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New Maintenance Strategies for Newly Diagnosed Myeloma Patients With Ashraf Badros, MD, University of Maryland
New Maintenance Strategies for Newly Diagnosed Myeloma Patients With Ashraf Badros, MD, University of Maryland image

Oct 21, 2022 / 11:00AM EDT
HealthTree Podcast for Multiple Myeloma

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Episode Summary

Maintenance therapy over the past several years has commonly included the use of Revlimid (lenalidomide) over a long period of time. Does more maintenance therapy or certain combinations help extend remissions or help patients deepen their responses? 

Ashraf Badros, MD, of the University of Maryland will join the HealthTree Podcast for Multiple Myeloma to talk with us about the rationale behind the AURIGA clinical trial using daratumumab and lenalidomide following stem cell transplant for patients who are still MRD positive. 

Myeloma experts are working to identify more personalized approaches for each type of myeloma patient. We know that patients who are still MRD positive following high dose therapy are more likely to have shorter remissions and the use of a different maintenance therapy may help patients who aren't getting their deepest responses do better over time. 

Thanks to our episode sponsor, Takeda Oncology

Full Transcript

Jenny: Welcome to today's episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Takeda Oncology, for their support of this program.

Before we get started on the show today, I'd like to make you aware of our HealthTree Community for Multiple Myeloma Program. This program includes topic-based and regional chapters for myeloma patients and hosts monthly webinars. We're on track to reach and educate over 115,000 myeloma patients through this program alone, in addition to the 850,000 unique visitors we have to this website. You may have noticed, we're moving over from to, and we hope you can use that new link for all of our support programs. Now, onto our show for today.

When I was diagnosed, maintenance therapy was not really an established practice. Since that time, we know that maintenance therapy can extend remissions and help patients live longer. Different strategies are now being used to personalize treatment. We're going to hear about one of those and possibly more of those options today with Dr. Ashraf Badros. Dr. Badros, welcome to the program.

Dr. Badros: Thank you. Thank you, Jenny.

Jenny: Let me just give a short introduction for you before we get started. Dr. Badros is Director of the Multiple Myeloma Service at the University of Maryland and is Professor of Medicine. Dr. Badros was in the top 1% of his medical school and is one of the top 1% of published authors in the field of hematology. He peer-reviews articles in over 24 hematology publications, with awards that include the Excellence in Clinical Medicine award, Humanitarian of the Year award from the Mildred Mindell Cancer Foundation, Teacher of the Year award in the Department of Medicine, and Clinical Publication of the Year award in 2017. He performs oversight for 12 oncology hematology fellows on research and publications on various topics. Dr. Badros has extensive clinical experience in bone marrow transplantation. He was involved in the initial trials of thalidomide, and has conducted many clinical trials for relapsed and refractory myeloma.

Dr. Badros is involved in the development of new therapeutics and have completed a gene therapy trial using G-3039, a Bcl-antisense. He evaluated the use of proteins and the proteasome inhibitor bortezomib, and currently is involved in combining various new therapies in multiple myeloma, like lenalidomide and histone deacetylase inhibitors in relapsed myeloma patients alone and in combination with dex and bortezomib. He's also the primary investigator for clinical trial, we will be talking about today. Dr. Badros, thank you so much again for joining and this discussion about maintenance therapy. Can you share a little bit about today's standard of care and maintenance therapy?

Dr. Badros: Yes. I just would like to mention that myeloma treatment has changed in the last 20 years from an incurable cancer to a chronic disease. Patients live with it. Now, we are talking about subsets of patients that are possibly cured from this disease. The standard of care has evolved. In multiple myeloma, we are seeing the benefits of research that has been done over 30 years ago. The standard treatment today really includes three stages.

The first one is called induction treatment, where we give various combinations of most of them chemotherapeutic agents that include lenalidomide or Revlimid with proteasome inhibitor, like bortezomib or carfilzomib with dexamethasone, and nowadays, we add daratumumab, so to three to four drugs up front. The purpose of this treatment is to put the disease on remission, and then we do consolidation treatment. If the patient is in a good shape to proceed with stem cell transplant, they go that route. If not, then we provide maintenance treatment.

Maintenance treatment is basically the topic of today, which is basically an effective treatment that is given long-term after achievement of a remission, with the goal of prolonging that remission, and hopefully prolong survival of patients with multiple myeloma. That's where we stand today.

Jenny: Yes, I think it's interesting that when I was diagnosed in 2010, maintenance therapy wasn't really a thing. It is a newer type thing, well, I guess in the last 12 years or so, but I think it's just so interesting. I think a lot of that came out of some of the work at UAMS. You practiced there.

Dr. Badros: Actually, I joined University of Arkansas almost 20 years ago now. At that time, Dr. Barlogie established what was called Total Therapy program. Total Therapy program is really the backbone of what we do today that includes induction treatment, transplant, followed by maintenance. At that time, maintenance was not accepted nationally, but in Arkansas, patients usually got maintenance treatment. At that time, we use chemotherapy, we use steroids, we used interferon. Unfortunately, all these drugs were quite toxic.

You're correct. Ten years ago, the concept of maintenance was not nationally accepted. Ten years ago, three publications came in New England Journal of Medicine. All of them are randomized trials. Two of them were transplant trials, meaning patients received stem cell transplant. One was in Europe in France, and one was in the United States. After achieving remission after the transplant, patients were randomized to receive lenalidomide, Revlimid, or observation. That was considered standard of care at that time, observation. The third trial was a non-transplant patient. They got chemotherapy, followed by randomization to maintenance, versus no maintenance. Again, using lenalidomide.

