First-Line or Frontline Therapy Options In Multiple Myeloma | 2023 IMF Patient and Family Seminar

Dr. Brian Durie: The strategy for these PFS meetings is that we want, if possible, to  bring in the people who are actually doing the work to study these different treatments. And so  recently, Dr. Voorhees has led a very important study where he's been looking at the use of four  drugs. And so one of the big questions right now is should we be using three drugs versus four  drugs, a triplet versus a quadruplet? And so it's very helpful to have someone like Peter, who  is not only the director o

f the cancer center, good luck with that, and it's so tough these  days in medical administration to have these responsibilities which come as you move forward  in your career, but the important thing is that he's able to continue to do his myeloma work. And  so look forward to your presentation today, Peter. Dr. Peter Voorhees: Thank you. Dr. Brian Durie: So please welcome Peter. Dr. Peter Voorhees: All right. Thank you very much, Dr. Durie, and  thanks the IMF for giving me the opportunity to

talk to you today. I'm going to be talking to  you about initial treatment of multiple myeloma. All right, so we're going to talk about the drugs  that we use to treat newly diagnosed myeloma, how we choose the best therapy for our patients  with myeloma. We'll talk about this evolving role of transplant for patients with newly  diagnosed myeloma. And then we'll go on and talk about treatment strategies for patients  who cannot or do not want an upfront transplant, those treatments for patients

who can  and want an upfront transplant. We'll talk a little bit about maintenance therapy and  then we'll wrap things up. So as you all know, treatment of multiple myeloma is a marathon,  it's not a sprint. And once you start therapy, this is a long-term process. So on the top of the  slide here, you can see for those patients that are transplant candidates, typically, we'll apply  what's called induction chemotherapy with three or four drugs with the goal of debulking the disease  and getting

the patient into a good remission. And then we'll proceed with the transplant, we'll  talk more about that, to drive the remission even deeper. After that, there may or may not be a  course, a brief course of consolidation therapy followed by maintenance therapy, which  can be given for an extended period of time. For the non-transplant patients, it's  the very same thing without the transplant. So let's talk about the drugs. So there's really  five core pillars of myeloma therapeutics. There's

the immunomodulatory drugs, and in the frontline  setting, Revlimid is the one that we typically use. These are called immunomodulatory drugs  because not only do they have activity directly against the multiple myeloma, but they augment  certain branches of the immune system such as T-cells and what are called natural killer cells.  So when we use these drugs as maintenance therapy, in part, we think that these work by  augmenting immunity to the multiple myeloma. There's the proteasome inhibit

ors. What's a  proteasome? A proteasome is this complex inside each and every one of your cells that basically  functions as the protein toilet of the cell. So as proteins are misfolded, mutated, et cetera,  they are funneled through this proteasome. And multiple myeloma cells, like plasma cells,  are professional antibody-producing cells, and they're very susceptible to the toilet  being plugged up. So they don't like it when their proteasomes are inhibited. We have several  different drugs in

the frontline setting. Velcade and Kyprolis are the two proteasome inhibitors  that we tend to use. There's the CD38 antibodies, and that includes Darzalex as well as  Sarclisa. There are the alkylating agents, Cyclophosphamide or Cytoxan, and then Melphalan,  which is typically given in high-dose form in the setting of transplant, which we'll again, we'll  talk about. And then there's the steroids, which either love or you hate, and that's typically  Dexamethasone and in some instances Predniso

ne. So how do we choose therapy for a newly  diagnosed myeloma patient? First and foremost, there's patient preference. This is a shared  decision-making process in this country, and this is why these seminars are so critical.  You need to empower yourself with knowledge so you can participate in that shared decision-making  process with your doctor. The decision to do an upfront transplant or not, that's important.  What are the other medical conditions that could potentially affect the side ef

fects  of particular drug classes? If a patient has diabetes and painful neuropathy related to  that, you're probably going to want to stay away from Velcade because we know that that causes  neuropathy. If you have significant heart disease, let's say you had a heart attack a couple  years ago and the pump doesn't squeeze as well as it used to, you may be a bit  cautious about Kyprolis in that situation. If you have bad kidney disease, you know you have  to be very careful about how you dose Re

vlimid. Do you have standard risk or high risk multiple  myeloma when we've talked about how we define that? And there's logistical factors that have  to be considered as well, including how far away are you from the infusion center. Are you going to  be able to get to the infusion center three times every four weeks for a Kyprolis-based therapy, for  example? So one of the things that I want to point out is that it really helps to put your best foot  forward. There's this concept that we talk a

bout in the myeloma community called Attrition. So  most people, when they relapse, they're going to be able to get a new regimen to get their disease  back under control, but we do lose some patients with each relapse. Now these data here that I'm  showing you, I think are flawed and exaggerated. I think insurance claims databases can  only get you so far, but the point is, is that there is some attrition that occurs  with each subsequent relapse. So putting your best foot forward, giving you t

he best chance  of the longest remission is very important. So let's talk about transplant. So what is  it? It's not really a transplant. You're not getting anything from a donor, right?  It's just a clever way of allowing us to treat your myeloma with very high doses of  a chemotherapy drug called Melphalan. We've been using Melphalan for over 50 years to treat  multiple myeloma, and it's very good at killing myeloma cells. It's very good at killing  myeloma cells at high doses. The problem is,

is that it's very good at killing stem cells  at high doses as well. So how do we get around that issue? So the way that we do that is after  we've controlled the disease with several cycles of induction therapy, we collect stem cells from  the patient and we store those away to be used. Patient comes in, they receive a high dose of  Melphalan chemotherapy to drive their remission even deeper. And as that Melphalan clears their  system, the stem cells that we previously stored are infused back

