Yale ASH 2021 Highlights: Multiple Myeloma

February 28, 2022

February 25, 2022

Hosted by: Natalia Neparidze, MD

Presentations by: Drs. Sabrina Browning, Elan Gorshein, Terri Parker, and Noffar Bar

Information

ID: 7486
To Cite: DCA Citation Guide

Download Transcript

00:00For joining this is Yale.
00:03Highlights of ASH 2021 presented by
00:05Yale Hematology and today's seminar
00:07is presented by the program for
00:10multiple myeloma and Gammopathy's,
00:11and we have really fantastic set
00:13of speaker presentations. Today.
00:15Our program presented by Doctor Gore,
00:18Shine our expert clinical expert
00:20in hematology doctor Terry Parker,
00:22who's the clinical leader of our
00:25program with extensive experience
00:26and expertise in clinical trials.
00:28Doctor no far bar.
00:29Who's our expert in cellular?
00:31Therapies and transplantation in
00:33myeloma and doctor Sabrina Browning,
00:35who has expertise in preclinical
00:37studies and alloyed doses.
00:39And I just like to share this
00:42structure of today's seminar.
00:43First, Doctor Gore Shine will present
00:46updates in smoldering multiple
00:47myeloma and newly diagnosed myeloma.
00:50This will be followed by Doctor
00:52Terry Parker with updates in
00:54relapse and refractory myeloma.
00:55Later,
00:56Doctor Barr will present updates on
00:58cellular therapies in myeloma and.
01:01Some followed by Doctor Browning,
01:03who will present updates on
01:05basic signs in myeloma and some
01:07clinical updates on AL Amyloidosis,
01:09and we will devote.
01:10Devote a few minutes in the end for the
01:13question and answer and discussion session.
01:15So again,
01:16welcome everyone.
01:17Thank you all for joining
01:19and Doctor Gore Shine.
01:21Please you may proceed.
01:55We can see our slides if you just can
01:58project in the slide view. On the bottom
02:02there you go, got it OK, perfect.
02:04Can you hear me now? Yes, OK alright,
02:08so thank you Talia hello everyone.
02:10So as Natalia mentioned, I'm going
02:13to rehash ash from a perspective of.
02:17Updates on smaller multiple myeloma
02:18and newly diagnosed multiple myeloma.
02:24Here are my disclosures.
02:30Alright, so multiple myeloma is
02:32consistently preceded by precursor
02:34states of monoclonal gammopathy
02:36of undetermined significance
02:38and smoldering multiple myeloma.
02:40And these essentially represent a continuum
02:43of progression of the tumor burden,
02:46with clonal evolution and heterogeneity.
02:50Now we understand the heterogeneity
02:53of smoldering multiple myeloma.
02:55In clinical practice,
02:56we often rely and apply on the 20 to 20 rule,
03:01which is 20% bone marrow plasma cells,
03:04a monoclonal protein of greater than
03:06or equal to 2 grams per deciliter,
03:08and a free light chain ratio of greater
03:10than 20 patients with two or more of
03:13these risk factors or components are
03:16essentially considered high risk,
03:18and this subset of patient population.
03:21Has been evaluated for early
03:24therapeutic intervention.
03:26Now, with respect to early
03:28therapeutic intervention,
03:29we know that Lenalidomide can be
03:34beneficial for patients with high risk,
03:36smoldering myeloma.
03:37So the rationale here is that
03:41triplet therapy which we use for
03:44multiple myeloma may yield a deeper
03:46responses and improved outcomes
03:48for the smoldering population,
03:51and I'm just going to highlight
03:53one study on the combination of
03:55X as a proteosome inhibitor.
03:57Lenalidomide and immunomodulator.
03:59Agent and dexamethasone in high
04:01risk smoldering multiple myeloma.
04:05Now, in the interest of time,
04:06I'm going to essentially only
04:09discuss the conclusion slide,
04:11but this triple therapy regimen
04:14in high risk smoldering disease,
04:17and all oral regimen demonstrated
04:19a very high overall response rate
04:21of more than 90% with deep response
04:23rates of greater than I'm sorry,
04:25deep remission rates of greater than
04:2840% now there were notable Grade
04:313 toxicities for these patients,
04:33but importantly.
04:34No patients discontinued therapy
04:37due to these adverse events,
04:40so so this is encouraging data.
04:43You know,
04:44suggesting they potentially more
04:46biologically sensitive phase of
04:48the disease to treatment and
04:50really highlighting an ongoing
04:51area of research in the smoldering
04:54multiple myeloma disease.
04:58Now a couple words on multiple myeloma,
05:02so we're going to transition out to multiple
05:05myeloma symptomatic multiple myeloma.
05:07We're all familiar with VRD
05:09as our backbone to therapy.
05:11Bortezomib, Lenalidomide,
05:12and dexamethasone proteasome
05:14inhibitor imid, and steroid.
05:16This is a very efficacious treatment regimen.
05:20Very durable,
05:21has a well established track record.
05:24Historically,
05:24neurotoxicity was a major concern here.
05:27But this has become significantly
05:29significantly less of an issue
05:32with the once weekly dosing,
05:33as opposed to twice weekly dosing
05:35as well as with the subcutaneous
05:38version as opposed to the Ivy.
05:40So VRD is are suitable backbone and
05:42that has been sort of the impetus for
05:45developing quadruplet based therapies.
05:47We know from some data that quadruplet
05:50regimens can be very active in the upfront
05:54treatment naive patient population,
05:57but there are.
05:58There are unanswered questions
05:59and we need more information.
06:01How does this regimen impact the
06:04high risk patient population?
06:06What about those that are stem cell
06:08transplant eligible versus ineligible?
06:10And clearly we need more long term
06:13results that we currently have for VRD,
06:16but you know it is not quite
06:18not quite there yet.
06:19For the quadruple therapy.
06:22So moving onto the updated Griffin
06:25analysis so this was published in Ash.
06:28Looking at the 24 month
06:30follow follow up for Gray.
06:47Just a brief background on this,
06:49so induction therapy followed by
06:52high dose therapy with autologous
06:55stem cell transplant and lend.
06:57My maintenance therapy is a standard of
07:00care regiment for newly diagnosed patients.
07:03The phase two Griffin study that was
07:06initially presented well over a year
07:09ago evaluated the efficacy and safety
07:12of Dara plus RVD versus RVD induction,
07:15followed by AUTOTRANSPLANT
07:17for newly diagnosed.
07:18Transplant eligible patients.
07:19The primary analysis after almost
07:2214 months of therapy showed that
07:24the quadruplet therapy significantly
07:26improved the stringent CR rates versus
07:29the triplet therapy by the end of
07:32the post auto consolidation phase
07:34with response rates of 42 versus 32%.
07:38We also saw that this quadruplet
07:40treatment deepened their responses,
07:43improved MRD negativity rates after
07:45one year of maintenance therapy when.
07:48The standard of care lanolin amide
07:50when daratumumab was added to
07:52the standard of care.
07:54Importantly there were no new safety
07:56concerns and daratumumab did not
07:59impact the ability to mobilize
08:03themselves and patients who received
08:05their induction were actually able to
08:07successfully complete the transplant.
08:09So here in Asheville they reported
08:12the updated efficacy and safety
08:14from Griffin after 24 months or
08:16two years of maintenance therapy.
08:19An overview of the treatment design,
08:21so again patients were transplant eligible,
08:24newly diagnosed disease.
08:26They received 4 induction cycles of
08:30they were randomized to either the
08:33quadruple it or the triplet with RV.
08:35They subsequently underwent stem
08:37cell transplant,
08:38followed by two cycles of consolidation
08:41treatment and then patients under work
08:44continue to darreff maintenance or lanolin.
08:48Maintenance for up to two years.
08:50The primary endpoint here was a stringent CR.
08:54Secondary endpoints included various
08:56response rates, MRD, negativity,
08:58progression, free survival,
09:00and overall survival on the bottom
09:02half of the slide.
09:03You note that the patient
09:05characteristics were were fairly
09:06well balanced between both groups.
09:12Now highlighted here is what's
09:13important to note here is that these
09:16responses deepened overtime after
09:18two years of maintenance therapy.
09:21For the DRVD, the complete response
09:23rates were 82% versus 61% for the
09:25triplet therapy and on the right
09:28here for the subgroup analysis,
09:31you can appreciate that the that these
09:35improved durable responses were seen
09:38irrespective of the various subgroups.
09:41Described.
09:43In the lower half of the slide,
09:45we note that there were more
09:47significant MRD negativity rates
09:49with increased treatment as well.
09:51Again for the quadruplet therapy,
09:5364% relative to 30% in the triplet
09:56therapy and when we look at
09:58the various subgroup analysis,
10:00this finding was also observed
10:03for patients over the age of 65.
10:05Advanced ISS High Risk center
10:09genetic analysis and.
10:11And then revised higher,
10:12so genetic risk profile.
