Welcome to The Myeloma Sessions: Evolving management of myeloma & COVID-19, brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Paul Richardson, María-Victoria Mateos, Evangelos Terpos and Ajai Chari who debate the key updates in the treatment and management of multiple myeloma in the context of the COVID-19 pandemic.
The topics of discussion include the evolving strategies to reduce risk of COVID-19 in myeloma patients, the Spanish, New York and Greek experience, International Myeloma Society (IMS) guidelines, treatment options for myeloma patients as well as key updates in myeloma treatment presented at ASCO and EHA 2020.
COVID-19 related mortality: findings from the Spanish Myeloma Group
“The first recommendation from the Spanish Myeloma Group was myeloma patient should maintain the disease under control as much as possible. And how to maintain the disease under control. If the patients are young patients, especially female, but I would say young patients, with no renal impairment, with active disease, I think that they have to receive the active therapy in order to maintain the disease under control. Of course with the appropriate hygienic measurements.For elderly patients, especially if they presented with renal impairment, males. I think that the mortality rate, if they become infected by COVID-19, was going to be extremely high. And this was the reason why the recommendation for this patient is to stay at home if possible, and to prescribe oral drugs combinations because I think that this patients should be protected of frequent visits to the hospital” – María-Victoria Mateos
The New York Experience & IMS recommendations
“When you look at all cancer patients, risk factor for worse complications was actually uncontrolled cancer.” – Ajai Chari
“How much of COVID complexity and mortality is really the virus, versus the actually inflammatory sequelae? Are the heavily treated patients able to mount the same response?” – Ajai Chari
The Greek perspective & therapies associated with increased risk or immunity
“I think that what we can say is that autologous stem cell transplantation, did not impact in the mortality rate of when the patients become infected by COVID-19” – María-Victoria Mateos
“From the Spanish myeloma cohort, I can say that over 80% of the patients had been receiving proteasome inhibitors, over 70% immunomodulatory drugs, and approximately 30% of the patients had monoclonal antibodies. And none of these agents influence in the inpatient mortality rate.” – María-Victoria Mateos
State of the art following EHA & ASCO
“For the CAR-T cells, and the bi-specific results of both ASCO and EHA abstracts, I believe that these two technologies will give us the possibility to, if not to cure some patients with multiple myeloma, just to prolong survival a lot because I have seen very promising results at the very end-stage of the disease” – Evangelos Terpos
“Historically we looked at a response rate of 25 to 30% of PFS, that’s three to three and a half months, and now we have bi-specifics, and CAR-Ts with response rates of 80 to 95%, with PFS around a year. In the same, if not worse population so I think it’s really a game changer of how big a deal this is” – Ajai Chari
“And as we think about the COVID era, our ability to sort of tailor therapy to minimize risk for our patients becomes all the more exciting” – Paul Richardson
Paul Richardson: Welcome everybody, to the Myeloma sessions on the Video Journal of Hematological Oncology, or VJHemOnc, as we love to call it. Today's discussion will focus on what we have learned over the last six months or so, on how to manage our myeloma patients, during the tragedy and huge challenge of the COVID-19 pandemic. And importantly, how this is evolving with time and experience. And then we'll go on to discuss some of the key data, recently presented, that can be implemented now, and how myeloma research is being impacted by COVID-19. But we hope to finish very much on a positive note, with some important words of encouragement for our audience, in terms of where we currently stand, and the future directions that we may be headed to. Not least of all, how much we've learnt over this last six months, of what has been, for all of us, has been a remarkably challenging and difficult time.
Paul Richardson: So in that spirit, it really is a pleasure, and a privilege to welcome the faculty today. I'm joined by Marivi Mateos, who leads the myeloma program at the University Hospital of Salamanca in Spain, and has really been an international leader in myeloma research, and has also been on the forefront of the experience in Spain, of how myeloma patients have been treated in the context of the COVID-19 pandemic.
Paul Richardson: In that same spirit, it's an absolute pleasure to welcome Ajai Chari, who is a leader of the myeloma team, working with his partners, including Dr Sundar Jagannath, at the Mount Sinai hospital in New York, NY. And Ajai, truly in the United States, has been on the front line of dealing with the immediate consequences of the pandemic in New York, and all that that has meant for that community. He will bring us, I think, some unique insights. Because not only has he provided outstanding care for his patients in New York, but he has a leadership role in the International Myeloma Society effort, to document the broad scope of the challenges facings the myeloma community, internationally, as well as within the United States.
Paul Richardson: Finally, in that same context, it's a privilege to welcome Evangelos Terpos, who joins us from the University of Athens, in Greece. And here Evangelos has also had a leadership role, not only in understanding the dimensions of the myeloma pandemic in Athens, and Greece in particular. But also actually in repurposing treatments strategies to actually take on the pandemic. And we'll get some very nice insights I think, from Evangelos, from the standpoint of research being done in Greece.
Paul Richardson: So, as a first starting point, I'd love to have Marivi, please start our discussion today. And we're going to first focus on evolving strategies, to reduce risk of patients with myeloma in the COVID era. And it would be lovely to here, Marivi, of your experience in Spain, and some of the things that have been implemented in the Spanish myeloma community to address this challenge.
