Yale ASH 2022 Highlights: Multiple Myeloma

February 13, 2023

Information

February 10, 2023

Hosted by: Dr. Terri Parker

Presentations by: Drs. Sabrina Browning, Noffar Bar, Elan Gorshein, and Natalia Neparidze

ID9479

To CiteDCA Citation Guide

00:00Welcome everyone to the 2023 Post American
00:04Society of Hematology annual meeting
00:07at CME series. We are starting off the
00:10series today with multiple myeloma.
00:12Our first two presenters
00:14are Doctor Nofar Barr and Doctor Sabrina
00:16Browning who will be reviewing abstracts.
00:19We will then have a question and
00:21answer period at the end of the
00:23presentation where we will be
00:24joined by two other panelists, Dr.
00:26Ellen Gorshin and Doctor Natalia
00:28and appraise. If you could please
00:30put your questions in the Q&amp;A.
00:32And save them to the end?
00:33That would be greatly appreciated.
00:35I will now turn it over to Doctor Barr.
00:42Hi everyone, I'm just gonna
00:44start sharing my screen here.
00:54Alright, it's good to be here.
00:57Good afternoon.
00:58Today I'm going to be looking at the
01:01newly diagnosed myeloma abstracts in
01:04Ashes 2022 this past December with
01:07a particular focus on subgroups.
01:14So I have no disclosures.
01:17The first subgroup I'm going to be
01:18speaking about are the frail patients
01:20and why is it important to have
01:22dedicated studies for these folks is
01:24that they have different outcomes,
01:26they have shorter survival,
01:27they have higher rates of toxicity
01:29and therefore higher rates of
01:31discontinuation of therapy.
01:33Traditionally,
01:33studies have categorized myeloma
01:36patients as either transplant or
01:38transplant ineligible patients,
01:40but this category really does not
01:43capture frail patients because the frail
01:45scores are not routinely checked in
01:48those non transplant eligible patients.
01:50For a long time the standard of care
01:53for non transplant eligible patients
01:55was with REVLIMID and dexamethasone Rd.
01:58But since the Maya study,
02:01we now have a new standard of care
02:03for patients which is Derek Tuma Mab
02:06REVLIMID and dexamethasone there Rd.
02:08So what the FM 2017 O3 study analyzed
02:13is removal of dexamethasone early.
02:16So they hypothesized if you take
02:18away dexamethasone from there.
02:20Rd.
02:21this will still be effective
02:23and it will reduce toxicities.
02:25Before we get into the study design,
02:27I want to talk about what is a frailty score.
02:29Some of you might not have had a chance
02:31to take a look at this in your clinic,
02:33so I am WG.
02:35Frailty score involves a few things.
02:37Age, activity of daily living,
02:40which involves feeding oneself,
02:42bathing oneself, instrumental activities
02:44of daily living which involve food,
02:46shopping, cleaning the house,
02:48doing your finances and the comorbidity
02:51index, which is what it means.
02:53Comorbidity is like lung disease.
02:55Diabetes, liver disease and so forth.
02:58Now, as you can imagine,
03:00this takes time to do this frailty score.
03:02There was a lot of questions involved.
03:03So the IM group devised a simplified
03:07score which involves age,
03:08which is fairly easy,
03:10ECOG performance status,
03:11which we do routinely,
03:12and then the comorbidity index,
03:14which is easily accessible from chart review.
03:16And if you had a score of two or more,
03:19you're classified as frail
03:21and otherwise you're fit.
03:23So this is the study design.
03:25They include a newly diagnosed
03:27patients over 65 years of age and I
03:30am I FM frailty score of two or above.
03:32It was a 2 to one randomization with
03:36REVLIMID decks or Dara REVLIMID.
03:40I do want to note that with the Dara
03:42Revlimid's group which ARM B right here,
03:44they did receive steroids for the first
03:47two cycles along with dexamethasone
03:49primarily to avoid infusion reactions.
03:52So their primary endpoint was PFS,
03:55but this is immature at the moment.
03:57So they did an interim analysis and
04:00they looked at response rate including
04:02MRD negative rate and occurrence
04:05of grade three or more toxicities.
04:07I want to highlight here some
04:09of the patient characteristics.
04:10So if you look at the median age,
04:13they were significantly older,
04:15median age of 81 compared to
04:18the Maya study which was 73.
04:21While the inclusion criteria in
04:23the study included two or for the
04:25frailty score was two or higher,
04:27actually the majority of the
04:29patients were three and higher.
04:31If you look at the risk categories,
04:33they were fairly similar in the two groups.
04:37So Dara REVLIMID clearly led to
04:40deeper response rates than REVLIMID
04:41dexamethasone you can see here first
04:44based on just the the response rates,
04:46you had higher CR and very good partial
04:49response rates and then Dara Rev Group and
04:52you also had higher MRD negative rates,
04:54attentive negative 5th using next
04:57generation sequencing 10 compared to three.
05:00MRD was assessed at one year in patients who
05:03had a very good posture response or higher,
05:06it is important to note that.
05:07Any missing data was considered MRD positive.
05:11So it's important because there is a
05:13significant group of patients that have
05:15missing data and for example, the Dr.
05:17Group had 20% missing data and the Rd.
05:21had 14% missing data.
05:22And I'm not about to compare
05:24different studies to one another,
05:27but I want to give us a framework
05:29of what the Maya study showed.
05:30So in the Maya study they assess MRD
05:33negativity, attend to negative 5th,
05:35but they used a different assay
05:37so they use flow.
05:38So flow tends to have a higher MRD negative
05:42rate just by the nature of its assets.
05:45So just something to note,
05:47but they had in the DRD group 24%
05:50MRD negativity versus 7 in the Rd.
05:53group. In terms of toxicity,
05:57which is very important,
05:58you can see that Grade 3 or above
06:01Texas City was higher in the Dr.
06:03Group,
06:04particularly with hematologic
06:06toxicities like anemia or neutropenia.
06:09And in this group,
06:10of course you worry about
06:12infections with this neutropenia,
06:13but they did not see an increase in
06:16grade 3 above infections in the Dr.
06:18Group compared to the R group and
06:20even when looking at patients who are
06:22very frail with scores of four and.
06:24Five,
06:24there was no difference in grade 3
06:27infections, so this is reassuring.
06:30So in conclusion,
06:31I think it is time to rethink duration
06:34deaths methadone especially for outpatients,
06:36longer follow-up of PFS is needed
06:39but higher MRD rates in the Dr.
06:42Group is very promising.
06:44I think the better comparator to Dr.
06:48like DRD and Maya would be a
06:50would have been a better design.
06:52However,
06:52this was not the standard of
06:54care when this was designed.
06:55They are going to be there are going
06:58to have a retrospective comparison.
07:00To the main study in the frail population,
07:03I think you know in you know right
07:05now when you see patients in clinic
07:07when you have that very frail over 80
07:09year old patient where you're really
07:11not sure about triple drug induction
07:13and you're thinking about a doublets.
07:16I would choose Dara Rev with a short
07:18duration of steroids as opposed to Rev Deck.
07:20So I I do think it's meaningful
07:23for for our practice today.
07:25The next set of subgroups I want
07:28to talk about another area of very
07:30high unmet need is the high risk
07:33population where we really have
07:36limited randomized studies guiding
07:38our treatment.