10:16The median progression free survival
10:18was not reached in either arm,
10:21although what's important to note
10:23here is that we do see a separation
10:25of the curves beginning one
10:27year after maintenance therapy,
10:29so this suggests a benefit for the
10:32Daerah 2 Mettler Toledo my maintenance
10:35arm and although it was not powered
10:37again not powered for progression free
10:40survival in the subgroup analysis,
10:42but you can also note here a generally
10:46a positive trend for darylynn.
10:48Maintenance versus Lenalidomide
10:50monotherapy as maintenance.
10:55So the summarize these conclusions,
10:57so the quadruple therapy as induction post,
11:00auto consolidation and barev maintenance
11:02is an effective regimen for newly
11:05diagnosed transplant eligible patients.
11:07The MRD negativity rates were
11:09highest for the quadruplet,
11:11followed by darreff maintenance.
11:13These patients had deeper
11:15levels of MRD negativity,
11:17greater deepening of the negativity
11:19over time as we saw approaching
11:21the two year maintenance phase.
11:23Similarly, their rates of sustained.
11:25MRMR D negativity and the subset
11:30analysis also trended favorably in
11:33for the high risk population as well.
11:37In terms of the progression free survival.
11:40Again, also this two year maintenance
11:43was well tolerated for those who
11:46received the daratumumab combination.
11:50So moving on to the Maia study.
11:52Now this these results were
11:54actually originally published
11:55last summer at the FAP meeting,
11:57but I'm gonna review it here also,
12:00within the context of this
12:03presentation by Doctor Usmania at MSK.
12:07Who essentially wanted to determine
12:09the effects of the Maya on patients
12:13with impaired renal function,
12:14which is relevant here?
12:16Because really up to up to
12:1850% of patients can have some
12:21baseline renal compromise that can
12:23impact our choice of treatment.
12:25So the the Maya the mitral.
12:27As you may know,
12:28evaluated the addition of Dara to Rev
12:31Dex and transplant ineligible patients.
12:33Newly diagnosed median follow-up
12:35of four and a half years.
12:38The Dara Rev Dex prolonged PFS
12:41and OS versus Rev Dex alone,
12:44and this was despite the fact that
12:46almost half the patients in the Rev Dex
12:49population received subsequent therapy,
12:52including a dare to Matt based regimen.
12:56So so important for for
12:59this patient population.
13:01When we look at the study design,
13:03Somaiya trial again included
13:05transplant ineligible,
13:06newly diagnosed multiple myeloma patients,
13:09randomized to Dara Rev Dex or Rev Dex
13:13and important here to note is that
13:17this treatment was continued until.
13:21I told disease progression.
13:23The primary endpoint for this study
13:25was the progression free survival.
13:27Various secondary endpoints,
13:28again looking at the the response rates,
13:31MRD negativity, overall survival.
13:36And here we note the updated results.
13:39So with respect to the
13:41updated five year analysis,
13:43the progression free survival was not
13:47reached for the Dara Rev Dex combination
13:51and was 30-4 months for the Rev decks.
13:57Cohort in terms of the overall
13:59survival benefit,
14:00we do really important here to
14:02note is that there is an overall
14:05survival benefit for Dara Rev Dex,
14:08which is documented as a 32% reduction.
14:11The risk of death relative to Rev Dex alone.
14:17And if you see here on the
14:19right side of the screen,
14:21regardless of whether patients received a
14:24Lenalidomide dose of 25 or a lower dose,
14:28there was a progression free survival
14:30benefit and an overall survival
14:32benefit for Darryl Rev Dex relative
14:35to Rev Dex and the figure on the left
14:39here really just highlights that this
14:41progression free survival benefit
14:43that we're seeing in Maya is is quite
14:46remarkable and really superior to.
14:48Some of the other recent phase
14:50three trials published in transplant
14:52ineligible patients.
14:56To summarize, so after five years of
14:58follow up the progression free and
15:00overall survival benefit for Darrell
15:02Rev Dex versus Rev Dex was observed
15:05and importantly relevant here.
15:07This was also observed in patients with
15:10compromised renal function at baseline,
15:12irrespective of the starting dose
15:14of Lenalidomide was a little bit
15:17less pronounced than those that had
15:19had a lower dose lower than 25.
15:22But really, highlighting the impressive,
15:26you know, practice changing.
15:27Results of Maya for transplant
15:29and eligible patients.
15:33Any interest of time,
15:35I'm just going to briefly review
15:37another quadruplet based treatment
15:39regimen presented at ASH just back
15:41in December involving ISATUXIMAB,
15:43which is another CD 38 monoclonal
15:47antibody and hear the IT evolved
15:50isatuximab with RVD or RVD
15:53relative to RVD in transplant
15:55eligible patients and this was the
15:59phase three GMMG HD seven study.
16:05And this phase three trial demonstrated
16:08a improvement or superiority in MRD
16:12negativity rates after induction with the
16:15addition of the aesthetics mab antibody.
16:182 RVD with the MRD response rate of
16:2150 point 1% relative to 35% and on the
16:24right side of the screen. You can also.
16:41Is the highest described to date in a
16:44randomized phase three trial at 50.1%?
16:47Importantly, the addition of Isatuximab
16:50had no significant impact on the
16:53safety profile or dose intensity,
16:55and there are ongoing studies
16:57evaluating this combination of
16:59treatment for transplant eligible
17:01and transplant ineligible patients.
17:06And finally, I think it's also
17:08important to discuss the master
17:11trial which involved daratumumab,
17:13carfilzomib, Lenalidomide,
17:14and dexamethasone togus
17:17transplant and MRD response.
17:19Adaptive consolidation.
17:23We know that there are two have
17:25improves outcomes when combined
17:26with a proteasome inhibitor and
17:29or an immunomodulator agents.
17:30We also know that MRD negativity
17:34has prognostic implications.
17:35Now, this study incorporated a
17:38response adopted therapy to achieve
17:41MRD negativity and really aimed
17:44to evaluate the Natural History of
17:46patients with sustained MRD negativity.
17:52Now, the treatment included Dara
17:54KRD and carfilzomib was dosed at
17:5656 milligrams per meter squared.
17:58Weekly patients received 4 induction cycles
18:01of Derek KRD followed by a colleague.
18:04A stem cell transplant.
18:06And up to 8 cycles of Dara KRD MRD
18:10was assessed at each of these blocks.
18:13Now, patients who had two consecutive MRD
18:17negativity findings were transitioned
18:20to this phase called MRD Shore,
18:25which was a treatment free interval.
18:29Observation and surveillance.
18:32Those patients who did not achieve MRD
18:35shirt continued to receive Lenalidomide
18:37maintenance as their standard of care.
18:40And here are the results.
18:42You can appreciate that.
18:43Overall, the majority of patients at
18:4680% achieved MRD negativity and the
18:50depth of response and MRD negativity
18:54improved at each therapy phase.
18:57As you can appreciate with these
19:00blocks and became compareable
19:02among the groups with no high risk,
19:05cytogenetic amalies 1 high risk
19:07genetic anality or two or more
19:09high risk genetic abnormalities.
19:11When we assess when they assessed MRD
19:14to at level of 1 * 10 to the minus,
19:19666% of patients achieved MRD negativity.
19:22Their proportion here in the various
19:26cytogenetic abnormality populations was
19:28somewhat lower and it did take longer
19:32to achieve for those with ultra high risk.
19:34As you can see here in the two
19:37plus high risk surgical abilities.
19:41In terms of MRD shore, so about 71 or
19:4472% achieve of patients achieve them.
19:46Are these sure and this was
19:49relatively similar across the
19:50three cytogenetic risk groups.
19:52The median follow up time here was
19:55about 14 months and the risk of MRD,
19:58resurgence or clinical progression was
20:0240 and 27% among the standard high risk
20:06and ultra high risk patient groups,
20:10respectively. And importantly,
20:13none of the patients who entered this
20:15phase of MRD sure ultimately died
20:17from multiple myeloma progression.
20:21So, in conclusion,
20:22next generation sequencing,
20:23MRD response,
20:24adaptive therapy is feasible in the
20:26overwhelming majority of patients in
20:28multicenter settings with 70 to 72% of
20:31patients or she reaching MRD shore.
20:33Patients who have standard and high risk,
20:36newly diagnosed myeloma had similar
20:38depth of response and low risk of MRD,
20:42resurgence or clinical progression
20:43when they were treated with
20:45the master trial quadruplets.
20:47Stem cell transplant and MRD,
20:49adaptive treatment cessation and
20:51quadruple therapy achievement of
20:53confirmed MRD negative responses.
20:56Enables us to explore stopping treatment
20:58as an alternative to continuous MRD
21:01therapy to continuous indefinite.
21:04Treatment importantly,
21:06here again, novel therapy,
21:07novel,
21:08effective consolidation treatments should
21:10be explored to improve outcomes and
21:13clear MRD to a negative state in these
21:16ultra high risk patient population.
21:21Thank you and I will welcome questions
21:23at the end of this presentation.
21:30And I'll transfer it over to Terry.
21:39Thank you, I will be focusing on
21:41updates in relapsed refractory myeloma.