into the patient. So those  cells that we collected were never exposed to the high-dose Melphalan, and that's what allows your  bone marrow to regenerate afterwards. So a lot of people like to call this high-dose chemotherapy  with stem cell rescue because it's really not a transplant. So we can transplant a lot of  people, we can transplant older patients, as it turns out. This is a CIBMTR analysis of close  to 16,000 patients. And what you can see here is that the mortality, the non-myeloma mo

rtality is  very low, whether you're 40 to 49 years of age or whether you're 70 years of age or older. That  said, there was a very small number of people that were 70 years of age or older in this dataset  suggesting that we're very careful about those patients that we select in their 70s for high-dose  chemotherapy, so take this with a grain of salt. We can transplant patients who have  abnormal kidney function. So again, this is a CIBMTR analysis of close to 1,500  patients, those who had nor

mal kidney function, moderately impaired kidney function, or severely  impaired kidney function. And on the right-hand side here, you can see overall survival at the top  and what we call progression-free survival at the bottom. And you can see that the lines for those  with normal kidney function, moderately impaired kidney function function or severely impaired  kidney function are superimposable. So survival, progression-free survival are the same  with transplant regardless of level of kidne

y impairment. That said, again, very  few patients with abnormal kidney function in this dataset suggesting that we're being  very careful about who we select in that particular circumstance. Dr. Durie told us about  the determination study. This is the phase three study that looked at upfront versus deferred  transplant in newly diagnosed multiple myeloma. He showed us that for those patients that  got upfront transplant, they stayed in remission longer. Okay? That said, when you  look on the r

ight-hand side of this slide, overall survival was the same whether you got an  upfront transplant or a deferred transplant. Now, if you're a transplanter, you view this as  a positive study. We transplant patients, they stay in remission longer. If  you're a transplant nihilist, you say, "We don't need to be transplanting everybody  anymore because the survival's the same, whether we do it upfront or whether we save it for  later". This is where that shared decision-making process has to come i

nto play. It remains a very  important standard of care for multiple myeloma. It does give you the best odds of the longest  remission upfront, but it is a nuanced discussion. We know that quality of life is impacted by  transplant. This is quality of life data from the DETERMINATION trial. And the circles here  represent the transplant point and the red line are those patients that got transplanted. And  what you can see here is that their quality of life scores, physical functioning, et cetera

,  get worse in the transplant period, but I also want to point out that those lines go right back  up to the non-transplant lines as maintenance is getting ready to be started. So yes, transplant  is very hard. I'm not going to lie to you, but people recover from transplant. And in the  long-term, they do just as well as those who did not get an upfront transplant. I think for  those that have high risk chromosomal features, I think the decision to do transplant  upfront is particularly importa

nt and we more strongly advocate for that upfront  transplant in that particular circumstance. So on the left-hand side of the slide, a very  clear improvement in being in remission and being alive for those that got the upfront transplant.  On the right-hand side is an overall survival curve showing a trend towards improved survival  when the transplant's done upfront for that group of patients. So let's talk about treatment  for those who are not eligible for transplant or for those who do not

want a transplant.  And Revlimid and Dexamethasone represent the core and why do they represent the core? So  there's a number of studies suggesting this, but this was the first trial which  looked at Revlimid and Dexamethasone, so a two-drug regimen versus an old  school, three-drug regimen of Melphalan, Prednisone and Thalidomide. And to make  a long story short, patients remained in remission longer when they got the two-drug  regimen here, Revlimid and Dexamethasone. I also want to point ou

t that Revlimid and  Dexamethasone was looked at continuously. So as long as the patient was tolerating it and  their disease was under control, they stayed on it indefinitely or they just got it for 18 cycles  or what's depicted here as Rd18, and you can see at the 1.5-year mark, that's where those curves  start to spread out. So what that tells us is that Revlimid and Dexamethasone is an active therapy,  but to Dr. Durie's point earlier, it's a therapy that performs best when it's applied for

a longer  period of time, provided the patient is able to tolerate it. Dr. Durie also told you about his  SWOGS0777 trial. So we obviously want to do better than Revlimid and Dexamethasone alone. And what  he was able to show is that when you add Velcade to Revlimid and Dexamethasone for those patients  that are not undergoing an upfront transplant, that not only did they stay in remission  longer, but that they were living longer. So survival was improved by adding Velcade into  the regimen. An

d the Velcade was only given for the first 24 weeks of therapy, so it wasn't  applied long-term. With just Velcade in that first 24 weeks, you improved survival of myeloma  patients and this has become a very important standard of care as a result. One of the problems  that we have with Velcade is the neuropathy, and when we give it twice weekly, it can be quite  severe. And in this study, the rates of more severe neurologic side effects was a third. So  there's this RVD lite regimen that we tal

k about, and this is single-arm phase 2 data from the  Massachusetts General Hospital Group and Betsy O'Donnell, they tweaked Dr. Durie's RVD, giving  the Velcade weekly for example. And to make a long story short, responses were very similar,  progression-free and overall survival look fairly similar, although with not as much follow-up, and  the grade three neuropathy rate dropped to 2%. So you can tweak these regimens to make them more  tolerable for our patients. So let's talk about the MAIA

trials. So Daratumumab or Darzalex is  an antibody therapy directed against a protein called CD38. CD38 is a protein that sits on the  surface of myeloma cells. So when we give Darzalex or Sarclisa, either as an injection under the skin  or intravenous infusion, that antibody will attach to the surface of your myeloma cells and target  them for destruction by the immune system. So the MAIA study was a randomized trial to see if adding  Darzalex to Revlimid and Dexamethasone for those patients n

