Morie A. Gertz, MD provides considerations on tailoring maintenance for patients with Myeloma and provides drug recommendations and treatments.
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My name is Marin Xavier, and it's my pleasure to be the moderator of the malignant hematology session. Our first presenter is the well known doctor Maury Gertz. He is a professor in the Department of Medicine and a consultant in the Division of Hematology at the Mayo Clinic. He will be speaking today on tailoring maintenance therapy of multiple myeloma. Dr. Gertz is a good friend of our conference. Uh, he has spoken multiple years and is always very enthusiastically received. If you do have a question during his presentation, please put your question in the Ask a question chat function as a part of this conference, and we will address your questions during the panel discussion to follow warm Welcome for Dr Gertz to start off our day of malignant hematology. Hello, I'm Maury Gertz from Mayo Clinic in Rochester, Minnesota. It's a pleasure being with you again, if only virtually. Hopefully next year we'll get together again in San Diego again. My thanks to course director Mike cost for inviting me to speak. This year, I'm talking about customized personalized therapy. Tailoring maintenance therapy for multiple myeloma patients will be focusing the entire talk on the options for maintenance treatment. Uh, my financial disclosures are here, and so the considerations that we have in terms of tailoring maintenance is specific to the patient. We have to consider what is their measurable residual disease or minimal residual disease status? Uh, what is their biologic risk usually defined by fish but their biologic risk if they're presented with plasma cell leukemia, extra medullary disease, dishes of tumor heterogeneity, multiple clones and what do multiple populations of myeloma cells mean for the need for broader maintenance treatments to ensure new clone doesn't emerge issues regarding age and performance status and what patients can tolerate? If we're thinking about escalating the intensity of maintenance therapy, there are a number of research questions currently being addressed about maintenance therapy, including Could car T therapy used at the completion of induction eliminate the need for long term maintenance therapy? Cytokine release syndrome. One of the major complications of, uh, Heimerich androgen receptor therapy is usually increased because of the high tumor mass of relapse patients. But if you're dealing with patients who have minimal amounts of residual myeloma, side of kind of release syndrome is a minimal consideration. There are even trials that are looking at by functional t-cell engages bite therapy, of which the approved treatment currently is Balanta MAB and whether that could be used stem cell transplant, then bite treatment and eliminate the need for maintenance. Those are aspirational goals. For right now, we're still focusing on maintenance with chemotherapy, and there are a number of questions that really require answers. First of all, if we're committing patients to long term maintenance therapy, although that may impact progression free survival, what will it do to their overall quality of life over time? Well, patients have a lifetime risk of Venus Trumbull embolism, so they're going to need lifelong anti coagulation on top of their maintenance therapy. What about the fatigue commonly seen with drugs like Len? A little mind? Are these patients then going to have a decline in quality of life because of persistent fatigue, loss of energy, that there disease free? But they're not feeling well. How many patients will you wrestle with continuous problems with skin rash or diarrhea, as occurs with exacerbate? And what will the risk of second primary malignancies be using long term maintenance therapies that are known to cause second primary cancers? We'll use some maintenance therapy. Shorten the second progression free survival after maintenance, so that if you relapse on maintenance, your outcomes are poorer than patients who have less intensive maintenance. I'll be showing you studies that addressed the question of minimal residual disease and whether that status might be incorporated into decision making. About how long do we give maintenance therapy for and finally in basis of high risk multiple myeloma, usually defined with fish genetics? Are there indications for augmented intensity maintenance therapies beyond what is considered today's standards? So let's go back to the beginning of Linda Linda Might maintenance therapy and myeloma. Both of these trials were published nine years ago. Now, uh, the I f M 2005 started in 2005 so it's 16 years old, and it demonstrated that Lenin solidified Maintenance produced a highly significant improvement in progression free survival when compared with placebo, although in that