Welcome to The Myeloma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc)! This exclusive roundtable session features world-renowned experts Mohamad Mohty, Thierry Facon & Alessandra Larocca,who discuss the latest in the treatment of elderly multiple myeloma following COMy 2021.
Featuring insights into how elderly myeloma treatment evolved to where we are today, frailty assessment, the challenges associated with the extremes of the frailty spectrum, and a look towards the future.
“From MP to, let’s say daratumumab, lenalidomide and dex, the median survival has switched from two to three years to probably close to seven years. And, what we are saying today that some elderly patients will possibly not die of myeloma, they will die of something else” – Thierry Facon
“This is really a fabulous story over 20 years, how by generating very strong, nice evidence-based data, you can transform the natural history of a disease. MP you add thalidomide, you show superiority, you compare it to len-dex, you show superiority. You add an anti-CD38, namely daratumumab, you show superiority.” – Mohamad Mohty
Frailty assessment: where do we stand today?
“In the last years, the International Myeloma Working Group proposed a frailty score that combine the evaluation of age, but also comorbidities and functional abilities through a simplified geriatric assessment to identify the patients who can be defined fit, and fitter, and frailer. And that have different outcomes, different tolerance to treatment, and adverse events.” – Alessandra Larocca
“We have to optimize these effective treatment according to the characteristics of the patients to have a very good or good disease control. But also to take into account the quality of life of the patients.” – Alessandra Larocca
“I think basically these new regimens, they will provide some pushback for transplanting the elderly, because most patients, and sometimes physicians will possibly not proceed to transplant because they will rely on daratumumab regimens.” – Thierry Facon
“So I think that now is very difficult to differentiate the treatment in fit, intermediate fit or frail patients. But, we can do probably some adjustment for these particularly frail patients. We can adjust the dose and the duration of treatment with dexamethasone, for example.” – Alessandra Larocca
MAbs, CARs and novel compounds: looking to the future
“I am quite convinced that, at least some of these bispecific antibodies will move up to first-line. And I do believe that in some years, that will be used to treat at least some elderly patients with myeloma” – Thierry Facon
“For elderly fit, if you do a bispecific in combination with DRd, what will be the outcome? The patient with some degree of frailty, you could say the combination of a bispecific and a CD38, will do a great job. We don’t know, but we may have to investigate this.” – Thierry Facon
Watch the full session
Mohamad Mohty: Hi, everybody. Welcome to this special broadcast of VJHemOnc. I’m Mohamad Mohty from the Sorbonne University and Saint-Antoine hospital in Paris, in France. And it is a great pleasure to be joined today by two distinguished faculty, Dr. Alessandra Larocca from a Consultant Hematologist at the University of Torino in Italy, and Professor Thierry Facon from the University Hospital of Lille, in Lille, in France. Thank you for joining us, this is a very special activity dedicated to the post-COMy 7th Congress. As you all probably know, we have just finished the 7th International Congress on Controversies in Multiple Myeloma, the famous COMy. And this has been a really an amazing program where we went through all the advances in the field of multiple myeloma. And it has been really fabulous congress and many cutting edge data and results were presented.
However, for the purpose of this special activity we thought to have a focus actually, on the diagnosis and management of the elderly multiple myeloma patients, the so-called non-transplant eligible patient. And why is this? Because I think, and we have seen this during the congress, the COMy Congress, this is the population where we have seen recently a tremendous advance in terms of the survival, and the bar now is extremely very high. So this is really good news, and we are always pleased to have such good news. But, I think we will have to continue to improve. And this is exactly the spirit of this discussion we’ll have together with Alessandra and Thierry about the past, the present, but also the future of elderly multiple myeloma.
So thank you for joining us and I’ll start first with Thierry because you’ve been following this elderly myeloma treatment story since the beginning and since the early days of MP. I’d like to hear from you… melphalan and prednisone. I’d like to hear from you, Thierry, this success story since mid-year 2000s, since the publication in the Lancet in 2007 showing that MPT for the first time proved to be superior to MP. Can you tell us the story? I think many people would love to hear it.
Thierry Facon: Okay. I was not at the very, very beginning because MP was established 1969, something like that, but at least okay. But…
Mohamad Mohty: You were a young gentleman.
Thierry Facon: I was quite young at that time. But you are correct in fact, for example, in the IFM we did one study, which was called IFM 95-01 published in Blood in 2006. And still at that time, the control arm was melphalan and prednisone, which is a way to say that it has been a standard of care for too many years, I would say. Myeloma treatment in the elderly has been very disappointing for many years. At that time, we said the median survival with MP was three years, but to be honest, I am not totally sure about that. Because when you look at the way to assess response, even the way to… Studies were usually not very big studies, et cetera. So what we are saying today about frail patients versus non-frail, I’m not sure the frail patients were extremely represented in these studies, for example.