María-Victoria Mateos Thanks Paul. And thanks also to my colleagues, Ajai and Evangelos for being here today. And in Spain, well as all societies did at the beginning of the pandemic, the Spanish Myeloma Group launched some recommendations for the management of patients with multiple myeloma, under the COVID-19 pandemic. These were recommendations, basically based on trying to maintain our patients with the disease under control. Because we thought that this was going to be relevant. But at the same time, we had to protect as much as possible, our patients from being infected by COVID-19. So we started with telemedicine, and many phone calls to the patients, in order to, well, deliver the drugs at home, if it was possible. And trying to avoid, as much as possible, visits of the patients to the hospital.
María-Victoria Mateos But, what we did also in parallel, and I think that this has been extremely important, was to collect all base line characteristics, as well as data come in from myeloma patients infected by COVID-19 in Spain. And this data would also put together with data from myeloma patients worldwide, in an International Myeloma Society effort. But from the Spanish Myeloma Group point of view, I can say that we collected data from 167 myeloma patients infected by COVID-19, and hospitalized because of pneumonia. And we decided to compare the outcome and baseline characteristics of these patients with a match group of over 167 known cancer patients.
María-Victoria Mateos And the first important finding was that myeloma patients infected by COVID-19 had a higher mortality rate than non-cancer patients. And in fact, the hospital death rate for myeloma patient, was 34%, versus 23% for the non-cancer patients. And also we tried to evaluate what were the potential factors to predicting high mortality rate in myeloma patients. And we found how being male, older than 65 years, as well as to have the disease active, the disease not under control, as well as renal impairment as co-morbidity, were the most significant factors predicting high inpatient mortality rate.
María-Victoria Mateos So based on this analysis, I think the recommendations we had done at the beginning from the Spanish Myeloma Group were valid. But I would say that from my point of view, and the first recommendation from the Spanish Myeloma Group was myeloma patient should maintain the disease under control as much as possible. And how to maintain the disease under control. If the patients are young patients, especially female, but I would say young patients, with no renal impairment, with active disease, I think that they have to receive the active therapy in order to maintain the disease under control. Of course with the appropriate hygienic measurements.
María-Victoria Mateos By contrast, for elderly patients, especially if they presented with renal impairment, males. I think that the mortality rate, if they become infected by COVID-19, was going to be extremely high. And this was the reason why the recommendation for this patient is to stay at home if possible, and to prescribe oral drugs combinations because I think that this patients should be protected of frequent visits to the hospital, in order to be COVID-19 free as much as possible. And these are basically the recommendations we did. The data we have found in our Spanish Myeloma Group, and the current recommendation based on the findings we have, in our experience.
Paul Richardson: Extremely important information, Marivi, and thank you, because that's a comprehensive and very thoughtful analysis.
Paul Richardson: If I may, if you could just repeat, the mortality that was encountered in the Spanish cohort of myeloma patients, was it 34%, or higher?
María-Victoria Mateos 34%.
Paul Richardson: Right. And your control group was 23%? Correct?
María-Victoria Mateos Correct, yes.
Paul Richardson: Yeah. And that obviously was statistically significant, I would imagine.
María-Victoria Mateos Yes.
Paul Richardson: Yeah. I mean, that certainly mirrors our own experience here in Boston, and certainly speaking for my own practice, where, in patients who were hospitalized, the rates of mortality were very worrisome. And very consistent actually with what you've just described. I would love to hear, now if I may, from Ajai. The sort of New York perspective. And at the same time, if I may, what you can share with us from the IMS point of view. The International Myeloma Society.
Ajai Chari: Sure, I think... To echo, I think Marivi's points, the patient and disease components are very important, and I think the other issue is the prevalence of the disease, right? So what you do in March, versus July, versus August, may be very different based on what's happening your immediate area. And in the peak of the pandemic in New York, I mean it was quite crazy. I mean, literally every day, it seemed like the floor of the hospital was being converted to COVID only. What used to be an oncology floor became a COVID only floor.
Ajai Chari: So the ER was overwhelmed, there was an outdoor tent. It was quite dramatic. And just the humanism component. I mean, we're physicians, but the nursing care is really outstanding. As physicians you go in and out of the room. But nurses are bringing in the meds, the social support, helping patients to the bathrooms. There were no visitors, there was a lot more delirium in the hospital, because all the non-english speaking patients didn't have visitors. So I think just it was a very striking time. And we didn't know a lot. So I think same as Marivi, we kind of tried to minimize visits to the hospital, minimize laboratories, converting to oral therapies, skipping parenteral treatment visits. Also we had a lot of patients who were scheduled for collection of stem cells and transplant. So those were canceled.
Ajai Chari: So really it came to a grinding halt. Clinical trial accruals were halted, and for each patient on clinical trial, we had to justify to the IRB, what is the risk benefit for this patient. And so in heavily treated patients, they were allowed to continue, but some patients we took breaks, and communicated with sponsors. So in the peak of the pandemic, it was really an unprecedented time. And fortunately, I think just as a testament to all of us here, as myeloma always is collaborative, we actually collaborated with all of our New York City institutions. And there's a manuscript, led by Malin Hultcrantz from Memorial. There was 127 patients, that was just from the New York institutions.