ot undergoing an initial transplant  would improve outcomes. And the only thing I want to point out on this very busy slide is that this  was an older group of patients treated with this particular regimen. So only 1% of the patients  in this study was less than 65 years of age, and over 40% of the patients were over 75 years  of age, so this was an older group of patients. And what you can see here on this slide is that  not only on the upper right are we improving the time and remission, but w

e're also improving  overall survival. And this progression-free survival that we're seeing here, you're going  five years out and we're still above 50% of patients in remission. I mean, that's the  longest progression-free survival that's ever been reported in a newly diagnosed study for  transplant-ineligible patients. And those overall survival outcomes are nothing like we've ever  seen before, so this is really strong data and you're going to see more and more patients  with newly diagnosed

myeloma getting this Darzalex-Revlimid cocktail. Now, if you can't  beat them, join them, right? So the question is, can we do even better? So why don't we bring all  of these drugs together? So CEPHEUS is a study, a phase 3 international study that's looking  at what happens for those patients that are not undergoing transplant when we add  Darzalex to Dr. Durie's VRD backbone. So this is a study that has fully enrolled and  we hope to see these results at some point in the near future. Sarclis

a, which is another  CD38 antibody, they're conducting a similar study called the [inaudible 00:16:42] trial,  looking at the VRD backbone with or without the CD38 antibody Sarclisa. So let's  talk about transplant-eligible therapy. So the first study that showed that this  proteasome inhibitor immunomodulatory drug, Dexamethasone triplet, was the right thing to do  for transplant-eligible patients was this GIMEMA trial. And this is an older study where they  looked at the addition of Velcade to

Thalidomide and Dexamethasone for those patients undergoing  stem cell transplant. They got several cycles of induction therapy with two or three drugs,  they got two transplants, tandem transplant, they got a couple of cycles of consolidation  therapy and no maintenance treatment. And to make a long story short, the addition of  Velcade again not only improves progression-free survival, but improves overall survival  in the long run. So patients are living longer when they had the Velcade adde

d to their  Thalidomide and Dexamethasone. And this is in the transplant patient population. And I want  to report that these outcomes, these survival outcomes are absolutely phenomenal and that's  without maintenance therapy. So CASSIOPEIA was a phase 3 study that took this one step further.  So Velcade, Thalidomide and Dexamethasone are very active. What if we add the CD38 antibody Darzalex  to that? Can we make things even better? So this was an interesting study that again looked at  the Vel

cade-Thalidomide-Dex with or without Darzalex in the setting of a single transplant.  But interestingly, they had a second randomization later to either no maintenance therapy or  Darzalex maintenance therapy for two years. And again, you see this notable improvement  in progression-free survival. So more people living with their disease under control with  the four-drug regimen compared to the three-drug regimen. And although it's too soon to make  any definitive comments about overall survival

, there's this trend that looks actually quite good  in favor of the four drugs versus the three drugs. So in the Alliance Cooperative Group here in the  United States, we performed the GRIFFIN trial, which was a bit different than CASSIOPEIA. We  don't like using Thalidomide in the United States much, it causes a fair amount of neuropathy,  as does Velcade. You put them together, the neuropathy can really be quite challenging. So  we wanted to look at Dr. Durie'S VRD backbone and see whether th

e addition of Darzalex to that for  those patients undergoing upfront transplant could improve patient outcomes. And we did not have a  second randomization at the maintenance stage. If you were on the Darzalex arm, you got Darzalex  and Revlimid for two years, and then you continued your Revlimid thereafter. If you were in  the standard of care arm, you got Revlimid. These are the baseline characteristics of the  patients, and this is the most important part of it. So on the left here again, we

have  progression-free survival. So when that line stays up high, those people are alive and their  disease is controlled and it's not progressing, right? And when you look four years out, for those  patients that got the four-drug induction therapy, the Revlimid-Darzalex maintenance for  two years, followed by the Revlimid, the four-year progression-free survival is 87%.  That's the highest progression-free survival that's ever been reported in a randomized study  in multiple myeloma. When you

look at those with standard risk disease, that progression-free  survival at four years goes up to 92%, 93%. So patients doing a lot better these days  with these improvements. Now that said, as you can see on the right-hand side of the  slide, overall survival's exactly the same. You have the ability to get Darzalex and Sarclisa at  the time of relapse, and we'll be talking about that in a short bit here. So showing overall  survival in these newly diagnosed studies has become incredibly chall

enging, and that's a good  thing for patients. And it's become incredibly challenging because patients are doing so well  that we have to follow them in a clinical trial for years and years and years before we can  see any potential differences. We also looked at patient-reported outcomes. I mean, so great.  We're controlling the disease better, patients are staying in remission longer, but we're adding  drug to the regimen. So adding drug means more side effects, right? So we looked at patient 

reported outcomes and quality of life metrics. And I've just shown a couple of examples on this  slide. So on the left-hand side of the slide, you see pain symptoms. And when that line drops,  that means there's less pain, okay? And what you can see is for both groups, the three drugs and  the four drugs, green and blue lines respectively, pain is improving over time. And that makes sense,  right? You've got pain because of your multiple myeloma, the disease comes under control and  you're goin

g to have less pain, right? But you can see that there's this trend towards improved pain  scores. For those that got the four-drug cocktail versus the three-drug cocktail, you would think  that we would make fatigue worse by adding drug, and that in fact, is not the case. People  probably had a fair amount of fatigue because of their active myeloma at initial diagnosis,  and that fatigue actually got better over time. It didn't get worse, and it favored the four  drugs versus the three drugs. S