21:47I have no disclosures and I will be
21:50specifically focusing on treatment
21:52of triple class refractory patients.
21:54This is defined as those patients that
21:56are refractory to anime, no modulatory,
21:58a Jack, a proteasome inhibitor,
22:00and STD 38 monoclonal antibody currently
22:03approved agents for this classification
22:06includes standard chemotherapeutic regimens,
22:08selinexor combinations,
22:09fanatical axe for patients who
22:12harbor a translocation.
22:131114 and two BCM a targeted therapies.
22:17Mentioned at Matthew Gelatin and antibody
22:19drug conjugate and I do sell a car T therapy.
22:22Fortunately for our patients,
22:23there are many agents
22:25currently in clinical trial,
22:26many of which were updated at
22:28this year's ASH.
22:29These include BCM,
22:30a targeted therapies in the form of PCM a
22:33CD3 bispecific T cell engager's non BCMA,
22:36targeted therapies and Carty or cellular
22:39therapies which will be discussed by
22:41doctor Bark later in the session.
22:44First, we'll start with a presentation
22:46by Doctor Moreau entitled updated
22:48results from Majestic One at phase one,
22:50two study of Palestine Map Ciclista Mob
22:52is at BCM a CD3 bispecific antibody here.
22:55Phase one and two data from the
22:581.5 MB perchik dose was presented.
23:02He eligibility criteria included that
23:04patient be triple class exposed have
23:06three or more lines of prior therapy and,
23:09importantly,
23:09no prior PC may therapy patients
23:13receive stubborn.
23:14Testing at 0.06 and 0.3 makes per
23:17kig subcutaneously followed by weekly
23:20treatment of 1.5 mix perchik subcutaneously.
23:23The primary endpoint for the trial was
23:26overall response rates 40 patients
23:28were accrued in phase one on 125.
23:31In phase two.
23:32The median treatment duration was 5.9 months.
23:3538 patients had high rossetto genetics,
23:3820 with ISS three disease,
23:41and this is a heavily pretreated
23:43patient population.
23:43With five medium prior lines of therapy,
23:46again,
23:47165 patients were triple class exposed,
23:50with 128 being considered triple class
23:53refractory and 50 penta drug refractory.
23:57Median follow-up with 7.8 months
23:59and overall response rate was 62%,
24:02with 58% achieving Avicii,
24:04PR or better and 28.7%.
24:07Achieving the CR, or better importantly,
24:09the overall response rate of 62%
24:12was consistent across clinically
24:14relevant subgroups,
24:15including those patients that had
24:17high risk cytogenetics and those
24:19that were penta drug refractory.
24:21The median time to first response
24:23was 1.2 months,
24:24with a progression free survival
24:26rate at nine months of 58.
24:28Lakeside percent in patients who
24:30did achieve a CR better MRD.
24:33Negativity rate was 41.9%.
24:37I'm looking at the safety data.
24:38The most common hematologic treatment.
24:40Emergent adverse event was neutropenia
24:43occurring in 65.5% of patients with the
24:46most common non unity logic treatment.
24:48Emergent Adverse bank was cytokine
24:50release syndrome occurring in 71.5% of
24:53patients and taking a closer look at CRS.
24:55The meeting time to onset was two
24:58days with the meeting duration of
25:00today's 60 patients did require
25:02supportive care with tocilizumab.
25:06The conclusions from this presentation
25:08was that the overall response rate with
25:10tip list amount was 62% with responses
25:13that were durable and deepened overtime.
25:16Treatment was well tolerated
25:17with no dose reductions.
25:19The most common adverse events again
25:22were CRS and hematological events.
25:24The CRS for all low grade and 97%
25:27occurred during the step of dosing
25:29or cycle one of treatment and there
25:31was only one grade three event which
25:33resolved I can events were rare.
25:36If they occurred,
25:37were all grade one and two and resolved,
25:40moving on to another PC MA targeted fights.
25:43And doctors and represented early,
25:46deep and durable.
25:47Response to this with low rates
25:48of cytokine release syndrome.
25:50With Regina on 5458.
25:52Regenerx on 5458 again as ABC made.
25:55CD3 bispecific antibody.
25:56This is a phase one,
25:58two first in human study with key
26:01eligibility criteria including three
26:02or more lines of prior therapy,
26:04and these patients had to be
26:06triple class refractory.
26:07Part One was a dose escalation
26:10utilizing a modified 4 + 3 design with
26:12dose ranges from 3 to 800 milligrams.
26:15Part 2 will be adjust expansion at
26:17the recommended phase two dose step
26:19up dosing was utilized for week one
26:21and two followed by weekly dosing and
26:24then every other week dosing after 16 weeks.
26:26Primary endpoints included.
26:28Safety,
26:28tolerability and to determine the
26:31recommended phase two dose data for 73
26:34patients in phase one were presented.
26:36The median number of prior lens
26:38was five and 38% of patients
26:40were pentag wreck refractory.
26:42And looking at the safety data,
26:44the most common hematologic treatment,
26:46emergent adverse event was
26:48anemia seen in 32% of patients,
26:50followed by lymphopenia and neutropenia.
26:53The most common non hematological treatment
26:55of urgent adverse event was fatigue.
26:57Interestingly,
26:58cytokine release syndrome was
27:00only seen in 38% of patients.
27:02This was question in the presentation
27:04I ash and there was not a good reason
27:07available as to why the rates of
27:09serous were lower here compared with
27:11other bispecific T cell engagers.
27:13It was postulated that it may have
27:16to do with the step up dosing
27:19and or premedications.
27:20And looking at the efficacy,
27:22the overall response rates.
27:24Was 51%.
27:25This increased to 75% when you look
27:30at doses of 200 to 800 milligrams
27:33with a VGPR better at 58.5%.
27:35The mean time to response was
27:37less than one month,
27:38with 70% of responses occurring
27:40within the first two months.
27:42The duration of Response was not reached,
27:44and in patients who achieved a CR or
27:47stringent CR who had available data for Dove,
27:4910 patients were MRD negative
27:51at 10 to the minus 5.
27:59So in conclusion, the author showed
28:02that regenerate in 5458 yielded early,
28:04deepened Drabble responses as seen
28:06as an overall response rate is 75%.
28:09Fifty 8% of cheated BGR are better,
28:12again at the higher doses
28:14of 200 to 800 milligrams.
28:1686% of responders achieved VGPR
28:18better with a C or better rate of 43%.
28:21The probability of responders being invented
28:23free at 8 months was reported as 90.
28:2622% they showed an acceptable and
28:28manageable safety profile as the maximum
28:31tolerated dose was not reached with CRS
28:33being reported in only 38% of patients,
28:36the majority events were grade
28:38one occurred within the first two
28:40weeks and resolved within one day.
28:42The phase two portion of the
28:45study is currently recruiting.
28:46And moving away from a BCM,
28:48a target doctor,
28:49Krishnan presented updated Phase
28:51one results from monumental one at
28:53first in human study of Calcutta
28:55Mad so till catnip is a G protein
28:58coupled receptor family.
28:59See Group 5D Member D as also
29:02known as GPRC 5D CD.
29:043 bispecific antibody she presented updated
29:06data at the first recommended phase.
29:09Two dose and initial results for patients
29:11treated as second recommended phase.
29:13Two dose of 800 micrograms
29:15per kilogram Q 2 weeks.
29:17Patients had to be relapsed
29:19refractory or intolerant to all
29:20established my limit therapies and
29:23have measurable disease previously.
29:24A recommended phase.
29:25Two dose of 405 micrograms per kilogram
29:29weekly subcutaneously was identified.
29:31Step up testing was utilized and
29:33premedication was given before all step up,
29:35dusting and the first full dose.
29:37The primary end point was to
29:39identify the recommended phase.
29:40Two dose is 30 patients received
29:42weekly dosing and 25 at the key.
29:44Two weekly schedule.
29:45Three patients in.
29:47Each cohort had high risk genetics.
29:49The meeting number of pirate
29:51therapies was six and five,
29:52and eight and four patients,
29:54respectively,
29:54had prior be CMA directed therapy.
29:58And looking at the hematological
30:00treatment emergent adverse events,
30:01the most common was neutropenia and
30:0467 and 44% of patients followed
30:07by anemia and lymphopenia.
30:09The most common nonhematologic treatment
30:11emergent adverse event was cytokine
30:14release syndrome seen in 77 and 72%.
30:16It should be noted that 75% of patients did
30:20have skin and or nail related findings.
30:23In the study,
30:24the most common being skin
30:26exfoliation in 37 and 36% of patients.
30:29And taking a closer look at the CRS again,
30:32it was 77 and 72%.
30:34The median onset was two days,
30:36with the median duration of two days
30:4063.3% and 60% of patients in the
30:42two cohorts did require Tuscaloosa
30:45Mab for supportive care.
30:47And looking at overall response
30:49data at the median follow-up was
30:50nine and 4.8 months.
30:52They shouldn't overall response rate of
30:5470% and 67.7% for the Q2 week dosing.
