Multiple Myeloma

January 19, 2021

Information

January 15, 2021

Presentations by Natalia Neparidze, MD and Terri Parker, MD

ID6089

To CiteDCA Citation Guide

00:00Actual. Post Ash meeting where a few
00:03minutes late but will try to finish
00:06on time because I know all of you
00:09have other things to go too so it's
00:11a pleasure to start this series.
00:13I think there has been a lot of new
00:15and great development in ash meeting
00:18and because of their virtual format,
00:20sometimes it's very difficult to
00:21catch up with all of those articles.
00:24So we are going to have six weekly sessions.
00:27The first one today will be about
00:29multiple myeloma and we will
00:31cover the other important.
00:32Disease elements in the next few sessions.
00:36So this meeting will be recorded.
00:40And we will have the recording
00:43available for subsequent viewing.
00:45Please remember that this is
00:47also see me credited so you can
00:50see it get CME credit for this
00:52hour and for subsequent meetings.
00:55So today our talk will be
00:58about multiple myeloma.
00:59It's a pleasure to have highly
01:02distinguished and expert.
01:03Basically speakers today with
01:05me from Yale University.
01:07So we'll start with the Doctor
01:10with Doctor Natalia Nippori.
01:11See who's an assistant professor of
01:13medicine and she's going to talk to
01:16us about updates in the frontline
01:18management of multiple myeloma.
01:20This will be followed by Doctor Terry Parker,
01:23our assistant Professor of Medicine at Yale,
01:25who's gonna cover the refractory
01:27and relapsed multiple myeloma then.
01:29Doctors know far.
01:30Power Hour,
01:31assistant professor of Medicine
01:32who specializes in car T cell
01:34therapy and transplantation,
01:36especially on the My llama front.
01:38She will.
01:38Cover those for us and this will go
01:41for around 40 minutes after that.
01:43At the end we're gonna have 15
01:45minutes for questions and answers,
01:46so if I can ask you to write
01:48down your questions,
01:50you can write him throughout the
01:51session and send them to us.
01:53And just to make sure we can go
01:55through all the slides will keep
01:57their questions and until the end
01:59we're going to have a panelist who
02:01is Doctor Sabrina Browning who's
02:03our instructor with a focus on
02:04amyloidosis and also multiple myeloma.
02:06All four speakers will be available at
02:08the end to take questions from you.
02:10And we look forward to a great
02:12presentation so Natalia please stop for us.
02:14Thank you.
02:19Thank you very much, Doctor Zaidan. Good
02:22afternoon and thank you all for joining.
02:25As mentioned, these are the panelists
02:28joining the discussion today and
02:30I will begin by up highlighting
02:32initial therapy and biology.
02:34Pathophysiology of myeloma.
02:36These are my disclosures.
02:37I would like to begin by highlighting
02:40the work by Doctor Kardashian
02:42from NCI who presented the work
02:45on the treatment of high risk,
02:48smoldering multiple myeloma.
02:49With carfilzomib, Lenalidomide,
02:51and dexamethasone, this was a phase
02:53two clinical in Carrollton study.
02:55The primary objective was the study was
02:58to determine the minimal residual disease.
03:01Negative complete response rates.
03:03Another key secondary objectives,
03:05including progression free survival,
03:07overall survival,
03:07duration of MRD.
03:09Negative state. This is the overall
03:12study design. This study was
03:14quite inclusive in that this study
03:17included all patients with high risk
03:20definition by any of these criteria,
03:22including Mayo Clinic,
03:24but Seamus Spanish high risk criteria
03:27they've defined by flow cytometry based
03:30on a barren plasma cell expression
03:32as well as Raj Kumar along Grennan
03:36Mateus criteria which include plasma
03:38cell percentage level of protein.
03:40Humana paresis as well as cytogenetic
03:43and imaging abnormalities so
03:45patients on this study received the
03:48induction therapy with carfilzomib,
03:50REVLIMID dexamethasone combination.
03:51For eight cycles of therapy followed
03:54by Lenalidomide maintenance with their
03:56usual 20 day cycles for up to two years,
03:59followed by observation at
04:01every three month interval,
04:02with annual staging imaging.
04:05Patients in this protocol.
04:07Preceded with stem cell harvest.
04:09After four cycles of therapy,
04:11bone marrow was monitored for MRD
04:14assessment with flow cytometry and
04:17PET CT scan imaging was incorporated
04:20for response assessment at the end
04:22of induction and then annually.
04:24Overall, 54 patients enrolled and treated.
04:27And what's what's interesting is
04:29that 37% of patients displayed high
04:32risk cytogenetic features and all
04:34of the patients met criteria for
04:36high risk smoldering based on these
04:39definitions and what's remarkable with
04:41this study is that sustained MRD,
04:43negative complete remission rates were
04:46on the order of 70% in this cohort and
04:49at two years and five years of survival,
04:53sustained MRD negative complete
04:54responses remained at 1779 and
04:5753% of patients respectively.
04:59And overall response rates with
05:01this regimen were 100% with 72%
05:04achieving complete response and
05:0694% of very good partial response.
05:08Overall survival and progression
05:10free survival are not reached,
05:12but at 80 or milestone,
05:1491% of patients remain progression free.
05:17The treatment emergent adverse events were,
05:19as would be expected for this
05:22triplet combination.
05:23Specifically,
05:23side effects of special interest in the
05:26form of cardiac toxicity were seen in.
05:29Only two 2 patients with heart
05:32failure and 4% of this population.
05:34So overall this data show that
05:36carfilzomib REVLIMID dexamethasone
05:38regimen is highly potent.
05:40An leads to very deep responses in high risk,
05:43smoldering multiple myeloma.
05:45Providing further background for this
05:47evolving treatment landscape for early
05:49intervention and treatment of high risk,
05:51smoldering patients who have high risk of
05:54progression of greater than 75% / 2 years.
05:57Next I would like to highlight
06:00the updates on the griefing trial,
06:03Griffin trial, early safety,
06:05and efficacy data were published
06:07in 2020 in Blood Journal,
06:10and as you know,
06:11this combination of this trial compare
06:14daratumumab over RVD compared to the
06:17old RVD triplet standard of care.
06:20This update focuses on the data
06:23on overall responses and MRD,
06:25negative responses at the end of
06:2712 months of maintenance therapy.
