules that you’ve led over the years and new bispecifics. You’ve already intimated that we’ve got new CAR T-cell therapy coming that may be as effective, if not even more effective, than what we have now and, importantly, safer. Then there are other small molecules coming, like CELMoD agents and so on. What excites you the most about really new approaches to therapy? Is it the next-generation CAR-T, or is it the next-generation bispecifics? Is it trispecifics? Is it tetraspecifics? What do you think?
Kumar: I think the CAR-Ts becoming safer is probably going to be one of the most effective therapies. But as we know, these are things that can only be given in tertiary centers. So the vast majority of myeloma patients may not have access to some of these cellular therapies. Just like transplant: Even in the US, only 30% of eligible patients ever got transplanted. So I suspect that’s going to happen with CAR-T as well. But I don’t feel as disappointed because we have bispecific antibodies, either used in combination, or the trispecific antibodies that are giving results — responses — as deep as what we are seeing with CAR-T. So it’s quite likely that everybody, irrespective of where they are, will be able to access the most effective therapy that is available. I think the trispecifics are important, both from the depth of response standpoint and also the theoretical possibility (to be determined in clinical trials) that the responses will be much more durable because they won’t get resistant, since we are going after two different targets. The same approach is happening with CAR Ts too.
Mikhael: It’s interesting you say that because historically, I remember when we used to say, okay, are we going to use bortezomib or lenalidomide in frontline? And we realized that bortezomib then lenalidomide, or lenalidomide then bortezomib, was inferior to adding the two of them together to begin with. The idea is, you said, of overcoming resistance. You have just presented, as a late-breaking abstract, the combination of talquetamab and teclistamab together at the European meeting. Do you think that if you had a single molecule that brought those two drugs together, these two targets together — let’s say BCMA and GPRC5D — let alone other targets like FcRH5, which is coming, that’ll be more durable than doing it with sequential two-drugs?
Kumar: I think so. I think going after two targets is going to be important in this disease. As you just said, with everything we have learned over the past two decades, it is clear that you cannot just go after one target. I think the myeloma is also too clever for us to be able to get away with just one or using different ones sequentially. So I think going at the myeloma cell with two or three different approaches simultaneously is probably going to get us to the deep response that is probably the best way to get the good long-term outcomes in these patients.
Mikhael: Do you think paradoxically that even though in a sense we’re combining two drugs and we’re hitting two targets, this actually might also mean less toxicity? I was quite impressed with the trispecifics because there seemed to be less toxicity, partly because they were giving the drugs less frequently and you’re more sensitively achieving adherence to the myeloma cell. You’re not hitting as many of the other cells in a friendly fire, as it were.
Kumar: Absolutely. I think we can operate at the lower end of the therapeutic window for each individual drug by using this multiple drug combination. And as a result, we are seeing less overall toxicity but still maintaining the efficacy. I think that’s what we are seeing with all these.
Again, I think it’s not just immunotherapy. There are a lot of biology of the plasma cells that we are understanding better, that are pointing us toward other therapies too. So venetoclax or BCL-2 inhibitors for patients with t(11;14), and MMSET inhibitors are being developed for patients with t(4;14) translocations. Obviously, there are drugs targeting the different signaling pathways that could play a major role, especially in patients with high-risk disease or disease that is outside the bone marrow — the extramedullary disease that is such a difficult thing to deal with in the clinic, where even the immunotherapy often tends not to give the results that we would like to see.
Mikhael: Well, you heard it here first from Dr Shaji Kumar. This was a fantastic conversation. Thank you so much for your insights. Today we’ve talked about enhanced diagnostics of being able to detect disease more accurately, more easily, and more conveniently for patients, with potentially less bone marrows.
We’ve talked about frontline therapy, moving toward more immunotherapy-based approaches with deeper and more durable responses. And even now in relapse, next-generation CAR-T, with a theme through all of our chapters today of a much more individualized and personalized approach to multiple myeloma.
I have been so excited to see what’s happened in myeloma in the last 20 years. It boggles my mind to think what’s going to happen in the next 5-10, if not 20 years, where hopefully we can start to use the word “cure” even more. We saw results this year of a long-term follow-up of CAR-T, where a third of patients were still disease-free at 5 years. We’re not saying they’re cured, but it has clearly caused us as a myeloma community to have to come to the definition of cure.
Today we’ve had the privilege of talking to Dr Shaji Kumar about the future of multiple myeloma. Thank you so much for joining me, Shaji. It’s always such a pleasure to share the stage with you. Thank you to our audience for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series. This is Dr Joseph Mikhael for the Medscape InDiscussion Multiple Myeloma podcast.
Listen to additional seasons of this podcast.
Resources
Updated Diagnostic Criteria and Staging System for Multiple Myeloma
Monoclonal Gammopathy of Undetermined Significance
Advancing MRD Detection in Multiple Myeloma: Technologies, Applications, and Future Perspectives
Genomic Landscape of Multiple Myeloma and Its Precursor Conditions
Cytokine Release Syndrome and Associated Neurotoxicity in Cancer Immunotherapy
The Role of CELMoD Agents in Multiple Myeloma
Discovery of a Novel Class NSD2 Inhibitor for Multiple Myeloma With t(4;14)
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