Yale ASH 2022 Highlights: Multiple Myeloma

Transcript

• 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&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&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.