trial there was not a survival advantage in their cohort. But the U. S study, which was a combined C A l g B E cog alliance trial, the use of lend a little mind maintenance post stem cell transplant provided not only and improved progression free survival, but it's statistically significant improvement in overall survival. When these trials were initiated, finite therapy for Leno Letterman maintenance was prescribed. So for these trials, we're seeing this with a fixed duration of two years of maintenance therapy. The recently reported E one a 11 Intergroup trial held in the United States, was reported at ASCO six months ago. There were two questions in their trial. This was a trial designed for patients not anticipating they have a stem cell transplant. But patients and induction were randomized to car fills, um, of Lund XKR D or partisan of Lund XV Rd. At the end of induction, they were randomized. Now what was reported at ASCO was that for induction in standard risk patients, there was no difference in K R D or V R D. But what has not yet been reported and his ongoing was the maintenance randomization and over 1000 patients reported the two arms will be leading a little meid fixed duration two years, and those patients will be compared for both progression for an overall survival to lentil intimate, continuous therapy until progression to try and address. Is there an optimal duration. Can we expose patients to shorter maintenance therapy and achieve comparable outcomes? Probably 36 months before we get this problem reported about the optimal duration of Lenin little mind maintenance therapy. I wanted you to see a little bit about some of the trials that are currently ongoing and proposed to try and address the issues of maintenance therapy. So in this trial, which is a trial as well at the end of one year of maintenance level, it Hamid patients will have m R D testing performed Patients who achieve Mardi negativity after one year of lend maintenance will get one more year of lead maintenance for a total of two years, and then they will stop therapy. Patients were positive will be randomized two x as a mid level. It might two drug maintenance therapy compared to lend a little mite alone every four weeks. And so we're looking at two issues here. Whether Midnegative patients can benefit from limited duration therapy and Mardi positive patients, if they are persistently positive, doesn't help to add a second maintenance drug in this case, eggs as amid to improve outcomes compared to the standard of living a little meat alone. Now I'd like to move into the data for bipartisan maintenance therapy for myeloma. So this is a relatively old study, now 12 years old from the Dutch German cooperative. And if you look at the very bottom roll, you can see that half of the patients receive thalidomide maintenance for two years and half received participant maintenance for two years. I want to just give you one caveat. Although this trial is quoted often about the value of more testament maintenance, it really wasn't initially designed to look at participant maintenance, because in the thalidomide arm, patients never ever received more testament. And in the partisan arm they received participant with induction, which is the P PS 3 41 was born testament as well as as part of maintenance. And so it was really bearing patients who never saw bore testament to patients who did. But in any case, there was two years of maintenance of thalidomide versus participant, and what this trial demonstrated is that the patients who received more testament had improved progression free and overall survival. So that doesn't really tell you anything you don't know. Bart is, um, it is important in the induction therapy of myeloma patients when compared to men. Christine Doxa rumors and dexamethasone so called there. But where the trial really showed, important changes is in the bottom roll 17 p minus, and we're going to look at overall survival at 36 months in the arm that did not receive autism and maintenance. The overall survival was 17% in the partisan have maintained patients 61%. And in the 4 14, which is an intermediate high risk feature, 40% overall survival of 36 months compared to 60%. And so this has been used and will be used in upcoming meta analysis. I'll show you that for high risk myeloma minus 17 p and 4 14. Bartosz um appears to add benefit in terms of overall survival. Post transplant So here's a meta analysis that was published less than one year ago. Looking at the three trials, the Zona Felt trial is the Hovan trial I just showed you. Plus, there's an Italian trial and a Spanish trial that look at Bart is amount based consolidation or maintenance. I'm not showing consolidation because there was no benefit of partisan consolidation, but when you look at the maintenance meta analysis for progression free survival in a. The meta analysis showed