Ajai Chari: And one of the striking things in that paper, which we can come back to, is that 20% approximately of the patients actually were precursor condition. So we're talking MGUS, smoldering, plasmacytoma. And that's really striking when you think about... When you go into this, median age of late 60s to 70s, hypogammaglobulinemia, immunosuppressive therapy, we didn't know what the impact of steroids was. So the concern was really that these relapsed/refractory patients were the most common cause of morbidity, mortalities and infection. Not to mention, some of our drugs actually increase the risk of respiratory infection. So going into this, I think there was a lot of unknowns, and the fact that that message came out in the New York paper is kind of interesting.
Ajai Chari: And then when we get into the IMS data, you asked Marivi a simple question, what was the mortality rate? And that question, if you ask, what is the morality rate of myeloma, it's actually a very complicated answer. Because what we started with was, there was a lot... Testing access is a big issue. So in US, I can tell you at Mount Sinai, even during the peak of the pandemic, I could very easily call one of my patients and have them go to a lab to get the nasal swab and go back home. And so over 50% of the outpatients with COVID in the IMS collection of 650 patients, over 50% came from the US.
Ajai Chari: So that is clearly going to effect your numerator denominator, because if you throw in a lot of outpatients, your mortality rate's going to be lower. So then we said, "Okay, let's maintain equipoise, let's only look at mortality rates in hospitalized patients." Now you see a big spread, as low as 27%, to as high as 57%. And that 57% comes from UK. And now we get into additional complexities of resource availability, healthcare allocation. And so the number of patients in UK, and I'm curious to hear Marivi's case too, Spain. Very few patients got ventilator access in these countries. So clearly that's going to be another issue. And now of course, there's a lot more emerging data about the need for vents, versus high-flow non-invasive ventilation. But back then, in the early part of the pandemic, we didn't really have that information. But strikingly, the number is almost identical, when you look at hospitalized patients, the mortality rate was about 34%.
Ajai Chari: So I think that's a very similar message. And then I think the other striking findings from this study were that, similar to what I echoed with the New York series, about 36% of the patients were diagnosed within the past year. So 2019 to 2020. And over 50%, so 54% of patients were receiving their first line of therapy. And so that's a pretty striking number, given that you think that the prevalence of myeloma, if you think about the distribution, you're typically going to have a lot more relapsed/refractory. And those were the ones we were really worried about. And it skewed actually in the opposite direction.
Ajai Chari: So we had precursor conditions from New York, a lot of newly diagnosed, or first line of therapy. And I think we can discuss further, I'm curious to hear other people's thoughts, it really begs the question of, how much of COVID complexity and mortality is really the virus, versus the actually inflammatory sequelae? Are the heavily treated patients able to mount the same response. And a great example of this is one of my lymphoma colleagues had a pair of sisters. One had heavily pre-treated disease, post CAR-T, the sister was healthy. Both got COVID. And it's the sister that ended up in the ICU. And I think... And the patient had minimal symptoms, right? So I think we need to study these more.
Ajai Chari: But just the other part that I would mention is, we looked at a lot of the... For the clarification, 33% mortality rate, we looked at univariate analysis, and what were the factors that predicted for worse outcomes. It was age, ISS three, high risk disease, renal disease, suboptimal myeloma control, and multiple co-morbidities. But, in multivariate, the only ones that came out were age, high risk disease, which I think is quite interesting, renal disease, and suboptimal myeloma control.
Ajai Chari: And that message actually came up in Lancet as well, where the, when you look at all cancer patients, risk factor for worse complications was actually uncontrolled cancer. The odds ratio was actually five-fold higher for death. So I think what we're learning... Now admittedly, we have to put a caveat. These are retrospective studies. And pretty much a lot of the, as we heard from Spain and US, we halted a lot of our visits, so with that intervention, this is what we've seen. And so there may be bias in whom we did that and did not do that. So there's always a caveat with retrospective studies. But it seems like similar to Spain, similar to all cancer, we cannot compromise the myeloma control, and that's when you come back, and I completely echo what Marivi said, is there's the disease control, but then that's when we bring in the patient factors.
Ajai Chari: So does this patient, are they older or younger, what is their renal function, what co-morbidities do they have? And then you put in the myeloma status, and then you put in the prevalence of the disease. And you kind of have to plug in all those data points to come up with the right treatment. And that may change, for a given patient over time. So, really, I think a lot of interesting findings that are... Fortunately the message is pretty similar, in so that's always reassuring that there's not differential outcomes in different countries.
Paul Richardson: Yep. Thank you, Ajai, that was very thoughtful.
Paul Richardson: In terms of the outpatient population that you identified in the IMS survey, what was the mortality like in that group? Or do we not...
Ajai Chari: It was very low. And I can get you that number in a second.
Paul Richardson: Yeah. That's good to know. Because I think from a patient perspective, I think it's important to emphasize that it's those patients who require hospitalization in whom...
Ajai Chari: The death rate went from 4% for outpatients, to 31% for hospitalized, not on ventilatory support, to 80% for patients on ventilatory support.
Paul Richardson: Yeah, that's incredibly important. Because I think that... Certainly our experience, and obviously Nikhil and Ken have represented us in the IMS survey reflecting our group's broad experience. And I think the important point is that we would agree with you Ajai, that our own experience has been actually quite favorable, and in fact to echo your point, having being on the unit every day with my nursing team, it's been incredible to look at how our nurses have responded. And not simply in the COVID context. COVID patients, that's of course been extraordinary as well. But actually with our own patients. Absolutely fearless, absolutely dedicated to their care, because to your point, it's been the ability maintain their myeloma control that's been our priority.