So you could say probably at that time the median survival for the elderly was two to three years, something like that. Then we got thalidomide and if you remember we got thalidomide December 1998 at [inaudible], and interestingly the story of thalidomide is also the story of Torino because the Antonio Palumbo published in 2006, an MPT study in the Lancet as well. We did a study as well, doing MP versus MP-thalidomide. And not exactly, but almost at the same time, bortezomib also was part of a very large MP versus bortezomib-MP study, so the VISTA study. So we had established MP-thalidomide and bortezomib-MP as new standard of care.
Then we got, I just say we got lenalidomide, and lenalidomide has been investigated in several studies. Some studies in the US. ECOG did one study. We did the first study. The first study was at that time, the largest registration Phase III international study for the approval of lenalidomide and dex, and the control arm was MP-thalidomide at that time. So, we made lenalidomide and dex approved, with many other colleagues around the world and basically interestingly with MPT, your median survival is approximately four years. With lenalidomide and dex, your median survival is approximately five years. And then we got, let’s say, I try to make it short, we got CD38 antibodies, especially daratumumab and we combined these, the daratumumab with both the VMP and lenalidomide and dex. And so the dara-VMP study was called the ALCYONE study, and the other, the lenalidomide and dex was called the MAIA study.
And so the addition of daratumumab did a very great job and so very, very significantly improved PFS, on at least what we know today, for survival rate from the ALCYONE study. So, that was a very… very great improvement in clinical outcome for the older patients. And for example, if you look at daratumumab, lenalidomide and dex, median PFS will be five years. And we do not know of course for median survival, but the expectation would be to see median survival six to seven years, something like that, probably maybe 6.5 to seven years. Also, keeping in mind that these patients have, some of these patients are really frail patients. So that’s the… From MP to, let’s say daratumumab, lenalidomide and dex, the median survival has switched from two to three years to probably close to seven years.
And, what we are saying today that some elderly patients will possibly not die of myeloma, they will die of something else. Because if you are diagnosed with myeloma at the age of 80, and you get, for example, this kind of daratumumab regimen, you may, if you can enjoy a median survival of seven years, you will have a possibility to die from something else. And then the next step will be, this is an ongoing story. And the next step will be the combination of, PI for basically, let’s say bortezomib, lenalidomide, daratumumab or isatuximab, not for all elderly patients, but for, let’s say the fit elderly, because these four drug combination regimen is likely too much for frail or very frail patients. And so the last… this is basically what we did in the last 20 years. Something like that.
Mohamad Mohty: This is really a fabulous story over 20 years, how by generating very strong, nice evidence-based data, you can transform the natural history of a disease. MP you add thalidomide, you show superiority, you compare it to len-dex, you show superiority. You add an anti-CD38, namely daratumumab, you show superiority. This is really amazing, but I think, and this is a good lesson for all of us in the field. And especially to our younger colleagues, that proof is really stronger than arguments. And whenever possible, we should really pay attention and try to build step by step to improve the outcome of these diseases. But I think you highlighted, you alluded to something, very important Thierry. I think that in the older era, in the ’90s, early 2000s, when we spoke about elderly patients. Actually, it’s probably not the same group of elderly patients we consider today. And I remember from my training, it would have been totally unusual to treat an 85-year-old myeloma patient. So the notion of elderly was around 65, 70, maybe. So Alessandra, you have done a lot of work, I think, on trying to categorize and to refine, to dissect this mixed bag, I would say of elderly myeloma. So, how did you do this work and where do we stand today when it comes to defining the different so-called elderly myeloma patient?
Alessandra Larocca: Thank you, Mohamad for the question. Yes, elderly population is extremely heterogeneous, because among the patients who are not candidate, not eligible for autologous stem cell transplantation, there is a larger variety of comorbidities, of dependence or independence, status of functional abilities, disabilities. And these characteristics are essential to define the fitness or the frailty of patients.
We did a lot of efforts, the myeloma community, to define the status. This functional status and comorbidities of patients, and to define and categorize patients who are fit and that were able to tolerate full dose treatments. Patients who are frail, so are dependent on other people, they have some disabilities, and so they can’t tolerate a full dose regimen, but they need to adjust treatment, an adjustment of treatment with a careful balance of toxicity and effectiveness of treatment. In between that there is probably an intermediate group of patients who need balance of efficacy and safety, but probably can tolerate treatment much more better, as compared than frailty patient. And different group, Italian group but also colleagues from other countries, Professor Zweegman for example, Professor Engelhardt from Germany, Professor Cook, and so on, work hardly in the definition of frailty and in the instruments that can be useful to define frailty.