a 28% reduction in Hazzard, 72% favoring participant maintenance in all patients. And when we look at overall survival, a similar reduction in Hazzard 29% that favored Bore Testament maintenance therapy producing an overall survival benefit. Keep in mind this is partisan alone. It's not compared with Lana Little Mind. It doesn't combine with Lana Little Mind, so it doesn't answer for this subgroup. Whether partisan MIB is better or worse than Leno Letterman, only that it is beneficial compared to no maintenance therapy in producing progression free and overall survival. Benefit reported in Blood in 2018, subsequently published in The New England Journal, was a transplant eligible trial looking at X as, um it oral therapy for milligrams weekly as maintenance therapy Post transplant. So here patients receive standard of care induction Heidel smell for land and then were randomized. 60% receiving excess cement, 40% receiving excess placebo for a maximum of 26 cycles, which would actually be exactly two years. So finite therapy for two years. Looking at progression free, an overall survival maintenance X as a mint versus placebo. And what was shown was that there was a 39% improvement in overall progression free survival. So a hazard ratio of 71 versus placebo, indicating the value of X as a maintenance therapy post transplant. One of the issues here, of course, is that it's only one Pillow week. Main toxicity is diarrhea. Otherwise it's quite well tolerated, and it would not be expected to have an increased risk of second primary malignancies. So access, um, it is clearly in maintenance. Alternative. Two. Little intimate, perhaps, for patients who I can't tolerate. Lennon later, my dude accounts or recurrent skin rash or very serious venous thrombosis embolism. Exacerbated is an FDA approved maintenance therapy for myeloma patients. Post transplant. I'm about to show you a systematic review and meta analysis of multiple trials that look at various maintenance therapy so I'll walk you through. 3457 and nine are all Len a little meid placebo maintenance trials. Number two myeloma, nine was thalidomide versus placebo. Eight and 11 were lend a little meat, plus prednisone versus Leno. Lie to me. 10 was thalidomide bore testament six bore testament prednisone. And then finally, the oldest trials were interfering and thalidomide interference. So let's look at the forest plot for multiple different maintenance regimens. And here you can see in progression free survival that all of them had some benefit favoring the use of maintenance therapy. But the greatest benefit appears to be with linoleum. My prednisone, with the hazard function of only 0.39 followed by Len A little mind with a hazard. Racial 0.47 I mean a 50% reduction in the risk of progression followed by thalidomide, thalidomide, partisan. Everything produced a little benefit, bought Len, prayed and land. The two of them had the greatest impact. But overall survival based on this analysis really could not be easily demonstrated. Probably the closest was the Leno little meat Meta announced for overall survival, which is the second line in Curve B, and you can see the hazard ratios 0.76 24% reduction in the risk of death. However, it was not statistically significant. The hazard function running from 240.51 to 1.16 things to consider when you give language to my maintenance is particularly if you're going to go more than a year is that it causes cumulative Milo suppression, and you should expect that patients are going to need dosage reduction. So although what we start with is 10 mg daily, 21 days out of 28 it's unlikely that you'll end up there for half of the patients. Older patients with less cellular marrow's and poorer reserve commonly required dulce reduction during maintenance for Milo suppression and three weeks on and one week off is insufficient rest to allow bone mail recovery. And so, over time you will see cumulative Milo suppression. So it's very typical that patients on maintenance have a slow decline in hemoglobin and neutrophils and platelets, and this often requires a reduction of 10 mg three weeks out of 4 to 5 mg, three weeks out of four. And there are plenty of patients who are getting 5 mg every other day three weeks out of four, uh, in order to maintain a platelet count above 50,000 and a neutral account about 500. So just to be aware, if you don't treat a lot of these patients, that 10 mg is the starting point. But it's quite common that it's not the ending point. I wanted to talk briefly about how really important maintenance therapy is so in the Griffin trial, which probably is the induction therapy that will become the standard of care in the United States. Dara V. R D. Was given the transplant eligible patients, and what I want to focus on are the red boxes in A and the Blue Arrow. So at the end of consolidation therapy, the stringent complete response