06:30So as you know,
06:31the trial enrolled patients with
06:33newly diagnosed transplant eligible
06:34multiple myeloma with good performance
06:37status and preserved kidney function.
06:39Patients were randomized in one to one
06:42fashion to either old standard of care,
06:44RVD or they daratumumab CD.
06:4638 monoclonal antibody in combination
06:48with standard RVD triplet.
06:50After four cycles of induction
06:51therapy patients went on to
06:53receive autologous stem cell transplant.
06:56This was followed by two more cycles of
06:59consolidation therapy with the same regiment.
07:01Followed by REVLIMID maintenance as a
07:03single agent as per standard of care.
07:06Versus daratumumab REVLIMID combination
07:08as maintenance strategy and as
07:10you can see with ongoing therapy,
07:12responses depend at the end of 12 months
07:15of maintenance with Dara, RVD regimen.
07:1763% of patients achieved stringent
07:19complete responses,
07:20and this was significantly better
07:21as compared with RVD triplet and in
07:24general response rates and depth of
07:26responses were greater with Dara,
07:28RVD regimen at all treatment time points,
07:31and the same is true for the sustained
07:34MRD negativity lusting for greater
07:36than six months and greater than.
07:3812 months with RVD regimen compared
07:41to the triplet.
07:44The 24 months progression free survival
07:47and overall survival data are reported
07:50and at this time point and follow up.
07:53These are not significantly
07:55different statistically,
07:55between the two arms, however,
07:58predicted PFS appears promising.
07:59As you can see, the overall survival
08:02curves are overlapping, however,
08:04more more time and follow up is required
08:07for further read out of the data.
08:10With regard to treatment,
08:12emerging adverse events,
08:13the hematologic toxicity.
08:15Of grade three and four
08:17degree were higher in Dara,
08:19RVD treatment arm as compared
08:21to the RVD triplet.
08:22Other non hematologic toxicities or also
08:25slightly higher compared to the RVD triplet,
08:28especially the upper.
08:29Story infections were higher with
08:31quadruplet versus triplet combination,
08:32however, when it comes to grade 3.
08:35Four pulmonary side effects
08:37such as severe pneumonia,
08:38they were not statistically
08:40significantly different,
08:41so this regimen based on
08:43this face to randomize study,
08:45offers a very potent
08:47frontline induction regimen.
08:48Which has been adopted in clinical
08:50practice as their reasonable
08:52frontline regiment for newly
08:53diagnosed patients who are transplant
08:55eligible with multiple myeloma.
08:57Next I would like to highlight the
09:00updates of the Forte trial presented
09:03by Doctor Francesca Gay from Italy.
09:06As you know,
09:0840 trial randomized 474 patients with
09:10newly diagnosed multiple myeloma.
09:13These were transplant eligible an
09:15younger than 65 years of age and they
09:19were randomized to one of the three arms,
09:23either carfilzomib,
09:24cyclophosphamide,
09:24dexamethasone or carfilzomib REVLIMID.
09:26Dexamethasone followed by transplant.
09:28Or carfilzomib REVLIMID dexamethasone
09:30for 12 cycles without autologous stem
09:32cell transplant and at the randomization.
09:35Part 2 patients with randomized to
09:37either single agent REVLIMID as per
09:40standard of care or combination of
09:42carfilzomib produce some inhibitor with
09:45REVLIMID as part of maintenance therapy.
09:48And at this 45 months of median
09:50follow up they sustained MRD negative
09:53complete responses for KRD 12 CRV
09:57with transplant was 68% and KRD
10:00412 cycles without transplant or
10:0254% and the same is true for the
10:06progression free survival data
10:08which favors the KRD plus autologous
10:11stem cell transplant at 78% and
10:14the next best is KRD 12 cycles.
10:18Where is carfilzomib,
10:20cyclophosphamide dexamethasone is inferior.
10:23And this data present overall very
10:25good partial response rates for the
10:28time point of randomization Part 2.
10:30As you can see the very good partial
10:33risk responses on the order of 9694%
10:36and what was observed is that MRD
10:38conversion rate from MRD positive to
10:40negative was significantly higher
10:42among patients who received carfilzomib
10:45REVLIMID combination for maintenance.
10:47The overall survival curves here are
10:49really striking for both KRD with
10:52transplant as well as KRD 12 regimen
10:54and slightly inferior for carfilzomib
10:57cytoxan Barbara Cytoxan regimen.
10:59So overall,
11:00this data show that carfilzomib REVLIMID
11:03dexamethasone induction is a very
11:05potent regiment for frontline therapy
11:07for patients with newly diagnosed
11:09multiple myeloma who are transplant eligible.
11:12Specifically,
11:12KRD improved with transplant,
11:14improved progression free survival
11:16as compared to the other carbs.
11:19And the responses were deeper and depend
11:22with continuous KRD maintenance regimen.
11:25Next I would like to highlight
11:27the report on the
11:29elderly non transplant eligible patients
11:32with newly diagnosed multiple myeloma.
11:35The phase three term Alene trial out of
11:39Europe presented by Doctor Thierry Facon
11:42who presented the data on this study
11:45where 705 patients were randomized to
11:48either exacum Abe REVLIMID, dexamethasone,
11:51triplet combination versus placebo.
11:53REVLIMID. Dexamethasone doublet
11:54combination in this transplant ineligible.
11:57Elderly population.
11:58And the study demonstrated median
12:01progression free survival of
12:03significantly improved to 35 months
12:05compared to 21 months in the triplet
12:08versus the tablet RRD combination.
12:10And this translated into deeper.
12:13Higher rates of deeper responses
12:15in the form of higher rate of very
12:18good partial response as well
12:20as higher rate of complete.
12:22An stringent complete remissions
12:24SOA based on this data exactly.
12:26My problem in Texas Methadone appears
12:28to be a reasonable frontline regiment
12:30for elderly newly diagnosed subjects
12:32who are ineligible for transplant,
12:34and it provides a convenient way of
12:37all oral combination which may be
12:39particularly relevant in the covid era.
12:42And finally,
12:43I would like to highlight some of
12:45the preclinical data which were
12:47presented during scientific session,
12:49first out of Mayo Clinic Doctor
12:52Bakes Eagles experience,
12:53who presented the role of dichro gut
12:55microbiome in shaping myeloma evolution.