Those three trials really established the maintenance role of lenalidomide. They showed that progression-free survival or the time the disease stays in remission, improved significantly. It was up to 53 months in the lenalidomide arm versus 24 months in the observation arm. Basically, you gain about a year and half remission when you go on lenalidomide maintenance. All the three trials were stopped early, because of the benefit noted, and established lenalidomide as a standard of care. There was no difference in overall survival, meaning we have not seen that if you get lenalidomide maintenance, you lived longer. The reason is patients received lenalidomide or Revlimid when the disease came back.

Over the years, over the last ten years, we have not seen conclusive evidence except for one meta-analysis that showed that overall survival is there. Definitely, we know that early use of lenalidomide in a maintenance fashion improve overall survival, compared to its use at the lab.

Jenny: Does the dosage of Revlimid as maintenance therapy make a difference?

Dr. Badros: We don't have data on that. But we usually start at ten milligrams. In the US, there is a practice to give three weeks on, one week off. There is another practice to give the treatment for 30 days. Usually, after the first two months of starting maintenance, we like to start at a lower dose of ten milligrams. If it's tolerated, meaning the white counts are good, the platelets are good, you can escalate the dose to 15 milligrams. It's worth noting that 25% of the patients who go on lenalidomide maintenance, stop the treatment due to side effects. It's not a treatment without side effects. That's another challenge for maintenance, especially if we're going to continue it indefinitely.

In the US trials, the treatment was given indefinitely until progressive disease. In the European trials, most of the trials will stop at two years or three years. That remains an open question at this point, if we should continue on their progression, which is our practice in the US, for to have what's called fixed duration, meaning give it for two years. If you're in complete remission, we stop the treatment.

Jenny: I think it's been in practice now for many years, lenalidomide maintenance, but it seems like new approaches are now coming to the forefront and being tested. First of all, why are these new approaches being tested? Then, do you see specific themes of maintenance therapy that are being tested?

Dr. Badros: I think after establishing the concept which is we need maintenance treatment, several attempts to improve the results of the Revlimid, as we mentioned, even if you go lenalidomide, eventually almost everybody does progress on lenalidomide and we see relapses occurring. The question is, can we improve on that? One of the areas that is still requiring a lot of work is high-risk patients. We know that patients with high-risk multiple myeloma as defined by cytogenetic abnormalities like deletion 17, do not really benefit much from maintenance treatments. There is always a continuous need for improving the results of maintenance to see if we can eliminate the malignant clone, especially the high-risk clone.

These trials resulted in multiple attempts to improve the results. One of them early on was using Velcade or bortezomib as maintenance. This is a trial that has been used in high-risk patients to see if we use Velcade, which is effective upfront treatment alone or in combination with Revlimid, can we improve the results of high-risk patients? Maybe, there is a signal for using it. We started implementing that approach about maybe seven or eight years ago. We started trying ixazomib (Ninlaro) which is an oral tablet, so it's easier to give as maintenance given once a week. Again, there was minimal improvements in survival. Bortezomib and lenalidomide are really falling out as drugs for use. Now, we're moving into carfilzomib era and combining carfilzomib with lenalidomide had been tried on multiple trials, probably the most known one is called ATLAS trial.

In this trial, we have seen improvement in progression-free survival, and maybe a signal for improvement in high-risk patients. Multiple trials have been published. That approach is ongoing. The big issue here is how long can you give this combination treatment? Most of the trials that use two or three drugs have a limited period. You try it for two years, 18 months, on the ATLAS trial - you go on the carfilzomib, Revlimid, dex for eight cycles, then assess the patient, check if they are MRD positive or negative. I think we'll talk about that. If they are MRD positive, they continue treatment for three years. If they're MRD negative, you stop the carfilzomib and put them on Revlimid.

These evolving concepts are definitely happening. We're also seeing daratumumab being moved up front, both in the induction part, so we are not using Revlimid, Velcade, dex, or carfilzomib. Revlimid, dex, we're adding a fourth drug which is called daratumumab. We are continuing that in some patients as maintenance. Again, significant improvement in the endpoints, which is what the trial is trying to achieve, which is prolonging the remission duration.

As our technology basically improves, we are moving from the area where we are looking at response, meaning complete response or partial response to what's called MRD negativity, which is eliminating all the cancer cells or minimal residual disease, any residual cancer cells in the bone marrow. I think we will be talking about that later. But this is becoming another area of research to help guide the duration and the intensity of the maintenance treatment.

Jenny: Yes, absolutely. Can I ask a different question for you to define the difference between consolidation therapy and maintenance therapy, especially as we launch into double or maybe triplet combinations of maintenance? Usually, that's how I would think about calling consolidation therapy right after transplant.

Dr. Badros: After a transplant, if you achieve a decent progression, which is defined as partial response for better. There are some trials that actually introduce two or three more cycles of the treatment you received early on. Let's say you received carfilzomib, Revlimid, dex upfront, for a transplant, then sometimes, you can give the patient two to three more cycles of carfilzomib, Revlimid, dex, followed by Revlimid maintenance. This consolidation concept is just to eliminate more cancer cells. It's not a concept that has been accepted in several randomized trials. There was really no clear benefit for consolidation versus going directly to maintenance treatment.

Jenny: I did not know that. Interesting. Wonderful. Well, let's keep talking about maintenance therapy, because I know what you're trying to do is when you talked about high-risk a little bit earlier, you're saying you're trying to personalize therapies for myeloma patients based on essentially their risk, how well they responded to their transplant, or whatnot. Generally speaking, how is maintenance therapy becoming more personalized, in your opinion?