07:39The only randomized study was a -,
07:421 and this was evaluated the
07:44addition of ELOTUZUMAB to Velcade
07:47REVLIMID index methadone VRD.
07:49Now we know we need to do better than VRD,
07:52but how do we do it?
07:53So one appealing option was switching
07:56out the VELCADE with carfilzomib
07:59which is a more potent proteasome
08:02inhibitor and outperform VELCADE in
08:04the relapsed refractory setting.
08:06Additionally,
08:06there was phase two studies showing
08:10high MRD negative rates in KRD.
08:12So it made sense to compare VRD to
08:15card and they did this in an endurance
08:17the endurance study and they.
08:19Actually did not find superiority
08:21of care due to the Rd.
08:23but they excluded high risk patients.
08:26So that question about how do we
08:28better improve our induction in
08:30the high risk patients was not
08:31really answered by this study.
08:33But people have not abandoned care
08:35being in in high risk patients
08:37for a variety of reasons.
08:39But in the memorial Stone Kettering
08:42Group where they are earlier,
08:44they were early adapters
08:45of Carradine induction.
08:47They were able to do a retrospective
08:49analysis and this was presented.
08:50Doctor Tan in this years ash of Care
08:53D versus verdine high risk myeloma.
08:56Their inclusion criteria for
08:58high risk included having gain
09:00of 1 Q translocations
09:0441414161420 and deletion 17P.
09:08They identified 154
09:10patients in this category.
09:136067 had VRD and 87 had KRD.
09:17About 50% of each of these groups
09:20underwent early stem cell transplant.
09:22Their primary endpoint was progression
09:24free survival and they also looked
09:26at response rate including MRD,
09:28negative rate and overall survival.
09:31So this is the patient characteristics.
09:33A few things to highlight.
09:34The carotid group were younger
09:37and then I want to look at the
09:40cytogenetic characteristics here
09:41just to see who are dealing with
09:43majority of the patients who are high
09:44risk or high risk by definition of
09:47chromosome 1Q gain or amplification,
09:49which is not unusual because this is
09:50one of the more common findings we see.
09:52The second most common was deletion
09:5417P and importantly about 1/4 of
09:56the patients of E in each group
09:59had two or more high risk.
10:01The genetic abnormalities,
10:02and this is now called the double
10:04hit or the ultra high risk patients
10:06which really have poor outcomes.
10:07So this is the response rates
10:09and the median PFS results.
10:11You see higher CR rates with
10:14KRD compared to VRD,
10:15higher MRD negative rates by flow,
10:19but it was not statistically significant.
10:21I think the most impressive
10:23results is the PFS,
10:25the KD having a median of 71 months
10:28compared to 41 months and this
10:32was you know highly statistical
10:34significance and they also saw
10:36an overall survival benefit.
10:38The five year estimate of
10:4085% compared to 63%.
10:41I want to just point out here in the
10:45ENDURANCE study remembers it is non
10:47high risk patients the PFS of both
10:50arms was 30-4 months and it's not
10:52quite clear why in this high risk
10:54populations that PFS is actually higher.
10:57So this was kind of brought up
10:58to the presenter and it was not
11:00there wasn't a great explanation
11:01but something to think about you
11:03know endurance was done in a in a a
11:06lot of community setting and this.
11:08Early as in a single institution,
11:11tertiary center.
11:13So next they did a multivariate
11:16analysis looking at different factors
11:18that are associated with better PFS and OS.
11:21So first type of inductions, OK,
11:23D is better, early transplant was better,
11:26having revised ISIS one compared to
11:28two or three was better and and that
11:31who are these revised access one in
11:33this high risk patient population,
11:35it's really those patients that
11:37have gained one cube because
11:38they were not included,
11:39it's not part of the revised ISS criteria.
11:42So you know who who these patients.
11:44And then the number of cycles
11:47having six or more induction
11:49cycles had better PFS and OS.
11:53So to summarize,
11:54I think the study is interesting.
11:55It does suggest that maybe Cardi could be
11:58better than VRD in high risk patients,
12:00but it is very limited by the
12:02retrospective nature of this design.
12:04I also think that you know they
12:06don't talk about which maintenance
12:08strategies they used and that will
12:11definitely impact PFS and OS.
12:12I think this study continues
12:14to support the notion that
12:16early transplant in high risk patients is
12:19beneficial and it does bring into question.
12:22What is the optimal number of induction
12:25treatments in high risk patients?
12:28Next I want to move to a more
12:30modern question is, you know,
12:32now that we're using quadruplex,
12:33how do high risk patients fare with
12:36the most commonly used quadruplets,
12:38the Dara VRD.
12:39So Dara VRD was studied in the Griffin study,
12:43which compared the addition of Dara
12:46to VRD in transplant eligible patients.
12:49In all patients they saw that there
12:52were higher MRD rates and also
12:54progression free survival benefit.
12:56But again this isn't all patients.
12:58There are only 15% of those patients
13:00and study that were high risk
13:02cytogenetics by the traditional high
13:04risk features like deletion 17,
13:06translocation 414 and four 416.
13:10So the Doctor Charity wanted to evaluate
13:14evaluated this subset group in the
13:17Griffin to really hone in on different
13:20high risk categories in the Griffin study.
13:24And I want to.
13:25Really it's a busy,
13:27a little bit busy slide,
13:28but let's just focus in on the
13:30side the genetic risk categories
13:31here as I highlighted they as I
13:34mentioned the initial high risk risk
13:36category were very few in both arms,
13:38but then they revised or high risk
13:40category to include chromosome abnormality
13:42and that really increased their,
13:45their patient population from 16
13:47to 42 patients in the Dara VRD and
13:5014 to 37 patients and then they
13:54categorize patients having zero.
13:56So no high risk features,
13:58HCA 1,
13:59high risk cell genetic abnormality
14:01or two or more as we call the
14:05ultra high risk patients.
14:07Clearly you can see the PFS in patients
14:10who are standard risk didn't seem to
14:13differ much between the two groups.
14:15Both of them had were were not reached
14:17in the meeting in the 15 months.
14:20Clearly the ultra high risk
14:21patients are too small to really
14:24make any conclusions about only
14:2510 patients in eight patients.
14:28But in the high risk in the one
14:30high risk cytogenetic abnormality
14:32group there was an improvement
14:35in PFS not reached compared to.
14:3848 months,
14:39and this is the only subgroup here
14:42that actually does not cross the
14:45hazard ratio does not cross one.
14:47So a different way of looking at
14:49the same data, if you're you know,
14:51a more visual person,
14:52is looking at the PFS curves and.
14:56What I want to show here in the kind of
14:59medium purple line the dare RVD with
15:02one high risk staging netic feature.
15:04Compare that to this green dotted line here,
15:08the derivative with sorry with VRD
15:12with one high risk feature there's a
15:15clear separation of the PFS curves,
15:17while there is really not a big
15:20difference with those patients
15:21who are standard risk and clearly
15:24the ultra high risk due poorly.
15:26Now look at the graph on the right.
15:28These are these are the amplification
15:30or gain of 1 Q and the grasp is actually
15:34pretty identical to the ones with
15:36the one high risk hydrogenic abnormality,
15:39which really showed you who those
15:41patients are. So in conclusion,
15:43I think this analysis shows that Dara
15:47VRD seemed to outperform VRD in high
15:50risk patients harbouring gain of 1 Q.