o the nice thing about these CD38 antibodies like Darzalex  and Sarclisa is that their side effect profiles are reasonably good in the grand scheme of things,  and we can add them to backbone therapies and get away with it from a side effect perspective for  most patients. So let's just talk briefly about maintenance therapy. There's a number of studies  that have been done for patients who've undergone an initial transplant where they were assigned to  no maintenance therapy versus Revlimid mai

ntenance therapy. Dr. Durie alluded to the differences  in outcomes for those in the IFM 2009 trial and the DETERMINATION trial where Revlimid was  applied for one year versus indefinitely. The CALGB also did a study looking at Revlimid  continuously versus no maintenance therapy. The MRC in the United Kingdom also did the same. And to make a long story short, overall  survival was improved with application of Revlimid maintenance therapy as  long as the patient was tolerating it and as long as

it was keeping the disease under  control. There are studies looking to see what the optimal duration of treatment is. So the ENDURANCE  trial is looking at three years of maintenance therapy versus indefinite maintenance therapy.  The SWOG Cooperative Group is looking at MRD, Minimal Residual Disease testing after two  years of maintenance therapy. And if you're MRD-negative, you're either assigned to  stopping your maintenance or continuing your maintenance. So can we use MRD testing  as a way

of making decisions about stopping a maintenance therapy? And then lastly, I want  to just briefly talk about the fact that there are going to be new therapies that are going  to be introduced into the frontline paradigm. We are doing so much better than we did before,  but we could continue to do better. So one of my slides I was going to show was what's called  the CARTITUDE-6 trial. So what is that? That is a study that's taking the Darzalex VRD  backbone for transplant-eligible patients, pa

tients are getting treated with several  cycles and then they're randomized to a transplant or they're randomized to Carvykti  CAR T-cell therapy. So we are going to see, and we'll hear more about CAR  T-cell therapy from Dr. Munshi, but we're going to see if a CAR T-cell product can  do better than a transplant for those patients. You'll hear about bispecific antibodies later.  You're going to hear about something called Teclistamab or Tecvayli. And there is a study  that's building on the MAIA

trial that I told you about that's looking at Darzalex, Revlimid  and Dexamethasone versus Darzalex, Revlimid and Tecvayli for newly diagnosed myeloma patients  not undergoing a transplant. And we're going to look to see if we can improve outcomes even  further for that group of patients. So with that, I think I'll go ahead and wrap up and then I  guess we can take some questions. Thank you. Mike Lewis: Hi, Mike Lewis. I'm from Pembroke Pines, Florida.  My question was about the Kappa/Lambda ra

tio. Dr. Brian Durie: Okay. Mike Lewis: For example, you can have a Kappa/Lambda numbers like 59 and  57, which is a ratio of 1.03. Suppose a patient has ratios that stay like that for a long time,  but both the Kappa and the Lambda are elevated. Dr. Peter Voorhees: Yeah. Mike Lewis: When do you become concerned about the risk of amyloidosis? Dr. Brian Durie: Yeah, so there are a few aspects to that. I don't...  Maybe you want to go first on that. Dr. Peter Voorhees: So there's a couple of expla

nations for why both the Kappa and the Lambda light chains  may be elevated, yet the ratio remains within a reasonable range. So one would be abnormal kidney  function. So if your kidney function's not normal, the kidneys actually metabolize these light  chains and so if the kidneys are not working well, they're not metabolizing them appropriately and  the baseline levels of both of those will go up. And there's some subtle changes that can occur  to the ratio when that happens and so we have to

be thinking about that when we're interpreting  the results of the testing. Anything that causes inflammation can cause those levels to rise.  And it's interesting, and I don't know if Dr. Durie's had the similar experience, but there's  some patients who are on Revlimid maintenance therapy where they're both just elevated a  little bit and the ratio is completely normal. That's not of concern, that is not an indicator  of progression. You really have to look at the affected light chain. So if

you have a  Kappa-expressing myeloma, whether it's IgG Kappa or free Kappa, you need to see that  Kappa light chain rising disproportionately to the Lambda to be concerned that progression is  occurring. There have to be very specific physical chemical features to the light chain in order for  it to cause amyloidosis, but if the myeloma is in a complete remission and those light chains that  we're seeing on the testing are not derived from the multiple myeloma, you really shouldn't have  to worr

y about amyloidosis in that situation. Dr. Brian Durie: Right. The other thing that can happen is that if it's a Kappa myeloma, the  Kappa couldn't be normal, but then sometimes when you're on maintenance, the Lambda will actually  drop, and so then it makes the ratio high. So you have a high ratio, but it's because the Lambda is  low, which seems to be impacted by the treatment. And so you really need to talk to your doctor  about that. But in this low range where you're seeing these, what we c

all fluctuations where  they're maybe going up and down a little bit, you just need to observe and really not jump  in too quickly because they will fluctuate up and down a little bit. They can sometimes be  affected by other medications that you're taking where the light chains are not getting kicked  out through the kidney as fast. And so you just need to be a little cautious about potential up  and down levels, especially at the lower levels. Speaker 4: And I just wanted to add, looking at th

e numbers over time,  and for those of you that don't know, amyloidosis is a misfolding of the proteins that  latches onto tissues like heart and kidney. And so I routinely check a 24-hour urine, we  look for extra good protein called albumin. That might be a sign of kidney involvement if  you're having new heart issues because people are living longer and we might not have seen an  amyloidosis diagnosis when you had the myeloma. So just discussing symptoms with your doctor  and then we can do t

he appropriate evaluation. Dr. Brian Durie: Right. All right. So hopefully, that's  helpful. Number two. Okay, go ahead. Sergio: Hi, I'm Sergio from Miami. I have a question about Revlimid because I see sometimes  you take it every day, sometimes they tell you to take it 21 days, then stop for seven days.  So what should we ask for, especially if it's spontaneous that you have to take it all the time?  I had to have a surgery, so they tell me, "Don't worry. Stop it for 10 days, then you  take it