Dr. Badros: I think as we discussed, there are so many new treatments for multiple myeloma patients. I think big challenge for us today is how to maximize the available treatments, not only to improve survival, which is a huge issue for us to improve survival of patients, but also to maintain quality of life. The burden of treatment is not insignificant, both from side effects, from second cancer that occur with lenalidomide treatment to the cost of those drugs. I have not seen patients who said, oh, I'm doing wonderful in Revlimid. Let's continue it indefinitely. There is always a price to be paid. The question is going to be how can we adjust our treatment to get the maximum benefit at the lowest cost, both to the patient and to the healthcare system?

One of the new areas that we are working on, and I think it's developing, is called minimum residual disease. We are trying -- there are a couple of trials done. One is called the MASTER trial. This particular trial, tried to use MRD or minimal residual disease to guide treatment. MRD, in general, meaning achieving minimal residual disease is not a new concept. It has been known for years that if you eliminate all the malignant cancer cells, or eradicate them, your outcome will be better than if you have residual cancer cells.

Nowadays, we have very highly sensitive methods to be able to detect one cancer cell in a million cells we evaluate. If you do a bone marrow, you can easily pick up those very few cancer cells. Looking at those cancer cells, some trials will try to make some decisions. If you are negative, meaning if you achieved MRD negativity, especially if we can confirm that this negativity is repeated either in six months or a year. You're what's called persistent MRD negative, not just one time, but two times. Some studies will stop treatment and observe the patient, which means have we cured this patient? Have we eradicated the malignant clone to the point we can keep an eye on the patient without any treatment. We don't tell them to go away, we just continue to monitor them and initiate salvage treatment when the disease comes back.

This is one way of adjusting treatments. There are many problems with using minimal residual disease in clinical practice, including technology, including availability. As time goes on, I think it's moving from the clinical trials to the main string. Actually, you probably know that the FDA has allowed us to use minimal residual disease as a biomarker in clinical trials to approve drugs, depending on how good they are in eliminating this minimal residual disease in patients. But there are many, many questions unanswered about minimal residual disease, including the fact that you can have bone marrow that has no cancer cells, and you have tumors seen on a PET scan, done in areas where we don't do bone marrows like in the ribs or in the spine.

MRD by itself might not be enough. I don't want to talk about the future, but nowadays, we are describing what we call next generation ways to pick up very low levels of tumors including something called mass spec, which is able to throw a blood test, pick up any residual myeloma cells secreting very low levels of immunoglobulins. There's also technology now to pick up circulating tumor cells, meaning that tumor cells leaving the bone marrow or the myeloma cells leave the bone marrow at very low levels and circulate in the peripheral blood. Now, we can look at the peripheral blood and measure that. These are all in development. They will change the way we do today. You know everything will be changing that myeloma world, it's literally changing every few years. We changed our definitions of remission. We change our treatment approaches. Now, we are changing our induction, changing our maintenance. That's all benefiting the patients really.

Jenny: Yes, completely. I mean, what you were saying is you might be able to assess risks based on multiple factors, an MRI, a mass spec test, an MRD bone marrow test, and other things all together to assess the genetic testing to assess that risk. That's a very interesting thing. I think one of the points you made about MRD testing becoming a new endpoint is maybe when I explain the significance of that, because to me, that shortens the speed of clinical trials with the length of time patients are living today, which is amazing. But it's harder to run trials. Do you want to talk about that a little?

Dr. Badros: In the old days, the gold standard for evaluating any new drug was to look at how long the patients survived. You're right. It was an achievable goal 25-30 years ago, and survival was very short, so we can have an answer. When the survival improved significantly, thankfully, we started to look at what's called progression-free survival, meaning how long does the patient stay in remission before the disease comes back. We started looking at progression-free survival, which has become more or less a surrogate endpoint for overall survival. A lot of drugs are being approved today, looking at progression-free survival.

Nowadays, we're starting to look at minimal residual disease, meaning can we judge how effective a drug is by its ability to achieve what's called MRD negativity? To give you an example, there is a big meta-analysis done that looks at patients that achieved MRD negative versus those who did not achieve MRD negativity in large number of trials, 12 trials, looking at thousands of patients. Dr. Munshi published that couple of years ago. The survival is impressive. If you are achieving MRD negativity, your overall survival is 98 months, compared to 80 months if you don't achieve MRD negativity. The remission duration is almost five years, compared to two years if you don't achieve MRD negativity.

MRD negativity, by itself, is a very important surrogate for both progression-free survival and overall survival. Again, I just would say that achieving MRD negativity in high-risk subsets like patients with deletion 17 has not translated into improvement on survival endpoints, because those patients do have an aggressive clone that sometimes comes back very quickly. MRD has not been standardized. We started to have some standardization, I think there's a national myeloma working group, has put some guidelines, because every trial has a different way of measuring MRD, has a different target. Some of them measure one cell in 100,001 cell and ten to the fifth, and one cell in a million. We are now moving into more sensitive ways to pick up very low number of cells.

There are many techniques. One is called next generation sequencing (NGS), where we look at the genetic signature of the tumor. One is called flow cytometry, which looks at the markers on the tumor cells, which can be done, and each one has pluses and minuses. I think we don't need to discuss that at this discussion.