15:53High risk patients with more than two
15:56cytogenetic abnormalities do poorly,
15:58and we can't make any conclusions
16:00for this analysis because of
16:02the numbers were too small.
16:04So this brings me to this category
16:07of ultra high risk myeloma and the
16:10optimum study was very clever study in
16:12the UK they it was a screening study.
16:15So anyone in multiple UK centers
16:17who had the who's being worked
16:19up for myeloma or was offered the
16:22participation in the study and they
16:24screen patients for high risk features,
16:26they're they're inclusion was
16:28to be double hit.
16:29So you have to have two of the
16:33following translocation 4141416.
16:34Station one gain of 1,
16:36so deletion one peak gain of 1Q and
16:39deletion 17P or high risk gene profile
16:41or if you had plasma cell leukemia,
16:45which really is these patients
16:47are excluded from every study
16:50they identified 107 patients,
16:52ten of which had plasma cell leukemia.
16:56So there's a few things going
16:57on in this study.
16:58I want to focus first on the study
17:00design of the optimum study,
17:01which you talked about up here.
17:03On top, they use five drugs in induction.
17:06So they added cytotoxin to Dara VRD.
17:10They added VELCADE in the
17:12Peri transplant period.
17:14They used six cycles of Dara VRD
17:16induction and then 12 more cycles of
17:20Dara RVD in extended consolidation,
17:22so basically excluding steroids
17:24in another year.
17:26Of consolidation to and then
17:28there are in until progression
17:31and notably they're not using a
17:34proteasome inhibitor long term.
17:36So ideally the authors would love
17:39to have done a randomized study,
17:42but there was no standard of care
17:43for these ultra high risk patients.
17:44They thought it was unethical,
17:46so they did not do so.
17:47So it's a single arm study,
17:48but they were very much interested
17:51in understanding how this would
17:53compare to a genetically similar
17:55group of patients with myeloma.
17:57So they looked at their myeloma ex
17:59study and they had genetic testing for
18:02all these patients identified and identical.
18:05Population with this ultra
18:07high risk phenotype,
18:08I'm not going to go into the details
18:10of that study because I do think
18:12it's an overall sub par comparator.
18:14But it's just for numerical purposes
18:17here that they used cytotoxin
18:19REVLIMID decks or carfilzomib,
18:22cytoxan, REVLIMID,
18:23dexin induction transplant and then
18:26either they got no maintenance
18:28which is really not what we do
18:30or REVLIMID maintenance so.
18:32Their objectives of the studies to look
18:34at MRD, to look at PFS and toxicity.
18:37I do want to note this is quite an
18:40intensive treatment and they did
18:42have several fallouts dropouts.
18:44So out of 107 patients,
18:47only 74 patients completed consolidation too.
18:51The dropouts in the induction transplant
18:53section was due to intolerance
18:55and dropout and consolidation was
18:57due to progression of disease.
18:59So this is MRD at different time points.
19:03You can see that the MRDD deepened
19:05as you move from end of induction
19:07to end of transplant at 63%.
19:09I don't want you to be discouraged
19:11by the lower percentage after
19:14end of consolidation because they
19:16mentioned there are dropouts.
19:18So you can see here 30% of the
19:21patients didn't reach that endpoint.
19:23So that's why you see numerically
19:25lower rates of MRD there.
19:27What is important we know
19:29sustain MRD is actually more.
19:30Relevance than just one time point
19:33of emerging negativity is that
19:3584% had sustained MRD negativity
19:38at the end of consolidation.
19:40So that is very important.
19:44Now this is the PFS course again
19:46I'm not surprised that the PFS
19:48is better with this optimum
19:50regiments than the the comparator.
19:52They did spread out in the in the
19:53myeloma X the ones that got prophesied
19:55that were not to secularism seemed
19:57to be a little bit better than not.
19:59Again not very surprising with
20:01produce some inhibitor but regardless
20:04I think it's very impressive the
20:0630 month PFS estimate of 77% and
20:09this does fare favorably to other.
20:15Other data out there for this really
20:18high risk patient population.
20:20In terms of toxicity,
20:21which is very relevant when people are
20:23getting this intense prolonged treatment,
20:25they showed you here the
20:28consolidation to adverse events.
20:30So there are some grade three side effects.
20:33There are not that many,
20:35most of them are hematological
20:37like neutropenia.
20:39There were some Grade 3 infections,
20:42about 12%,
20:42most of them being respiratory tract
20:44infections and they don't separate out,
20:46you know, the viruses from the bacteria,
20:49but that I think that would be relevant.
20:50Especially in the era of of a pandemic.
20:54So it seems to be fairly toggled.
20:56They did.
20:56One thing to note, they did allow for very.
21:01Flexible dose reductions,
21:02even for Grade 1 toxicity to allow patients
21:05to continue on treatment for longer.
21:08So in conclusion,
21:09I think these type of single ARM
21:11studies can serve as comparators
21:12for future randomized studies and of
21:14course balancing the efficacy and
21:16toxicity in this patient population.
21:19Now the last study I'm going to go into,
21:22I'm going to shift gears to a
21:23different subtype of high risk
21:25patients and these are the functional
21:27high risk myeloma and these are not
21:29the patients you know that they're
21:30high risk when you first see them,
21:32they they demonstrate themselves
21:34because they or they relapse early.
21:37So patients who have early relapse
21:39after transplant within one year
21:41have horrible prognosis.
21:43You see here 26 months overall
21:45survival compared to 91 months
21:47if you didn't have this early.
21:49About relapse,
21:50So what this Karma 2A study analyzed
21:53is the use of either cell or abukuma,
21:57which is the first CMA directed
21:59car T cell product for myeloma.
22:01They used it in this patient population.
22:04The inclusion criteria includes
22:06elaps 18 months after initiation
22:08of frontline therapy.
22:10And you had to have revilement
22:12based maintenance.
22:13The primary endpoint was a CR
22:15and secondary endpoints include
22:17duration of response,
22:18progression free survival and toxicity.
22:21So patient characteristics
22:23are presented here,
22:24few things to highlight in
22:25terms of high risk features.
22:27There were 32% high risk disease in
22:29this functionally high risk patients.
22:31There were 40% with missing data.
22:35It they did have information about
22:38their response to upfront therapy
22:40and 24% of the patients have CR
22:42to their first line of therapy.
22:44Most patients have progression of
22:46disease within 12 months of transplant
22:49and no patients were refractory to an
22:52anti CD 38 like there are two now.
22:54This is the efficacy data.
22:56The CRH which I think is the most relevant
22:59in terms of the response rate is 45%.
23:03Just put here in Gray,
23:05what is the CR rate that was seen in
23:07this agent in the relapse that heavily
23:09pretreated population which is 33%?
23:13Just like the other car T products,
23:15we see the deeper response,
23:16the longer duration of response.
23:18Overall, the median duration of the
23:20responder responding patients was 15 months,
23:23but if you had a CR then it goes to 23
23:26months and if you had a PR for example,
23:28it's as short as three months.
23:30So really depth of response
23:33is extremely important.
23:35PFS is roughly a year,
23:38so 11 months here which is quite
23:40similar to what was seen in the relapse
23:43refractory patient population and
23:45you know I think again this includes
23:47all those non responders as well.