Paul Richardson: At Dana-Farber, we've actually been allowed to keep our protocols open, they've left it to us to judge which ones we should and shouldn't use. So we've obviously curtailed transplant, we've curtailed CAR-T, not ruled it out. But simply very, very selectively used it. And we've then focused on, for example, three weekly infusions of belantamab mafodotin for example. The therapies that don't necessarily trigger CRS, don't make us necessarily trigger the kind of immune dysfunction that could exacerbate problems. And we focused on oral therapies as well, with considerably success. And we've been able to continue to enrol really high quality trials for our patients. Because our biggest problem, has frankly been loss of disease control. That by patients not coming to get their therapy, we've seen their myeloma get out of control, and inflict considerable harm.
Paul Richardson: In that context, Evangelos if I may. Please can you give us the Greek perspective, and what you've learnt in your center of Athens, which is the premier center in the whole of Greece. So it'd be lovely to hear your perspectives please Evangelos.
Evangelos Terpos: I represent... Thank you Paul. I represent I think the center with the less experience in COVID, because we are a country with very low number of COVID cases in general. And in our population, we had only... I checked within the Greek myeloma study group, only two cases, asymptomatic cases in multiple myeloma, who were diagnosed because in every patient at the time of diagnosis, and every cycle of treatment on day one, we are having a PCR test for COVID. For the detection of COVID. So we detected only two cases who were positive, in whole Greece, where, as I told you, we're a country with only 200 deaths. And only 4,000 cases in general, in whom more than 1,000 are tourists.
Evangelos Terpos: So in general, I don't know why, but because we took measure. For example with only five days earlier, compared to Belgium, and our country has only... I will talk about deaths, because this is something that nobody can say that you don't have a lot of deaths to detect the cases. But for deaths we had only 200 cases, 204 to be honest. While in Belgium it's around 10,000. And we talk about countries with exactly the same population, 11 million. So we don't have a real problem.
Evangelos Terpos: I had the privilege to lead a paper on behalf of the European Myeloma Network regarding recommendations from experts in all Europe about the management of myeloma patients during the COVID-19 pandemic. And I think that although this was an opinion paper, because we have not had any data at the end of April that this paper was developed and published online, in Leukemia issue, of 21st of May. As Marivi, and Ajai mentioned now we are going to have more data, and we may need to update these guidelines after having data.
Evangelos Terpos: But I think what we have included in this paper regarding our opinion, I think that this remains, rather the gold standard today. Meaning that all patients, at least at diagnosis and before, is new line of treatment, they have to have a test for the PCR, for the COVID-19, for the SARS-CoV-2 virus. And then depending on what we are going to find, we have to manage our patients. For example, if the patient is asymptomatic, and... As I said, the one thing that has COVID-19 positive PCR test. Then I think that if the patient has not very aggressive myeloma, and newly diagnosed patients, then we can delay treatment for 14 days. I think this is not a big issue.
Evangelos Terpos: But if the patient has acute renal failure, and aggressive characteristics, then probably we need to start treatment with very, very close follow up, in order not to miss the asymptomatic COVID-19 infection. But for patients with systemic disease, I mean full symptomatic disease, I think it is a real problem. Because as Marivi mentioned, if we have a young patient, then we have to deal with the problem of going to transplant or not. To start aggressive therapy, or not. If the patient is elderly, I think the main problem for us would be the acute renal failure, because otherwise I believe that the patient can start with an oral treatment, or we can delay treatment for 14 days.
Evangelos Terpos: But for young patients, mainly with aggressive disease, I think who have a problem regarding transplantation, mainly in areas where the COVID-19 pandemic continues to exist. And I wanted to ask both Marivi and Ajai, if I may, if there are any characteristics of the myeloma patients that have developed the disease. Meaning, if neutropenia is important factor for developing the disease, or lymphopenia. If we have any other characteristics regarding specific therapy. For example, if monoclonal antibodies, or immunomodulatory drugs are more prone to make the patient sensitive to develop the disease. Do you have from your cohorts such data? Because I think that this is something very interesting for all the physicians, and all the time I've been asked if neutropenia for example, is a risk factor for developing COVID-19. If transplantation is a factor for developing COVID-19 more easier, more frequently, compared to the others.
Paul Richardson: Thank you very much, Evangelos, I'd love comments, first from Marivi, and then from Ajai.
María-Victoria Mateos Yeah, from the Spanish myeloma cohort, I can say that over 80% of the patients had been receiving proteasome inhibitors, over 70% immunomodulatory drugs, and approximately 30% of the patients, monoclonal antibodies. And none of these agents influence in the inpatient mortality rate. The mortality rate was quite comparable, across the different groups of patients, considering the treatment. So I can't say that we... Well it is not recommended to avoid any specific anti-myeloma regime, because of the impact in the inpatient mortality rate. At least, in our citizens, Ajai can comment on the International Myeloma Society cohort.
