Chapters Transcript Video DFCI ASH 2020 - Myeloma Highlights thanks for the opportunity to present this data. It was once again a very exciting meeting as it relates to new developments in multiple myeloma. I'm going to cover several topics today starting with one trial uh and newly diagnosed disease. And then I'm going to cover two trials in autologous transplant and four trials in relapse disease including one conventional regimen previously FDA approved and then I'll focus on autologous carty and several trials involving novel by specific antibodies in myeloma. So in the newly diagnosed space we had an update at the meeting from Jonathan Kaufman who was presenting on behalf of the Alliance Myeloma group. An update on the griffin trial. Um As you may know, the Griffin trial is a randomized Phase two study in which patients were randomized to receive classic R. V. D. Therapy times four cycles followed by a single autologous transplant Followed by two cycles of consolidation therapy with R. V. D. And thereafter Lenny Little mind maintenance versus classic R. V. D. Plus dara to mob Followed by transplant followed by two cycles of consolidation and thereafter maintenance with Lenin, Little Mermaid and Dara to mob. The primary endpoint in this study was stringent complete response rate at the end of consolidation and secondary endpoints included marty negativity, overall response rate. As you can see here, patients who received uh the dara to mob plus R. V. D. Regimen shown on the left had superior outcome in terms of response rate at all time points throughout the study, including the end of induction therapy in the aftermath of transplant, the end of consolidation And at 12 months after maintenance therapy At that point, the rate of complete response or better was a striking 82 In the RBG arm. The rate of complete response or better. Whether it was a very respectable 61 with regard to M. R. D. Status. We saw similar results in that following transplant following consolidation and following one year of maintenance therapy rates of Mardi negativity were higher in the dera to mob group. You can see that following one year of maintenance therapy the M. R. D. Negative rate was striking 78% versus approximately 40% in the R. V. D. Arm. Longer follow up will be necessary in this trial to determine whether these improvements in depth of response translate into meaningful improvements in PFS and overall survival. It is certainly anticipated that that will be the case uh with regard to progression free survival And longer follow up will be necessary to see that. But we do see that as of 24 months there is beginning to be separation in the curves as it relates to uh progression free survival. So we'll continue to follow the outcomes of the Griffin trial and it has already I believe impacted treatment in patients with newly diagnosed disease in ways that we'll discuss in a little bit, the italian myeloma group or the jemima group provided an update on an important trial called the Forte trial. The four day trial was also a randomized trial in which patients received either four cycles of car fills a website talks index followed by transplant and forced cycles of consolidation with the same or four cycles of car fills in that revlimid decks followed by transplant followed by for additional cycles of KRG as consolidation Or finally in the 3rd Arm 12 cycles of induction therapy with car fills amid rev dex with no transplant. There was a second randomization in this study to either revlimid or revlimid plus car fills maintenance therapy As you'll see here. The response rates in the two KRD groups, the patients who were transplanted and those who were not were quite similar in terms of both overall response V. G. P. R. Rate as well as rates of marty negativity and superior to the response rates that we're seeing with the car Phyllis and cyclophosphamide decks um combination. So unequivocal evidence of success related to this construct of protozoan inhibition plus immuno modulator orI therapy plus dex method zone. What was interesting was that with longer follow up of this study, it was shown that patients who underwent transplant as opposed to those who received 12 cycles of K. Rd therapy without transplant had more sustained Mardi negativity and this then translated into a benefit in progression free survival. That was statistically significant. We also had an update from the french Myeloma group, the I. F. M. Team on the 2000 and nine. I F. M. D. F. C. I study. The results of this study were initially published in New England Journal of Medicine in 2017. The american portion of this study, which was led at our site, has yet to be published as we incorporated maintenance until progression in the american portion of the study and longer follow up is necessary before publication of our results. But this was an update on the french data. Um you're familiar with the design of the study. All patients received RBD therapy times three cycles all patients underwent stem. So harvest and those in army then received five additional cycles of RBD, whereas those in arm B underwent titles, therapy and transplant, followed by two additional cycles of our VD therapy. And then all patients in the French portion of the study received just 13 months um of maintenance therapy with little little mind before being observed without treatment. The primary endpoint of the study was progression free survival. And with a long period of follow up now, You can see that the benefit in terms of progression free survival continues to hold at about 12-13 months um added progression free interval. However, uh there is no difference in terms of overall survival with a median follow up of nearly 90 months. These results are similar to what we observed in the 2017 New England