23:49I think it would be interesting to see
23:52the PFS for those who are responding.
23:56In terms of toxicity,
23:57there was initial concern that when
23:59you're using these cartee products
24:01earlier in the line of treatment
24:03that the T cells might be fitter,
24:06they might be healthier and actually
24:08have higher toxicities like CRS
24:10and and the neurotoxicity icams,
24:13but they didn't see that in this study.
24:15So there were roughly the same
24:17amount of percentage of events in
24:19the CRS and the neurotoxicity group
24:22as was seen in the prior study
24:25and actually there were lower.
24:27Or at least numerically lower number
24:30of high grade events like grade 3/4 in
24:33both groups compared to the prior study.
24:36I do want to mention infections
24:38is still an issue of post party.
24:41There was a grade 3-4 infections at 22%
24:44and in fact 2 deaths from this with
24:47pneumonia and another from studemont sepsis.
24:51So in conclusion,
24:52in this functionally high
24:53risk patient population,
24:55either cell achieved 45% CR rates
24:57and this was higher than what was
24:59seen in the first line of therapy.
25:01For these patients.
25:02It seems that there are less grade
25:053-4 toxicities compared to the
25:08relapse refractory population.
25:10The PFS seems similar to what was seen
25:12in the heavily pretreated population,
25:15but these patients are very high risk,
25:17they they are very difficult
25:19to treat and salvage so.
25:21I think we really need randomized
25:22study to see what is the best
25:25treatment for these patients and
25:27ideally identify those that have
25:28that will have a CR rate.
25:30So I want to close with this one last slide.
25:33This is what I think is the future.
25:35It's this risk adaptive therapy directed
25:38according to response type of study.
25:40This is the radar study that was presented
25:43by Doctor Wong from the UK don't want
25:45to go into the details of all this is
25:47a busy slide but the concept here is
25:50extremely important that you separate out
25:52the standard risk from the high risk,
25:54high risk patients.
25:55We don't want to stop treatment on,
25:57we need better treatments standard
25:59risk that have.
26:00MRD negative disease can maybe even stop
26:02treatment and standardized patients
26:04who don't achieve MRD negativity
26:06how is how are we going to deepen
26:08their response how are we going to
26:10get them together MRD negative state
26:12so you know when and randomizing
26:15doing a randomized fashion so.
26:17The this and other type studies like
26:20this are ongoing and I think the next
26:22decade hopefully we'll have an answer to
26:25how to personalize treatments for myeloma.
26:28And with that I will close my section of the
26:31talk and we'll move on to Doctor Brownings.
26:40OK, great. Well, thank you Doctor
26:42Barr and and welcome again everyone.
26:44My name is Sabrina Browning and with the
26:46remainder of our time that we have left,
26:49I'm going to review with you data on
26:51relapse refractory myeloma and we'll
26:53also briefly touch upon a new therapeutic
26:56in light chainer ALE amyloidosis.
26:58And I have no disclosures to report.
27:00So a major focus in myeloma at
27:02Ash this year was the diverse and
27:05advancing immunotherapeutic landscape
27:07for relapse and refractory disease.
27:10And as you all are familiar B cell
27:13maturation antigen or BCM A has been
27:15a critical target on myeloma cells.
27:17And as Doctor Barr mentioned we now
27:19have two approved anti BCM a car T
27:21cell products eye to cell and cell
27:23to cell as well as an anti BCM A
27:25by specific antibody articles amab
27:26and while I won't cover this today.
27:29There was promising early phase data
27:31presented on the combination of teclis
27:33tamal with daratumumab and Lenalidomide
27:35and there are other combinations
27:36with this by specific antibody that
27:38are also actively being studied.
27:40As well as the number of new BCM ART
27:43invites but importantly the abstracts
27:45that I will focus on today with with
27:48you all highlight some T cell to
27:50redirection therapies that harness
27:52new myeloma cell antigen targets.
27:54And these include G protein coupled
27:57receptor family C Group 5 member D or
28:00what's referred to as GPRC 5D and SC
28:03receptor homologue 5 or FCR H5 as well
28:07as some non cellular therapies that
28:09help reverse tumor mediated immune.
28:11Paralysis that occurs in in myeloma,
28:14and these include the novel cereblon,
28:15Eli Gaze modulators,
28:17or what is referred to as as cell months.
28:21So to to start we will discuss the phase
28:23two results from the monumental one
28:26study which represented by Doctor Ajai
28:29Chari and this evaluates talked amab.
28:32Talked Amab is a first in class T cell
28:35bispecific antibody that targets GPRC 5D.
28:37And as previously discussed this is
28:39highly expressed on myeloma cells and
28:41thought to have limited expression on
28:43normal cells cells and that includes
28:45hematopoietic stem cells and in
28:47December of this past year the phase
28:49one data from the monumental study.
28:51Were published in the New England Journal
28:53and demonstrated an impressive overall
28:55response rate of 64 to 70% with both
28:58weekly and every other weekly dosing.
29:01And so for the phase two portion
29:03of the study,
29:03patients had to have an ECOG of zero
29:05to two with measurable disease and
29:07three or more lines of prior therapy.
29:09And this included a PROTEOSOME inhibitor,
29:12an imid and an anti CD 38 antibody.
29:15And the three cohorts in this portion
29:17of the study that you see outlined
29:19here included a 0.4 milligram.
29:214 kilogram weekly subcutaneous dosing
29:24and 122 patients enrolled in this.
29:26In this group 0.8 milligrams per kilogram
29:29every other week subcutaneous dosing
29:32where 109 patients were enrolled.
29:33And then a third group of patients
29:35who had received prior T cell
29:37redirection therapy and
29:39were administered either of the
29:40two mentioned dosing schedules.
29:42And the aim of this study was to assess
29:46efficacy and safety of this novel agent.
29:49And so the the table on the left here
29:51on the slide outline some of the key
29:54patient and disease characteristics from
29:55the phase two cohorts of this study.
29:58Median age was 67 and 8.4% of the 0.4
30:03milligram per kilogram group and 6.2% of
30:06the 0.8 kilogram milligram per kilogram
30:08group were black or African American.
30:10And as one would expect in a heavily
30:13pretreated population with an average
30:15of five prior lines of therapy high risk
30:17features including extramedullary disease.
30:19High risk cytogenetics and isss stage
30:22three disease were observed in about
30:241/4 to 1/3 of patients as documented
30:26here in the table and approximately
30:293/4 of the patients have triple had
30:32triple class refractory disease.
30:34However despite this population again
30:36with with high risk disease and there
30:39wasn't an impressive overall response
30:41rate as seen in the figure here on on the
30:44right at 74.1% and 73.1% in the two dosing.
30:49Groups and VGPR are better was
30:52achieved in approximately 60% of
30:54patients which also indicates a high
30:56depth of response with this agent.
30:58These responses were maintained across
31:00across subgroups except for those
31:03with Extramedullary disease where
31:04the overall response rate was reduced
31:07some at 50% and responses were rapid
31:09with the median time to response of
31:12a little over a month and a median
31:14time to best response of approximately
31:162.5 months and thus far responses
31:18have also been durable.