María-Victoria Mateos And concerning the autologous stem cell transplantation, in our series, 30% of the patients had been received the autologous stem cell transplantation, in the inpatient mortality rate was lower than in the overall cohort, and the inpatient mortality rate was only 18%. And the patients who died when they had received autologous stem cell transplantation, and I think that Ajai has commented this before, these patients had been received the autologous stem cell transplantation in the prior months before being infected by COVID-19. So patients with recent, newly diagnosed myeloma, that have received it maybe in the year before being infected, and, well, they were receiving most of their maintenance with lenalidomide, and they died. But well I think that it is not true to say that the transplant can potentially protect from the inpatient mortality rate, for patients infected by COVID-19. But I think that what we can say is that autologous stem cell transplantation, did not impact in the mortality rate of when the patients become infected by COVID-19.
Paul Richardson: If I may, Marivi, just to be sort of draw down on that, because I think that's an incredibly important point. But I also think it's fair to say, isn't it, that obviously, certainly in our selection process for transplant, we pick, we select patients who are fit, healthy, typically have good renal function and so on, and tend to be younger. So I think one has to be a little bit careful about that, but it's certainly reassuring to hear that the mortality has been really quite substantially lower in that group.
Paul Richardson: It's very interesting, because in the determination study, where we have early versus delayed transplant. In our cohort of patients, we have seen COVID infection in both arms, but actually at low rates, very low rates, and we've had no mortality in either arm, be it early transplant or late. Zero. So I think it points to the critical factor, in my opinion, which is disease control.
María-Victoria Mateos Absolutely.
Paul Richardson: If you have good disease control, and you have diminished immune dysfunction. That's sort of a double negative, if you will. But if your immune function is more stable. I think the outcomes are likely to be better. So I think that's an incredibly important point.
Paul Richardson: Ajai, could you just comment further?
Ajai Chari: Sure. Yeah, to pick up on your theme of the transplant and confounding age. So in IMS, 87% of patients for whom we knew the treatment status were on active therapy, the vast majority, almost 90% had treatment held at the time of COVID diagnosis. Recent transplant, even within a year prior to it, they actually had a lower death rate. However, it's confounded by the age difference. It was a 10 year age difference between transplant and non-transplant. And so when you adjust for the age, that difference really disappears.
Ajai Chari: We also didn't see a difference even within six months. We had about 86% had exposure to prior PIs, 80% prior IMiDs, 30% anti-CD38. And in univariate analysis, PI, IMiD and CD30 were not associated with outcome, although there was a slight univariate trend towards IMiDs showing decreased mortality. But in multivariate analysis there was no difference. And all the other drugs, and CAR-T... I've personally have had two patients, post-CAR-T who had COVID. They were both outpatients, and did very well.
Ajai Chari: And if I may just add two other quick points, because I think to Evangelos's question. I think some of the granularity of the questions you're asking is harder to get in a global dataset. But we actually recently published the Sinai Experience in the Journal of Hematologic Oncology, with 60 patients at Sinai, looking at detailed laboratory parameters, et cetera. And so we did not see any particular... It was lymphopenia, at the time of COVID diagnosis, which I think has been reported widely. But the only kind of laboratory thing that seemed to be correlating with worse outcomes, is persistently elevated D-dimer.
Ajai Chari: So, as you know, that the endothelial damage and the anti-thrombotic therapy is very important in management of COVID. And that changed during the time period of the pandemic. Where initially we weren't doing that, everybody was getting hydroxychloroquine azithromycin at the hospital. But then towards the end of the pandemic, everybody was getting anti-coagulation.
Ajai Chari: And then the two final points I would make, I think these are important for management issues, because one of the questions... I remember for one patient of mine, who was admitted with COVID, she recovered from the pneumonia, and then needed a procedure. Kyphoplasty or radiation, either one. And they required a negative swab. So they want two negative swabs before you could do a procedure, because of the risk to the staff. So Friday, the swab was negative. Monday was the swab was positive. And so I think what this brings up is, as with any test, what do we know about it? And so in our patients that had serial PCR testing, the median time to becoming PCR negative was 43 days. So it's quite a bit of time. So if you're waiting for that, it's going to be a long time.
Ajai Chari: And then the other kind of striking thing, Sinai fortunately had very early on, we had internal antibody development. And believe it or not, out of 23 patients with myeloma, who had antibody testing, do you know how many had positive antibodies? 22. The only patient that did not have an antibody was my patient who had smoldering myeloma with a high level of marrow involvement, that hadn't yet started therapy. But every other patient... And when I bumped into our infectious disease doctor in the hospital, I was like, "Aren't you surprised? Our patients are usually hypogamma, don't respond to vaccines, many of them are on CD30 and antibody therapies. Some have had CAR-Ts, and everybody's getting antibodies." So, actually in the general population, in the same... The responsive antibody development is over 90%, over 99%. So there was an interesting paper I saw that COVID response may have increased plasmablastic response. And so I'm wondering whether, whatever few plasmablasts are floating around, or somehow... But it was striking that the antibody... Of course, caveat we don't know what to do with these antibodies, and how long they last. But that's the data that we have.
Paul Richardson: But that's great news for our patients. I will say that our management strategy has been, for example we'll be using IVIg, to be offering patients optimized infection control in every sense. And I wonder if that's also impactful in what we're seeing. Because obviously our patients, particularly our more advanced patients are extremely savvy about keeping away from infection, and self-isolating. And your newly diagnosed patients, are to some extent naïve. They don't know, and they don't quite understand the same issues. So I wonder if that's a little bit of a confounder in some of the information we have. Because certainly, one of my patients said to me, "I'm just treating this as if I was post my transplant. And that's how I've handled it, and I've been completely fine." And that's the kind of veteran patient, who's many years into this natural history.