back". So what's going on there? Dr. Peter Voorhees: So that's a great question. So in the CLGB study that looked at Revlimid maintenance versus no  maintenance therapy, they gave the Revlimid continuously with no breaks. And again, we saw  an improvement in progression-free and overall survival. The MRC or Medical Research Council  study that was done in the United Kingdom did the very same thing, but they used three  weeks out of four dosing, and the results are virtually superimposable. My v

iew is that  getting that one-week break from Revlimid therapy is advantageous from a side effect perspective.  And I mean, there may be some differences from one myeloma physician to another, but I typically  do not use continuous maintenance therapy. Dr. Brian Durie: Right. I think that especially the benefit is similar, but  I think in terms of the side effects, particularly the white blood cell count, I think  the continuous Revlimid can really be more likely to produce a drop in blood count

s. And so in the  SWOG trial, for example, we had three weeks on in that one-week rest period, which I think is  very important. And then sometimes over time, if you're on Revlimid for years, which some  patients are in the room here, you can go to two weeks on and two weeks off is another  way of doing it. The rest period can be quite important to allow your bone marrow to recover,  but also to allow you to stay on the maintenance. Dr. Peter Voorhees: Yeah. The challenges that the FDA has appro

ved Revlimid  maintenance therapy is continuous dosing, so some of the clinical trials that are being  done to build on Revlimid maintenance therapy have been forced into the situation where  they have to use continuous dosing. So that SWOG study that I was telling you about  where patients can potentially come off of their maintenance therapy after two years  if they're Minimal Residual Disease-negative, that's a study of looking at Revlimid versus  Darzalex and Revlimid as maintenance therapy,

but the Revlimid is continuous because of the  nature in which the FDA approved the maintenance. Speaker 4: And there's different doses according to if you had a transplant or not. And  depending on if you're a study or not. So talking about side effects, like Dr. Durie said, we have  people on five milligrams or 10 milligrams. And so we take all that into consideration. So the dose  that works for you is the dose you should be on. Dr. Peter Voorhees: Yeah. Sergio: So as a patient, I understand

my doctor has to put me  on Revlimid, 10 milligrams in my case, every day forever, but I can choose to  take it three weeks and stop one week? Dr. Peter Voorhees: I think if you're having side effects, particularly in the low white blood cell  count that Dr. Durie was alluding to, it's definitely worth a discussion. I mean, I  think that they're both very effective choices and it's really just a matter, again, of this whole  shared decision-making process with your doctor. Dr. Brian Durie: Yeah

. Speaker 4: Yeah. Good job. Dr. Brian Durie: All right. At the back it looks like. Luis Perez: Good morning, Luis Perez from Boca. I have a couple of questions  related to the GRIFFIN trial because that's very relevant. That's my situation. I just went  to through the RVDD regimen. Unfortunately, I had a oncologist or someone recommend to my  oncologist to go through eight rounds of this before they collected my stem cells, and I had one  round in the hospital of something else where my kidneys

weren't doing well. I'm worried about my  stem cells being damaged, and I'm wondering if it makes sense to go to the transplant knowing that there's a potential in my stem cells  were damaged because of the extra rounds. Dr. Brian Durie: Right. Dr. Peter Voorhees: Yeah. Dr. Brian Durie: Yeah, go ahead. Yeah. Dr. Peter Voorhees: So both in the CASSIOPEIA trial, which was Darzalex with Velcade, Thalidomide  and Dexamethasone, and then our GRIFFIN trial, which was Darzalex with Revlimid, Velcade 

and Dexamethasone, there was an impact on stem cell mobilization and collection when  Darzalex was added to Thalidomide or Revlimid, and it's that interaction that we  think is important. The CD38 antibody, we don't think that that's actually causing stem  cell damage per se. It is creating challenges with collection. And we have been strongly advocating  that for those patients that go on four-drug therapy who are considering transplant, whether  it's upfront or whether it's for a relapse, they

really should be collected as quickly as  possible in the process because there can be challenges with collection down the road.  That doesn't mean that they're damaged, they're perfectly healthy, functional stem cells.  It just makes it logistically harder to do. Luis Perez: Okay. [inaudible 00:34:58]. Dr. Brian Durie: Right. But in terms of being worried about it, I mean, to do the transplant, we do have cutoffs  in terms of the number of stem cells. So we're not going to do a transplant if w

e don't have enough  stem cells to be able to give the recovery, right? Dr. Peter Voorhees: Yeah, no, that's exactly right. And if for whatever reason  you're not able to get enough collected, patients are staying in remission for  very long periods of time these days, you can revisit that process down the road as  you've had further time removed off Darzalex. Luis Perez: What's enough? Speaker 4: Like 2 million [inaudible 00:35:35]. Dr. Peter Voorhees: What's enough for a transplant? Yeah. So i

t  depends on who you talk to, about two to three million per  transplants, typically, what we'll use. Speaker 4: And there are medications to tell your bone marrow to make more cells to capture it from the blood,  like Plerixafor is one that we use, and just the growth factor shots too. So we can get those out,  but we target about trying to get 5 million at our institution so that you can have a couple for  this transplant and some for later if you need it. Luis Perez: Okay, thank you. That's

very helpful. And then my  second question is related to the pain, and my myeloma was caught very late and  I've had a lot of damage to my bones. Dr. Brian Durie: Okay. Luis Perez: How long before I'm not in constant pain? It's been a year and a half. I just want  to know when I'm not going to be in pain anymore. Dr. Peter Voorhees: So I think, and your struggles are shared by I'm sure many people in this room, and  I hear this from my patients day in and day out, it's a very long process for th