31:20Of the median progression free survival
31:22at the time of presentation was 7.5
31:25months and 11.9 months in the 22 cohorts
31:27with a median duration of of response
31:29that was not reached in patients who
31:32had achieved a complete response or
31:34better and median overall survival was
31:36not reached for the study cohort to date.
31:39Importantly for the patients who had
31:41received prior T cell redirection
31:43therapy which included 70%,
31:45seventy .6% of patients who had
31:48received prior car T and 35.3%.
31:50Would have received prior by specific.
31:52The overall response rate was
31:55still high at 62.7%.
31:56Responses were higher in those that received
31:59prior car T compared to buy specifics,
32:03although the number of patients in in
32:05the study that received prior price by
32:07specifics was small with an end of 18.
32:12It's important to consider safety
32:14for this agent given its novel target
32:16as we discussed and fortunately
32:18as you can see outlined here,
32:20high grade adverse events were uncommon
32:22but when they were present they
32:24were mostly hematologic in nature.
32:26And with that being said,
32:27still there was less than 1/3 of patients
32:30that had high grade heme toxicities
32:32and most of the toxicity was limited
32:34to the first few cycles of treatment.
32:36High grade infections were also
32:38uncommon in this study and as
32:40you can see that included a low
32:42number of opportunistic infections.
32:44COVID infections occurred in
32:45approximately 10% of patients with
32:47only two deaths from COVID and actually
32:490 deaths reported in the phase one
32:51portion that was published in the
32:53New England Journal back in December.
32:55As mentioned,
32:56rates of IVIG use were also relatively
32:58low with with less severe and this
33:01less severe infection signal that
33:03we're seeing in that with this agent
33:05is somewhat distinct from our anti
33:08BCM a targeted by specific antibodies
33:11that are now in utilization.
33:14The most common adverse events were
33:16cytokine release syndrome or CRS
33:18as well as altered taste.
33:21Or discuss Jia skin and nail
33:23related events as well and and the.
33:26The CRS events appear to be restricted
33:29largely to step up dosing and full
33:31first full dose with a median time
33:34to onset of two days immune effector
33:36cell associated neurotoxicity or
33:38what we refer to as icans occurred
33:40in about 10 to 11% of patients,
33:43but again we're mostly low grade.
33:46So in conclusion,
33:47tell Ketama B which is a a first in
33:51class by specific antibody again
33:54targeting novel GPRC 5D on myeloma
33:56cells demonstrated an impressive
33:58overall response rate of more than
34:0070% in patients with heavily pretreated
34:02relapsed and refractory myeloma.
34:04And high overall response rates were
34:06also seen in those who had received
34:08prior T cell redirection therapy
34:10which is an important cohort to
34:12learn more about responses have
34:14been durable and the agent.
34:16Because generally been overall well
34:18tolerated with CRS that seems to
34:20be manageable and fewer infections.
34:22Although it does have unique safety
34:24profile and those include things
34:26like skin and nail related events
34:28as well as taste alteration or dusia
34:31as previously mentioned.
34:32Although these were generally managed
34:34with supportive care and there was
34:36a low overall rate of discontinuation
34:37due to the adverse events and and
34:40therefore there are additional studies
34:41that are now ongoing to looking at
34:43the look at talked amab both in combination.
34:46In combination with a variety of
34:49different anti myeloma agents.
34:51And so next I want to briefly share
34:53with you the following abstract.
34:55This was presented by Doctor Jesus
34:57Berdeja and this is now a novel car
35:00T cell therapy therapy that's
35:02targeting GPRC 5D and and this has
35:04a this car T construct as seen in
35:06the figure here on the right.
35:08And this data came from a phase
35:10one multicenter open label study
35:12and the data was presented on
35:1433 patients enrolled in
35:16the part a dose escalation cohort eligible
35:19patients had relapsed refractory myeloma.
35:21With three or more prior lines of therapy
35:24and prior BCMA therapy was allowed,
35:26there were five dose levels that were
35:29tested from ranging from 25 to 450
35:31million car T cells and thus far the
35:34state the overall safety and efficacy
35:37profile have profiles have been favorable.
35:40Treatment emergent adverse events were seen
35:42in close to 88% of patients and 73% of of
35:46patients had grade 3 or 4 adverse events.
35:50And in comparison to Cal talked tamag,
35:53hematologic adverse events and
35:55and particularly neutropenia
35:56and thrombocytopenia.
35:57Thrombocytopenia seemed to be more more
35:59common with a a dose limiting toxicity
36:02of prolonged grade 4 neutropenia and
36:05thrombocytopenia in two patients.
36:07Again CRS was the most common
36:09non hematologic.
36:10Reverse advent at 63.6% and the median time
36:14to onset with this cartee was three days.
36:18Although grade three and four CRS events
36:20were only observed in 6% of patients.
36:22Icans was infrequent with only two
36:25two patients and was reversible
36:27in both instances.
36:28Instances with steroid treatment,
36:31again because of the GPR,
36:33the unique target that that this car T
36:37targets there were skin and nail related.
36:40Adverse events as well as taste alterations,
36:43but these seem to be less common than
36:45talked amab and all were low grade
36:47and the majority did not require
36:49any sort of treatment.
36:51The maximum tolerated dose has not
36:53yet been exceeded in this study and
36:55there have been no deaths thought
36:57to be related to study treatment.
37:00Importantly,
37:00the overall response rate of the total
37:04cohort what was high at 89.5% with a CR
37:07rate a complete response rate of 47.4.
37:10Percent and there were four patients
37:12that were evaluated for minimal
37:14residual disease or MRD and all
37:16four of those were MRD negative.
37:18So in conclusion,
37:20responses with this novel cartee
37:22seem durable and and seem to
37:24also deepen over time,
37:26making this a promising
37:27treatment moving forward,
37:28including in those patients that are
37:30already exposed to BCM a treatment.
37:35The the next abstract that I will
37:37present was discussed by Doctor
37:39Susan Trudell and it looked at 1
37:42cohort in a safety and efficacy
37:44trial of savasta amab and SAVASA.
37:46Amab is a bispecific antibody seen
37:48here on the right that targets yet
37:51another new myeloma antigen known
37:52known as FC RH Five which again is
37:55exclusively expressed in B cell lineage
37:57and is thought to be near ubiquitous
38:00on myeloma cells and at ASH in 2021
38:03there was initial data presented.
38:05On the phase one dose finding study of
38:07savasta mab and revealed a favorable
38:10efficacy and safety profile in those
38:12patients with heavily pretreated
38:14relapsed and refractory myeloma.
38:16This year's abstract reviews
38:18reviewed a cohort in this study who
38:20received a single dose of the IL 6
38:23receptor blocker to Solus amount
38:25at 8 milligrams per kilograms.
38:26And and this was given 2 hours prior
38:28to the first of Austin maps step up
38:31dose which is 3.6 milligram and these
38:33patients were then compared retrospectively.
38:36To a previously enrolled group who
38:38did not receive tocilizumab and the
38:40objective which was based on preclinical
38:42data was to determine whether there's
38:44this would reduce the the frequency
38:46of cytokine release syndrome or CRS
38:48which as we've discussed now in several
38:50abstracts is one of the most common
38:52adverse event with bispecific antibody
38:54treatment and it's thought to be
38:56mediated by IL sex and other cytokines.
39:00And as you can see here on the the
39:02bottom savasa amab is its administered
39:04with a single step up dose.