Paul Richardson: So I think there are all sorts of-
Ajai Chari: That brings up a couple of interesting points, because there was actually... Early in the pandemic, there were these grand rounds, I think one of them was from Boston, and somebody brought up that pre-clinically, there was even concern that IVIg may potentiate viral entry. And that's been shown, for example, with measles. So we didn't know what to make of that, but what we found was actually hypogammaglobulinemia at a high level, because it's so prevalent, didn't really predict. But actually in our data, severe hypogamma, less than 400, did predict for worse outcomes. So I don't think we have data to hold IVIg right now, if it's appropriately indicated.
Ajai Chari: And then the other interesting thing of course is that, I know Evangelos has been doing some work, but in those patients that have now gotten to convalescent plasma, of course, their antibodies become positive right away, after the treatment. But I think these are really patients who are not getting IVIg or convalescent plasma, are still able, even if they're hypogamma, with all of that, they're still able to generate this antibody. So kind of crazy.
Paul Richardson: I...
Evangelos Terpos: I think that Ajai has mentioned two important things. The first is the immunity over the patients with multiple myeloma, and the second is what you have to do with the thrombogenic potential of the virus. I think that this is extremely important. I will say some words about the second, and some... Because we talk about myeloma patients. And we have seen, in patients without myeloma, that even after two months after their, for COVID patients, after their hospitalization, they continue to have thrombogenic factors into their blood. Some of them continue to have D-dimers elevated, after two months of the last day of the hospital. So I mean that it seems that during the course of the disease, the thrombogenic potential is very high. And that's why at this point, all hospitalized patients, not with myeloma, but with any with COVID-19, all the societies recommend the use of low molecular weight heparin.
Evangelos Terpos: So I think for the myeloma specific information, we have the question. Do we need to treat all patients with low molecular weight heparin, if they are under IMiD, for example administration. Like patients who are on maintenance, with lenalidomide, when we are in the COVID pandemic. I think this is one important question which we don't have of course, any answer. That's why I wanted to ask Ajai and Marivi if they have the cause of death in their cohort of patients, in order to know if these patients had thrombotic events, and it was echoes of that.
Evangelos Terpos: The second regarding immunity, we had sent a letter yesterday, in New England Journal of Medicine, we don't know which of course if it's going to be accepted or not. But it is, I think, an important observation. We sent this letter in another letter that was reported in New England Journal of Medicine. And suggest that in 35 patients, with mild COVID, there was a dramatic reduction in the anti-SARS-CoV-2 antibodies, within two months. So we are running a convalescent plasma study, and we had checked 256 possible donors, who had specific criteria. And 74 of them gave their plasma, that were positive for antibodies, at a median of 12 days post the screening test. So it was between eight and 19 days the range, from the day of screening, till the day of plasmapheresis.
Evangelos Terpos: And even within this two weeks, we had a dramatic reduction in the level of the antibodies, in all, except for five patients. Five donors, let's say. Previous patients with COVID-19. So, and this p-value was 0.0001, below that in both IgG and IgA. And we used two techniques. Not only one targeting the S1, the spike, the S1 domain of the virus. But also one targeting the N antigen, and one targeting the RBD. All of them were reduced dramatically, even after two weeks of, I mean from the day of screening. The day of screening was 54 days, the median after the first day of symptoms. Or of PCR positivity, if the patient was asymptomatic. So this suggests that we have a rapid reduction of the antibodies. Of course, this does not mean that the patient lose their immunity against the virus. But it gives you an idea of what's happening. So I want to make these two observations.
Paul Richardson: Evangelos, that was very, very insightful, and very detailed, and I appreciate it very much. But I think obviously we have the antibody construct, we have the innate immunity which may be much more important that people have previously appreciated. I would like to sort of build on what you've just alluded to.
Paul Richardson: Marivi, in terms of treatment choices, we've alluded to this obviously earlier. But certainly we've embraced the fact that all therapies make sense, particularly active ones. In the context of your analysis, did the IMiD story, to build off a point that Evangelos made, did the use of IMiDs, was it associated with any way, worse outcome, vis-a-vis thromboembolic events in the patients that were hospitalized in your study?
María-Victoria Mateos Yeah, this is a good question. And well unfortunately, we have not collected the final cause of death in our patients, so we don't honestly know if more patients treated with IMiDs maybe died because thrombotic events. What we realized was that, well COVID-19 infections resulted in quite a thrombogenic risk. And most of our patients with myeloma in our series, were treated with low molecular weight heparin. So I think that honestly, we don't know if our patients died from thrombogenic events.
María-Victoria Mateos And concerning the second question, if we have a plan to add low molecular weight heparin as a thromboprophylaxis for all patients receiving immunomodulatory drugs in myeloma. Honestly, we have not done these recommendations yet, because... Well, we continued with aspirin, if patients were receiving maintenance with lenalidomide. And what we do we, as soon as a myeloma patient, or whatever patient, no myeloma, suspected of being infected by COVID-19, we start immediately low molecular weight heparin. Because we realize since the beginning, the thrombogenic effects caused by COVID-19.