30:59With Fiji, Fiji PR rates of 53.3 and 52.4.
31:03The trial also showed that the overall
31:05response rate held in patients who
31:08were triple class refractory at 65.2
31:10and 66.7% and in patients who are
31:14penta directory factory at 83.3%.
31:16Although the numbers are low.
31:18Five out of 6 patients.
31:20The median time to response was
31:22zero point 9 and 1.2 months,
31:24and the median duration of
31:25response was not reached.
31:27So in conclusion,
31:28the until catnip 800 microgram per KQ,
31:31two week dosing appeared to have
31:33comparable efficacy and safety
31:34compared to the weekly dosing
31:36at 405 micrograms per kilogram.
31:38No new safety signals were reported.
31:41Overall response rates range from
31:4367 to 70% across triple class and
31:45pencil drug refractory patients
31:47and a phase two expansion study
31:49of both of these recommended.
31:50Ways to Jesse is ongoing.
31:53And moving away from the bispecific
31:56antibodies and a presentation
31:58was done on loaded,
32:00loaded excuse me alpha which is immuno
32:04cytokine shows clinical activity.
32:06Updated results from my first
32:07in human phase one study.
32:09So Mataka Alpha is a first in
32:11class in unison in you know
32:13cytokine designed to deliver
32:15attenuated interferon alpha to CD.
32:1738 positive cells patients were
32:18eligible if they had three or
32:20more prior lines of therapy were
32:22refractory or intolerant to at least.
32:24One P&M and and could have prior
32:28daratumumab exposure within
32:29a washout period of 90 days.
32:31For patients who had received
32:32more than five months of therapy
32:34in the escalation portion,
32:35the primary ejective was determine the
32:38maximum tolerated dose and the dose
32:41escalation phase at 3 + 3 design was used.
32:43Looking at four different
32:44schedules in the expansion phase,
32:46they looked at a dose of 0.4 and
32:48makes per cake every three weeks,
32:50with or without dexamethasone.
32:51Data was presented in 29 patients,
32:547 of 20.
32:55Five patients were that had cytogenetic
32:57data were considered to be high risk.
33:00The meeting number of prior lines with
33:03therapy was 728 patients had prior
33:05CD 38 monoclonal antibody treatment.
33:0726 of those patients were considered
33:10to be monoclonal antibody refractory
33:12and 15 patients had prior anti
33:14PC and major active therapy.
33:17The maximum tolerated dose was
33:18exceeded at six weeks per kid Q4
33:21week dosing due to disciplining
33:22toxicities of a Grade 3 infusion
33:24reaction and prolonged grade.
33:264 thrombocytopenia and neutropenia.
33:29As a 1.5 mix per KQ,
33:31four week dosing,
33:31one patient did have a great
33:33treat bleeding event but was able
33:35to remain on treatment and three
33:37patients had grade 3 infections.
33:39The most commonly seen treatment
33:40emergent adverse events at the
33:421.5 MB per kid Q4 week dosing,
33:44where hematologic with thrombocytopenia
33:47and current 76% of patients and
33:49neutropenia and 69% all grades.
33:51Infusion related reactions
33:53did occur in 31% of patients.
33:55Most of these were grade one and two.
33:58The median follow-up was 4.2 months and
34:01the overall response rate was 38% of note.
34:04The overall response rate held
34:06at 38% in patients who were CD
34:0938 monoclonal antibody factory.
34:11The median time to response was one month.
34:13In those patients who achieved a PR
34:15or better with a median duration
34:17of response not being reached,
34:18the median progression free
34:20survival was 5.7 months.
34:23So in conclusion,
34:24Modaco Alpha showed promising
34:26single agent activity
34:27and patients who were heavily pretreated,
34:30including patients who
34:31were refractory toasty.
34:3338 monoclonal antibody had
34:35a manageable safety profile.
34:36Q For Weeks was identified as the
34:39optimal dosing interval and further
34:41enrollment identified the maximum
34:43tolerated dose as three mics per keg.
34:45A randomized phase two trial is
34:47planned in order to determine
34:49the optimal single agent dosing.
34:52Lastly, Dr Lonial presented herbicide
34:54in combination with dexamethasone in
34:57patients with relapsed refractory myeloma.
34:59Results from the district expansion of the
35:03CC-220MM-001 trial.
35:04Roberta Mine is a novel
35:06cereblon E3 leg is modulator,
35:08also known as the cell Mod.
35:10This was a phase one two study that,
35:11evaluated at EBR with different
35:13combinations of treatment.
35:15Previously, the recommended phase two dose
35:17was identified as 1.6 milligrams days,
35:19one through 21 every 28 days.
35:21When given in combination
35:23with dexamethasone here,
35:24she reported safety and efficacy
35:26and the dose expansion cohorts.
35:28Cohort D, which is Eber plus tax
35:30and cohort I which was Eber plus
35:32tax in patients who had prior BC
35:35made treatments for both cohorts.
35:36Patients had to have three or more lines
35:39of prior therapy and again for cohort I.
35:41All patients had treatment with her
35:44prior PC may targeted Agent 107.
35:46In patients were treated in cohort D
35:49and 26 in poker I 32 patients and six.
35:52Patients respectively,
35:53had high risk cytogenetics in
35:55the two cohorts.
35:56The median number of pirate therapies
35:57was six and seven in Cohort I6.
36:00Patients had prior card T 18
36:02and antibody drug conjugate,
36:04and eight bispecific T cell engager.
36:08The most common adverse events
36:10working talajic with neutropenia
36:12occurring in 59 point,
36:138% in cohort D and 42.3% in cohort I.
36:18Infections were common at
36:2157.9% AL grading Health,
36:23Part D and 50% in Coker I.
36:27I'm looking at the response data.
36:28The overall response was 26.24,
36:31cohort D and 25% in cohort I.
36:33Again this year they post
36:35be CMA treated patients.
36:37Additional data was presented for
36:38Cohort D with a median duration
36:40of response of seven months and
36:42median time to respond to 4.21
36:44weeks and a median progression
36:46free survival of three months.
36:48The authors concluded that in
36:49heavily pretreated patients,
36:50again 97% were Triple Classic factory.
36:53The combination of ever, ever,
36:55and Dex demonstrated clinically
36:57meaningful and durable responses.
36:58The treatment was well tolerated
37:00with adverse events that were deemed
37:03manageable with dish reductions
37:05and interruptions and treatment.
37:07Authority of grade three or four
37:09treatment emergent adverse events
37:10were primarily hematological and this
37:12supported the future development.
37:14Iber based regimens including combination
37:16studies with PRISM inhibitors and CD.
37:1838 monoclonal antibodies.
37:22I will stop there.
37:23As previously stated,
37:24all questions will be answered
37:26at the end of the program.
37:28Please encourage you to submit
37:30this in the Q&A portion and now I
37:32will turn it over to Doctor Barr.
37:48Thank you Terry so. Let's get started.
37:52I'm focusing on car T cell therapy in
37:56the relapsed refractory myeloma patients.
37:58I want to highlight that patients
38:01who are refractory to image produce
38:03them inhibitors and anti CD 38
38:05antibodies have a poor prognosis.
38:08These are triple class refractory
38:09patients and when these patients if
38:11they get another line of treatment,
38:13the chance that they will respond
38:15to another agent is roughly 30%.
38:17If they respond,
38:18the median progression free survival
38:20is often less than six months,
38:21with median overall survival
38:23often less than one year.
38:25Now I want to show you how
38:27this is no longer the case,
38:29as most of you already know that in
38:332021 the FDA approved the first car
38:35T cell product in myeloma this is.
38:38Called either sell formerly known as BB
38:422121 and now the train name is a Beckman.
38:46This is a car T cell product that
38:49has four one BB costimulatory
38:51domain and it binds to BCMA on the
38:54cell surface of the tumor cell.
38:56It's approved for patients who
38:58are refractory to image PRISM
39:00inhibitor and anti CD 38 antibody's.
39:0376% of the patients responded about a
39:06third of the patients achieve deep responses.
39:09CR and stringent complete response.
39:12Most of those patients were emordi
39:14negative potential negative 5th
39:16using next generation sequencing.
39:18Now,
39:18these patients had initially dose escalation,
39:21so not all of them received the same dose.
39:24If you look at the total population,
39:26the median progression free survival,
39:28survival was 8.8 months,
39:30but if you hone in on the target dose,
39:32the patients that received
39:33the target FDA approved dose.
39:35It is about one year.
39:36All the population median overall
39:40survival 24 months.
39:42Now we also know that deep responses
39:44lead to longer duration of response,
39:45and here I show you a graph where
39:47patients who have a CR complete
39:49response or higher exemplified
39:51by the light blue line compared
39:52to very good partial response by
39:54the Purple line and the partial
39:56response by the dotted purple line.
39:59Clearly you see that these curves
40:00spread out and the meaning
40:02of two years of follow up.
40:04Those patients who have a CR or higher had
40:06a median duration of response 21 months.
40:09So that's almost two years now.