39:06Initially at 3.6 milligrams and then
39:08to a target dose of 90 milligrams,
39:10and it's given intravenously
39:12every three weeks.
39:16So 31 patients were enrolled in the
39:20total amount pretreatment arm with
39:2244 patients in the comparator arm and
39:24in both groups as you can see in the
39:27table here on the left included heavily
39:29pretreated patients with a median time,
39:32excuse me, a median line of therapies
39:34being four and six respectively with
39:36fairly similar patient and disease
39:38characteristics except for those that
39:40I've highlighted for you here on the in
39:42the table on the left and as you can see
39:44the tocilizumab pretreatment group did.
39:47Have somewhat less extramedullary
39:48disease as well as less penta,
39:50refractory penta drug refractory disease and
39:53fewer patients in the tocilizumab are arm.
39:56Had received prior anti BCM cell therapy
39:59and the most commonly observed adverse
40:01events in both groups were neutropenia,
40:03anemia, thrombocytopenia and CRS and of
40:06no neutropenia which is a known side
40:09effect of tocilizumab with significantly
40:11higher in the Tosi pre treatment group,
40:13but was said by the authors to be
40:15reversible and manageable with growth.
40:17Doctor um when appropriate and this did
40:19not lead to Savasta Amab discontinuation.
40:22The infection rate was also reportedly
40:24higher than the comparator arm,
40:26although compared to other cohorts
40:27in the study there was a similar
40:30infection rate and grade three grade 3
40:32infections also occurred at a similar
40:35rate between these two study groups.
40:36And as you can see in the figure
40:39here on the right,
40:40the overall rate of CRS was
40:42significantly lower in the Tosi Pre
40:44treatment group at 38.7%.
40:46Compared to the non Tosi group
40:49at 90.9% CRS was limited to grade
40:51one and Grade 2 events in both,
40:54in both cohorts in both groups with
40:56the median time to onset of one day.
40:57And the beneficial effects of Tosi
41:00on CRS were continued with subsequent
41:03doses in cycle one.
41:05In the tocilizumab pretreatment arm.
41:07I can't was seen in frequently in both
41:10groups occurred in only two patients
41:11in the Tosi arm and six patients in the
41:14non-toxic arm and interestingly the
41:16authors demonstrated in the toasty.
41:18Pretreatment arm that after the 1st
41:213.6 milligrams of fastmac dose,
41:23there were higher peak levels of IL
41:256 which were hypothesized to be due
41:28to inhibition of IL 6 clearance by
41:30the tocilizumab.
41:31However,
41:31there was also near complete
41:33suppression of CRP which is produced
41:35by IL 6 receptor binding and thereby
41:38suggesting that there was effective
41:39blockade or blockage of the IL 6
41:42inflammatory signal signaling pathway,
41:45also importantly pretreatment
41:47with tocilizumab.
41:48Did not appear to negatively impact
41:51clinical response rates with an
41:53overall response rate rate of 54.8%
41:56and a very good partial response
41:58or a VGR or better rate of 32.3%
42:01observed in the Tosi group.
42:03And that was compared to an overall
42:05response rate of 37.2% and VG,
42:08VG PR or better of 25.5% in the
42:11the non-toxic arm and median time
42:13to best response as well as median
42:15duration of response was similar
42:17between the two groups.
42:19So in conclusion,
42:20pretreatment with a single
42:21dose of tocilizumab
42:23prior to the initiation of savasa
42:25amab significantly reduced the the
42:27the rate of CRS in patients with
42:29relapsed refractory myeloma likely
42:31thought to be through suppression
42:32of the IL 6 signaling pathway,
42:35but did not seem to negatively impact the
42:37anti myeloma activity of this Asia agent.
42:39And so the authors noted that two
42:42salesman may may play an important
42:44future role in CRS mitigation as pre
42:46dosing and may potentially help us move.
42:49By specific treatment to
42:51the outpatient setting.
42:54The the next abstract was presented
42:57by Doctor Paul Richardson and this
43:00was on amazing amide or what?
43:02What's referred to as Messi
43:03and Messi is a a potent novel.
43:06Sarah Blunt Eli Gaze modulator or what
43:08we know as a cell mod and this was looked
43:11at in combination with dexamethasone.
43:13In this abstract Messi is an oral agent
43:15and as could be seen in the figure here,
43:18it binds and activates Sarah blown
43:20and it leads to what happens is
43:23it leads to maximal degradation.
43:24Of important transcription factors
43:26and that includes ICAROS and ilos that
43:29are both really important in myeloma
43:31pathophysiology and pathobiology.
43:33And this results in enhanced myeloma
43:36cell killing and immune stimulatory
43:38activity when compared to our common
43:41immunomodulatory drugs such as Lenalidomide.
43:44And in this phase one two trial,
43:46Messi was evaluated alone and in
43:48combination with dexamethasone and
43:50the recommended phase two dose for
43:52for Messi was selected at 1 milligram
43:54daily for 21 days.
43:55Out of a 28 day cycle with a notable
43:58overall response rate in the phase
44:01one portion of 54.5% and to be
44:04eligible for the phase two dose
44:06expansion portion of the study that
44:08was reported in in this abstract,
44:10patients had to be relapsed refractory
44:12and have had received three or more prior
44:15lines of treatment and be refractory
44:17to at least one immunomodulatory agent.
44:19Again prior exposure to CMA therapy
44:22was allowed and dexamethasone was
44:24administered at 20 to 40 milligrams.
44:26Dependent on age in combination with Mezzi,
44:30the main objectives of the study
44:32included advocacy and safety
44:33of this novel combination.
44:37So 101 patients were included in the
44:40MEZZI plus DEX cohort and they're patient
44:43and disease disease characteristics
44:45are outlined in the table on the left.
44:48Median age as expected was 67 years and
44:51these were heavily pretreated patients
44:53with a median time since initial
44:57diagnosis of myeloma of 7.44 years,
44:59a median of 6 lines of prior
45:01treatment and 100% of patients
45:03were triple class refractory.
45:05There were only approximately
45:0620% of patients with.
45:08Stage three disease although 39.6
45:11had extramedullary disease and this
45:13included in in their study soft
45:16tissue bone related plasmacytoma
45:18in in addition to true soft tissue
45:22extramedullary disease and 36.6% of
45:25patients had high risk cytogenetics
45:2829.7% of patients had received prior
45:30anti BCMH treatment mostly in the
45:33form of antibody drug conjugates.
45:35And in terms of clinical activity,
45:37as you can see on the figure
45:38here on the right,
45:39the overall response in the total
45:42population of what what's 40.6% with a
45:46high quality responses that included a
45:50stringent CR complete response and VGPR.
45:53And in those with Extramedullary
45:55disease overall response rate was still
45:57notable at 30% and patients who had
46:00received anti BCH treatment although
46:02small in in number with 30 patients.
46:05Portal had an overall response rate of of
46:0750% and while follow-up is short to date,
46:11the median progression free survival
46:13observed was 4.4 months and median
46:16duration of response was 9.2 months
46:19when patients achieved VGPR better.
46:22And Doctor Richardson presented some
46:24correlative data from this abstract as well,
46:27showing that Messi is active in patients
46:29who are either refractory to pomalidomide
46:31or POMALYST and in those receiving
46:34pomalidomide as in their last regimen.