Paul Richardson: That's exactly our approach to. And we were a little concerned, because there was obviously this concern about ACE 2 upregulation, and it's relationship to infection. And so we were worried about whether aspirin would influence that. And those fears have not been borne out I don't think, from most databases that I'm aware of. So we've done exactly what you've done, Marivi. Used standardized coagulation approaches, warned patients, and then when and if they're hospitalized, exactly what you've done, taken a proactive step, and gone to the more aggressive approaches for thromboprophylaxis. But I don't the microangiopathy of this disease, this endotheliitis of COVID-19 is very relevant. Both Marivi and have I are participating in a project called DEFACOVID, which is targeting novel agents to go after this endotheliitis. And the particular drug we're working with, in partnership with a wonderful colleague of Marivi's, Jose Meraldo, in the University of Murcia, is called defribotide, which many of you may be familiar with.
Paul Richardson: And preliminary results from that study in Spain have been quite amazing actually. Very, very sick MICU patients. So, in that spirit, further comments-
Ajai Chari: If I may just add one brief comment from the IMS data set as well, there was... When you look at the IMiD patients, there's actually no increase in mortality.
Ajai Chari: If anything, univariate analysis was decreased mortality.
Paul Richardson: How interesting.
Ajai Chari: I think... Keeping in mind the nature of these studies which is retrospective, and there's probably a lot more discontinuation of drugs that are parenteral. You might have skewed it in the opposite direction, right? Like the IMiDs between thrombotic, and those were the drugs that were not discontinued might have been associated. But it's coming back in the opposite direction. So it seems again, the message is control the disease. And I think at the time COVID, certainly do anti-coagulation, but right now I don't think we have data to support doing more anti-thrombotic therapy than would have been indicated pre-COVID.
Paul Richardson: Absolutely. And so, in that spirit, just as we think about... Evangelos has touched on convalescent sera, we obviously know the great data with remdesivir, and tocilizumab, and all these exciting new approaches. I think it's worth mentioning that there's been some repurposing of myeloma drugs. Or certainly, drugs targeting lymphoid malignancy. And the BTK inhibition story is particularly exciting. And I mean there are multiples trials going on. Certainly just acknowledging my own colleagues, Steve Treon, has led our own BTK effort based on his own actually very elegant pre-clinical work. And those studies are ongoing. We don't know results, but there was a nice paper of six cases in Blood, a few months ago, with Steve as the first author, suggesting there might be some benefit.
Paul Richardson: But I think we have to be very careful, because we have a cautionary tale, don't we Ajai, with selinexor, where we saw some very interesting and very compelling early data with selinexor. But the larger, randomized phase two trial, which was placebo controlled, has actually been now stopped, because of futility. Which suggests to me that obviously we'll need to know more about the details of that. But we were very excited about selinexor based on preliminary data, but obviously that hasn't panned out.
Paul Richardson: Ajai, do you have any comments on that?
Ajai Chari: Yeah, I mean the selinexor, there's been very interesting pre-clinical work already that it blocks viral replication, blocks inflammation, in mouse models when you inject mice with lethal doses of flu, it can abrogate that. And so, I had one particular patient that was admitted with COVID-19, very heavily treated penta refractory. And she presented with both COVID, but also epidural disease, that was progressing. And so she got hydroxychloroquine and azithro, and her fever curved, it never dropped, her CRP continued to rise and her platelets were low. So in starting selinexor, we started a low dose, which is the 20 TIWs, the treatment in the study. And promptly after starting that, all of those normalized. Fever had stopped, CRP down trended, platelets recovered actually, because you typically would see the opposite. So all of that normalized. And then she was able to go onto her full dose of selinexor.
Ajai Chari: So that's an off label use, obviously of... And just ramping up. But it needed to be confirmed with randomized studies, obviously. And I think, it may again, go back to the interplay between disease and COVID, right? Her disease was just not controlled. And yet she was also having COVID at the same time.
Paul Richardson: I completely agree, and I think we have to be very careful, because these trials have been conducted incredibly quickly, with very rapid enrolment. And it's a heterogeneity of COVID that we're learning about. So I wonder if when all is said and done, there'll be subgroups of patients who might benefit, and some who clearly don't. And just as the story around how hydroxychloroquine, and azithromycin has been so complicated, with clearly some positive, some negative, and some of the more recent American data, been quite remarkably positive, from well done studies without sort of crazy data. I think you're absolutely right, Ajai, I think the story will be a mix of these things as we try to learn what goes best.
Paul Richardson: Well I think in the interests of time, we're almost at our hour of allocated time. I just wanted to thank you very, very much for an outstanding discussion. And I think as we finish up, are there any of latest advances in the myeloma space, specifically myeloma therapies, that you think could really be a hopeful message for our audience on the one hand. On the other hand, be particularly relevant as we face the continuing challenge of COVID.
Paul Richardson: So if I may, Marivi, anything that strikes you from the recent EHA, ASCO banner headlines in myeloma that may be particularly relevant to what we're talking about today?
María-Victoria Mateos Well, from the myeloma management point of view, I think that ASCO and EHA were very productive in, well, new agents, and especially new data. And I would say from the first line of therapy, to late advance stage of the disease. If we focus on late advanced stage of the disease, I think we have interesting data coming from new, immunomodulatory drugs in new CELMoDs, from oral administration. Very effective even in patients already refractory, to do the conventional ones, lenalidomide and pomalidomide. We had the opportunity to see interesting data about belantamab mafodotin, especially about durability of the response in patients who responded. As well as positive data coming from the combinations, whether proteasome inhibitors or even the checkpoint inhibitors pembrolizumab.