40:14I've showed you before that only
40:16about a third of the patients
40:19got into this deep responses,
40:21so it's interesting to to figure
40:22out who who are the patients that
40:24went into these deep responses.
40:26Perhaps? Who are those that don't
40:27respond as well to have that mind,
40:29and this was presented by Nina Shaw.
40:31This year is ash and she looked
40:33at disease characteristics at
40:35baseline and correlated it with
40:37patients who had the CR or not.
40:39What they found is that
40:40patients who did not have a CR.
40:42Tended to have a higher soluble BCMA knob.
40:46May is a receptor on the
40:47cell surface of tumor cells,
40:49but it can be cleaved and then
40:51circulates in the bloodstream as soluble.
40:53BCMA is often seen with higher burden
40:56of disease and the conservative sink,
41:00so if you're giving the targeted car T
41:03right instead of going to the tumor,
41:05it's going to this soluble BCMA,
41:06so you can imagine how this
41:08would prevent its efficacy.
41:10The other thing they noted is that
41:13patients not achieving CR tended
41:14to have a high an increase of
41:17inflammatory inflammatory markers by
41:19having higher fare to know D dimer.
41:22Now these could be patients who are
41:24sicker and more burden of disease,
41:26and you might think maybe perhaps this,
41:28in you know,
41:31inflammatory microenvironment
41:32can impede T cell functionality,
41:35but again, these needs.
41:37This needs to be further dissected.
41:39These are just.
41:40The start of trying to understand
41:43biomarkers for response need
41:45to be tested in larger cohorts.
41:48They did find that having a
41:49higher vector copy number in the
41:51drug product was more associated
41:53with patients who had a CR.
41:55Now we know that number of
41:56car T is not the full picture.
41:58We also understand that quality of
42:00T cells are important and this is
42:02a diagram showing you the T cell
42:05differentiation from the naive T
42:06cell all the way to the T effector cell.
42:10These earlier T cell,
42:12the memory like phenotypes have
42:13some key qualities that make it
42:15quite attractive for car two
42:17products example though long lived
42:19so they last longer.
42:20They have ability to self renew
42:22and they have a T cell plasticity.
42:25Furthermore, these memory,
42:26like T cells,
42:27were correlated with peak expansion
42:29and sustain response in karty studies.
42:34So this brings me to the next abstract,
42:37which was presented by Doctor Raj and it
42:40looked at using API 3 kinase inhibitor,
42:43maybe 007, which is known to enrich memory
42:47like T cells and combine it with Ida cell.
42:51It in vitro and this product was now termed
42:55BB 2121 seven and the hypothesis is that
42:59higher memory like T cell in the cell
43:02product will improve duration of response.
43:05The patient characteristics here
43:06were similar to other karty studies.
43:08I want to highlight a few things.
43:10This was a dose escalation study,
43:12so 46 patients out of the 72
43:16received the target dose. High risk.
43:19Better genetics were found in
43:2139% of the patients.
43:22This is slightly higher.
43:23That was than what was
43:24reported with the back comma,
43:25which was around 27% and
43:28extramedullary disease was 22.
43:32Safety profile with BB 2121
43:34seven with similar to Avec mom.
43:36Not going to go into the details
43:38but briefly CR S 75% mostly grade
43:41one and two I cans which is the
43:44neurotoxicity that we see with car
43:46T cells with 15% very comparable.
43:48Said opinions are very common in
43:50general with all CAR T cells filling
43:53to the lymphodepletion that they
43:54get before and the Grade 3 and
43:57above infections which is clinically
43:59very meaningful is about 30%.
44:04In terms of efficacy.
44:06We're all response rate was 74 percent,
44:0939% with a CR and most of
44:11them being emerging negative.
44:13But this doesn't look very
44:14different than Beckman information,
44:16but really,
44:16what this study is looking at
44:18is duration of response,
44:19which I'll show you in this slide.
44:21So in median follow up of about two years,
44:24the median progression of meaning,
44:27progression of free survival for patients
44:29getting the target dose with 18 months
44:32and in the back MACI put in Gray.
44:34Here was 12 months and this is
44:36not a head-to-head comparison.
44:37Any means,
44:38but I want to give you this as
44:40a framework to kind of digest
44:43the the results here.
44:44Now in patients who achieve deeper responses,
44:47CR and above the median duration
44:49of response was 30-4 months and in
44:52the back of my disk was 21 months.
44:55They did see that memory like T
44:57cells in both the car T product
44:59and peak expansion in the patient
45:01was associated with better response
45:03and duration of response.
45:05So this is a good example of how
45:07you can build on an already
45:08established party product.
45:10The next topic will be focused on
45:13information updated information on
45:14the car T cell product that will be
45:17approved next and this is self sell
45:19sell to sell is also an anti BCMA CAR T.
45:23It also has a four one.
45:25BB costimulatory domain.
45:26The difference is it has two binding
45:30domains here extracellularly,
45:32so this was a two year follow-up
45:34of the Phase 1B2.
45:36Patient characteristics are represented here.
45:39They had almost 100 patients,
45:41heavily pretreated similar
45:43to other party studies.
45:44Perhaps the percentage of
45:46triple refractory right.
45:47This is triple class refractory
45:49little bit higher 88%.
45:51They do comment on penta refractory
45:54that's refractory to two image 2
45:56peas and one and CD 30 antibody.
45:59So this is 42% they had 23% high risk
46:04energetics, mostly deletion 17 P.
46:06And they did have 19 patients
46:09with extramedullary disease,
46:1113 patients had extramedullary disease
46:14plasmacytomas outside of the bone,
46:16which is a higher risk feature.
46:19So efficacy I showed you
46:20part of this last year,
46:21but there are some updates.
46:22Overall response rate 89.
46:25Sorry 98% which is great.
46:28So literally two patients here
46:31did not respond.
46:32However, one of those patients
46:35wasn't invaluable because were they?
46:37They couldn't really assess response
46:38because he's not measurable disease,
46:40but they did clinically response.
46:42Really only one patient did not respond to
46:45this and deep responses as you see here.
46:4892% stringent complete response.
46:50Is really unprecedented.
46:52The median time to first
46:54response was one month,
46:55and the median time to best
46:57response was about 2 1/2 months
47:00and then at 2 year follow up the
47:03median progression free survival,
47:04overall survival and duration
47:06of response was not met.
47:09They further looked at MRD at
47:1210 to negative 50 based on next
47:15Gen sequencing in 61 patients.
47:1792 I'm really negative 30 patients
47:20had sustained.
47:20From our deep at six months
47:23and above and 18 had sustained
47:25MRD at 12 months and above.
47:28Now looking at progression free
47:30survival based on depth of response.
47:32So patients who had a CR stringent CR
47:36as exemplified by the Green Line here,
47:39had a two year progression free
47:41survival of 71% compared to
47:4360 for the total population.
47:45Now going deeper,
47:47sustained MRD responses at six
47:49months and 12 months had a
47:51progression free survival of 91
47:53and 100% at 2 year follow up.
47:56So this is really fantastic.
47:58You might be wondering what is
48:00driving that the blue curve down.
48:02You know a lot of these patients
48:03did the cheap,
48:04really great responses and they did do a
48:07subgroup analysis trying to understand this,
48:09and they found that the two year
48:11progression first level was lower for
48:13patients who had baseline plasmacytomas,
48:15high risk cytogenetics and
48:17high tumor boarding.
48:19So this is important to keep in mind.
48:20Certainly these patients benefit,
48:21but they might not benefit as well as others.
48:27Safety. CRS was extremely common
48:31and most everyone had it mostly
48:33grade one followed by grade two.
48:35They did have a good amount
48:37of use totals map at 70%,
48:40which is higher than what's
48:41reported with the beckmeyer.
48:42Around 50% that I cams
48:45neurotoxicity was comparable.
48:4717% infections grade 3 or above 20%.
48:50There was six deaths related to cell to cell.
48:54Predominantly driven by infections and
48:56it followed by CRS and art existing,
49:00they saw 15 events,
49:02secondary primary malignancy and 11
49:04patients which were felt unrelated
49:07to me from from cell to cell.
49:09And the thought is that this is
49:11not out of the usual for this.
49:15Multiply relapsed heavily pretreated
49:18myeloma patient population.
49:20One thing to note that it's
49:22different with silty cells opposed
49:23to either sell or Beckman is that
49:26the CRS it has a later onset.
49:28The median of seven days after infusion
49:31compared to two days after a back comma.
49:33So it is a great possibility to give it
49:35in alkylation setting and it is being
49:38tested in clinical trials like that.
49:40Last thing to comment about
49:42Silver cell is this movement and
49:44neurocognitive adverse effects.
49:46When the cell to cell was first given
49:48to patients, they saw the incidence of.
49:50He's at 12% and actually was concerning the
49:54risk factors that they found to develop.
49:57This was high tumor burden.
49:59High car,
49:59T cell expansion and persistence,
50:01development of AI camps and
50:03CRS grade two or above.