12:58In this study,
12:59they used VK mix transgenic mice
13:01which spontaneously developed
13:02democracies and myeloma.
13:04The first observation was out of Italy,
13:07where they observed that the
13:09rate of progression to myeloma
13:10was significantly delayed.
13:12In the pathogen, free vivarium,
13:14and so Mayo Clinic,
13:16Arizona joined forces with Jackson
13:17Labs and Debrided this Miz and
13:20subsequently transplanted them with
13:22primary myeloma samples and they
13:24treated mice with antibiotics or not.
13:26And they observed significant
13:28percentage increase in survival
13:30of mice treated with antibiotics
13:33as compared with the control.
13:35Later they identified that Prevotella,
13:37one of the microorganisms in the gut
13:41microbiome significantly impacted
13:42the burden of multiple myeloma.
13:45So this data hypothesize that the
13:47certain micro bacteria in the gut
13:50microbiome such as prevotella Trib,
13:53actor bacteria, Bacteroides,
13:54and Clostridia, can provide uncontrolled.
13:56Stimulation of the TH.
13:5817 responses and regulatory T cell
14:01responses and this signal from got
14:03may translate into increased child 17.
14:06Another immune changes which further
14:08promote growth of myeloma cells and
14:10progression of disease and this
14:12concept provides important Ave for
14:14the therapeutic interventions for
14:16prevention of disease and finally
14:18elegant work presented by Doctor Irene
14:20Ghobrial of Dana Farber who performed
14:23single cell RNA sequencing on the
14:25spectrum of specimens from healthy
14:27volunteers to M Gus to smoldering myeloma.
14:30Two full blown clinical multiple myeloma
14:33and highlighted the composition and
14:36evolution of immune microenvironment
14:37changes during which with time and
14:40progression of disease there is
14:42significant increase in the numbers
14:44of regulatory T cells as well as
14:47increased percentage of NK cells
14:50that predominantly express CX,
14:52CR4 and CX3 CR,
14:53as well as increased subsets of CD16
14:55monocytes and this data provides
14:58significant background through
14:59which one could design immune
15:02therapeutic interventions to possibly
15:04eradicate irregular.
15:05Regulatory T cells and other
15:07immune interventions in order to
15:09prevent the disease progression.
15:10So with that I will stop and would
15:13ask Doctor Terry Parker to highlight
15:15the updates on relapse refractory
15:17multiple myeloma Andale amyloidosis.
15:19Thank you. Thank
15:23you to Talia.
15:52Unless you get the top.
15:59I will be reviewing updates
16:04from ASH and relapse refractory
16:10multiple myeloma anael Android.
16:15I have no disclosures.
16:16There are multiple abstracts this year
16:19in relapsed refractory multiple myeloma.
16:21They range from new combinations
16:23of FDA approved agents to immuno
16:25therapies with antibody drug,
16:27conjugate San, bispecific,
16:28T cell engager's.
16:30I will start by reviewing two
16:32abstracts utilizing currently
16:33FDA approved agents in selinexor.
16:35An easy Texas map.
16:37Stamp was a phase one B2 clinical
16:39trial that evaluated varying doses
16:42and dose schedules of selinexor,
16:45pomalidomide and dexamethasone.
16:46Primary objective of the trial which
16:49identify the recommended phase two dose
16:52and evaluate the overall response rate.
16:5465 patients were accrued 20
16:56at the recommended phase.
16:58Two dose.
16:59The meeting number of prior therapies
17:02was three and 75% of patients
17:04were refractory to Lenalidomide.
17:06The table here illustrates the very.
17:08Doses of weekly selinexor with the
17:11recommended phase two highlighted in red,
17:13which ends up being 60 milligrams of
17:16selinexor weekly comma, 4 milligrams.
17:1821 out of 28 days and X 40 milligrams weekly.
17:23The overall response rate was 54.3% in
17:25palm naive patients with progression
17:27free survival of 12.3 months.
17:30There overall response rate decreased
17:32to 35.7% and those that were
17:34Palmer factory in patients dosed
17:36at the recommended phase two dose.
17:39The overall response rate was 60%
17:41treatment related adverse events
17:42were similar to what has been
17:44seen with selinexor in Palm.
17:46These included nausea,
17:47mild depression and fatigue.
17:48I chose to highlight this trial as
17:51it presents an all oral regimen
17:53which is appealing to our patients,
17:55especially in the relapse refractory setting.
17:57I also wanted to point out the different
18:00selinexor dosing compared to the storm trial,
18:02which was 80 twice a week and
18:04the Boston clinical trial,
18:06which was 100 milligrams weekly.
18:08There was an improved overall response rate.
18:10Free survival compared to historical
18:13data with palm index which is
18:1531% informance respectively.
18:16In patients refractory to
18:19Lenalidomide and worked as a matter.
18:21Doctor Martin presented at the interim
18:23analysis from the Akuma trial patients
18:26were eligible for this trial if they
18:28had one to three prior lines of therapy.
18:30No prior history of carpal zenmap,
18:32and we're not refractory to anti CD 38.
18:36302 patients were randomized to
18:37receive isatuximab carfilzomib dex
18:39versus carfilzomib dex with the
18:41primary endpoint of progression free
18:43survival and secondary endpoints
18:44of overall response.
18:46VGP RCR emoji negativity rates from
18:48those not familiar East Texas map is
18:51an IgG one monoclonal antibody against CD.
18:5338 minimal residual disease was assessed
18:55for this trial in the bone marrow aspirates.
18:59If patients who achieved at least Avicii
19:01PR by next generation sequencing at
19:0310 to the minus mix sensitivity level.
19:06Yeah, central lab.
19:08The best overall response was 86.6%,
19:11with 72.6% of patients achieving
19:13AVGPR and 39.7 as CR.
19:16In these attacks,
19:17map ARM MRD negativity rates
19:19were 41.4% compared to 22.9%.
19:22The CR rate of 39.7% was felt to
19:25be under estimated given Eastern
19:27text mode interference.
19:29Therefore, for 27 patients with an ear,
19:32see are defined as a positive
19:36immunofixation for IgG cap on I.
19:39Or potential CR were evaluated.
19:40The Anaspec 15 of the 27 were
19:43found to be M protein negative.