María-Victoria Mateos We had also BCMA targeted therapy through T-cell engager. So bi-specific monoclonal antibodies also very attractive data. As well as the CAR-Ts, we had the opportunity to see the data from the pivotal KarMMa study, with, from my point of view, impressive efficacy results from the overall respond rate, and CR rate if we consider the population included in the study. The main challenge from my point of view is the durability of the response, and we will see how we are going to maintain the response. But we had also the opportunity to see new combinations like carfilzomib, with the monoclonal antibody anti-CD38, isatuximab, impressive data.
María-Victoria Mateos And also even in the adjuvant setting we had the opportunity to see how maybe three drug based combination, plus the monoclonal antibody, anti CD38, for high risk patients, whilst they would have the opportunity to see how elotuzumab seems to add not much more benefit to the conventional VRd in the adjuvant setting, in the standard risk, and also in high-risk patient. And I don't know, maybe much more new data that Ajai, or Evangelos can compliment about the disease. Just a brief, well, summary of the most relevant data.
Paul Richardson: Well that was lovely Marivi, and I think I would echo everything you've said. And just before I ask Ajai and Evangelos for their comments, I think one of the very interesting points about our standard platform of RVD is its favorable performance against KRd. And my only point about that is really that the toxicity signal from carfilzomib based therapy, I think we all have learned, it has an endothelial platform. And as we think about COVID, that's not a trivial consideration to bear in mind. And I think as we think about therefore, how we strategically position drugs, certainly RVD is the most... Seems certainly the least expensive of the triplets upfront. And at the same time seems to be validated by the results of the ENDURANCE study. Conversely, I certainly firmly believe in carfilzomibs value in relapse in particular. And I think it's helped us frame some of those considerations as we go forward. And as of course, as you so nicely point out, the success of some the oral therapies as well, helping us to target disease, better disease control.
Paul Richardson: But Ajai and Evangelos, I'd like in the last couple of minutes, if you don't mind, if I could ask you each in about a minute or so, to give us your sort of sense of what was good, and particularly noteworthy out of both EHA and ASCO. Perhaps, Ajai, I could ask you to go first?
Ajai Chari: Sure. I mean, Marivi did an outstanding job summarizing, I think, all the important data. The only I would add was that, to put these new studies into context, historically we looked at a response rate of 25 to 30% of PFS, that's three to three and a half months, as significant enough to give us novel H and accelerated approval. And now we have bi-specifics, and CAR-Ts with response rates of 80 to 95%, with PFS around a year. In the same, if not worse population, because these patients have had all those drugs. So I think it's really a game changer of how big a deal this is. And I think it'll be very exciting to see these drugs move up early, to see what those do. And I think at ASH this year, we're going to hear... Because there's been a lot about BCMA, but there's very exciting new targets that are non-BCMA, and I think those will be very important for patient care.
Ajai Chari: And then lastly, I think we really need to do a better job of high-risk disease. And I think it'll be interesting to see how these agents fare. We saw a glimmer of 17-P, potentially with selinexor, really a must better hazard ratio, than we did with other patients. So I think we need more these studies that are really powered to look at high-risk, so we can start improving that subgroup.
María-Victoria Mateos Yep.
Paul Richardson: Thank you Ajai. Evangelos, last but no means least.
Evangelos Terpos: I totally agree with Marivi and Ajai, from what they said, and I just wanted to echo Ajai for the CAR-T cells, and the bi-specific results of both ASCO and EHA abstracts. I believe that these two technologies will give us the possibility to, if not to cure some patients with multiple myeloma, just to prolong survival a lot. Because I have seen very promising results at the very end-stage of the disease, with penta refractory patients. But also, this gives us the possibility to use these techniques, this technology, in earlier stage of multiple myeloma. And I believe that-
Paul Richardson: Bring it forward.
Evangelos Terpos: Possibly for the high-risk patients, or at least a fraction of high-risk patients, may give us some very good solutions. Of course, this has to be proven. But I think that the technology, plus the different targets that they may use, outside of the BCMA, they will give very good solutions for the high-risk population. This is my, I believe, this is my belief for the CAR-Ts especially.
Paul Richardson: Well I think, in that same spirit, this construct of new approaches to cellular therapy are so interesting. And of course, just to share with our audience, we now have oral agents. Note, the cereblon E3 ligase modulators, iberdomide, and most recently 480, which are so powerful in what they're doing that they're sort of, I'm not going to say they're CAR-T in a pill, because that would be too strong. But they are remarkably potent and active in what they do. And as we think about the COVID era, our ability to sort of tailor therapy to minimize risk for our patients becomes all the more exciting.
Paul Richardson: So with that in mind, I think it's been a wonderful session. I want to thank Marivi, Ajai and Evangelos for a fabulous discussion over the course of the last hour or so. And especially to thank our audience, for joining us for myeloma sessions today, and in particular to thank our colleagues and partners from VJHemOnc, for making this discussion possible. So thanks everyone, and have a wonderful rest of the day.
Evangelos Terpos: Thank you.
María-Victoria Mateos Thank you.
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