rate was 42.4%. At last follow up, it went to 62.6%. So maintenance therapy increased stringent complete response rate by 20% 40 to 60 even in the non Dara are just the v r D r. At the end of consolidation, stringent complete response was 32%. Maintenance boosted at the 45.4%. So you can really see how critically important maintenance therapy is to increase response depth. Too stringent complete response, and I'll be showing in a later slide. Why stringent complete response is really the end point of choice for myeloma patients, and so maintenance therapy really is essential. This is the Cassie appear trial instead of the U. S. Trial of Dara V. R D. This was Dharavi TD, since in Europe, thalidomide is used in induction in preference to learn a little might. But once again we see the same results. When we look at the patients who had achieved the stringent complete response, maintenance therapy deepens. The fraction of stringent complete response in the Dharavi T D are from 28.9% to 43.3% and even in the non Dara are it increased maintenance did the stringent complete response from 20.3 to 33%. So maintenance has an incredibly important role in deepening responses at the completion of transplantation. And why am I focusing on stringent complete response? It's because the depth of response matters. And in fact, we've known for a very long time that complete responders do better than other patients, the GPR or PR. But when you dice and break out the complete responders into complete responders, near complete responders and complete responders who are Mardi Negative and Mardi positive with incomplete response, only the Mardi Negative Group actually showed benefits. And so a complete response that's not Mardi negative didn't do any better than a patient who had a V g p r. They had identical outcomes for progression free and overall survival. The group that really stood out is the blue line that achieved Mardi negativity. So when I show you in trials that maintenance therapy deepened stringent comps complete response for actions from 42 to 62 30 to 43 these are very meaningful results because it increases the Mardi negativity. And you can see in this slide from 2017 that the median progression free survival was 63 months, and at 10 years, 60% of the patients were still alive. So our goal clearly is an M r d negative c. R. So here's another trial that I just wanted you to see, looking at ways to try and improve the depth of response following treatment. So in this trial, patients who are completed induction therapy get an M R D analysis that their Mardi negative off study because we have nothing to measure. But if they're Mardi positive, then they get randomized to lend a limited 10 to 15 mg plus eggs as amid this is indefinite therapy and that's compared to the standard of Luna Luna might alone to drug maintenance versus one drug maintenance exacerbate Len versus lead. And the end point of this trial is, of course, progression free survival. But just as important, what fraction of patients will convert from M R D positive into MRT negative? And what impact will that have on their progression free survival overall outcome as well as their duration of response? So to drug when exacerbated versus Len, this is another trial and again, just to give you a sense of how broad the ideas are regarding maintenance. So here, patients, the first question here is, Do you need four drugs? Can you get by with three drugs? So this is an ecology trial, and you start with Sarah Tomb, a mob mentality, my decks and really one of the questions being asked, Here's do you need to have bipartisan MIB for every single patient during induction, and what happens is after they have completed nine cycles, they get Mardi assessments all right, and after Mardi assessment, these patients get randomized and stratified based on their M R D status, and in one our patients will have bipartisan, it added. to Darryl Index. But what the key is here is look at the maintenance therapy. It's Dara Touma Map Len, a little mead indefinitely to progression again, a two drug maintenance regimen. But instead of letting Partisan of, Lennox says now, it's Len Dara. Too much maintenance therapy for high risk and standardize patient in the second arm. Patients will not receive Portas amid they stay with the RD for nine more cycles and will then move on to maintenance therapy and, again, maintenance here. Is there a tumor mob mentality meid continuous treatment until progression. And, of course, this answers to questions. One is what is the role of Bore Testament since we've developed are a tumor mob, and secondly, what will be the outcomes from a to drug maintenance therapy, including start to map? This is another trial that's ongoing right now. So again, the patient has stem cell transplant per institutional guidelines and then is randomize and again we have two different maintenance