ose that have had  significant bone damage at initial diagnosis. We can treat your disease into complete  remission, but at the end of the day, there's been significant structural damage  done to your spine or other bones in your body, and that can take many, many months to improve.  But I have patients that are a year out, two years out from therapy, and as the disease  remains in remission and it continued healing in remodeling of bone, it just slowly gets better  over time. There are some pat

ients who do have some level of chronic pain related to their  bone disease, even when they're treated into complete remission. I'm not saying that  that's going to be the case for you, but that can occur, but you're still early in the  game, and especially if your pain's better now than it was at initial diagnosis, you can expect  a continued improvement in the months ahead. Dr. Brian Durie: Right. And depending on the problems, if it's due to a collapsed vertebra, we can do  Kyphoplasty to try

to recover the height of the vertebra, and sometimes that can be very helpful  to improve the pain. It just depends on what is causing the pain. And it's always important to  remember that there are other causes for pain. So people who have myeloma can also have  lumbar problems, they can have all kinds of other things that are causing pain, and so  it's good to see a neurologist or an orthopedist or someone who can assess what's going on  and make sure what is causing the problem. Speaker 4: A

nd I agree, and we talked very briefly about pain yesterday,  but we have pain colleagues that I work with real closely. Medications that are classified as  antidepressants, there's one called Cymbalta, can be very effective in some people. And then  the same medicines that we use for neuropathy, the Gabapentin, to disrupt those  pain signals in your brain. Also, physical therapy to strengthen the muscles  that support the spine and the joints, all those things can work real well, but talk  to y

our providers. If they don't know you're in pain, then we'd have to have that  discussion about strategies to help. Dr. Brian Durie: But in the big picture, I just want to emphasize one of the things that I started with  today is that this is one of the big incentives to start the treatment earlier before issues emerge  and can cause problems. I mean, I remember not so many years ago when we have these meetings, we  had to open the doors wide because so many people were coming in here in wheelch

airs, they had all  kinds of issues. We don't see that anymore. And when couples come in, we don't know which one  is the patient because they both look great. Dr. Peter Voorhees: That's true. Dr. Brian Durie: In the past, that was not true. It was very obvious who the patient was.  And so, I mean, for the future, I think we're going to hopefully be preventing this kind of  situation where it can be difficult to manage. Speaker 4: Yeah. Dr. Brian Durie: All right. Speaker 7: What would you want

again? Yeah. Speaker 8: Yeah. Name please [inaudible 00:40:06]. Harep Walters: My name is Harep Walters. I live in Deerfield Beach. I lived in Holland  from '65 on until the late '70s. And when I was in Netherlands there in the late '50s and the  early '60s, Thalidomide had misformed children, babies, and fetuses by the thousands,  if I'm not mistaken, 40,000. And now, it is a medicine for multi myeloma. What does it  do to our bodies if it creates misformed fetuses? Speaker 4: Yeah, the Thalido

mide. Dr. Peter Voorhees: Yeah. So this is a great, great, great question. So the story of Thalidomide  and the immunomodulatory drugs is really quite fascinating. So Thalidomide unfortunately caused  terrible birth defects. And the way in which it caused these horrible birth defects is by stunting  the growth of blood vessels. So as the fetus is growing arms and growing legs, the blood supply  has to feed that, right? But the blood vessels were not growing appropriately. And in the 1980s,  ther

e's a strong interest in anti or angiogenic therapies for cancer. So if you could choke off  the blood supply to cancer, you could control it. So Thalidomide was taken off the shelf and  it was applied in a number of different cancer types in various clinical trials. And in multiple  myeloma, it worked and it worked very well. And it wasn't only until, I think it was maybe 2015,  2016, something like that, where a very clever group of investigators in Japan determined how  Thalidomide works, how

it causes birth defects. It binds to this protein inside of cells called  Cereblon, and it changes the proteins that are directed to the proteasome, the toilet that  I was talking about for degradation. And as it turns out, so that explains, so as the  biology is explained, but in the myeloma cell, the Thalidomide, the Revlimid, the Pomalyst  comes in and binds to Cereblon and then it targets these important proteins called  Ikaros and Aiolos for destruction. And these transcription factor prot

eins are very  important for myeloma survival, and that's why they don't like Revlimid, Thalidomide and  Pomalyst. So now that we know the target, so we've been using it for years and  we didn't exactly know how it worked. Now that we have the target, we can develop  better drugs that target Cereblon even better. And that's what these CELMoDs are. So Iberdomide  and Mezigdomide are actually better at binding to the Cereblon protein and targeting Ikaros and  Aiolos in the myeloma cell for degrada

tion. All of these drugs are with risk, right? Thalidomide  had the unfortunate history behind it, but there's a lot of chemotherapeutics  that if you applied to a pregnant woman, would cause horrible fetal harm, but we've  got decades of experience with these now in patients with multiple myeloma. And  I think we've got a good handle on what the short-term and the long-term  risks are associated with these drugs. Dr. Brian Durie: Yeah. They are remarkably safe, but I think that the over time, t

here's a question of whether  you would have maybe a risk of getting some other kind of cancer, but that risk is really  rather low. Even taking Revlimid for five years, 10 years, very long periods of time, that  risk is not so elevated. One of the most interesting things about these images is that  we'd been studying myeloma cells for years, and all different factors can impact myeloma  cell growth. And people were looking at this drug and that drug to see if it would  be good in treatment. And

then suddenly, completely out of left field, this drug,  Thalidomide, which is being studied as a sedative, produces dramatic benefit in myeloma  and draws attention to this pathway, which has been delineated carefully here more  recently. And so this was a pathway which had never been thought of as being important in the  past, and so this is what you call serendipity. Dr. Peter Voorhees: Yeah. Speaker 4: Yeah, exactly. Dr. Peter Voorhees: Absolutely. And so extending on that there, there's a