And then recently in the last years, the International Myeloma Working Group proposed a frailty score that combine the evaluation of age, but also comorbidities and functional abilities through a simplified geriatric assessment to identify the patients who can be defined fit, and fitter, and frailer. And that have different outcomes, different tolerance to treatment, and adverse events, and so on. And now that we have these important and new treatment, I think that we have to optimize these effective treatment according to the characteristics of the patients to have a very good or good disease control. But also to take into account the quality of life of the patients. So we have to give effective treatment, but preserving also, not only the quantity of life, but also the quality of life, and this is particularly important for frail patients.
Mohamad Mohty: So what I understand from you Alessandra, and this is really a very well nicely described, is that assessment of frailty, but also geriatric assessment, and the use of some of these daily activities, the scoring systems are crucial to refine the categorization of these patients. However, when I talk, discuss with some colleagues, some of them are really afraid about the time consuming process. These days we have more and more patients, less and less time. How can we reassure our colleagues? And the question is to both of you, because you see these elderly patients, how can we reassure that first of all, this is not as heavy and long or difficult as one would expect or might expect, but also how smart assessment can take you a long way, because this will help to improve the outcome of the patient. Who wants to start, Thierry?
Thierry Facon: No, your point is well taken. What is interesting with a frailty assessment is that the more you work on this, the more you have to, it’s a very interesting and very important topic. And I am not totally sure we have reached the best possible, I don’t know. For example, what sometime ago has been published in Blood paper, by colleagues from Boston, geriatric colleagues from Boston, from Harvard university. And they looked at gait speed and I’m not saying gait speed is best, but you can handle this in different ways. You could say, okay, if I put comorbidities, so what you have age, comorbidities, gait speed. If you take the best possible questionnaire, not too much, shall we? Okay, what will be the conclusion?
And so I feel we… I think we still have to work on this, but it’s definitively something extremely important. And also I wanted to, just to illustrate that it is important that we have today studies for frail patients and studies for fit patients, and you will find more. And when we analyzed the recent studies, in fact, you will always find a kind of frailty analysis. So the first study, the ALCYONE study, the MAIA study, they have led to some kind of frailty analysis. And also when you look at, or colleagues from EMA or FDA they have, they do not know exactly how to handle this, but they perfectly know that the frail patients are underrepresented in clinical studies, and they know that it is a very… it has value and it is something we have to work on.
Mohamad Mohty: Okay. Thank you, Thierry. Very clear. So Alessandra, I know you are in the middle of a busy clinic. So how do you do…in your daily practice to assess these patients? Can you give us a sort of a flavor? How, what is your pragmatic approach?
Alessandra Larocca: So when I visit the patient for the first time, I try to know him, about collecting more information, about his history, his medical history, and also some social aspects. Because sometimes patient has severe pain and the day before the onset of the myeloma, he was fit and well, for example. And so I try to have a view also of the patients before the diagnosis of multiple myeloma.
And when I collect these information, I try to do my geriatric assessment. So collecting information about the comorbidities, there is functional, basic abilities or more complex abilities. And so when I talk with the patients and try to put into the computer this information to have this geriatric evaluation. And so I think that collecting information and doing a geriatric, brief geriatric evaluation, of course, is quite easy. Because the information that we can capture from this evaluation are very important for me to understand which type of treatment is able, will be able the patients to tolerate. And so I prefer these evaluation to the cut-off age, for example, 75 80, because I think that this is not enough. And also to my judgment, my view, the view of the doctor of the patients. I prefer to have something that is more precise.
Mohamad Mohty: Excellent. Okay. So, let’s now consider what I personally would also consider as difficult scenarios, which are the two extremes, the elderly, and very fit patients where you would hesitate with a so-called elderly treatment, or maybe something similar to what you would give a young patient. But the other extreme is the very frail elderly patient where you would even hesitate maybe to give a sort of standard of care in the elderly. So for question to Thierry, how do you handle today, the elderly, but fit, even very fit patient? And I think one part of the question is about transplant, performing transplant in this population. Where do we stand today?