50:06So Jameson and Team decided that they
50:08need to do something about this and
50:10develop patient management strategies,
50:12including enhancing bridging therapy to
50:15reduce tumor burden before they get the
50:18Kartik and early and aggressive treatment.
50:20For CRS and I cans and
50:22probably is with driving,
50:23the higher use of toasting in this agent.
50:26With this there have been no further
50:28toxicities in the current incidents
50:31in over 200 patients treated on
50:33several clinical trials at 0.05,
50:36and this is important because this is
50:38what held up after your approval of
50:40this drug last year and now seems to
50:42be much better in much better shape
50:45and will likely be approved next week.
50:47I do want to highlight that
50:49solar cells being used.
50:50Earlier in in the treatment course
50:52for myeloma and we will have a study
50:55open here using cell to cell as
50:57part of upfront treatment myeloma.
50:59The last topic I will talk about
51:01is another car T product that is
51:04targeting the GPRC 5D protein.
51:06This is called mcar H 109.
51:11GPRC 5D is expressing my luma cells
51:13as well as skin and hair follicles.
51:15It's a. It's a receptor that actually
51:17no one really understands what it does.
51:20This is a small study.
51:22At Memorial Sloan Kettering 16 patients.
51:25But what is unique is that these are
51:27really heavily pretreated patients.
51:29Very high risk population,
51:32so everyone was panda exposed.
51:34Almost everyone was triple class refractory.
51:3760% had higher risk,
51:39may targeted therapy.
51:40Most of that car T 77 had high risk.
51:44Better genetics,
51:45including one Q amplification which
51:47you know it's very high risk.
51:49About half had plasmacytoma months and.
51:52About 20% had non secretary Malama,
51:55which is really a patient population not
51:57represented in the clinical studies.
52:00So this is a swim plot of swimmers
52:02plot of responsive follow-up
52:04of 18 months dose escalation.
52:07You see here the doses go up
52:09with higher doses.
52:10It does seem that there are deeper
52:12responses you can see by the green bars.
52:14The follow up is relatively
52:16short for these patients.
52:17Overall response rate about 70%.
52:20About 1/4 achieved a complete response.
52:22All populations,
52:23so more to follow on that
52:26safety was manageable.
52:28Sierras 93% similar to cell to cell.
52:31There was one patient that had a
52:35grade 3IN neurotoxicity in terms of
52:38off off tumor on target side effects,
52:41nail changes, rash taste changes.
52:43We're seeing all grade one all transient.
52:48So this is a great product is furthering it.
52:51It goes into.
52:52Further development with the
52:55multicenter study.
52:56So with that I will end my part of the talk.
53:05And move on to doctor Browning.
53:14OK great so thank you again
53:16to all for for joining
53:17and those who may be able to stay on a
53:20little bit past the 1:00 o'clock hour.
53:22So with the remaining time I will
53:24review a few abstracts highlighting
53:25basic and preclinical work in multiple
53:28myeloma and then provide an update
53:30on the management of patients with
53:32light chain or ALE amyloidosis.
53:35And I have no disclosures to report,
53:37so this slide outlines the abstracts
53:39I will review with you today.
53:40I'd note that there were many exciting
53:43preclinical updates in myeloma with
53:44a focus really on immunology in the
53:46myeloma immune microenvironment,
53:48as well as advances in genomics
53:50and myeloma pathogenesis.
53:52And I will highlight abstract 159,
53:54which provides us with an updated
53:56analysis from a practice changing
53:58study in AL Amyloidosis.
54:00So to begin,
54:01obesity is is closely linked to
54:03my Loma pathogenesis and has also
54:06been associated with increased
54:08mortality in multiple myeloma.
54:10It is thought that obesity increases
54:12the production of proinflammatory
54:14cytokines and adipokines adipokines
54:16and leads to ectopic accumulation of
54:18adipocytes in the bone marrow which can
54:20change the bone marrow microenvironment.
54:22And in this abstract presented
54:24by Doctor Hsu from the Sun Yat
54:27Sen Cancer Center in China,
54:29the authors aim to investigate
54:30the role of bone marrow.
54:31Adipocytes in myeloma Genesis and explore
54:34potential novel therapeutic agents
54:36targeting the bone marrow microenvironment.
54:39They evaluated patients with newly diagnosed
54:42multiple myeloma and healthy controls.
54:44The myeloma patients were separated
54:46into two groups based on BMI and
54:48underwent testing from bone marrow
54:50that included RNA sequencing,
54:52metabolomics and flow cytometry analysis.
54:57And there was an increase in bone marrow
54:59adipocytes in patients with myeloma and
55:01and metabolomic analysis revealed that
55:03several metabolites work very closely,
55:05associated with BMI with glycerolipid
55:08metabolism enriched in myeloma
55:10patients with obesity RNA sequencing
55:12data from the bone marrow.
55:14Adipocytes showed that patients with
55:16myeloma had an increased expression of
55:19fatty acid binding protein or FAP four,
55:21and this is seen in figures A&B with FA PB
55:244 having an important role in linking lipid.
55:27Metabolism with immunity and inflammation
55:30and obesity further enhanced the
55:32expression of FA FA BP4 in these studies
55:35to further evaluate the potential role
55:38of fabp 4IN pathogenesis in myeloma,
55:40the authors studied of fabp 4 knockout
55:43and wild type mice who were fed a high
55:45fat diet for 12 weeks and you can see
55:48here in figure see that the knockout
55:51mountain mice had less tumor burden by
55:53PET scan and as displayed in figured D,
55:55they also had improved overall survival.
56:00The authors then applied and FAP
56:024 inhibitor known as BMS 309403,
56:05which resulted in significant
56:07attenuation of the tumor burden
56:09and improved survival and obesity
56:10induced myeloma mice as outlined
56:12in the two figures on this slide.
56:14So, in summary, these data suggest
56:16that bone marrow adipocytes,
56:18which are increased in obesity,
56:19may shape metabolism and immunity
56:22in the bone marrow microenvironment
56:24environment and play a role in
56:26promoting myeloma pathogenesis.
56:27This certainly requires further
56:29investigation, though it does raise.
56:31An important question regarding
56:33whether modification of obesity
56:34and other such associated risk
56:36factors can serve as a preventative
56:38strategy in multiple myeloma.
56:42In this next abstract that was
56:44presented by Doctor Simone Mini
56:46at Fred Hutchinson Cancer Center,
56:48the combination of immunomodulatory,
56:50the immunomodulatory drug,
56:51Lenalidomide, and an antigen
56:53antibody was studied in mice.
56:55After undergoing autologous
56:57stem cell transplantation.
56:58As many of you know,
56:59high dose chemotherapy and autologous
57:01stem cell rescue has been shown to
57:04provide progression free survival
57:05benefit in multiple myeloma.
57:07Though in myeloma disease,
57:08relapses are expected,
57:09and there is definitely a
57:11need to enhance the antitumor
57:12efficacy of stem cell transplant.
57:14As you can see in the figure here,
57:16autologous stem cell transplant
57:18via lymphodepletion and immune
57:21reconstitution reconstitution is
57:23thought to establish a myeloma
57:25immune equilibrium with an
57:26inflammatory microenvironment.
57:28However, tumor escape is inevitable,
57:30and exhaustion of CD 8 positive
57:32T cells is thought to play a
57:35major role in disease relapse.
57:36TIGIT, which is an inhibitory receptor,
57:38is upregulated on exhausted T
57:41cells and is thought to play a
57:43major role in disease of relapse,
57:45with studies showing a strong
57:47association between myeloma burden and
57:49expression of TIGIT on CD 8 positive
57:52T cells and mice status post stem
57:54cell transplant there for you guys.
57:56As you can imagine,
57:56TIGIT has emerged as an attractive target
57:59for immunotherapy in multiple myeloma.
58:02So in this study,
58:03myeloma mice underwent high dose
58:04Milo ablative radiation and then
58:06received bone marrow grafts,
58:08followed by the administration
58:10of a antigen monoclonal antibody,
58:12twice weekly for five weeks,
58:14starting on the day of transplant or day
58:16zero and then Lenalidomide administered
58:17daily for three weeks beginning on day,
58:20plus 14 and synergistic anti myeloma
58:22activity was observed with this combination.
58:25As you can see in figure B,
58:27there was a significant reduction
58:29in the rate of tumor growth
58:30and also improved median.
58:32Overall survival in the mice who
58:34received this combination post
58:36transplant and the authors also found,
58:39through flow cytometry and flow,
58:41some clustering,
58:42that this combination increased T
58:44cell memory and reduced exhaustion
58:46as displayed in the representative
58:48heat map on the bottom right
58:51in Figure C and lastly,
58:52the combination of of an anti
58:55TIGIT monoclonal antibody and the
58:564th generation image or cell mod
58:58I iberty mid which was discussed
59:01by Doctor Parker earlier.
59:02In our discussion is now entering
59:05human trials shortly.
59:10So to move, move along light chain or
59:12a lymphoid ossis is a rare systemic
59:15disorder of clonal plasma cells
59:17that generate aberrant or abnormal
59:19immunoglobulin light chains which
59:21misfolded form insoluble amyloid fibrils.