Jenny: That's fine. Does it matter how fast you get into MRD negative status? Like, let's say you do your induction therapy, and you have a stem cell transplant, and you're testing for MRD positivity or negativity, does the time it takes you to become MRD negative matter? Do you see a correlation between patients who become MRD negative quickly versus those who become it over maybe a four or six month period or something like that?

Dr. Badros: I think that's a crucial question in what we're discussing. With our first issue is it doesn't matter how you achieve MRD. We know from the French trial, which was the first trial to look at the impact of MRD on survival after transplant. If you achieve MRD negativity, with RVD alone, without transplant, you have more or less the same progression-free survival and overall survival as you achieve it after transplant. The difference in the two arms of the trial was if you go for a transplant, your chance of achieving MRD negativity is much higher than if you don't go for transplant. We know that if you achieved MRD negativity, you do well.

The question that you're asking, unfortunately, I don't believe we have an answer for yet, which is the timing. We know that achieving MRD negativity is important, which is probably a reflection of the tumor biology, meaning that tumor is really sensitive. It's chemotherapy or stem cell transplant that achieves the remission. Would you have the same outcome if you keep giving the patient three lines of therapy? Try RVD, it doesn't work, and dara, and carfilzomib, to try to push the outcome to an MRD negativity, which is what you're asking, which really, we don't have an answer for that.

We know that if you are MRD negative after the treatments we have today, your outcome is quite good, because your disease biology is telling us, I'm sensitive, I'm responsive, I'm not high-risk, I'll achieve a long remission, but pushing patients to achieve MRD negativity is the question of clinical trial, including the trial, I think we will discuss in a minute, which is the dara RVD. I'm sorry, dara-len maintenance versus len maintenance for patients who are MRD positive after transplant, trying to address that issue. What happens if you try to push patients to achieve MRD who did not achieve MRD with what you have today?

Jenny: Well, let's jump into that trial. This is called the AURIGA trial. Am I saying that correctly? You explained it that you're using a double combination of lenalidomide with daratumumab, post-transplant, and this is a Phase 3 study, correct?

Dr. Badros: It's a Phase 3 trial. One step back before I go on the trial. Most of the trials that have been published previously, using quadruplet therapy, meaning adding daratumumab, to Revlimid, to Velcade, and dex, will continue maintenance after the transplant, meaning you cannot really look at the impact of dara or Revlimid after transplant, using this trial if you did not give the patient data beforehand. It's like a package. It's a total therapy. You cannot separate the impact of each component of the treatment. It's a package. It's a total therapy. You have to give the three components so see the outcome.

In our trial, which is national trial, it will enroll 200 patients randomized between two treatments. One is dara, lenalidomide, and one is lenalidomide. The treatment has fixed duration, meaning it's given for 36 months. To go on the trial, you have to have myeloma that received induction, no daratumumab was given during the initial induction treatment. After the transplant, you have to be in a VGPR or very good posture remission. We are selecting a group of patients that have very good response to transplant, which is achievable today in over 80% of the patients after transplant.

VGPR is between 60% and 80%, depending on what regimen you use. It's not a very difficult goal. Then, we evaluate the bone marrow of those patients after the transplant. If the patient is MRD negative, meaning there is no tumor cells in the bone marrow, they are not a candidate to go into trial. We have selected patients that are responding very well, but they still have residual tumor cells in the bone marrow. Those patients will be randomized to receive daratumumab-lenalidomide versus lenalidomide alone. This is ongoing trial. I believe the trial almost finished enrollment. I think we enrolled. Last enrollment, there are 15 or 20 patients left. There was a problem with COVID resulted in some delay and other sites. I think we enrolled the largest number of patients on this trial.

The trial actually evaluates MRD negativity. How many of those patients that are MRD positive will become negative after you start the treatment? We look at 12 months, we look at 24 months, and 36 months. Then, we are going to see the impact of adding dara to the lenalidomide, which we suspect will have a synergistic activity to improve the outcome of those patients, because what is left in the bone marrow after you see high-dose chemotherapy was melphalan after you see reduction usually with a proteasome inhibitor, and Revlimid are usually resistant clones.

Jenny: Oh, interesting.

Dr. Badros: That's a different area of research. Why do you have a residual clone? What made the clone resistant? This particular question is under investigation. What is the biology of this clone? Why is this clone resistant and what makes it unique? Is it different than the original myeloma? That's why you're adding dara with len, their mechanism of action, hopefully, it will be synergistic.

Jenny: You're saying, you can do any kind of induction. As a newly diagnosed myeloma patient, you can have any genetic features, correct?

Dr. Badros: That is correct. The patients who have high-risk versus standard risk, but we're just evaluating the data for that.

Jenny: Yes, so you're just taking all comers. Then, you're saying you can do any induction therapy but you can't have had daratumumab in that beginning treatment, and then stem cell transplant. That's quite a bit of therapy in itself. Then, you're saying whatever's left, if you still have disease, then you have something that's more resistant to these standard treatments or therapies that are doing this with this two-drug combination with daratumumab is a good idea. Can you just explain the role of lenalidomide a bit, because I know it has direct killing of myeloma cells, but it also amps up your immune system, I guess, you would say. If you want to explain anything more on that, and then how would daratumumab work in that idea about maintenance therapy, mop up everything that's left, and then synergistically, how do they work together?

Dr. Badros: There are so many questions there.

Jenny: I know. Sorry.