whole new area of  cancer therapeutics where they're basically taking proteins that previously were thought  to be undruggable, and they're developing drugs that will direct these proteins to destruction  through the proteasome. So you're going to see this whole new field of cancer therapeutics  unfold as a result of this serendipity. Dr. Brian Durie: Right. Speaker 4: Yeah. It's actually really amazing that we have these old drugs and finding  these new druggable pathways, and that Cereblon tha

t the doctors talked about, we are studying  that now in newly diagnosed myeloma patients that can't get transplants and so we're moving  these drugs up. So instead of that Revlimid up front or Thalidomide up front in the studies Dr.  Voorhees had mentioned, you or somebody at your support group might have access to one of these  new trials. So especially if you're smoldering or MGUS, just keep getting monitored so we can  get you treatment earlier with these new drugs. Dr. Brian Durie: Right. A

nd the serendipity with Thalidomide, it could easily have been missed.  So Dr. Barlogie, he got the Thalidomide from the gentleman in Boston who was studying angio- Dr. Peter Voorhees: [inaudible 00:46:00]. Dr. Brian Durie: [inaudible 00:46:01]. Dr. Peter Voorhees: Yeah. Dr. Brian Durie: And he gave it to this first patient who he was interested to give it to and it didn't work,  it didn't work. So the decision was, well, he got all this Thalidomide, oh, well, we might as well  give it to this p

atient in the room next door. Speaker 4: We didn't do that now. Dr. Peter Voorhees: No. Dr. Brian Durie: And so they gave it to the patient in the room next  door who had a dramatic response. And so these little details are just so  interesting and ultimately very important. Speaker 4: Yes, very interesting. Speaker 7: [inaudible 00:46:38]. Speaker 10: Almost 24 years, I had Dr. Barlogie. I had a transplant. Dr. Brian Durie: Yeah. It's great to see you again  live at the meeting here. Okay. Spea

ker 10: 24 years, and Dr. Barlogie started transplants set up before I  came out of smoldering, but because of insurance, they wouldn't let me have it there.  And I had to have it somewhere else, but they still followed the protocol. And I did  not go through the tandem, I just did the one. And then because it was so far back a long  ago, I went 18 years with no medicine. My miracle medicine right now is  Darzalex and Velcade. I am down to 0.5. Speaker 4: Wow. Dr. Brian Durie: All right. Speaker

10: My IgG is normal. Dr. Brian Durie: All right. Speaker 10: And Dr. Hoffman is my doctor. Dr. Brian Durie: All right. Very good. Very, very good. So- Speaker 10: One more thing, tomorrow night on Call the Midwife  on PBS, they are starting it off with multiple myeloma. This is back in  the early '60s, and they talk about it. Speaker 4: Wow. Dr. Brian Durie: Yeah. So one comment I'll make related to this, which I think is  so important, and I know there are a number of people in the room where

this applies, is  that we're very much focused on wiping out the myeloma to get this MRD undetected zero, 10 to the  minus six, we're looking at 10 to the minus eight, drive this all the way down. However, we've  looked at this a few times, and actually Dr. Hartmut Goldschmidt at the University of  Heidelberg, he has patients where he studied them at 10 years, 20 years, some of them all  the way out to 30 years, and so he had samples where we could study these long survivors  and see if they we

re MRD-negative or not. And the crazy thing is that about half the  patients who were the longest survivors were not MRD-negative. They had a little bit of  myeloma left. And I think that we're paying much, much more attention now to how is the immune  system regulating these little bits of myeloma so that you can stay in remission for many years.  And so we can decide that we don't want to expose you to potentially toxic treatment that we can  allow you to live with your myeloma. And maybe ther

e's some things we can do to enhance the  immune system to continue to keep it in check. Dr. Peter Voorhees: Yeah. Speaker 4: Yeah. And just a quick point about the Darzalex, for those of you that  are on it or don't know, it's loosely expressed, it targets the CD38, which sits on the cell of  the myeloma. But anyhow, when you're testing a serum protein electrophoresis, that sometimes  gets detected, so much of that 0.5 that's in her blood might be partly measuring the Darzalex  and might partly

measuring the myeloma. So discuss your labs and individual labs with  your healthcare team. You might actually be zero if we could wash that Darzalex out of  your blood, but that's just a side point. Dr. Peter Voorhees: Yep. Dr. Brian Durie: Yeah, that's a good point. Now as we move in, we  haven't really talked about it much, mass spectrometry. This is going to  be for next year's seminar, I think. Speaker 4: Oh, can't wait. Dr. Brian Durie: But when we're using very, very sensitive testing fo

r IgG with mass spectrometry, you can tell the  difference between the myeloma and the Darzalex. Dr. Peter Voorhees: Yep. Speaker 4: Yes. Dr. Peter Voorhees: Yep. Dr. Brian Durie: Anyway, okay. Speaker 7: Number four in the middle, Carol [inaudible 00:50:34]. Carol Friedland: Okay. Carol Friedland from Boynton Beach. I  was diagnosed in 2016 Kappa light chain with no M-spike. So I went through RVD,  then a stem cell, then RVD again- Dr. Brian Durie: Could you... Yes. Carol Friedland: ... RVD aga

in, and then Pomalyst and Darzalex, which I'm on right now, but I'm relapsing very slowly. They told me  the next drug will be Kyprolis and Cytoxan. Dr. Brian Durie: Okay. Carol Friedland: So I hadn't heard about Cytoxan and I found out that it's going  back to chemo again, so I'm a little, "Ah". Dr. Peter Voorhees: Yeah. Speaker 4: What do you think? Dr. Brian Durie: Okay. Yeah, go ahead. Yeah. Dr. Peter Voorhees: So you're following a very traditional pathway and the therapies that you're ment