19:45Increasing the CR rate to 45.8%.
19:49So talking points from this
19:50trial without the combination of
19:52East Texas map carfilzomib index
19:54resulted in improvement in overall
19:56response rate CR V GPR in Aberdeen.
19:59Negativity rates had an
20:00impressive CR rate of 45 point 8%.
20:03Again in patients with one to three
20:05prior lines of therapy and MRD,
20:08negative negative CR rate of 24%.
20:10MRD negativity in both arms was
20:12associated with a longer progression,
20:14free survival and the potential
20:16to achieve MRD negativity,
20:17which should be independent of
20:19adverse prognostic characteristics.
20:20Catches ISS stage three disease.
20:22We don't involvement or a gain of 1 Q 21.
20:26And moving on to the Immunotherapy's
20:29Doctor Kumar presented first in
20:31human phase one trial of MEDI 2228,
20:33which is an antibody drug conjugate
20:36that targets the extracellular
20:38domain of human be CMA.
20:39The primary endpoints were
20:41safety and tolerability.
20:42The trial enrolled 82 patients
20:4441 in the expansion.
20:46Copart two patients had great for
20:48thrombocytopenia at the 0.2 mix perchik dose.
20:51Therefore, the maximum tolerated dose
20:53was 0.1 for mixer cake given Q three weeks.
20:56Treatment related adverse events
20:58included photophobia.
20:59Thrombocytopenia rash dry on pleural
21:01effusion at the maximum tolerated dose,
21:03the overall response rate was 66% with
21:06the duration of response at 5.9 months.
21:09Unlike the currently FDA approved
21:11ADC of Blanton map,
21:12no Keratopathy was observed.
21:14However,
21:14photophobia credit 60% of patients at
21:17the 0.1 four make for kiddos with a
21:20median time to onset of two months,
21:23which is roughly 2 cycles.
21:25This did improve in 37% of
21:27patients and resolved in for.
21:29Is holding up the medication
21:31this agent is moving forward,
21:33looking at varying adjusting schedules.
21:36They must pass it.
21:37Ash this year was for the
21:39bispecific T cell engager's.
21:41This chart is adapted from 1% in by
21:44Doctor Chary during his educational
21:46session on you know, therapies.
21:47Here.
21:48I have listed all the bytes
21:50that RBC may targeted that were
21:52presented at this year's ASH.
21:54Therefore,
21:54oral abstracts and one poster
21:56do just time constraints.
21:57I will be just talking about to Clifton AB,
22:01which had the largest patient accrual.
22:04So as mentioned to custom AB is
22:06ABC May CD three byte 84 patients
22:09received an Ivy dose with 44
22:11receiving subcutaneous dosing.
22:13The median number of prior treatments
22:16for these patients were six and
22:1881% were triple class refractory.
22:20By that I mean they were refractory
22:22to an image of proteasome inhibitor,
22:25an anti CD 38 monoclonal antibody.
22:27Step up Justin was utilized prior
22:29to the first full dose to decrease
22:32the risk aside entirely syndrome.
22:34Notice TRS in subsequent slides,
22:36adverse events and no see Russ did
22:39occur in 55% of patients with the
22:41Ivy dose and in 50% receiving the
22:44subcutaneous dose with the median time
22:46to onset of one to two days respectively.
22:49However, no Grade 3 events were noted.
22:52Neurotoxicity hurting 5%
22:53with two Grade 3 events.
22:55Injection site reactions in 32 and there
22:57was one death attributed to pneumonia.
23:00The recommended phase two dose based on
23:02setting safety advocacy and pharmacokinetics.
23:04Is 1500 micrograms per kilogram at this test,
23:07the overall response rate was 73%,
23:10as outlined here,
23:11with the median time to responsive one month.
23:15So again, take home points.
23:16The recommended phase two dose moving
23:19forward will be 1500 micrograms
23:20per kilogram weekly, subcu.
23:22This was a heavily pretreated
23:24patient population,
23:25as 39% work at refractory,
23:27and in this patient population that
23:29overall response rate was 73%,
23:31which is very encouraging with 23% CR
23:33and 55% VG PR at the recommended phase,
23:36two dose eat at the 11 evaluable patients
23:39were energy negative and there's a
23:42potential for durable responses as
23:4415 out of 16 patients were alive.
23:46No progression at the median
23:48follow up at 3.9 months.
23:50The other two by specifics that
23:52I would like to highlight include
23:55a bispecific targeting STR.
23:57H5 which stands for St receptor
23:59homolog 5 which is a type one membrane
24:02protein expressed on plasma cells with
24:05near 100% prevalence for myeloma.
24:07So Savasta map is this bispecific
24:10antibody that targets approximately
24:11the domain of FCR H5 in C3.
24:14Given Ivy Q,
24:15three weeks again with one step up,
24:18dose 53 patients were accrued
24:20with 51 being a valuable.
24:22And 21% of now had prior PC may
24:25directed their adjusting schematic
24:26is illustrated here and the maximum
24:29tolerated dose was not reached.
24:31Therefore,
24:31dose escalation is on going in
24:34this trial safety to note 76%
24:36of patients did have CR,
24:38S 28% had another event which
24:40occurred in the setting of CR S
24:43and 23% infusion related reaction
24:45in individuals who received at
24:473.6 milligrams step up.
24:48This at least a 20 milligram full dose.
24:51The overall response rate was.
24:5353% there was a 63% overall response
24:56rate in patients who had received
24:59prior PCMI directed therapies.
25:02So this represents a new
25:03target for multiple myeloma,
25:05with the maximum tolerated
25:06dose not being reached.
25:08Importantly,
25:08Seeress did occur and 76% of patients,
25:11but there was only one grade three event,
25:14which was an elevated transaminase
25:16that resolved encouragingly responses
25:18were observed in patients who
25:19had prior be CMA as we will need
25:21therapies for patients who progress
25:23after car T and Adcs responses
25:25were seen irrespective of target
25:28expression levels in patients
25:29that have been assessed to date.
25:31The last by specific is till cotton
25:34AB which binds GPRC 5D which stands
25:37for G protein coupled receptor family.
25:39See Group 5 member in D which is an
25:42orphan receptor whose transcript is
25:44expressed in primary myeloma cells.
25:46This again was a phase one dose
25:49escalation study to identify
25:50the recommended phase.