Dr. Badros: To answer your question, you're right. Lenalidomide is one of those very complex drugs. Mechanism of action is definitely the direct killing of the tumor cells. Through a mechanism, probably nowadays, we have a little bit of idea about it through some Ikaros, and through certain mechanism that has direct tumor cells. We know for sure that adding lenalidomide with a proteasome inhibitor like carfilzomib and bortezomib has synergistic activity through inhibition of the proteasome inhibitor, that is a mechanism for some of the effects of lenalidomide.

Also, lenalidomide, as you correctly mentioned, is an immunomodulator. If you use lenalidomide in the maintenance setting, the purpose of it in addition to hopefully controlling whatever cancer is left and killing the rest of the cells, it could change the immune environment of the tumors. That happens through activation of certain T-cells, which is cytotoxic, meaning some of the T-cells in our body are capable of killing tumor cells. The problem is there are so many subtypes of T-cells. Adding daratumumab in that setting can eliminate some of what's called suppressor T-cells. We know that CD38, for example, which is the target of daratumumab, it targets a protein on the myeloma cells. It can directly kill the tumor when you give daratumumab, but it can also kill some of the suppressor T-cells leading to T-cell activation of the cytotoxic cells.

The combination of dara, len, or daratumumab lenalidomide can activate this immune system. In addition to that, we know that lenalidomide has a very important role which is affecting the bone marrow microenvironment. It has multiple effects on the cytokines or the proteins that are secreted, it affects the blood vessel formation, which basically makes the bone marrow which is the soil, if you can say it, or the place where the plasma cells divide, less hospitable to the tumor cells.

That's the reason we use lenalidomide after transplant, and the rationale for combining daratumumab. We are going to see if the trial becomes positive or able to convert a lot of MRD positive patients or MRD negative, and whether that translates into improvement in their survival. The trial is powered to measure the MRD negativity rate. That's one of the trials that I think the FDA will accept MRD negativity as a way to approve this treatment for maintenance, if the trial is positive, we don't know yet.

Jenny: When you have your stem cell transplant, how long after the stem cell transplant can you join this trial? Because this is a very practical thing for limitations. How far out can I be to even consider during this trial?

Dr. Badros: Up to six months, we can enroll patients. We usually do the bone marrow around day 100 which is our standard and our center. Some centers do it around day 60. Some centers do it later, but we usually do it around day 100. Then, we send a sample for MRD testing. MRD testing takes time. You have to have the original samples because we are doing next-generation sequencing. The endpoint of the study is measuring one times ten to the fifth. This can measure up to one times ten to the sixth, meaning one tenth of cell in a million. Then, we wait until we get the results, make sure the patient meets the criteria for MRD positivity.

To go on the trial, the good news in our site, which I cannot talk to other sites, but in our center, over 50% of our patients after transplant are MRD negative. We screened close to 30 plus patients to enroll 15. That's a theme you see a lot nowadays in patients with myeloma, that they're myeloma is eradicated basically with the available treatments. We just need to hopefully maintain this low or absent level for a couple of years, or three or four years of maintenance. Then, if we stopped treatment, that would be a great advantage for patients if we can stop maintenance treatment, as I said, to decrease the side effects and maintain good quality of life.

Jenny: Yeah, absolutely. Every patient wants that. You talked about the difference between MRD positive and MRD negative patients earlier in the show. But what's the average time to progression for MRD positive patients?

Dr. Badros: From the meta-analysis -- meta-analysis is when you get a lot of trial that presented data. It appears that if you are MRD positive after transplant, it's about two years median, meaning 50% of the patients will still be doing well later on. If you are MRD negative, it's close to five years. I think it's about two to three years difference. Again, the maintenance doesn't put into account the intensity of the maintenance. But we know from this meta-analysis that high-risk patients have not done better with MRD negativity, meaning if you have deletion 17, which is a true high-risk patient, and deletion 17 patients usually, even if they achieve MRD negativity, they need to be aggressively treated after transplant.

Maintenance treatment, if I'm going to just take us back to that point, if a patient has a standard risk, meaning everything is good, we usually give maintenance. The fact that you're MRD negative doesn't mean we don't give you maintenance. We give maintenance for somewhere between two to three years. I think nowadays, we can repeat the MRD after transplant and maybe at two years. If you're MRD negative after three years, I like to do it three years. Some people took two, but I think after three years, maybe it's reasonable to stop the treatment. Why? Because long term use of lenalidomide has been associated with complications. We know that second cancer, especially myelodysplastic syndrome, increases in this subset of patients about 5% to 8% after transplant, and lenalidomide maintenance.

We know that some side effects that occur with long-term use are very annoying, including diarrhea, which is really one of the main reasons after two to three years of tolerating Revlimid, you start having diarrhea which is related to bile malabsorption that occurs in patients. Sometimes, they respond well to bile binding called cholestyramine. But sometimes, they don't, and we have to stop the treatment. Sometimes, patients have excessive fatigue. They just can't do anything. They sleep 12 hours at night and sleep during the day. I think we have to discuss with the patient, maintenance is a way to prolong the remission duration. If you're having a lot of side effects, then we stop the maintenance. Sometimes, we try different types of maintenance besides Revlimid, but that was standard risk.

In high risk, if we don't have a clinical trial like the one we are talking about, and we don't have options, I believe that we are at a stage where we can get patients doublets for maintenance. I think proteasome inhibitors, something like carfilzomib or Revlimid will be quite appropriate assuming that the patient is able to tolerate carfilzomib, good kidney function, no heart problems, no shortness of breath. Using carfilzomib somewhere between eight to 18 months has been shown to improve MRD negativity, at least in some trials. The ATLAS. I don't want to mention names but there are trials out there to show that this particular regimen can actually convert some patients to MRD negative. More importantly, it can prolong the remission duration in some high-risk patients, including those with deletion 17. I have seen that personally, patients that have been able to overcome some of the high-risk signature by using doublets for maintenance including carfilzomib and lenalidomide.

