Multiple Myeloma: Treatment Advances and Clinical Trials

July 01, 2021

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Presentations by: Drs. Noffar Bar, Sabrina Browning, and Tara Anderson, MSBS, PA-C

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00:00Joining us today to talk a little
00:03bit about multiple myeloma.
00:04I am new for Barnwell,
00:06the myeloma doctors here at Yale and we will
00:09be talking about three different topics,
00:12each about 15 minutes long and then
00:15will have 15 minutes of discussion Q&A.
00:18So I will be talking about understanding
00:21myeloma come my colleague, Doctor
00:23Sabrina Browning will be talking about.
00:27More specific.
00:28About the new treatments out there
00:32for multiple myeloma and or.
00:35Really excellent physician assistant
00:37Tara Anderson will be talking about
00:40Texas cities of certain drugs and
00:42then we'll have our the rest of
00:44our team join us for the question
00:46and answer and doctor Terry Parker
00:49and Doctor Natalia will parts so.
00:52With that we will start our.
00:55Session.
00:572nd.
01:07Alright. So my goal for the next
01:1115 minutes is to give you some
01:14insights into understanding what is
01:16multiple myeloma and some general
01:18principles of how we think about
01:21treatment for multiple myeloma.
01:26I have no disclosures.
01:29I'd like to start by talking
01:31about the bone marrow,
01:33which is where my llama lips,
01:34now the bone marrow,
01:36is a spongy part of the bone,
01:38and it's in charge of making some
01:40important cells in our body.
01:42It makes red blood cells,
01:43which carry oxygen and give us energy.
01:46It makes platelets which prevent
01:48bleeding and it makes white blood
01:51cells which help fight infections.
01:53Now, one of the white blood
01:55cells is called plasma cells,
01:57and these plasma cells help our
01:59bodies fight infection by making
02:01antibodies and antibodies are proteins
02:03that bind to foreign substances,
02:06for example, like a bacterial infection,
02:08and it helps kill it and
02:10clear it from the body.
02:12Now, under normal circumstances
02:14we have a small amount of these
02:17plasma cells in the bone marrow,
02:19roughly 5% or so,
02:21and they make a variety of antibodies.
02:24So uhm, no antibody is like the other.
02:28Now, if one of these plasma
02:30cells is now becoming cancerous,
02:32it's abnormal normal.
02:33It's able to replicate itself
02:35and make a clone out of itself,
02:37and in doing that it over crowds the
02:40bone marrow with too many of these
02:42abnormal plasma cells and they no
02:45longer make variety of antibodies,
02:47but rather they make a lot
02:49of 1 type of antibody.
02:52And this is what we called the
02:54monoclonal protein M spike and protein,
02:57all different names for the same thing.
03:00And this antibody can be one of the common
03:03antibodies that are found in our bodies,
03:06most commonly,
03:07IgG IGA is often also seen and more
03:10rarely IG M and IG D Now a part of
03:13that protein is called the light chain,
03:17and it's either Kappa or Lambda.
03:20So a monoclonal protein can be identified,
03:23for example,
03:24is an IgG Lambda and IGA Kappa,
03:26and that is that that
03:29clone for that individual.
03:32So how does multiple myeloma affect the body?
03:34How does it make someone feel?
03:37I'm gonna talk about some of the common
03:40manifestations of multiple myeloma,
03:42but I want you to remember that
03:44not all of these are found in every person.
03:47OK,
03:48so the first thing is high calcium level OK,
03:51and I and I put this.
03:53See for that here and
03:55sometimes high calcium levels.
03:56It's not that bad.
03:57It's not going to make anyone
03:59feel anything differently,
04:01but if it's very high it can make
04:03someone feel unwelcome cause confusion.
04:05You can cause some Constipation
04:07or abdominal discomfort.
04:08So I put the picture there to
04:11just to signify that the next
04:13is represented by the letter R.
04:15So are standing for renal,
04:17another word for renal is kidney,
04:20so my Loma cells and the proteins that
04:23they produce can cause damage to the kidneys.
04:26Next,
04:26a four anemia,
04:27so that's low red blood cell count and
04:30therefore you have less oxygen going around.
04:332/2 essential organs.
04:34People feel tired in this situation.
04:36They're not able to do.
04:38Their daily activities.
04:41And lastly,
04:42be standing for bone pain or bone lesions,
04:45and a lesion is any kind of
04:47abnormality seen in the bones.
04:49And so in myeloma you can have either
04:52holes in the bones and this can make
04:54the bones weaker and you can have
04:57fractures which can cause pain,
04:59but sometimes more rarely we see
05:01actually accumulation of these
05:03abnormal plasma cells forming a ball
05:05or a mass and this can be within
05:07the bone or outside of the bone
05:10and we call these plasmacytomas.
05:12So you can see the CRA beat spells crab
05:15and this is the famous crab criteria or
05:18crab symptoms that we often talk about.
05:21Or you might have read.
05:24Now the definition of myeloma has
05:27changed over time for many many years.
05:30Basically, yes,
05:31you had to have these abnormal plasma cells,
05:34but you had to have met one at
05:37least one of the crab criteria
05:39that we just talked about.
05:42Things changed in 2014.
05:43The criteria changed and now we
05:46have slim crepe.
05:47How did we get slim?
05:49So to really understand why
05:51and how Slim came about,
05:53we have to go back and
05:55understand the precursor,
05:56the condition that comes before
05:58multiple myeloma called this
05:59the precursor states myeloma.
06:00We know that all patients who have
06:03myeloma before they developed
06:04in myeloma had these abnormal
06:06plasma cells exist within a small
06:08quantity small quantity and it
06:10didn't cause any trouble so you
06:12wouldn't know you had them unless
06:15you actually go and look for them.
06:18The majority of patients with M Gus
06:21actually don't progress to myeloma,
06:24but some.