ioning are  very appropriate therapies. So you got Darzalex, Pomalyst and Dexamethasone as your second line  therapy, it sounds like, and it's starting to creep its way back up. So Kyprolis is a proteasome  inhibitor, which is very active in relapsed multiple myeloma patients. So a Kyprolis-based  strategy is a very appropriate treatment option for you. Cyclophosphamide or Cytoxan is one of  the agents that we will combine with Kyprolis in certain circumstances. I think once we get  beyond two l

ines of therapy, if you haven't considered clinical trials up to that point,  it's very much worthwhile considering clinical trials at that point because the best partner for  Kyprolis, for someone whose disease has developed resistance to both Darzalex and Pomalyst, the  best partner for Kyprolis is a little less clear. The other thing I'll point out, and we'll hear  more about this later today, the KarMMa-3 trial, which was a study that was looking at Abecma,  or ide-cel, which is one of the t

wo FDA-approved CAR T-cell products versus investigator's  choice best standard of care and that study was a positive trial. So patients who got Abecma  stayed in remission longer than those who got the traditional myeloma drugs that was just recently  published in the New England Journal of Medicine, and regulatory authorities, as we  speak, are looking at those data sets, looking at the safety, looking at the  efficacy to determine whether we can get a regulatory of approval of Abecma earlier

in  the course of therapy. And if it holds true, you may actually have access to Abecma as your  third line therapy in the not too distant future. Dr. Brian Durie: Yeah. So that would be obviously very helpful. And  hopefully, as we've talked about with, it's going to be more accessible as well.  So it would be approved and available. Speaker 4: Right, yes. Yeah, for sure. And so if we have the University  of Miami and the Cleveland Clinic Weston, and so those places do have clinical  trials, I

would look into what they have. Carol Friedland: [inaudible 00:53:48]. Speaker 4: Not anymore. Dr. Peter Voorhees: No. So your myeloma is making an antibody, it's making Kappa light chain  antibody. And for most clinical trials, I mean, if you get Abecma that's FDA-approved, it doesn't  matter what your Kappa light chain level is when you go into treatment. On a clinical trial, it  typically has to be 100 milligrams per liter or 10 milligrams per deciliter or higher in order to  be on the study

because it has to be measurable. Dr. Brian Durie: Right. Speaker 4: And depending on how they count your therapies, you had  the RVD and transplant and some more RVD, and you might qualify for four prior  lines of therapies, so you might fit the definition now of a candidate for Abecma,  depending on where you go and who you see. Dr. Brian Durie: Just a comment that we are working to make clinical trials more real-world-sensitive where  we need to have trials where they're available in a real-wo

rld situation where if patients were  maybe a little bit tougher to have traditional response criteria, that we do open it up to  include and assess the response as best we can. Speaker 4: Yes. Dr. Brian Durie: Okay. Speaker 7: So I think we have one more question from number- Dr. Brian Durie: One last question. Yeah. Speaker 7: ... is it two? Yes. [inaudible 00:55:04]. Dr. Peter Voorhees: That's fine. Speaker 8: Is that good? Speaker 7: Yep. John: Hi, I'm John from Orlando and we're in the  Mai

tland Fellowship Group. Speaker 4: Hi. John: And my question is a lot of the drugs that we take produce some collateral damage.  How often do you recommend having echocardiograms? Dr. Brian Durie: Okay. Speaker 4: So I guess it depends on what medication you're taking. So  one of the drugs, this Kyprolis or Carfilzomib, might be the one that you're referencing.  And so it depends on what your baseline heart function is and what your risk factors are.  And we have blood tests that we can measure

the stress around your heart. There's one called  an NT-proBNP. So if you have amyloidosis, that's a different discussion. So it really depends. We  have some guidelines that say you don't even have to check echocardiograms, but it depends on if  you have any symptoms and other health conditions. Dr. Peter Voorhees: If you're going to have a heart-related complication of Kyprolis-based  therapy, it typically happens within the first four cycles or so. So if you've been on  Kyprolis for an extend

ed period of time, the likelihood that it's going to  cause heart damage is very low, actually. It declares itself pretty  early in the course of the treatment. Dr. Brian Durie: And it is manifested as more of an acute situation where it's clear that related to the infusion  that something's happening, the pressure changes, pulmonary hypertension, something is observable  and you know maybe even stop the infusion. Dr. Peter Voorhees: Yeah, but repeat echocardiograms would be dictated by symptoms

.  If it's someone who's experiencing increasing shortness of breath, palpitations, other  red flags that something's not quite right, that would trigger us to take a  really close look at the heart. Speaker 4: Yeah. And if you've had longstanding high blood pressure  or previous heart disease, but this might be the right drug for you, you should be followed  by a cardiologist as well. So tough question. Dr. Brian Durie: Right. And so my experience is that if you do have any even slight indicato

rs of changes in  blood pressure, systemic or pulmonary [inaudible 00:57:09] or tachycardia, I mean, I have a very  low threshold. I don't want to be giving more. Speaker 4: Right, that's right. And that's the other thing is there's so many different doses of that Kyprolis,  once a week, twice a week, and some people that get shortness of breath and don't tolerate it do  better actually twice a week at a lower dose. So again, share your symptoms with your prescribing  team and they'll individual

ize your care. Dr. Brian Durie: So thank you for your questions. Thanks to the panel  for guiding through the answers here. Thanks to Peter for an excellent overview of  initial therapies and we will exit right...