25:52Two dose then rolled 157 patients.
25:54102 received an Ivy dose
25:56and 55% cutaneous dose.
25:57The dose in schematic is outlined
26:00here with the highlighted in green.
26:02Being the recommended phase,
26:04two dose of 405 micrograms per
26:06kilogram and looking at key safety
26:08side of Henry Lee syndrome as seen
26:10in 68% of patients but no grade
26:13three at the recommended phase,
26:14two dose T styles duration 38 an
26:17injection site reaction in 21.
26:19The overall response rate was
26:2069% of the recommended phase.
26:22Two dose, and 200 Tupac
26:24refractory patients did respond.
26:25The medium kind response was
26:27one month similar to what's been
26:30shown with other BI specifics.
26:32Take her messages for this trial.
26:34Is that again,
26:35this represents another two new target
26:37in my lumbar for advice specific,
26:39it is a subcutaneous dose which
26:41may allow for Q two week dose sing,
26:43which would be more patient,
26:45convenient as the other bytes I've
26:47discussed are all weekly dosing.
26:49Again, responses were observed
26:50in heavily pretreated patients,
26:51including those where pepper
26:53factory and there's a possibility
26:54of durable responses as there was
26:56no progression at the medium,
26:58follow up at 3.7 months and they know.
27:02Have a duration of response
27:04that's over two years.
27:06The time remaining I'll just quickly
27:08touch upon three trials for a lamb alloy,
27:11two in the frontline setting
27:12and one in relapsed refractory.
27:14The Andromeda's trial was a phase
27:16three randomized trial for newly
27:19diagnosed Ale Android patients.
27:20Trainer idiot patients were
27:22randomized to receive cyber deed.
27:24Cytoxan process of dexamethasone
27:26plus or minus daratumumab which
27:28is a CD 38 monoclonal antibody.
27:31The primary endpoint of this trial was met,
27:34which was haematological CR at
27:3656.9 versus 18%.
27:38I want to evaluate the impact of
27:40achieving a deep reduction in serum
27:42free light chains on a composite
27:44endpoint of major organ deterioration
27:46progression free survival in order
27:48to evaluate at the production the
27:50evaluated a involved free light
27:52chain of less than 20 milligrams
27:54per liter and the difference between
27:56the involved versus uninvolved free
27:58light chain of less than 10 and what
28:01they showed it is patients with in
28:03the daratumumab arm achieved all of these.
28:0671.3% of patients had an involved.
28:08Reaching less than 20 and 65.6% had
28:11the difference being less than 10.
28:13This resulted in improved major organ
28:15deterioration progression free survival,
28:17which is illustrated in the graph here.
28:20So conclusion for this trial.
28:22The addition of daratumumab decide
28:24where D resulted in improvement in
28:27haematological response utilizing
28:28a variety of measurements.
28:30This resulted in improved rates of
28:32cardiac in renal organ response.
28:34In addition,
28:35haematological progression was
28:36improved 23 versus 47% and rates
28:39of cardiac arrhythmia failure will
28:41also improve with the addition
28:43of daratumumab at 3% versus 13%.
28:45This represents potential and you
28:47standard of care for these patients
28:50without friends. Treatment for Alienware.
28:52The second trial apps for Android is Cal 101,
28:56which is a nail Android 5 World reactive IgG.
28:59One monoclonal antibody.
29:00This was first mentioned at ASH in 2017.
29:02This is a phase two study.
29:04Determine the recommended phase
29:06three dose when given in combination
29:08with cyber DM Part A or with cyber D
29:10plus daratumumab in Part B patients
29:12were started at a dose
29:13of 500 mics per meter squared and
29:15this was escalated to the maximum
29:17tolerated dose with 1000 mics per
29:19meter squared weekly for four weeks
29:21and then every other week there
29:23were no infusion related reactions.
29:24Treatment related adverse events were all
29:27less than grade two and included rash,
29:29nausea, vomiting, and diarrhea.
29:31I've seen here also in patients
29:33with renal involvement had an organ
29:35response defined as a percent
29:37decrease from baseline in 24 hour
29:39approaching area of greater than 30%,
29:41and there was one cardiac response.
29:43I probably MP.
29:44So this compound is moving forward
29:46at the recommended Phase 3 to 7000
29:49mixed per meter squared weekly,
29:51and then times for than every other week.
29:54There are currently two phase
29:55three trials open,
29:56one for male stage 38 patients and
29:59the other for stage 3B patients,
30:01so I'm sure we will be hearing
30:03more about this compound to come.
30:05The last trial in relapsed refractory
30:07Elana Lloyd was with ice attacks
30:09map and this results from the
30:11Southwest Oncology Group 1702 trial.
30:13All patients who have received
30:14at least one prior line of.
30:16Therapy.
30:17And hadn't had one organ system involvement.
30:21Received text messages to 20
30:22minutes per meter squared.
30:24The primary endpoint was
30:25haematological overall response rate,
30:27which was 77% with a one year estimated.
30:30Overall survival of 97% when
30:32your estimated progression.
30:33Free survival of 85%.
30:34The safety and response data was
30:36similar to that previously reported
30:38with Darren to in our monotherapy
30:40in relapsed refractory Elana LA
30:42Justice and provides another
30:44treatment option for these patients.
30:46With that I will finish and pass it along
30:49to doctor Know Far Bar to finish up.
31:03and when the focus for the most
31:06part on car T cell therapies for
31:10relapsed refractory myeloma patients
31:12and then close with a few comments
31:17on autologous stem cell transplant
31:19for the newly diagnosed patients.
31:23So I want to remind everyone that
31:25patients who are we have been
31:28refractory to image producer members.
31:30An anti CD 30 antibodies have extremely
31:33poor prognosis with immigration,
31:35median progression,
31:35free survival of two to six months
31:38and most of them not living past
31:41one year and some terminology to
31:43remind you as those are refractory
31:46to the three classes of drugs or
31:49called triple or factory and those
31:51are refractory to two images.
31:53Two peas and anti clone the anti CD 38
31:57antibodies are called penta refractory.
31:59I'll be using those terminologies
32:02in my next slide.
32:04So the first study I'm going to
32:07be highlighting here is using
32:09the car T cell called Ida cell.