Jenny: That's very interesting, what you said. Can you share where this trial is open?

Dr. Badros: I actually don't know. I know it's open multiple sites.

Jenny: We'll find the link and share it.

Dr. Badros: It's called will list the sites.

Jenny: We have a clinical trial finder also in myeloma, so we'll find the link. When we send out the transcript for the show, we will include the link to the show. To me, this poses an interesting challenge, because for most newly diagnosed patients, this diagnosis is a complete shock. It's usually a disease we have never heard of before. Clinical trials are sometimes considered by patients as like, oh, maybe if I run out of options later, I'll consider a clinical trial. Do you want to talk to the point of why clinical trials are so important to consider at every stage of your disease? This is a prime example to me of a good reason why.

Dr. Badros: I think your point is extremely well taken. I just will mention one trial called the MAIA trial, which is for patients who are not candidate for transplant. This trial enrolled -- it was a large trial published in New England maybe six, seven years ago. This trial enrolled patients all over the world, actually. We opened the trial on our site. The trial was open for a year. We enrolled two patients. Most of the patients when they're newly diagnosed or treated in the community, I see them when they're being referred for a stem cell transplant, which really is a big burden in the US in general, to be able to reach patients upfront to be able to do this very, very crucial clinical trial. Most of them are done in Europe, as you probably know. But it is important, because that's how we advance the field. None of those trials include sugar tablets or placebo.

All those trials will include an effective treatment combined with a novel approach. We discussed using RVD, which is a standard of care. We added daratumumab to RVD, which is the GRIFFIN trial. We opened the trial on our site. We enrolled a good number of patients on it. This trial has helped advance the field. It's not a randomized trial. We don't have the randomization yet to establish that, but it's very clear that I think daratumumab to Revlimid, Velcade, and dex in the GRIFFIN trial has improved outcomes with patients.

The good news is we were able to enroll patients across all spectrum, including African-American patients that usually have a lower representation of clinical trials. Thirty percent of the patients in the GRIFFIN filed with African-American. We actually have a separate manuscript describing the outcome of those patients. They do extremely well. The patients that go on clinical trials benefit from the new treatment. They do better than patients that are treated off clinical trials. In addition to physician monitoring, you have a whole team of researchers, of industry or FDA monitoring those trials. There are definitely advantages.

In this coming year, and I am going to jump in and discuss something not on my agenda for you, which is the maintenance, but we are starting to look at CAR T-cells. We have trials for CAR T-cells. As you know, those trials are very difficult to get on. But we were lucky enough to open many of those trials. Actually, the outcoming trials, because CAR T-cells have been extremely effective in patients who progress in later stages of the disease. Like any treatment, there's CAR T-cells now moving upfront, and really, it's very exciting for us to see CAR T-cells being used upfront to see if the newly diagnosed patients, especially those with high-risk disease, can benefit from this very effective treatment.

Nowadays, after induction, we are having randomized trials to compare CAR T-cell with Abecma which again is BCMA, versus transplant. Someone will say oh, I'd like to get CAR T-cells. We don't know if CAR-T cells will be extremely helpful upfront. We are trying to study that. This is another way to improve the outcome of patients. These are all crucial trials to enroll to, because it helped advance the field. Maybe we are hoping that we will be able to achieve remissions after CAR T-cell that will be longer than what we see today. Well, I'm telling you, we have remissions up to six, and seven, and eight years. We have patients now living beyond seven years. Hopefully, we'll improve that and convert an incurable cancer from a chronic disease to a curable disease. That's the goal of the clinical trials is to improve the outcome.

I just will add that the reason we are adding this trial -- there is another trial, by the way, looking at patients that have minimal residual disease after transplant, to give them CAR T-cells to see if we can rid of those malignant clones. There is a real interest of moving CAR T-cells, which you probably know, we are one of -- probably the only center in Maryland at this point that have been doing a lot of work in CAR T-cell and myeloma. We are treating patients in the relapsed setting and we're looking forward to moving it up front, either before transplant or after transplant not as maintenance, but what may be consolidation, to see if we can eliminate the malignant clone that is left after we use our best treatments upfront. We get dara, RVD, transplant, you still have myeloma, let's do CAR T.

These are all attempts to improve outcome of patients. I think you always like to mention, Jen, if I remember that, coming to a transplant center and treated in the center that sees a lot of myeloma patients had been associated with improved outcome for patients. I echo that, especially with the development of very complicated treatments that require very, very knowledgeable team to manage the side effects of those treatments, because they are not without side effects. I'm not talking about CAR T as a treatment given as an outpatient, it's a hospitalized patient for a week with significant monitoring and paying attention to every change to be able to manage the side effects. The more experience we have, the better it is for the patients. That hopefully answers your question about clinical trials.

Jenny: Yes. That's a great answer for clinical trials. I just think that there's a particular challenge for these newly diagnosed patients, because like you're saying, there are trials for newly diagnosed patients who are super high risk for CAR T. This trial is an important option for patients to see if maintenance can be better than standard of care, which is what they get. But I think for patients who are being treated in a community oncology setting, and not in an academic center like you're saying, the doctor might never even bring up the fact that oh, yes, you're a newly diagnosed patient, yes, this is a huge shock, yes, we need to start you on therapy, but here's some different options that you could consider as part of your strategy.