Thierry Facon: Okay, it’s not an easy question because you have also to stick to what has been approved in a certain extent. So it’s true to say that this patient will be treated more or less like younger patients today. And so you could say that in the next few years, they will be able to receive the combination of a CD38, bortezomib, lenalidomide and dex. So this kind of DVRd platform, or isatuximab-VRd. Under study we have… the ongoing studies we have for elderly fit patients, they have basically either ixazomib-VRd, or daratumumab-VRd, and some academic studies in Spain, for example, for elderly fit, they have KRd even in combination with daratumumab as well. So then the other aspect of the question-
Mohamad Mohty: I think Thierry, you meant isatuximab-VRd.
Thierry Facon: Isatuximab, yeah. Sorry. Then the other part of the question, is transplant versus no transplant. That’s not an easy question. We have to say that transplant remains a standard of care as of today. But on the other hand, if you look at elderly patients, and if you go back to what you can achieve with regimens such as DRd, what will be exactly the added value of melphalan 200? And would you like to take the risk of melphalan 200, even if this risk is limited to for patients that are between the age of 70 and 75. So, that’s a difficult question. I think basically these new regimens, they will provide some pushback for transplanting the elderly, because most patients, and sometimes physicians will possibly not proceed to transplant because they will rely on daratumumab regimens or something like that.
Mohamad Mohty: Yeah, I think you’re definitely right, because the results of the new regimens are so high in terms of PFS that you may wonder…
Thierry Facon: On the other hand, you could say that if you add melphalan 200 to DRd, you may do a better job as well. So it’s not… So that says it’s not an easy question, but in the real life, I do believe we will see probably less transplanting in elderly patients in the next five years as compared to what we did before.
Mohamad Mohty: Okay. So Alessandra, now the question is about what we heard from Thierry, and I think everybody’s convinced dara-Rd, or to a lesser extent, dara-VMP, daratumumab-lenalidomide-dexamethazone, daratumumab-bortezomib-melphalan and prednisone are the recommended regimens by EHA-ESMO, and they are approved. But assuming now you’re handling the 87 year old, very frail patient. What would be your favorite or whatever appropriate regimen in this patient who has diabetes, who may have maybe cognitive problems, hypertension, I think you would guess a kind of patient, because age comes always with many comorbidities unfortunately.
Alessandra Larocca: So I think that now that we have this daratumumab base, the induction treatments, they are very well-tolerated particularly daratumumab combined with the oral lenalidomide and dexamethasone. So I think that now is very difficult to differentiate the treatment in fit, intermediate fit or frail patients. But, we can do probably some adjustment for these particularly frail patients. We can adjust the dose and the duration of treatment with dexamethasone, for example. Since in Italian study, for example, without daratumumab, evaluated that Rd followed by lenalidomide maintenance after nine cycles compared with Rd continuously and the absence in the experimental arm of dexamethasone, did not impact significantly progression-free survival and overall survival. So probably we can spare steroids after the first year of treatment.
And these can possibly be applied also to the daratumumab-Rd treatment. However, there are study ongoing, who are evaluating also daratumumab-lenalidomide sparing steroids. So probably we will have this data. We can adjust also the dose of lenalidomide to the clearance creatinine of patients that is decreasing with the aging of these patients. So I think that we can adjust the treatment in some special cases in which frailty is very, very present. We have an extreme frail patient, I think that we can also consider only to give the doublet lenalidomide-dexamethasone that is of course, an effective treatment, well-tolerated, oral so without access, with limited access to the hospital. And I think that in some limited case, Rd the doublet, may be an option.
Mohamad Mohty: Well, thank you very much Alessandra for raising this issue, because when we think about improvement, we always think about novel drugs, novel regimens. But I think you’re bringing a major point where sometimes in a very non-expensive way, you can also improve the outcome, skipping steroids, decreasing the dosage, maybe giving more time between cycles.
Alessandra Larocca: Yeah.
Mohamad Mohty: All of these small tricks can be very helpful. Okay. In the last five minutes of this fantastic discussion my friends, I’d like to think about the future. And we heard during COMy a lot about bispecifics, CAR T-cells, many novel small molecules, obviously all of them are being currently tested in the relapse/refractory setting. But how do you see the future for the elderly patient, especially in terms of frontline therapy? Can we integrate at some point these advances to further improve the outcome, but also maybe achieve clearly operational cure in the majority of these elderly myeloma patients? Thierry, what are your thoughts?
Thierry Facon: Of course, we have a lot of interest in bispecific antibodies and CAR-T strategies. So the question of CAR-T in the elderly is… it’s not an easy question. If you look at numbers of patients having received CAR-T for over the age of 70, you will not find a lot of patients in fact. And if you look at, if you would like to say, “okay, how many patients over the age of 75 did receive CAR-T?” Of course, you will have one colleague in the US he will say, “okay, I treated a 78-year-old patient, but that one…” It’s very… the points raised by Alessandra was that you have one third of patients over the age of 75, you have a lot of frail patients. So I do not see a large use of CAR-T strategies in elderly at the end of the day.