therapies. One is leading a little meat and the others lend a little meat and Dara to my mom for two years and at the end of two years of Leno, Letterman or Leno Letterman maintenance therapy patients will have M R D assessment and based on Mardi, another randomization for patients who are ever deposited in the Leno Letterman arm. They'll continue and the little mike. But for people who have achieved them, rd negativity, which could be 60% of patients, the second randomization has stopped maintenance therapy after two years with Len or continue on. So now we're kind of looking at things the way people who treat CML do that when they achieve a molecular remission. Is it safe to stop the tiki? We're asking the same question now. If you've achieved MRT negativity at two years, can maintenance therapy be stopped? Patients observed have a resume. If they relapse, will that affect ultimately overall survival? And in the Dora Touma, Magdalena Little made the same questions being asked. If your M R D positive you will stay on land a little, my dart UMA may have indefinitely. If your M R d negative, there will be a second randomization to either stop and a lot of my dexamethasone or continue learned a lot of my dexamethasone indefinitely again. Two years versus indefinite therapy, trying to address what is the optimal duration. Number one and number two are two agents for maintenance. Len Dara. Better than When alone. This is something This is recently published and is a Mayo Clinic trial simply looking at outcomes after stem cell transplant in patients that were high risk defined by minus 17 p. And we're looking at progression free survival. And at the end of the day, what we see is that patients who were high risk by minus 17 p who received single agent maintenance be that land or partisan or X as, um, it had a median progression free survival of just over two years. 25 months. But pacers had combined maintenance. That meant to drug maintenance for minus 17. P had a highly significant median progression free survival of 39 months. In other words, 14 months more without myeloma recurrence, suggesting that this progression free survival is linked to getting to drug maintenance. With a hazard ratio of 0.41 a 59% reduction in progression, I'll draw your attention to the, um, Forte trial. Briefly, this is an Italian trial that looked at three different inductions. Car fills um, Len Dex transplant versus car fills, um, a blend decks. No transplant versus car fills cyclophosphamide decks transplant. I don't want to go through the induction, not the point of the talk. But look at the bottom row where I have the blue arrow at the end of induction therapy, whether you were transplanted or not transplanted, you were randomized, and you received one of two maintenance therapy maintenance therapy. One was Len illegitimate, but maintenance therapy to was actually lend a little meat combined with car fills amid. So a second to drug regimen we haven't discussed Car fils aime Blend a little meat and again, if you look at the hazard plot, you can see the overall survival was better with car fills in Midland maintenance hazard ratio for survival of for progression free survival of 0.63 37%. And you can see that there's trends for every mile over stage, every fish and every ldh. This isn't blown up. Same trial and again you're looking at car fills, Um, a blend maintenance versus Leno. Little might maintenance, which is a median of 31 months of follow up, and basically every subgroup favored dual maintenance therapy with car fills um, a blend versus land and then noticed that patients who had high fish had about the same outcome as standard fish. So adding car fills, um, it appears to neutralize in maintenance the adverse impact of high risk genetics. And again you can see them. The Kaplan Meier curved at a 30 months progression. Free survival was 81% compared to 68% which gave you an overall hazard function of 680.63 or 37% reduction in risk of progression. So not to say that this is a standard, but car fills in Dublin, also being explored. I looked at clinical trials gov. Just to give you a sense of how wide the thought processes about looking at maintenance therapy. And so I found a few I wanted to go over. There's a phase two maintenance trial of Exacerbate versus Eggs as a land for myeloma patients. There's a trial on stopping maintenance therapy in myeloma patients and MRT negative remission. I bear to mind is the fourth generation image Thalidomide, Loma Linda, my palm a little mind, and now I, Berta mind is the next image, and that's being looked at as a maintenance therapy after stem cell transplant and newly diagnosed myeloma patients. And then one study I found that was a combined board testament cyclophosphamide maintenance. So there are many, many options that are being explored. Exoticism of Linda Linda made an exorcism of in combination with Linda