journal publication. Uh It is noted that um Approximately 80% of the patients in the trial who didn't undergo upfront transplant underwent autologous transplant. Um as second line therapy which presumably has a significant impact on the overall survival analysis and also speaks to the fact that whether or not a patient undergoes transplant as second line therapy, they're just an abundance of excellent options for salvage therapy and this disease at this point in time, there was a robust discussion led by Vincent raj Kumar from the International Myeloma working group at the Ash meeting. And I think in light of ongoing data from trials like griffin um the Maya study of R. D. Vs. Dara R. D. And transplant ineligible patients results of the endurance trial which were presented at 2000 and 20 Asco by Shaji Kumar. A comparison of R. V. D. Vs. K. R. D. And these transplant studies that the general approach to newly diagnosed patients who are transplant eligible remains much the same. The preference based on the endurance trial, which showed equivalent PFS results and response rates with KR KR D vs. R. V. D. Is such that R. V. D. Is generally the preferred frontline treatment at this point in time. However, on the basis of results from griffin which are really showing striking results in terms of depth of response if not yet benefit in terms of progression free survival. A dara to mob containing quadruple it regimen which proved to be safe in the griffin trial can certainly be considered in um uh certain clinical situations, notably those patients who have higher risk disease or potentially those who start on R. V. D. And have a suboptimal response to treatment after two cycles. Many patients should be considered for transplant. As has long been the case though, patients with standard risk disease characteristics can be uh collected or undergo stem cell harvest but forego transplant as a consolidation approach. Um And then for non transplant patients we generally do prefer three drug regimens when possible although certainly there are situations where that's not possible. Um And the R. V. D. Modified approach that was published by Betsy O'donnell from MGH and BRitish Journal in 2000 and 17 is generally our preferred approach though certainly with the Maya data published in 2019 of Dara to mobile index, this is a very legitimate an excellent option for newly diagnosed disease as well In the relapse space. Um Our group in the Panorama three study group Um published the results of the Panorama three trial, which was a randomized comparison of three different doses and schedules of Panna. Been Ystad in combination with Bart is um of index method zone as you recall, Panna best at plus 40 is a mob and dexamethasone was FDA approved in 2000 and 15 for patients who have received three or more prior lines of treatment based on a significant four month PFS benefit scene with the addition of panna, been a stat this disease or this drug um is often forgotten I think in the midst of all the developments in the field but certainly has significant activity in a number of patients and the advantage that it can be given orally. However, there were concerns about toxicity of the combination A. P. I. Plus Panna been Ystad because of um in particular the S thenia, the diarrhea and nausea. So the intent of this trial was really to look at different doses and schedules of panna Bennis stat that would enable this regiment to be better tolerated. It's also noted that in the original panorama based three trial Velcade was administered intravenously rather than subcutaneous lee. So there was interest in determining whether with subcutaneous administration the regimen would be better tolerated. So these were patients who had 1-4 prior lines of treatment, including an image subcutaneous board as much as I mentioned. And the doses and schedules of panda Ben a stat that are shown here. The standard dose and regimen is 20 mg three times weekly. In this trial we also assessed 20 mg twice weekly and 10 mg three times weekly with a um primary endpoint of overall response rate. After eight cycles of treatment. As you can see here, the response rates were very similar for patients who received the 2 20 mg doses of panna, been a stat And superior to those that were seen with the 10 mg dose. What was interesting however, Was that patients who received the 20 mg three times weekly dose, which is the standard. It's significantly better in terms of duration, response duration of response at 22 as opposed to 12 months. So this was deemed to be the superior regimen in this case though it certainly does carry the risk of added toxicity, Which is remains a challenge with this regimen. And when we use it um we tend to, for elderly or frail patients will start at a lower dose, perhaps 10, perhaps 15 and work our way up to 10. I mean up to 20 mg with appropriate supportive care uh interventions. Mhm. Turning toward other studies and relapse diseases I mentioned before, I'm going to highlight and discuss uh one carty trial and two studies that are evaluating novel by specific antibody approaches. And this really um as with other human logic malignancies is a look towards the future and perhaps more so in myeloma than other diseases. As car T therapy is not yet FDA approved, but we're getting close. And this trial um it was an update on the original Bluebird. BB 21 21, a study of id sl in patients with relapsed disease. um uh Dr lin along with dr raj raj from um MGH and Dr Mancini from our site uh were involved in this trial. Um and as you are undoubtedly familiar, um, IDA cell is an autologous Kartik construct that's transducer with a lentil viral vector encoding a car specific for BCM A, which has been the most common target for T cell approaches in multiple myeloma and has