And if you say something very simple, okay, that could be stupid. But if you say the CAR-T strategies will be mostly for the younger patient and the bispecific could be in a certain extent for the elderly, you are probably, we will see in the next five to 10 years, but that could be something like this. Bispecific antibodies are of course, very, very interesting drugs. So if you look at the studies we have today, you can achieve response in, let’s say, Ken Anderson said yesterday, 60 to 80% of patients. And so that’s a lot of patients, if you want to use bortezomib, lenalidomide, or even daratumumab as a single agent, you will not get 60 to 80% response rate. So they have, okay, they can do a very effective job in treating all patients.
Then, the point I would like to highlight is that you… It’s probably different to develop a bispecific antibody versus an IMiD or a PI. And you need to be cautious. For example, when you want to deal with the frail patients, okay, we still have to do some work to be able to manage bispecific antibodies in the elderly, frail, and very frail, I would say. Because usually people say, okay, these drugs will only provide CRS grade one or two, and not so many infections, but CRS grade two at the age of 80 is very… is terrible. So you need to… kind of fine tuning. You need a good development plan to be able to adapt these bispecific antibodies to the elderly and somewhat frail patient.
That said, you could play the game in replacing either len or replacing either the CD38 or whatever. For example, you could say, okay, I don’t know if you will agree with me, but when you combine bortezomib, lenalidomide, and daratumumab, the weak part, this is not very weak, but the weak part is the bortezomib at the end. So you could say, if you, even if for elderly fit, if you do a bispecific in combination with DRd, what will be the outcome? And the outcome could be great. If you want to play with more… Okay, the patient with some degree of frailty, you could say the combination of a bispecific and a CD38, will do a great job. We don’t know, but we may have to investigate this, or we may have to investigate the lenalidomide in combination with bispecific antibodies. But I think all of these studies will have to be done and we will see. But I am quite convinced that, at least some of these bispecific antibodies will move up to first-line. And I do believe that in some years, that will be used to treat at least some elderly patients with myeloma.
Mohamad Mohty: But also, we can figure out maybe CELMoDs, iberdomide replacing lenalidomide. And tomorrow we have maybe a third generation proteasome inhibitor. And so on. This is, this is really amazing. So Alessandra, if you have to design your ideal or favorite futuristic protocol, what would be your combination, and assuming I’m making all, everything available for you to design your protocol.
Alessandra Larocca: Yeah. I agree with Professor Facon that now the job is very hard after daratumumab-based treatment or anti-CD38 monoclonal antibody. It’s very hard to have something that is more effective, less toxic and more powerful. And so…
Mohamad Mohty: Let me remind you one thing, both of you, because I have a good memory. And I remember in 2008, when the VISTA trial was published by the New England Journal by Jesús San Miguel, in the New England Journal of Medicine. I heard a lot, these statements saying it will be hard to do better…
Alessandra Larocca: to add something.
Mohamad Mohty: …because obviously, our statements are mainly based on our control, and tomorrow when your dara-Rd will become like the basic, and you see the results every day, you would say, “I want to do better.” So, sorry, I’ll close my…
Alessandra Larocca: I agree with you, and I will try to be much more optimistic. So I encourage, of course, that new treatments and new drugs will be available. For now, immunotherapy is the best option that we have. CAR-T, I agree that is at the moment, since we will not have an adjustment, a way to optimize, and make them easy for everyone, is much more indicated for fit and young patients. And I have the hope that this specific therapy will be feasible for everyone. And I agree with the suggestion of possible improvement with the combination with these older regimens, these older drugs, lenalidomide and so on, to further improve the efficacy, but I don’t have new and innovative ideas after Professor Facon.
Mohamad Mohty: Okay. Well, thank you very much. And actually, may I suggest that hopefully we’ll be able to do this same discussion in four or five years…
Alessandra Larocca: Yeah.
Mohamad Mohty: … to see…
Thierry Facon: Yes.
Mohamad Mohty: …how the feedback…
Alessandra Larocca: We’ll see.
Mohamad Mohty: Absolutely. Because I think it’s very important to remember the history, the chronology, and this is so exciting, and every day, I think all of us will feel blessed and privileged to be in a such dynamic field. So again, thank you very much for this lovely discussion. I hope everybody has enjoyed it, and hope to see you all very soon in great shape, and please stay safe, and keep well.