Because to me, this myeloma treatment thing is a complete strategic game. You need to have your very best treatments up front. You need to do whatever is possible for you upfront. Every move is an important move. I don't know. In my opinion, this is a really important thing to consider, but if you are in the community where these trials are not happening, then that may never even be a conversation. You may not know enough as a patient to say, hey, maybe there are some clinical trials that I could join.

Dr. Badros: Absolutely right. I think I think one of the blessings that we have in myeloma is that we have so many options for treatment. A lot of physicians in the community feel comfortable with those options. Tell the patient, hey, we have so many drugs. You don't need to do anything. Let's try this first. When you fail, we can see what we can do. But you're right. Maximizing the treatment we have, and as you try to emphasize, personalizing the treatment. When we have a clinical trial, it doesn't mean that every patient will go on the trial. We assess patient risk, we assess the cytogenetics, we assess the response after transplant, we look for minimal residual disease, we're trying to understand what kind of clone is left. All this biology of matching a biological endpoint in the patient with the best treatment is an ongoing effort. We don't have answers yet. There are so many unanswered questions. The only way to answer them is to go and take a trial.

I guess we'll add one crucial issue for us, which is the community. I'm very lucky living in Baltimore, because we have a very high-level medical community. As we always say, in a 40-mile radius, we have MIH, we Hopkins, we have Maryland, we have Georgetown, George Washington, Howard, we have very strong medical community that really keeps physicians updated. But even in that community, we are still seeing gaps in discussion of myeloma treatment. I think that probably goes to what you're saying about trying to go to a tertiary center, which is a method I think has been done many times.

The last thing that I will mention is African-American patients. We still have a very serious gap with African-American presentation on clinical trials. As you know, African-American patients represent 20% of all myeloma patients today. It's expected it would be 25% within the next couple of years. They're representation on clinical trials, both newly diagnosed and relapsed, more than the relapsed, is less than 2% to 3%. We really have a long road to go to reach this population, but the question is going to be, is that important? It is crucial, because biology might be different. Response to treatment might be different. We don't have this data. We need to get the data. We need to show that racial and ethnic disparity does not exist to respond to treatment.

Another disparity that is crucial, and unfortunately, there is no answer for it, is socioeconomic disparity. Some patients cannot come to the tertiary center. Some patients do not have the insurance or the money to receive adequate treatment today. These are bigger issues. They fall into the disparity of cancer care in general. That's an area our center is very focused on, which is the disparity, both ethnic, racial, and socioeconomic. I think, as a myeloma community, we have an obligation to provide the best treatment for patients, irrespective of all those disparities.

Jenny: Yes, absolutely. We've decided to focus on this, so we created a Black myeloma health site specifically for this, because Black myeloma patients are two, three times more likely to get a myeloma diagnosis. This is absolutely critical. What you're saying is so true. Genetically speaking, I think African-Americans tend to do better with treatment. They're diagnosed younger, so maybe that's part of the reason they're doing better, but maybe it's genetics. You don't know what's the optimal treatment for a standard risk Black myeloma patient. You just don't know that until you get the data out of these studies and trials. The whole idea is to improve care.

Dr. Badros: As I just mentioned, in the GRIFFIN trial, which is dara, Revlimid, dex, there is a subgroup analysis that's published separately looking at African-American patients. You probably have access to the paper. You're absolutely right. I think the message should be, if Black patients receive the same treatment that Caucasian or Asian patients receive, they do better, not well, they do better. There is one-year better outcomes in  Black patients compared to Caucasians, and they receive the same treatment. We are helping patients and we publish the data years ago, actually maybe seven, eight years ago now, published the outcome of Black patients compared to Caucasians after transplant. We have noted that if they come to transplant, they do much better. The problem is they don't come to transplant, either because their physician doesn't refer them or they have some fears about specific academic centers. But if they receive the same treatment, you do extremely well.

Jenny: Yes, I know. We're trying to address that. we have a new program that we'll be running called HealthTree REACH to try to address some of these disparities in care for black patients and Spanish speaking patients, and then even to address some of these socioeconomic issues that you covered, because it is really important to reach all my little patients and educate them to the potential that they have. It means longer life. That's what it means to them. It means years of longer life. That's the goal. Thank you so much for your amazing work. I do want to open it up for some caller questions. If you have a question for Dr. Badros, you can call 347-637-2631 and press 1 on your keypad. Let's get started with one caller question. Go ahead with your question. Hello, did you have a question? Caller, go ahead with your question.

Caller: Hi. thank you. I'm wondering, on the clinical trial you talked about with Revlimid, if the patient has a bad reaction to the Revlimid, are there options other than going off the trial? Can they lower the dose or do they have any options?

Dr. Badros: Yes. The trial we have stopped patients on ten milligrams, and we have an option to upgrade the dose, increase the dose to 15 milligrams after two months. We also can decrease the dose to five milligrams, and we can decrease the dose to five milligrams every other day. We really have not seen the bad skin reactions to take patients off study on this. It's really weird for us to see that to be honest with you. Yes, reactions can occur. But you have to remember that most patients nowadays receive Revlimid upfront during induction. We will have an idea if they are reacting to Revlimid or not. There is the occasional patient that do very well during induction and then have a skin rash during maintenance. Those patients, we stopped, we let the rash go away, and then we started to lower those. If the rash comes back, we can give it every other day. Most of the time, we can desensitize the allergic reaction and patients can continue on the treatment.