proven to be quite successful. So, patients who had received three or more prior lines of treatment in this study Received conditioning therapy with fluid rabin and cyclophosphamide, and then were infused with varying doses of the car to construct ranging from 50 to 800 million. This was, as would be expected, a very heavily pre treated group of patients. You can see here that the median time to from diagnosis was 5.5 years. The number of prior lines of treatment here shown here uh in a row towards the bottom was six very heavily retreated group of patients. And many of these patients were refractory too timid P. I. And anti cd 38 therapy. These were the responses. And as you can see for the study as a whole, the overall response rate was 76 percent. In the group of patients who received the higher doses of 458 100 million cells. Those response rates were 90% and 100% overall. So very impressive. Uh overall response. And as you can see here as well, the depth of response was really Quite remarkable. You can see in that 450 million sl group, the rate of cr or better was nearly 40%. And in the group of patients who received the 800 million dose, it was 100%. So small number of patients, but nonetheless, very impressive data and not surprisingly, as is typically the case and these studies, but super important in a group of patients who have been as heavily pre treated as this group of patients was those who achieved a greater depth of response tended to do better. In terms of duration response. You can see that the median Duration of response for those patients who achieved cr better was 15 months. Again quite remarkable for a group of patients who had received six prior lines of treatment um in terms of toxicity, Um as with other carty approaches, side opinions are to be expected uh and the recovery of counts can be delayed, but generally speaking patients recovered counts within 2-3 months. Um CRS is quite common. Uh We saw Approximately 76% of patients in this clinical trial experienced crs. But the rate of higher grade cytokine release was relatively low at 6.5%. And similarly um the rate of higher grade neurological toxicity, which can come in the form of encephalopathy or seizures um Was relatively low at 3.2%, whereas the overall rate of neuro toxicity was 43%. And interestingly, as you see on the bottom right, there were there was only one death that was considered to be potentially related to study therapy, an episode of cardiopulmonary arrest, whereas the rest of the patients who died within the first month for six months after treatment, I do too progressive myeloma. So I think on the whole um the safety of this approach um is being closely evaluated and I think we're coming out okay So um this the data from this trial as well as the Karma to Phase two trial that Dr. presented at Asco and will likely be published. You can keep your eye out for that will likely be published in the coming weeks, will be reviewed by the FDA this winter and will likely provide the basis for approval of The BB. 21. I do sell carty construct in relapsed and refractory multiple myeloma for patients who have had three or more prior lines of treatment which of course is very exciting and long awaited. Um Nick Eel is the current president of the International Myeloma working group and uh he and his team are working on a manuscript manuscript. Currently that is going to provide insights and guidance into the types of patients with myeloma who should be ideally considered for this type of approach and Nakheel working along with other members of our myeloma program who are leading the myeloma carty program both in terms of the science and the clinical aspects and that includes Omar Nadim and Adam Sperling are working on generating such a document for our dana Farber practice which we will disseminate so that we can be coordinated with our colleagues in the community in terms of how we get this off the ground once carty's FDA approved because I think for all of us it will be an exciting moment in the field. Um There were a number of other exciting carty presentations um and of course we don't have time for them today. I wanted to focus on this one because it was the original one and and and the B B. 21 21 will be the first proof. So I wanted you to have some familiarity with it heading into these upcoming months. But there were a number of really exciting carty presentations, including one by a chinese company called Carsten that has generated the first humanized carty approach in multiple myeloma and saw a very impressive results. I had wanted to talk also about a very interesting trial which you can look up. We just didn't have time has faced for it. But there's a very interesting trial led by our colleague at Medical College of Wisconsin part Mulaney and Hari of the first allergenic um carty approach in multiple myeloma. And the results were quite impressive and of course that would potentially offer some advantages In the sense that the generation of the party product would be done for these patients and we wouldn't require the 3-4 week delay that is typically necessary, not delay, but the 3-4 week time period typically necessary to generate the construct. And for as much excitement as there was about carty in myeloma, there was an equal amount of excitement regarding the by specific antibody approaches. And there were numerous clinical trials which if you're interested I would either recommend and encourage you to look at. It was really remarkable data. And for me and preparing for this talk it was a little bit difficult to choose. Um you know, which ones to to share with you. But I chose to that I think are sort of reflective of what's going on in this domain. Um And one of them is a B. C. M. A target which is you know most most common