59:24These fibrils then deposit into
59:26extracellular tissues and organs resulting
59:29in impairment of vital organ function
59:32and sometimes or often death with
59:34the introduction of novel therapies,
59:35there has been improvement in
59:37overall outcomes and prognosis
59:38for ALE amyloidosis which were.
59:40Historically, very, very grim.
59:42In an abstract 155,
59:44which was presented by Doctor Starin from
59:46the Boston University Amyloidosis Center,
59:49there was a 40 year Natural History
59:51study that was reviewed on outcomes
59:52for patients with a lambdoid seen
59:54at their center and what they found
59:56is displayed on on the slide.
59:58Here was that in a cohort of
60:00a slightly over 2300 patients,
01:00:02the five year overall survival improved
01:00:04from 15% between 1980 and 1989 to 48%
01:00:08in the most recent decade that was studied,
01:00:10which was 2010 to 2019.
01:00:13Median overall survival improved from
01:00:151.4 to 4.6 years and the six month
01:00:18mortality rate dropped from 23% to 13%.
01:00:21When comparing between these
01:00:23two time periods, however,
01:00:25amyloid remains a challenging disease,
01:00:26both due to delays in diagnosis
01:00:28and and challenges with treatment,
01:00:30notably,
01:00:30in patients with cardiac involvement
01:00:33and further advances in therapy
01:00:35are really crucial.
01:00:36So the Andromeda study is a phase three
01:00:40randomized open label controlled trial
01:00:42that compares our prior standard of
01:00:44care for amyloid which was Bortezomib,
01:00:47cyclophosphamide and dexamethasone.
01:00:50Ortved versus VCT,
01:00:52VCD,
01:00:52plus the anti CD 38 monoclonal
01:00:55antibody daratumumab which was
01:00:57administered subcutaneously in
01:00:59patients with newly diagnosed tail.
01:01:01Amyloid and cardiac stage one through 3/8
01:01:04disease were recruited for the study.
01:01:06And both arms received for
01:01:09six cycles with the study,
01:01:11the protocol or daratumumab arm
01:01:13getting VCD Times 6 studies 6
01:01:15cycles and then monotherapy with
01:01:17their two mab every four weeks
01:01:19for a maximum of 24 total cycles.
01:01:21Prior analysis at 6 and 12 months
01:01:23revealed that the addition of
01:01:25subcutaneous there are two in
01:01:27map to VCD resulted in deeper and
01:01:29more rapid hematologic response
01:01:31is also improved organ,
01:01:32responses and prolongation of major
01:01:35major organ deterioration progression.
01:01:37Free survival and this data led to
01:01:40Derrived being the first approved
01:01:43therapy for a limoy dose in nine
01:01:46countries with FDA accelerated
01:01:48approval granted in January of 2021,
01:01:51and so the current abstract presented
01:01:54by Doctor Raymond Comenzo from Tufts
01:01:56University provided an update after
01:01:59a median follow-up of 25.8 months.
01:02:03So these tables outline the demographics
01:02:05and baseline characteristics of patients
01:02:07that have been enrolled in Andromeda,
01:02:09and they were well balanced
01:02:11between the two treatment arms.
01:02:13The median age of in the dairy
01:02:15VCD arm was 62 years and both arms
01:02:18had a slate mail predominance.
01:02:20I would like to point out that
01:02:22only three to 4% of patients on
01:02:24both arms in this study identified
01:02:25as black or African American,
01:02:27which is important in considering the
01:02:29the generalizability of these results,
01:02:31and was a a discussion when
01:02:33this abstract was presented at.
01:02:34Gosh, I think really highlighting the
01:02:37importance of improving improving
01:02:38diversity in our clinical trials,
01:02:40and that includes in trials
01:02:42of plasma cell disorders.
01:02:4466% of patients had involvement of two
01:02:46or more organs with cardiac and renal
01:02:48involvement being the most common,
01:02:50and importantly,
01:02:5136% of the patients in the dairy VCD
01:02:54arm had stage 3A cardiac disease at
01:02:57the median follow-up of 25.8 months.
01:03:0177.2% of patients in the dairy VCD arm
01:03:03had received daratumumab monotherapy.
01:03:06After six cycles of Derrived and 36%
01:03:09of patients and either in both groups
01:03:12had discontinued study treatment.
01:03:14So over two years of follow up,
01:03:16more patients achieved a hematologic
01:03:19complete response in the Derrived arm at
01:03:2160% compared to only 19% on the VCD arm.
01:03:25And you can see this hematologic
01:03:27complete response response is
01:03:29deepened overtime in the dairy group.
01:03:31Patients achieving a very good partial
01:03:34response or better improved from 77%
01:03:36of the time of primary analysis to
01:03:3879% in this updated analysis analysis.
01:03:42Importantly,
01:03:42hematologic complete response was higher
01:03:44with therapy CD and all prespecified
01:03:47subgroups and those included groups
01:03:50with cardiac involvement at baseline.
01:03:52Those who had cardiac stage three disease
01:03:54and those with translocation 1114,
01:03:56which makes up about 50 to 60%
01:03:59of our ale amyloid population.
01:04:04And as you can see in these graphs,
01:04:05the cardiac and renal response rates
01:04:08in patients receiving derived were
01:04:10significantly higher at both 6 and 18
01:04:13months when compared to the VCD arm at
01:04:15the 18 month mark presented at this ash,
01:04:18both cardiac and renal response
01:04:19rates were more than twice as
01:04:21high as the organ responses that
01:04:23were achieved with just VCD alone,
01:04:25and it's important to to remember that
01:04:27organ response and Dale amyloidosis
01:04:29can be delayed or lagged behind.
01:04:31Hematologic response in that organ responses.
01:04:35Are thought to really improve quality of
01:04:38life in this complex patient population.
01:04:42There were a greater number of deaths
01:04:44related to disease progression
01:04:45in the VCD arm,
01:04:46though with a longer time on therapy,
01:04:48the absolute number of deaths while on
01:04:51treatment was higher in the Derrived arm?
01:04:53Serious treatment,
01:04:54emergent adverse events occurred in
01:04:5647% of patients on the Derrived arm.
01:04:59And 36% of patients receiving VCD
01:05:02alone with pneumonia being the
01:05:04most common serious adverse event
01:05:06that was observed in both groups.
01:05:08The rate of discontinuation due to
01:05:10treatment emergent events was similar in
01:05:12both groups and the most common adverse
01:05:14events observed in the study are outlined,
01:05:16and the tables at the bottom of this slide.
01:05:21So in summary,
01:05:22after more than two years of follow-up
01:05:24hematologic and Oregon response has
01:05:26continued to increase with their trauma
01:05:28BCD when compared with VCD alone.
01:05:30Fortunately,
01:05:30there were no new safety concerns that were
01:05:33identified with this longer follow-up,
01:05:35and overall survival will be analyzed and
01:05:38major organ deterioration progression.
01:05:40Free survival will be updated
01:05:42after approximately 200 events,
01:05:44though at the median follow-up
01:05:46presented here of 25.8 months,
01:05:48there were fewer deaths that
01:05:49were observed in the derived.
01:05:51Farm as outlined here.
01:05:52And so this updated analysis really
01:05:55confirms the treatment benefit
01:05:57of this regimen out to 18 months,
01:05:59and supports derrived as a new
01:06:01standard of care for our patients
01:06:03with newly diagnosed ALE amyloidosis?
01:06:08So the final abstract that I will
01:06:10touch upon was presented by Doctor
01:06:12Jason Valent from the Cleveland Clinic,
01:06:14and it reviewed the safety and tolerability
01:06:17of Cal 101 in combination with anti plasma
01:06:20cell therapy for patients with a lamb.
01:06:22Lloyd Ossis and this was from a one year
01:06:25results from an open label phase two trial.
01:06:28So, as we previously discussed,
01:06:30amyloid fibril deposition and
01:06:31organs results in organ dysfunction
01:06:33with significant morbidity and
01:06:35mortality for patients with a lamb.
01:06:37Lloyd and our standard of care anti
01:06:39plasma cell therapy is just discussed.
01:06:42Really decreases the production of
01:06:44amyloid oh genic like chains by
01:06:46targeting abnormal bone marrow plasma
01:06:48cells but doesn't address the amyloid
01:06:50fibrils already present in and organs.
01:06:53So Cal 101 is a chimeric monoclonal
01:06:55antibody and it binds annio appetite.
01:06:58That's present on both Kappa
01:07:00and Lambda light chain fibrils,
01:07:02resulting in proteolysis and removal
01:07:04of the amyloid fibrils from tissues
01:07:06and organs in a phase.
01:07:08One study of this agent Cal 101 was
01:07:10well tolerated up to 500 milligrams
01:07:12per meter squared in patients who
01:07:14had relapsed or refractory ale,
01:07:15amyloid and in the phase two component.