The other issue is going to be dropping the count. We know that patients that get dara, Revlimid, have drop in the white count, and we can adjust the dose of Revlimid for that. This regimen is also immunosuppressive, so there is risk of infection. We have to be conscious of that. As I said, none of those regimens are without side effects. We know that if you receive daratumumab for example, your response to COVID is going to be blunted. This is something we consider. Patients that are on the trial are giving antibody infusion rather than vaccination. We give them Evusheld to try to give them protection against COVID. There is a lot of issues with each of those arms that we pay attention to when we treat patients.

Caller: Okay, great. Thank you.

Jenny: Great question, and thanks for the answer. I think that's an important concept too. You talked about this already. But when you say you get better care, sometimes on clinical trials, I think it's really true. You really think ahead in that trial design, and you think, okay, what are we going to encounter, and how do we handle it going forward? Instead of being surprised by it later. That's good to hear. Caller, go ahead with your question.

Caller: Hi there. I think this is me. First, great questions and great answers, really appreciate it. It's a two-part question. One is if you have higher risk 4;14, and amplification 1q, and so post-transplant, your bone marrow biopsy was 18, but you stayed on KRd, they're going to take another bone marrow biopsy. If you become one out of a million, would it be okay? I think you said it would be okay to go off the Kyprolis. That's question one. The second part of this is I read something returning to where the translocation is in 4;14. It really would determine if you are a high-risk on a 4;14. Can you comment on that? Thank you.

Dr. Badros: 4;14 is one of the translocations that we know that proteasome inhibitors are extremely effective in those patients. Actually, I didn't talk about that, but the ixazomib trial, given orally for maintenance, there is one group of patients that did well on that trial, which were the patients with 4;14, because proteasome inhibitor is extremely effective in this subset of patients. Using carfilzomib, Revlimid, dex, is extremely important. I probably will follow what they did in the ATLAS trial, which just gives eight cycles of treatment. If you're MRD negative at eight cycles, at four cycles then eight cycles, so repeated negativity with PET scan negative, I think it's reasonable to go on lenalidomide alone.

In general, I like if the patient has high-risk in tolerating the KRd well, to use it a little bit longer, somewhere between 12 and 18 months. But with 4;14 which is quite sensitive, I think it's quite reasonable to consider coming off carfilzomib, but my preference is to at least eight by the trial that is published or go up to 12 and 18 months if you're tolerating it. After the first rush of carfilzomib, which is given weekly, you can go to day one and day 15. Instead of taking it three times a month, you can take it twice a month, with lenalidomide and a low dose of dex, and that's also acceptable.

Caller: Did you comment on where the break is in the translocation?

Dr. Badros: Actually, yes. I think that this is something I cannot answer to be honest with you. I've seen the data but none of them are enough to make a story that if you'd have a breakpoint and particular area, you will respond versus you don't respond. The same story with the 1q. I know the 1q story is also evolving story. These are all in development in clinical trials, but I don't think that they are enough to make decisions about initiating maintenance and stopping treatment, or starting it.

Caller: Okay, thank you much. Again, excellent. Appreciate it.

Caller: Hello?

Jenny: Oh, sorry. Caller, one more question. Caller, go ahead with your question.

Caller: Okay. Hi. Can you hear me? I don't know if I'm on mute or not. Can you hear me?

Jenny: Yes. We can hear you.

Caller: Hi. This is Steve from Nashville. Since you brought up the topic of the problem of African-Americans, and their treatment, and all sorts of stuff, I'm a Caucasian, a White Caucasian, but I joined the group, the African-American group here at HealthTree, and I am getting a real education about it from some Black patients. I just wanted to make one suggestion that came out of one of the meetings that we had, especially for older African-Americans. If you go back historically to the 1940s, 1950s -- by the way, I was offered trials my first day that I was diagnosed, and I turned them down for the very same reasons. I'll explain what it was. I just assumed that one would get treatment since it's called clinical trials, and the others would get a placebo.

Historically, if you go back, Blacks and African-Americans in the 1940s and '50s, were never given the good treatments. They will get the ones picked out and given the placebos or whether it was the trials for any of them. I just would like to suggest, I know it's impossible, probably logistically to do, but perhaps, clinical trials is not a good title for clinical trials. As the weeks went by, and I got into the chemo, and I found out what clinical trials, that I was not going to get a placebo, I was going to get the standard treatment, perhaps something that could be better, of course, I agree. I just want to make that suggestion that clinical trials mean something to White folks than to older African-Americans.

I would suggest that at some conference, they consider -- I'm retired now, but I was in the health care profession. I'm a retired dentist for 42 years at a hospital and Air Force, and private practice, and perhaps change the name just to make it obvious that you're not getting a placebo. Thank you very much.

Jenny: Yeah, thanks for your comment. Dr. Badros, do you have any closing comments about that?

Dr. Badros: No. back to maintenance, standard of care, one drug lenalidomide is good. Double it for high-risk patients with proteasome inhibitor either bortezomib or carfilzomib is standard of care. There are clinical trials going on introducing antibody. There are going to be trials for maintenance, for MRD with CAR T opening soon. Please stay tuned.

Jenny: Thank you so much for joining us today. Your clinical research is so important to move the bar forward for myeloma patients. this is actually why we do this show to highlight the good work you're doing and the important research that you're moving forward so that we, as myeloma patients, can benefit from it. We're just so appreciative for everything you do. Thank you so much for joining us today.

Dr. Badros: My pleasure. Thank you.

Jenny: Thank you for listening to the HealthTree Podcast for Multiple Myeloma. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.









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