32:12In short,
32:13formerly known as BB 2121 an
32:15If you see here the construct,
32:18it has a binding domain against
32:20the CMA on the tumor cell and the
32:23intracellular domain includes the
32:25costimulatory molecule form 1B B.
32:27This was a phase one study and study design.
32:31Patients underwent local pheresis
32:32and then the cell product was
32:35taken to manufacturing.
32:36And then delivered back to the patient's car.
32:39T cell infusion before the patient
32:42gets the infusion, they get lifted,
32:44depleting therapy with food,
32:46European and cytoxan.
32:47And this is pretty routine
32:49schema for most Corti studies.
32:52In this study there were 62 patients.
32:55Majority of the patients received the
32:571:50 and the 450 million cells per cagey.
33:01This was a heavily pretreated population
33:03with median line of prior therapy of 670%.
33:07Being triple refactoring 27% had high
33:10risk cytogenetics and 37% or high
33:14risk by having extramedullary disease.
33:18So looking at the safety and efficacy,
33:20all patients have cytopenias and this
33:22is from the link for depleting therapy
33:25which is routinely used for Carty.
33:27I'm more focusing going to be
33:29focusing on this CRS decided kind
33:32release in German that I cans,
33:34which is the neurotoxicity we
33:35see with car T cell therapies,
33:38so 75% of the patients had CRS with
33:41about 6% having Grade 3 and above.
33:43In terms of the neurotoxicity,
33:45which can manifest as an several Catholic
33:48picture, but can be as severe as.
33:50Brain edema seizures 34%.
33:53I can't with very rare incidents of
33:59having Grade 3 or above less than 2%.
34:03Infections are very common in
34:05this patient population.
34:07Is we all know and 75% had infections
34:10with 23% being Grade 3 or above.
34:14Now look at the efficacy,
34:16it's quite impressive with an
34:18overall response rate of 76%.
34:21In this relapse population with the
34:23CR rate of 33% at the median Phillip.
34:27And that the response rate was
34:29dose dependent.
34:30So with higher doses they saw a
34:33higher overall response rate and
34:35the median follow up of 18 months.
34:37The great meeting duration of
34:40response was about 10 months and
34:42this was not affected by age,
34:44extramedullary disease stage
34:45and 50% of responders retained
34:47the response at over two years.
34:50This graph here shows you that the
34:54deeper responses actually lead to
34:56longer duration of response with those
34:58with CR exemplified by the blue line.
35:01Here having a median duration of
35:04response of almost 15 months.
35:06The median progression free survival was
35:0988 months with a very impressive meeting
35:13overall survival of 30 four months.
35:16Perhaps these patients were able
35:19to then get further treatments to
35:21lead to this impressive overall
35:23survival in this patient population.
35:25The next Accardi study is the
35:27car to Tud one study,
35:29and this uses a different car T product
35:32called still to sell it 2 bonds to be CMA,
35:34but it has two binding domains.
35:36As you can see here,
35:38and it also uses a four 1B B like
35:41the Ida cell.
35:42This study there was close to
35:45100 patients enrolled with a
35:48median follow up of 12.4 months,
35:51also heavily pretreated population
35:53with the meeting lines of prior
35:56therapy of 687% were triple refractory
35:58with 42% being penta refractory.
36:0123% high recited genetics and
36:0313% and extramedullary disease.
36:07Now let's look at the toxicity of cell
36:09to cell. So very high rates of CRS.
36:11Nearly all patients got this,
36:13but for the most part they were
36:15grade one and grade two with
36:16only 5% having Grade 3 or above.
36:18As you can see,
36:19there is 70% use of totsuzen Maps,
36:21but they were even using the dose
36:24who's map for some of the great
36:26ones which we do sometimes do.
36:27I can't see Neurotoxicity was seen at
36:3016% with two percent Grade 3 or above,
36:33which is similar to the prior study as well.
36:36They do comment on this other nurse
36:39Texas City that is more delayed and also
36:42sometimes not reversible like that.
36:44I can occur in about 12% of the
36:47patients in this involved movement
36:49or neurocognitive changes.
36:50There are investigating this further
36:52in in their subsequent studies as well.
36:54There is 20% of Grade 3 and
36:57above infections an.
36:58Of their 14 deaths,
36:596 or related to sell to sell
37:01what stands out in this study.
37:03It also is that there was a later onset
37:06of CR S with a median of seven days
37:08compared to two and other studies.
37:10They hypothesize this is because of
37:13the timing of the T cell expansion.
37:15Now the efficacy is very impressive,
37:18with an overall response rate
37:20almost 196.9% with the stringent
37:22CR of 67% on high rates of MRD,
37:25negativity responses are ongoing
37:27in 72% of patients.
37:29They have not reached their
37:31median progression free survival,
37:33and they estimated the 12 month
37:35progression free survival at 76%.
37:38As you can see here by the next graph
37:41that the progression free survival
37:43was improved for those patients who
37:46were in deeper response like that.
37:49Sponse as opposed to the very
37:52good partial response.
37:54So.
37:55I've showed you two Carty studies
37:57that have very impressive results.
38:00However,
38:00there is still room for
38:02improvement on car T
38:03cell products.
38:04Of course, not everyone responds.
38:06Not everyone responses deeply,
38:08and we still have significant
38:10toxicity that we need to mitigate.
38:12So not all T cells are created equal as
38:15you move toward the more early T cell,
38:19the T cells in earlier development,
38:21for example, like the steps on memory T cell,
38:24these memory like.
38:26Cells have certain qualities
38:27that make them attractive.
38:29There long lived.
38:30They have ability to self renewal
38:33and in others Carty studies these
38:35memory like T cells correlated with
38:38peak expansion and sustain response.
38:40Additionally,
38:41there's potential for less
38:43toxicity because there's gradual
38:45differentiation into the effectors,
38:46thus more gradual tumor killing
38:49and perhaps less static on release.
38:52So this concept was used in
38:55the next study that PBC MA 101
38:58prime Phase 1 two study.
38:59They use this technology called piggyback,
39:02which preferentially makes
39:03stem cell memory T cells.
39:05It's made with transposons,
39:06which are plasmids instead of lentivirus,
39:08which is what the prior
39:10Carty product we're using,
39:12and this one has a large carrying
39:15capacity so we can deliver
39:17a lot of genetic material.