Linda. Mind for maintenance therapy is a three arm trial, including Len A little my dozing at 25 mg every other day, which is done in part because that will reduce the cost of maintenance therapy by 50% using a higher dose every other day rather than a lower dose every day. Aissa, Taksim and the second anti CD 38 monoclonal antibody approved for the treatment of relapse myeloma and used in combination with Palm A little mind is being studied as maintenance therapy monthly after three cycles and then for three years as maintenance therapy. There are head to head comparisons of one a little bit versus excessive as single drug maintenance therapy, and there's also a trial to look at a very important question. So you have a patient that is online maintenance, 10 mg and their biochemically progressing. Do you need to change treatment, or can you escalate the dose of line a little might from 10 back to the original induction dose of 25 mg. And will that allow patients to stabilize? And so it's a question of re escalating the maintenance dose at first progression. Other trials are weekly bore Testament maintenance. I'll tell you off study at Mayo. When we use partisan and maintenance, it's a single dose. Subcutaneous li. Every two weeks. There are other trials of car fills, um, and maintenance Pamela Hmeid maintenance, as well as one that kind of alternates eggs as emotive orally weekly for two courses, then followed by Lionel itemized for two courses. Then you get to excessive to learn a little bit, too. Exes, Um, and too little intimate for two years to see if Syncopation of the drugs makes the difference in outcome. We're close to being done. Bart is, um, of in combination with Linda. Linda might as maintenance therapy, two drug maintenance and high risk, newly diagnosed myeloma. I'll think a lot of centers are doing this already off study, but this is a true trial. Looking at two drug Len and participant maintenance and in high risk patients, car fills and Glenn A little might ice Attucks a man. So it's a toxin. Have K rd after intensification with the four drug regimen, the maintenance is exacerbated. Car fils aime blend until progressive disease. So three drug maintenance therapy for high risk myeloma and it's Ice Attucks. A mob car fills in Atlanta little mike and then the randomized trial, which I had alluded to. A maintenance treatment with exacerbated along or exacerbate Plus Dara Tumor map. Two progression or 24 months of therapy Finally weekly. Oh, I went the wrong way. Excuse me, I'm going to summarize now with my last couple slides. This is the current Mayo Clinic M smart. You'll find it at m smart dot org about how we're doing maintenance therapy. Basically, all patients are recommended to have V R D therapy and, of course, now maybe dharavi rd therapy and an extremely old patient dara rd therapy. But for patients who are standard risk, we follow that with maintenance therapy until progression. This is not evidence based. This is Mayo Clinic consensus recommendation of line a little bit maintenance to progression. But for high risk patients were using vortices based usually Bartosz amid plus Lionel itemized maintenance until progression partisan every other week and then let a little meid 21 out of 28 days for patients with high risk genetics for 14, 14, 16 and minus 17 p and for the transplant eligible patients we're using for standard risk in the bottom row when maintenance and when it's done until progression. For patients of high risk, it's participant maintenance with a little bit tool progression. And that's how we're really handling all of our patients. So I'm going to summarize now. The standard of care still is single agent lentil into my maintenance. But for patients who can't tolerate, lead the skin rash, intractable cramps, profound fatigue, diarrhea that can be managed with bile acid binding Regine residence for testament or excess, um, of our both reasonable options, I think, for high risk patients to drug maintenance needs consideration. But the optimal to drug regimen is not defined defined. Currently, I'm using Leno Letterman participant, but it could be Lennox as, um, a blender or a tumor mob car filled with a blend. I don't know, but currently I'm using Lenin participant. Also, please remember that in patients with reduced marrow reserve that lend dose reductions are frequently necessary after a year of therapy due to cumulative Milo suppression. Although unproven, the general trend in the U. S. And in trials has been indefinite maintenance until relapse. Even though this is not proven and it's not evidence based, the trend has been away from 24 36 month maintenance and finally stopping maintenance and patients who have achieved Mardi negativity is a consideration. And there are trials that are addressing this. Now. I want to thank you so much for your attention, and I hope to see you again next year.