46:36As their last regimen of treatment.
46:39At a median follow-up of 7.5 months,
46:4390.1% of patients had discontinued treatment,
46:45although the majority due
46:46to progressive myeloma.
46:485 patients were reported
46:50to have adverse events.
46:51Related events,
46:52excuse me.
46:535 patients were reported to have
46:55adverse event related deaths,
46:57including two with PJP pneumonia,
46:59an additional with pneumonia and
47:00one due to COVID-19 infection
47:02and one due to septic shock.
47:05And while a majority of patients did require
47:07dose interruptions due to adverse events.
47:09Those reductions were less
47:11common and a few patient,
47:14a few patients discontinued
47:15drug due to adverse events as is
47:17outlined here and as you can see
47:18in the tables here on the bottom,
47:20treatment emergent adverse events
47:22were primarily hematologic in
47:24nature with neutropenia being the
47:26most common although this was felt
47:28to be manageable again with those
47:30adjustments and growth factor support.
47:32Additionally infections were the
47:34most common non hematologic adverse
47:36event with infections of any grade
47:39seen in about 2/3 of patients.
47:41Other observed side effects are are
47:43listed here in the in the tables,
47:46although they were less common
47:48and less severe.
47:49So to summarize,
47:50Mazda Magnemite or Messi is an
47:52oral potent novel cell mod which in
47:55preclinical studies has a distinct
47:57profile from our immunomodulatory agents.
48:00And when combined with dexamethasone
48:03overall response rate was notable
48:05at 40.6% in the total cohort and 30% in
48:08patients with extramedullary disease,
48:10the safety profile.
48:11Is manageable with most higher grade
48:13adverse events being hematologic in
48:15nature and most commonly neutropenia
48:17which did require some dose adjustments
48:20and GCF support when when needed.
48:22Given these findings,
48:23Mezi is now being evaluated in
48:25combination with standard myeloma
48:26therapies including in phase three
48:28trials with Bortezomib and carfilzomib
48:30and this appears to be a promising
48:32agent in patients with heavily
48:35pretreated relapsed refractory myeloma
48:37including those who may be refractory
48:40to to imids including POMALYST.
48:42So I'll I will shift gears a bit
48:44now with this last abstract and
48:46discuss like Chainer ALE amyloidosis,
48:48which as you guys likely know is
48:50a rare progressive disorder where
48:52clonal plasma cells in the bone
48:54marrow produce immunoglobulin light
48:55chains that misfold and and and
48:57then form amyloid fibrils that
48:59become insoluble and deposit in
49:01extracellular tissues and organs
49:03resulting in significant dysfunction.
49:05And we have made advances in the treatment
49:07of AL amyloid with exciting data from
49:09last year's ASH on the Andromeda trial.
49:12Uh which showed improved team
49:14hematologic and organ responses with the
49:16addition of daratumumab to cyber deem.
49:18However,
49:19these available therapies target the
49:21clonal plasma cells in order to stop
49:23or halt production of light chains,
49:25new light chains but they don't
49:27address the amyloid that's already
49:29been deposited and in and organs
49:31that lead to significant morbidity.
49:33And in patients with advanced
49:34cardiac disease,
49:35high mortality with a median overall
49:37survival in patients with Mayo
49:39stage four disease of only 5.8
49:41months and the abstract.
49:42We'll discuss was presented by
49:44Doctor Morie Gertz from the Mayo
49:46Clinic on Beartown bertam amount,
49:48which is a humanized monoclonal
49:50antibody administered intravenously
49:51every 28 days and binds conserved
49:54epitopes on both Kappa and Lambda
49:56immunoglobulin light chains and that
49:59leads to neutralization of circulating
50:01light chain aggregates as well as
50:04depletes the insoluble amyloid deposited
50:06in the organ organs thought to be
50:09through phagocytosis by macrophages.
50:11And the study schema here on the
50:13top outlines the phase three vital
50:15study which is a multi center
50:17double-blind placebo-controlled
50:18trial in patients with newly
50:20diagnosed treatment naive AL amyloid.
50:22All patients enrolled had cardiac involvement
50:24and were stratified by Mayo stage,
50:26renal stage and six minute walk test.
50:29260 patients total were enrolled
50:31and randomized to receive birtamod
50:33amab in addition to standard of care
50:35or placebo with standard of care.
50:37There was an interim futility
50:40analysis back in 2018.
50:41That actually resulted in early
50:43study termination given concern that
50:45the primary endpoint which was all
50:47all cause mortality or time to all
50:49cause mortality would not be met in
50:51a in a reasonable amount of time.
50:52And so afterwards a post hoc analysis
50:56was performed on 77 patients that
50:58had Mayo Stage 4 cardiac amyloid.
51:01And this has previously been reported
51:02to show as you can see in the
51:05Kaplan Meier curve here a survival
51:07benefit with significant reduction
51:08in time to all cause mortality
51:10in this cohort. With 74% of patients
51:14in the Bertambah group being alive
51:16at month nine with only compared to
51:18only 49% in the placebo arm with the
51:21hazard ratio that you see listed here.
51:24So in this year's abstract Dr.
51:26Gerson is coauthors showed using
51:27the data from the post hoc analysis
51:30that reduction in time to all
51:32cause mortality at nine months.
51:34I'm favoring the pertama amab arm
51:36persisted in these Mayo stage four
51:38patients ever even after adjusting
51:39for a variety of demographic
51:42and disease characteristics.
51:43As you can see in the forest plots
51:46here that come from small numbers but
51:49have again impressive hazard ratios.
51:52There was also in the post tech analysis.
51:55Patients who received Birtamod had
51:57less deterioration in quality of
51:59life and improved 6 minute walk test.
52:01And so with the available data for
52:03Tim Amab has been safe and well
52:06tolerated even in these patients
52:07with advanced cardiac disease and
52:10it has this data has served as the
52:15foundation for the Affirm ALS trial
52:18and we have this trial open here
52:20at Yale as well as in a number of
52:23our our care centers in Trumbull.
52:25Saint Francis Francis and a female is
52:28looking to enroll patients with newly
52:30diagnosed treatment naive al amyloid
52:32with with Mayo stage four disease
52:35with the criteria listed here and
52:37and looking again to see if we see
52:39this this survival benefit that was
52:41demonstrated in the post hoc analysis.
52:42And patients will be randomized
52:442 to one to receive vertamae in
52:46addition to standard care.
52:47And I do think this is an incredibly
52:50important trial for a very complex
52:52very hard to treat population and I
52:54would be happy to talk with anybody.
52:56Interested who might have eligible patients
52:59or have questions about the the trial?
53:01So,
53:02so in summary,
53:02we saw many exciting abstracts at ASH
53:05looking at new myeloma target antigens
53:07from biospecific antibodies and car
53:09T as well as abstract looking at
53:11improved manufacturing and management
53:13of side effects including CRS.
53:15I I will end so that we can move to
53:18the questions and answers by just
53:20saying that although not covered today,
53:23there were up to 30 abstracts on
53:25looking at health disparities in
53:27multiple myeloma which remains really
53:29a critical unmet need and ongoing.
53:31Investigation is really imperative.
53:33The QR code I've included here links
53:35to a video by Doctor Joel McHale
53:37and the International Myeloma
53:39Foundation addressing some of these
53:42really important abstracts.