in myeloma. One is a non BCM a target which I think is also very very exciting because of course, you know we need um targets other than be CMA for T. Cell therapies in myeloma. So this was presented by a gi char e. It's called the Phase 1 1st and Human Study of Tell quite a MAB, which is a G protein coupled receptor family. See Group five member D. Or g p R C five D. Um and CD three by specific antibody. This is a depiction of the Um the GPRC- five d molecule itself, which is interesting in that it's expression is limited in healthy individuals primarily to plasma cells and hair follicles. Um And it's over expressed are highly expressed in patients who have multiple myeloma. As people go through the continuum of precursor to myeloma. The expression level increases and high levels of expression and pre clinical models has been associated with adverse prognosis. The other interesting thing about is that there are no known shed pep ties which reduces the likelihood of a sink effect for this particular molecule. And this is a representation of the tower, quite a mob molecule itself. And this is an overview of the design of the trial. Um And as you can see both intravenous and subcutaneous um formulations were assessed in this study so similar to the car T cell patient population, these patients were heavily pre treated. You can see that the median number of years from diagnosis was seven. High percentage of these patients had extra medullary disease which I think as patients with myeloma are living longer and longer, we're seeing more and more frequently. And there are at least some preliminary preliminary data in the field to suggest that you know an extensive amount of extra macular diseases associated with poor prognosis and the median number of prior lines of therapy or was six as I mentioned before. And um 82% of patients were triple class refractory to Emit P. Um and um c. d. therapy 33% were Penta drug. Refractory to revlimid palm vell. Car fills a mob and dara to mob. So again just as to highlight the fact that these are heavily pre treated patients. Overall the safety profile looked reasonably good. Um As would be expected side opinions were rather common and we did see you know higher grade side opinions. Not unexpectedly. The rate of cytokine release was 54% overall But only 3% grade three or higher. And there was some neuro toxicity. Um in about 6% of patients In terms of response uh for the highest dose level of subcutaneous, the overall response rate was 73% At the 405 microgram per kilogram dose subcutaneous which was the joes chosen to move forward to in Phase two. That was 70% with a VGPR rate or better of 40 1%. So, very impressive results in terms of responsiveness and as you can see here with both the ivy on top and sub Q patients on the bottom. Um These responses proved to be uh quite durable overall. And in many cases as you can see with the swimmers plot patients are deepening their response as they receive further treatment. And then lastly, I'll present this trial which was presented at the ash meeting by Dr Garfield which was an update on the Phase one study of Ciclista MAB Which is a by specific antibody targeting CD three expressing T cells um and be CMA expressing myeloma cells. This is a depiction of the molecule itself and here is a representation of the design of the study, pretty similar to what we just saw with the Tell quite a mob trial and likewise similar in that both intravenous and subcutaneous formulations are being assessed. The study population was likewise very similar to the study. Um The percentage of patients who had extra medullary disease for the study as a whole was about 12% 32% had high risk cited genetics, 85% had previously undergone transplant and the median number of prior lines of therapy, I was six Triple class exposed was 96% and Penta drug exposed with 70%. um 81% of patients were triple class refractory and 40% were refractory to rev palm Velcade car fills me and Derrick too Man. Um The safety profile for checklist, a mob was similar to what we saw with quite a mob. The rate of crs was 55%, but there were no cases of higher grade cRS. in this study side opinions were again quite common And the neuro toxicity rate was also similar to what we observed with tell quite a mob which was around 5%. Um and none um in patients who received the subcutaneous formulation in terms of response, the overall response at the 1500 microgram per kilogram subcutaneous dose, which is what was the recommended phase two dose was 73 With a v. gpr rate or better of 55%. And as was the case with tell quite a mob. These responses proved to be um uh both durable on the one hand and improved over time with ongoing exposure to the drug so clearly. Um And again these these studies are representative of many others in the by specific antibody space that were presented at the meeting. Very exciting. And I think just to put it into context, I look back um you know, eight years to our original experience in developing dara to mob which is proven to have a significant impact on the field as a whole. Underscored I think by the results of the griffin trial that we began the session talking about where it moved from. Relapse too newly diagnosed and may make it into the smoldering space eventually as well. But with single agent Garrett um Ahmad with steroid premed in a similar patient group and that original Phase one trial, the median number of prior lines of treatment was for And the overall response trait in that trial was 35% and here we are six or seven years later With patients having received a lot more car fills them a lot more palm plus the CD 30 AIDS and we're seeing response rates with the by specific antibodies that are double what we saw with dara to mob when it was first developed. So clearly