39:20This too was directed against BCM of course.
39:23So this is the study design.
39:25I don't want to go into detail,
39:27but I want to highlight a few things.
39:30Not only were they looking at
39:32different doses who dose escalation,
39:33but they had the various cohorts
39:35as you can see here.
39:37Now I want to point out that there are
39:39using Lenalidomide in different time points,
39:41not only for anti tumor activity but also
39:44for improvement of T cell functionality.
39:46So what I do on the focus on is the
39:48response in Texas City on the 1st graph.
39:51Do you see different overall response rate?
39:54In different doses and they range from
39:57anywhere 40s to 70% overall response rates.
39:59They did not feel like there was a
40:03dose dependent relationship here.
40:04Thought that we're seeing a good
40:07responses even with low doses
40:09and marked late you see that they
40:12were really low rates of CRS.
40:14It's 17%.
40:15So this exemplifies how a manufacturing
40:18technique can manipulate the T cell
40:21product to optimize the toxicity
40:23and efficacy and potentially bring
40:26this cellular therapy to the
40:28outpatient setting at some point.
40:32There are potential issues with car T cells,
40:35right?
40:35So it takes time to manufacture the cells.
40:38Some patients don't have that time.
40:40You know we see this patient
40:42needs treatment right away.
40:44We can't schedule the Pheresis
40:46in manufacturing and so forth.
40:47Additionally,
40:48the quality of autologous T cells
40:50might be decreased in this relapse,
40:52refractory patient population and
40:54re treatment can be difficult,
40:56sometimes hard to collect enough
40:58cells and be able to expand them.
41:01So this brings us to the off the
41:04shelf Alo 7:15 Carty targeting
41:06the CMA in this Phase one study.
41:10This is the construct here.
41:13What the the two key attributes is
41:15a knockout of CD 52 which allows
41:17for selective room for depletion.
41:19All lymphocytes have CD 52 by
41:21the way and it
41:23also has a knock out of the
41:25TCR gene to eliminate GV HD.
41:28It used a slightly different
41:29regiment for Lymphodepletion,
41:31so it's flu side plus the anti
41:33CD 52 versus Cyan anti CD 52 but
41:36the one I'm highlighting here.
41:38The flu sign anti CD 52 is the one
41:41they're presenting now but there is
41:43potential for maybe a less toxic went
41:46for the cleaning therapy here so also
41:49heavily pretreated population and
41:51almost all the more pent pent Xposed
41:54about half of them had high recited
41:56genetics and 23% and extramedullary disease.
41:58There were 31 patients available for safety.
42:01And they had 47% serious with no grade.
42:04Three. No, I can't.
42:06And no GV HD.
42:08So a very promising toxicity profile.
42:10Again, this is a very good drug that I
42:13think we're going to see more studies
42:16with an more follow up will tell
42:19us more information, of course. Um?
42:22The efficacy of alacarte in 10 patients,
42:26so they had various doses.
42:29There are temptations in the dose Level
42:323 and it follow up of 3.2 months.
42:36The overall response rate was 60%
42:38with a very good partial response
42:42or higher or 40%.
42:44Now on the shift gears,
42:46a little bit to the good old autologous
42:50stem cell transplant for myeloma.
42:53This is an update of the FM 2009 study
42:56that was originally presented in 2017,
43:00so now it's a follow up of almost 90
43:03months just to remind people to phase
43:06three study newly diagnosed patients.
43:09Arm A is looking at testing RVD
43:12induction followed by maintenance
43:14Lenalidomide for one year,
43:16and RB is RVD induction followed
43:19by transplant,
43:20followed by RBD consolidation
43:22and then maintenance.
43:23In the limit for a year so their updated
43:27median progression free survival was
43:3047.3 months in arbutus to transmit arm
43:34versus 35 months in the non transplant arm.
43:38They had very nice overall response.
43:41I'm sorry very nice eight year.
43:44Median overall survival
43:45about 6060% in both groups,
43:46so they were not difference.
43:48There is no difference there and I
43:50just want to highlight that about 1/3
43:53of the patients in the transplant
43:55arm did not relapse after 8 years of
43:58follow up and these are patients that
44:00are not being treated continuously.
44:02They're only getting one year of maintenance.
44:05This is not the practice we do here
44:07in America and I think there's going
44:09to be more information with the US
44:12portion of this study looking at continuous.
44:15REVLIMID and whether that is
44:17going to affect this progression.
44:20Free survival benefit.
44:21Now,
44:21in terms of MRD transplant did improve
44:25the energy negativity rate from 20 to
44:27about 30% and in this graph you see
44:31the progression free survival based
44:33on MRD negative state and the transplant.
44:36So in red you see those
44:38patients who are MRD negative.
44:40While I'm blue there emordi positive.
44:44And you can see that the transplant,
44:47exemplified by the solid line
44:50improved progression free survival
44:52even in the MRD negative patients.
44:55Next study I'm going to highlight
44:57was already presented by
44:58Natalia, but I want to focus on one aspect.
45:01Here is the Forte study.
45:03Not going to go into the design.
45:05This was already discussed,
45:06but one take home messages this
45:09so while you see in the first
45:11graph here the response rate,
45:12the response rates,
45:13and an MRD negative status was similar
45:16in KRD versus kerdi plus transplant.
45:18The one year sustain energy
45:19negativity was higher for the kerdi,
45:21plus transplants as you can
45:23see here in the second graph.
45:26And this translated into improved
45:28progression free survival for all subgroups,
45:30including the high risk patients.
45:32So I think to conclude on on this
45:35section is that transplant is
45:37still a great treatment for upfront
45:40patients who can tolerate it.
45:42And with this I will close my
45:45talking will move towards our Q&A.
45:50Great thank you know far and
45:53thanks everybody for beautiful presentations.
45:55I do not see any active questions.
45:58Doctor up they had an earlier question
46:01which I answered the smoldering
46:03trial date that I presented.
46:05Patients who are newly diagnosed as
46:08opposed to those in long term follow up.
46:11I'd like to hear opinion from
46:14Sabrina what's been your strategy
46:16in terms of managing high risk,
46:19smoldering patients in your?
46:20Practice, thank you to tell you,
46:23I think that's an important question,
46:25and obviously one where
46:26multiple combinations are
46:27being studied. You know, I think with
46:30the data available on Lenalidomide
46:31or Lenalidomide, dexamethasone.