53:43So thank you again all for your time and
53:45I look forward to answering some questions.
53:57Thank you Sabrina and Nofar
53:59for those excellent reviews.
54:01We do have time for questions,
54:03so I would encourage everyone
54:04to please place your questions,
54:06if you have any in the Q&amp;A portion
54:08that can be found below in the screen.
54:11As we wait for questions,
54:13I will start by asking a few.
54:15Maybe we'll start with Elon and Natalia.
54:18We heard a lot about side effects
54:20from the bispecific T cell engagers,
54:23the cartes and even the cell mods
54:25in relationship to infections.
54:27So how would you propose we manage
54:30that risk to help keep our patients
54:32safe as these therapies move forward?
54:42I mean I guess I can start.
54:43We know that there's a risk of a
54:46hypogammaglobulinemia with this patient.
54:47So I think that keeping a
54:49close signing IG level,
54:50making sure that it's you know
54:52consistently at least 400 or
54:54even 500 compliance with you know
54:58antiviral anti microbial prophylaxis
55:01and I think also just educating
55:05you know the various colleagues.
55:06And members of the community
55:09and the oncology team about the,
55:11you know, the risk for infection
55:13complications in these novel agents.
55:21I think they tell you you're a mute.
55:32Help, you're still muted.
55:47And. Natalia, you were still on mute.
55:51So unfortunately we're not been
55:52able to hear what you have said.
55:56And we can move
55:57on. We did have one question from the
56:01audience which is asking if calcium
56:04deficiency is seen in multiple myeloma.
56:09Umm. I don't know if anyone wants
56:13to take the question regarding
56:15calcium and multiple myeloma.
56:20I mean I think that usually with
56:25myeloma we see
56:26hypercalcemia and I think if it's poorly
56:28controlled we can see hypercalcemia. You
56:31know the bisphosphonates and the bone
56:33modifying agents can cause hypocalcemia,
56:35but but typically we would see hypercalcemia.
56:40Thank you, Elon.
56:43So I may ask a question that's a
56:44little bit unfair to the group.
56:46And we can have each of the panelists
56:48answer with all of these new targets
56:50and they relapsed refractory setting.
56:52How do you propose that we sequence
56:54them and most of these studies have
56:57been done after potentially BCM a.
57:00But again, I would be interested
57:01in everyone's thoughts as
57:03far as they're optimal.
57:04And maybe we can start with Elon and
57:06Natalia and then go to no farms, Sabrina.
57:15Another Natalia sorted out her
57:16mute option, but. I guess not.
57:21So I think obviously that's an
57:24ongoing area of of evaluation and
57:26research with these novel agents.
57:27We are looking at them in
57:29earlier lines of therapy,
57:30you know in clinical trials,
57:32cartoon etcetera.
57:34I think that it depends
57:35on a couple of factors.
57:36You know how did the patients
57:38respond to prior treatments,
57:39what prior treatments have they had.
57:42You know, high risk,
57:43standard risk,
57:45I think that the
57:47data is pretty encouraging and
57:48promising for biospecifics and cartes.
57:50So I think that. You know,
57:53if they're candidates for that,
57:54we should try to push for that.
57:57But a lot, a lot will be. Coming
58:00and we'll have a lot
58:00more information in the upcoming,
58:02you know, months and annual meetings.
58:06Thank you, Ellen, and no far Sabrina.
58:09Yeah. So I think at the end of the
58:12day the answer is we don't know as
58:14you know they're they're all quite
58:16effective and we don't really know which
58:19subtypes of patients would do better.
58:21But we do have some information that
58:24patients who have gained 1Q have
58:26high expressions of the FC RH 5.
58:28So perhaps you know being a little
58:31bit more specific in terms of patient
58:34selection to some of these again more
58:37studies really need to be done in subgroup.
58:39Populations.
58:40I think it is encouraging that the
58:43infection risk is is lower with tell
58:47kalamas supposed to Tequesta amab.
58:49So for patients where you're more worried
58:52about that maybe in a post transplant
58:54setting where you know there's other
58:56additives infection complications.
58:58So I think more to come we don't know.
59:05You know, I would completely,
59:06completely agree.
59:07You know, I think there's a question
59:09of not only how to sequence
59:10our car T and by specifics,
59:12but now sequence in terms of targets.
59:14So, you know, I agree with
59:16Doctor Barr that I think.
59:17You know thinking about choosing a
59:19carte or by specific I think depends
59:21a little bit on the patient's disease
59:23at that time and the time that it may
59:25require for them to get the the treatment.
59:28I think you know it's exciting
59:30now to have different targets that
59:32do have a unique safety profile.
59:33You know and I think a lot of these
59:35newer targets are showing response in
59:37patients who had prior BCM a cell therapy.
59:39So you know I think we have the most
59:41data obviously from our CMA products,
59:43but I think there are going to be patient
59:45populations where these new targets I
59:46think are going to be important and perhaps.
59:48You know,
59:49our first choice moving forward.
59:51Wonderful.
59:52Thank you all.
59:52Will you have another question from
59:54the audience with the results of
59:56the I FM 2009 and determination,
59:59how do you see MRD driving transplant
01:00:02and sequencing of therapies in general?
01:00:05So I don't know if Natalia
01:00:07or Nofar you have a response?
01:00:09Yeah, I can talk about this.
01:00:12So I think MRD is going to be
01:00:15driving how we treat patients.
01:00:18I think what we see is in
01:00:20both of those studies,
01:00:22patients who are MRD negative
01:00:24just do better in the IM 2009.
01:00:2830% of patients who had VRD in
01:00:31transplant and one year only one
01:00:34year maintenance still remain
01:00:36in remission 8 years after. So.
01:00:39So clearly we are over treating
01:00:40some patients and we need to figure
01:00:43out who those patients are and I
01:00:45think even with transplant, right.
01:00:47So if we achieve MRD negativity
01:00:50with quadruplets,
01:00:51I think we need to assess
01:00:53this transplant better.
01:00:54What is the marginal benefit of
01:00:56transferring those patients?
01:00:56These studies are underway.
01:00:58We will find out,
01:00:59but it will take many years.
01:01:01Right now I, you know I do discuss costs,
01:01:04you know risk benefit with patients
01:01:06when I talk about transplant
01:01:08especially in standard risk MRD
01:01:10negative patients as patients who
01:01:12are considered that presumably
01:01:14transplant and relying.
01:01:19And I'm sorry, I had difficulties
01:01:20with odd earlier, but I
01:01:22I do agree with what's been said.
01:01:24MRD does have a value and its primary
01:01:27significances in predicting progression
01:01:29free survival and overall survival.
01:01:31So we do use it in practice
01:01:32as a prognostic tool and with
01:01:34enough data with more mature data, we,
01:01:37we, we, we will most likely in the
01:01:40future use the data to discontinue
01:01:43certain patients with low risk cytogenetics
01:01:45and durable sustained MRD negative state.
01:01:50Hey, wonderful. Well,
01:01:51we are after time as it is one of three.
01:01:56So I will like to thank all of our
01:01:59panelists for their presentations and input
01:02:01today and thank you all for joining us.
01:02:04Please tune in next Friday
01:02:06for the next in the series.
01:02:09Have a good afternoon everyone.
01:02:11Thank you. 581.