01:07:18It was tolerated up to 1000 milligrams
01:07:20per meter squared when administered
01:07:21in combination with standard of
01:07:23care and I plasma cell therapy,
01:07:25and this was the patients recruited had
01:07:28cardiac stage one through three a disease.
01:07:32So 25 patients are included in
01:07:34the analysis that was presented
01:07:36at ASH and all had a confirmed
01:07:38diagnosis avail amyloid at least a
01:07:41six month minimum life expectancy.
01:07:43And there were the patients
01:07:44recruited were not planned for
01:07:46autologous stem cell transplant in
01:07:48the first six months of the study.
01:07:50Patients were excluded if they had
01:07:52concomitant multiple myeloma or
01:07:53symptomatic orthostatic hypotension.
01:07:55And subjects received four
01:07:57weekly doses of Cal.
01:07:58101 and then biweekly dosing
01:08:01until clinical deterioration,
01:08:02toxicity or death,
01:08:03and as you can see in the schema
01:08:05in the top left of this slide,
01:08:07Part B of the study added daratumumab
01:08:09to the standard of care therapy
01:08:11based on the Andromeda trial.
01:08:13The mean age of the study
01:08:15group was 65.2 years,
01:08:16with the majority being male.
01:08:1880% of the patients had cardiac
01:08:20amyloid involvement in 92% of
01:08:22these individuals had cardiac
01:08:24stage two or three a disease.
01:08:2696% of patients had treatment
01:08:28emergent adverse events with the
01:08:30most common ones being listed in
01:08:31the table at the bottom right.
01:08:33Here,
01:08:33the only 24% of those were felt
01:08:36to be related to treatment and
01:08:38most adverse events were were
01:08:40low grade with the the thought
01:08:43that the cardiac safety of this
01:08:46agent was really more warm or well
01:08:50tolerated than expected overall.
01:08:52So though there was a limited
01:08:54number of patients,
01:08:5518 of the 20 patients with cardiac
01:08:58involvement showed stability or
01:09:00improvement based on the NT Pro BNP values,
01:09:02with some of the 35% of those who responded,
01:09:06reportedly showing dramatic
01:09:07improvement and similarly eight of
01:09:09nine patients with renal involvement
01:09:11at baseline achieved renal responses
01:09:13with more than 30% reduction in
01:09:16their proteinuria and some patients
01:09:18having very rapid and deep responses.
01:09:21So to summarize,
01:09:21Cal 101 appears to be very well tolerated.
01:09:24And safe in combination with
01:09:26our standard of care anti plasma
01:09:28cell therapy which is now.
01:09:29There are two memorable plus V CD
01:09:31and it has yielded cardiac and renal
01:09:34responses in a majority of patients.
01:09:36Cal 101 is now being studied
01:09:38in phase three trials.
01:09:39For patients with Mayo stage
01:09:413/8 and also stage 3B disease.
01:09:44Cardiac disease which was previously
01:09:46excluded from this and from a patients
01:09:49that were previously excluded from
01:09:51this and from the Andromeda trial.
01:09:54So I will stop there and.
01:09:56We will move to questions and answers.
01:10:01OK, thank you everyone
01:10:04for great presentations.
01:10:06I will start by asking know
01:10:07far could you tell us your
01:10:09perspective on how would you
01:10:10envision CAR T cell therapies in
01:10:12the coming years in the future
01:10:14for transplant eligible patients?
01:10:17I think it's a very good question.
01:10:18I mean, many studies are looking at that.
01:10:20I think moving clearly you see
01:10:22unbelievable responses in patients who
01:10:24typically didn't respond like this.
01:10:26So one could imagine even better
01:10:28responses and longer duration of
01:10:30responses and more fit patients with a
01:10:32better immune system and given up front.
01:10:35So then I think this is what?
01:10:37The future is going to be.
01:10:38It's going to be evaluated upfront in
01:10:41transplant eligible and ineligible patients.
01:10:45Right, and can you comment either?
01:10:46Either the M car or the cell to cell.
01:10:50Were there any any subjects included
01:10:53with them? CNS involvement.
01:10:57No CNS involvement. These are excluded.
01:11:03I think within our practice we
01:11:05have had patients who had a CNS
01:11:07enrollment and they've been treated.
01:11:08These are anecdotal,
01:11:09but I'm sure it's evolving.
01:11:15I also wanted to ask a question of
01:11:17doctor Browning Sobrino how how do
01:11:20you approach treating your frontline.
01:11:22A Lloyd doses patients.
01:11:25Yeah, I think you know.
01:11:25I think that's that's an important
01:11:27question because of the role
01:11:29that that autologous stem cell
01:11:31transplant has played in amyloid.
01:11:32In terms of, you know,
01:11:34improve improvement in progression,
01:11:35free and overall survival,
01:11:37but I think now you know the the
01:11:39hematologic and organ response
01:11:41rates in Andromeda with their
01:11:43VCD are really impressive,
01:11:45and I think importantly,
01:11:46the responses occur rapidly,
01:11:48which is an important in terms
01:11:50of subsequent organ responses.
01:11:51So I would say that you know,
01:11:54I think in in.
01:11:55Most of our patients we should
01:11:57use Darragh VCD and then the
01:11:59question becomes of those
01:12:00patients who should go on to get
01:12:02autologous stem cell transplant.
01:12:04And I think what we and other
01:12:07centers have adopted is in
01:12:08patients who have achieved a
01:12:10hematologic complete response.
01:12:11The thought is that there may
01:12:14not be additional benefit to
01:12:16to auto transplant and that
01:12:17those patients have transplant
01:12:19available available to them if
01:12:21they were to relapse subsequently.
01:12:24Great and a question for Terry
01:12:28with this in this competing
01:12:29environment of therapies for
01:12:31relapsed refractory myeloma. Where
01:12:34where do you position
01:12:36by tone? Approach.
01:12:41Yeah, and that's a good question.
01:12:44So it's you know, a lot of these
01:12:46trials are still in early phase,
01:12:48and they're still in really
01:12:50heavily treated patients.
01:12:52So I think we don't know
01:12:53which ones gonna win, right?
01:12:55All the bispecific seem to have very similar
01:12:58toxicity profiles as far as CRS minimal.
01:13:00I can't hematological toxicity.
01:13:02I do see the by specifics being moved
01:13:05into that one to three lines of therapy,
01:13:08especially if we can improve
01:13:10upon the duration of response.
01:13:12Similar to kind of what never
01:13:13was saying with the car.
01:13:14T and then I believe the question of
01:13:16car T versus advice specifics really
01:13:18gonna come up and the vice specifics.
01:13:20Maybe for those individuals who really can't.
01:13:22Wait for the car tne treatment
01:13:26sooner rather than later,
01:13:28as a majority of their responses
01:13:30were seen within a month of therapy.
01:13:32And so I think it's going to depend
01:13:34on how extensive the disease is,
01:13:36how quickly a patient needs therapy,
01:13:37and how fit they are overall.
01:13:39But I think we have a question in the
01:13:42chat if you see it for Doctor Gore shot.
01:13:45So the question asks outside
01:13:49of the clinical trial context,
01:13:52when would you use Dara?
01:13:54RVD in clinical setting? General
01:13:57standard of care.
01:14:00He said, is that meant to be
01:14:02Dara, RVD, or this is our VP.
01:14:05Well I guess spread needs Prednisone,
01:14:08Prednisone or dexamethasone platinum.
01:14:12So I I think that I mean look.
01:14:15Obviously we have a couple of options here.
01:14:17You know, like we discuss VRD backbone.
01:14:19Well established, efficacious.
01:14:20You know if you're if you're a little
01:14:23more concerned about high risk,
01:14:25there are some centers that would go KRD,
01:14:29but to me I think that the quadruple it we
01:14:34see the durable improvement in response is,
01:14:38you know, approaching the 24
01:14:40month of maintenance therapy.
01:14:41So if a patient has.
01:14:43If a patient can tolerate a quadruplet.
01:14:47You know whether they're
01:14:48standard risk or high risk.
01:14:50I would strongly consider that.
01:14:53Yeah, I agree, I think the quadruplet
01:14:56therapies for monoclonal antibody
01:14:58backbone are entering the frontline
01:15:00care and with more and more data
01:15:02accumulating and data maturing to show.
01:15:04So far it's the murded superiority.
01:15:08But we know from separate trials that
01:15:11MRD negativity is associated translates
01:15:13into much improved progression,
01:15:15free survival and overall survival.
01:15:17So I think the field is really evolving and
01:15:21which one will emerge as the next favorite.
01:15:24Therapy is a big question.
01:15:26I think one has to consider
01:15:28that high risk patients.
01:15:31You know situation may still not be optimal,
01:15:33so further work needs to be done
01:15:36for the high risk population.
01:15:38Say I think it's hour and 15 minutes,
01:15:40which is the time we provisioned
01:15:42for this seminar.
01:15:43I don't see any other questions.
01:15:45Any other discussion from
01:15:46the from the panelists here?
01:15:51If not, we will conclude and thank you very
01:15:53much for participation. Everyone, thanks.
01:15:56Thank you everyone. Thank you.