this is very, very exciting I think has a lot of potential. And it's nice that it's being developed uh in parallel with carty because clearly um there will be, you know, um uh opportunities for us to think moving forward about which patients are going to be best for these different approaches. Um, so with that I'd just like to say a few things first and foremost as always to patients who participated. Um and these really impactful trials. So our colleagues in the community who collaborate with us on patient care and support us in that way. Very important way in the conduct of these trials. Our colleagues at other sites who led uh collect some of these trials and shared slides with us members of our team at Dana Farber in the Myeloma program, Our industry colleagues as well. We've partnered in these studies and I'd like to thank my academic assistant anne for helping and assembling this presentation. Thanks much to everybody. Thank you Jacob that was outstanding presentation. We have a couple of questions um with regard to the by specifics couple things. Is there any corneal toxicity with these particular drugs? And uh how do you see sort of the development of these? Will they move forward earlier in the trajectory of the disease? And how might that compare with the use of Kartik? Yeah, I think with regard to the first question we have not yet seen corneal toxicity. Obviously that's a major concern with balanta matt Matthew Dalton, Where the rate of Cornell toxicity is over 50%. Um but these drugs are obviously distinct from balanta mob and we've not seen corneal or other item. ocular toxicity fortunately. Um, with regard to the second question, undoubtedly these results are so striking. I have no doubt that as time goes on, once they're established and relapsed disease, there will be potential for them to move forward in the same way that other drugs in our field and others have done that being said. I mean, I think the cautionary tale here is that, you know, it's still early for the by specifics, relatively early. You know, we've been working on these the carty trials in the field for roughly 34 years and rightfully so in a great deal of attention is being paid on not only short term, but longer term toxicities that could emerge over time. And the same will need to be done with the the by specifics. And I've been part of the development of another by specific antibody from Genentech. It's a non BCM a targeting by specific um and um it's striking to monitor because all of these approaches are new and while on the whole um you know, the rate of higher grade toxicities um is relatively rare when you see it. It's for the first time, right? I think that's the challenge here. Like we're testing these drugs for the first time and I think it will take time for us to get a better handle on the short and long term toxicities with by specific antibodies in the same way that we are doing with with carty. But I think eventually if the toxicity profiles um hold up the way they have thus far and we learn more about supportive care approaches. I think it's quite likely that once they are approved and patients who have had for example, three or more prior lines of treatment, they'll eventually move forward. And to the final question. I think that was part of Uh this one is you know, how does this compare to Cartier as I mentioned before? I think you can see with carty the the depth of response is incredible. You know. And at that 800 cell dose to get uh there's only three patients but to have a cr rate Or better of 100%. I mean that's unprecedented. And um so I think there are clearly differences here. But uh the toxicity of course and also the duration of manufacturer required for carty will play into these decisions to probably the cost as is an issue in lymphoma as well. And maybe one last question regarding Covid vaccine and I think this is something that we are all struggling with. I know the NCC and recently put out recommendations guidelines to really vaccinate everyone with maybe the exception of waiting on transplant patients. But how are you? How is your group thinking about that? We're doing much the same. Um We're getting input and guidance from the sponsors of these T cell directed therapies to Cartier and the by specific antibodies that are that are interestingly sort of specific to each study. So I really can't comment on a general approach there because we're listening to the guidance of our industry colleagues who's you know uh scientific teams I think are are advising but with regard to transplant we're doing the same thing, you know in many instances currently with the expected surge we're advising patients collect cells but unless they're really high risk, not necessarily transplanting this winter. You know, I think we're taking that approach more. So for those patients of course get the vaccine if it's a higher risk. Myeloma patient really needs an autologous transplant Can't delay. Um you know if the transplants more than 33 months out we'd recommend getting the trans the vaccine. If it's less than three months out we just skip it and be careful and get vaccinated at a price that I don't know what you're recommending. And but in our group we're recommending three months after transplant for the Covid vaccine. Yeah, we're doing the same for Cartier and transplant though. We're doing a small pilot study to measure tigers and patients who have had monoclonal antibodies. You know I would think Garrett chairman bob and protects the mob would be potentially major interfere ear's with a response though with this new type of vaccine, the mmr the RNA vaccine I think. We don't know. Um So more to come. We're trying to figure this out. But I guess at this moment we're recommending that everybody go ahead Published Created by