46:32I think I've still had some
46:35pause in terms of the lack of
46:37overall survival data available
46:38in terms of benefit, you know,
46:41I think it's important to acknowledge
46:43that our discussion of treatment in
46:45patients who are asymptomatic is is
46:47very much different than patients
46:49who have active or clinical myeloma.
46:51And so I think the importance of
46:54overall survival benefit is really
46:56important to include in that discussion.
46:58So I would say my practice has
47:01been to discuss the data available,
47:03including the trials that are
47:05looking at different combinations
47:07outside of Lenalidomide,
47:08but I would say in general I
47:11continue to observe most patients.
47:13Thank you, ultimately we do need to
47:16understand more about the biology of
47:18disease of each individual case to
47:20address the prevention of progression.
47:23Another question comes through the
47:25chat question for I would posit
47:27it to Doctor Parker.
47:28How would you view the sequencing and
47:31where should we position car T cells
47:34versus the bispecific antibodies?
47:36Given that the response rates
47:37are quite significant for both?
47:41Yeah, I think that's a very good question.
47:44Very difficult one to answer and also be
47:47interested to hear no cars take as well.
47:50You know currently we don't have any trials.
47:53Obviously comparing head to head
47:54car T versus the specifics and
47:57looking at the BI specifics that are
47:59against BC mayor targeting the CMA.
48:01They do have somewhat similar response rates
48:04an it's but I really think how we position
48:08him is going to come down to one safety.
48:11What is the cytokine release?
48:12What is the neurotoxicity in
48:14these agents and then two is?
48:16Can we move party to the
48:18outpatient setting with these?
48:20Engineer does know for discussed
48:21bites are a little bit maybe a little
48:24bit more user friendly I guess.
48:26Is there off the shelf versus the
48:28Carty has to be manufactured so also
48:31keeping in mind it may come down
48:33to one patient needs therapy now
48:35device specifics that are targeting
48:37other things besides BC MA did have
48:40activity in those patients who had.
48:42Why are car T so it is feasible
48:44that you could do party followed by
48:46a fight with a different targets.
48:48But again I think we need a lot
48:51more data know for what
48:53is your take.
48:53Yeah I think you're right.
48:55I think we're still early.
48:57Unfortunately it's hard to compare
48:58head to head these studies because
49:00some of these are off the shelf.
49:02Some of these need time so it's study to do.
49:05I think one thing to keep in mind is
49:08that bites you have frequent dosing,
49:10whereas Carty is at one time.
49:12Infusion so that's been
49:14attractive for patients.
49:15Also, it's important to remember
49:16that you know for bites you you
49:19need a good indulgence T cells.
49:21So it went in terms of sequencing.
49:23Someone were to sequence.
49:24You want to give some time if someone
49:27gets it Carty and they're getting one for
49:30depleting therapy in their progressing,
49:32giving them a bite is not
49:34going to be very useful.
49:36So waiting a few months for improvement
49:38in their in their counsel lymphocyte
49:40count would be important to remember.
49:42Although I know these patients
49:44are very sick and some treatment.
49:46Thank you Terry and no far another
49:49question from Doctor Gowda.
49:51In the with the advent of BCM a
49:54targeted drug conjugates antibodies.
49:56How do how do we select again BC MA targeted?
50:01Whether we propose using an antibiotic
50:03conjugates or at the CMA cart.
50:06I think to some of this
50:08you already alluded to,
50:10but any further comments?
50:16I again I think it's hard.
50:19I think whenever we choose a
50:21treatment for our patients,
50:23it's looking at the patient looking the
50:25disease and looking at the convenience
50:28and toxicities of the drug and an adjusting
50:30it to them individual preferences.
50:33Another question from Doctor Gorshin
50:35with the updated Griffin data,
50:37does this impact our decision upfront
50:39therapy for high risk disease.
50:41KRD reverses Dara RVD.
50:43I think KRD still remains a very powerful
50:46induction therapy with very good.
50:48Fresh listen with sustain standards
50:50with continued therapy off.
50:52Note when you look at the composition
50:55of patients in the trials,
50:57the port a trial had about 30% of
51:00high risk patients that they all
51:02equally benefited with Dara RVD.
51:04This is a face to randomization
51:07and there were 15% of patients who
51:10harbored high risk cytogenetic profile
51:12and in their forest plots of data
51:14which I didn't present in the slides.
51:17It appeared that as though higher
51:19risks are genetic profile patients.
51:22May not have experienced the same
51:24magnitude of benefit in terms
51:27of deeper responses,
51:29so I would say there seem to
51:32be equally potent regiments.
51:34My own.
51:35Practice preference has been KRD for
51:37high risk patients generally and this
51:40I hear from some other institutions as well,
51:43but again practice patterns very in
51:45more data on the long term follow up
51:48is needed from the Griffin trial to
51:51you know where we don't have yet the
51:54progression free survival benefit.
51:55Eras for the for the four day trial,
51:59we have significantly longer follow up,
52:01so I think both regiments could be
52:04used interchangeably depending on the
52:07practice pattern off the institution.
52:09One question from Doctor Gowda.
52:13At relapse, for instance,
52:15if a patient was previously exposed
52:18to anti BCM, a targeted therapy,
52:20what is the BCM? A expression?
52:23Has this been looked at in the literature?
52:26I would ask either one of the speakers,
52:29but perhaps more so so far.
52:32So I know they are looking at it.
52:35I I don't recall if they published it,
52:37but there's a lot of and they're
52:39also looking at Solomon Soluble.
52:41Be CMA in the blood, but I can't recall.
52:46What's published? Yeah,
52:48I don't believe there is
52:50any published data on this.
52:52To my knowledge.
52:53I know each individual company is
52:55conducting their Olalla Sideclick
52:56preclinical and correlative
52:58studies to examine this,
52:59but not entirely clear yet.
53:03So with that, I think we're
53:05a four minutes after the hour.
53:07Thank you for the excellent
53:09presentations. All of you.
53:11I really appreciate everybody joining.
53:13I hope this was an informative
53:15session and hope to see you all
53:17for the subsequent sessions of
53:19the ash highlights. Thank you.
53:22Have a great day everybody.
53:24Thank you for organizing doctors item.