06:27Do you move on to the next
06:28step and the next step is what
06:31we called smoldering myeloma.
06:32Now smoldering my luma and us both
06:34don't have any crab criteria.
06:35What we called the precursor states,
06:37but the difference between them
06:39is smoldering element has more
06:40plasma cells as you can see here.
06:42If you go by the correct by,
06:44the technical definition should
06:45have more than 10% plasma cells
06:47in the bone marrow.
06:49But what does this mean to the person right?
06:52How does that affect you?
06:53Uhm, well,
06:54the risk of progression to myeloma is
06:56slightly higher in the smoldering group,
06:58where we have a 10% an average
07:00risk of progression to myeloma.
07:02Compared to 1% in the US population.
07:07Now looking at the Group of smolder
07:09malama little bit more closely,
07:10yes, we have a very well.
07:13Defined, you know, definition for this,
07:15but the folks in this group are quite
07:18diverse and not everyone is the same,
07:20so we have.
07:23Patients here that actually behave
07:25their disease behaves more like M Gus,
07:27and they never progress to multiple myeloma.
07:30On the other hand,
07:31we have patients who behave
07:33more like myeloma,
07:35and they actually progressed to
07:36those crab symptoms fairly soon
07:39after the diagnosis of small drink.
07:41So many researchers in the community
07:43of myeloma have focused their
07:45attention to this group of patients
07:47trying to figure out who really
07:50should be in the myeloma group.
07:52And that's where this slim criteria.
07:54That's why they identified
07:57three important qualities.
07:59Come in, that's. Here so S stands.
08:04But sorry, three important qualities
08:06that that predicts the rapid
08:09progression to multiple myeloma.
08:121S stands for 60% or more plasma
08:14cells within the bone marrow.
08:16Li stands for a light chain ratio
08:18over 100 and M stands for MRI,
08:21showing more than one lesion,
08:22and this is important 'cause we used to
08:25just use X rays to look for these lesions.
08:28These holes in the bones.
08:30Now we know this is not enough and we
08:33need to use more advanced imaging for
08:36these particular patients to identify.
08:38No lesions that would move
08:41you into the myeloma category.
08:44So now that we have no diagnosis of myeloma,
08:47what do we do?
08:48When is our goal for treatment
08:50for this disease?
08:51So anyone that has myeloma has a
08:53certain amount of disease at diagnosis.
08:55What we called the disease burden,
08:57and we measured this through
08:59one of the blood.
09:00So we look for that M protein.
09:02The bone marrow looked the amount
09:04of plasma cells in the bone marrow,
09:07and thirdly imaging, right?
09:08So we look at the amount of bone disease,
09:11but we also look for these.
09:13The solid form of myeloma.
09:14The PLASMACYTOMAS,
09:15which is important to know.
09:17And.
09:18Yeah,
09:18my goal is to kill as many plasma
09:21cells as we can to get these deep
09:24responses and to keep people in
09:27response for as long as possible.
09:30Unfortunately, this you know some point.
09:32The disease does come back.
09:34We do not think myeloma is a
09:36curable disease at this time.
09:38So when the disease comes back,
09:40we do have other treatments and
09:42we bring the disease back down
09:45and this pattern goes on and on.
09:50I want to take just a few minutes to talk
09:53about response assessment for myeloma.
09:55How we assess the response?
09:56So as I mentioned, we look at the blood.
09:59We look at this protein.
10:00We also look at the bone marrow to look
10:02at how many plasma cells are there.
10:04So once we start treatment we measure the
10:06lab 'cause it's very easy to look at blood
10:09work and we see how the protein falls.
10:11If you've had a 50% reduction,
10:12we call this a partial response.
10:15Uhm, if you've had disappearance
10:16of this protein and then when
10:18you look at the bone marrow,
10:19you don't find any of these abnormal
10:21plasma cells when you look with your eyes.
10:24It's then we call this a complete response,
10:27which is great.
10:28Nowadays we actually have even more
10:31sophisticated tests tests that look
10:33at really microscopic level of disease
10:35looking at the DNA of the plasma cells,
10:38and if we don't find this DNA
10:40in the bone marrow's.
10:43We call this the deepest response.
10:46Call it minimal residual disease,
10:48negativity murdy negative negativity
10:51and you might have heard about this.
10:55This measurement and I just wanted
10:57to bring it up here so people
10:59understand what this really is
11:00and what are we looking at.
11:02And we do this in clinic and it's also
11:04been investigating clinical trials
11:05and this is a very important point.
11:11So how do we get these deep responses?
11:14How do we choose initial therapy initial
11:16therapy in my limits called induction.
11:18OK, so we're lucky we have a lot of
11:21different drugs and they're very
11:23effective at killing plasma cells,
11:25and they've been used in induction.
11:27I categorized them here under different
11:29colors and shapes to signify that each
11:32group represents a drug that acts a little
11:34bit different in how it kills my llama,
11:37and we like to combine the drugs
11:39in these different groups.
11:41To get the best responses as we can.
11:44And I'd say for the most part,
11:47we really and think that
11:50combining proteasome inhibitors.
11:51Juicy down here,
11:53along with Imids,
11:54a module to her drugs and steroids
11:56as being very effective and one of
11:59the most commonly used treatments has
12:01been Velcade REVLIMID index method zone.
12:04I think one of the more recent
12:06advances is adding daratumumab,
12:08the monoclonal antibody to this regiment,
12:10and this is also been shown to have
12:13very very great responses,
12:15and so you know on one hand the coin one
12:19side of the coin I'm telling you about.
12:22Obviously want very effective treatment,
12:24but we also want to look at the
12:26other side and how this dream is
12:29affecting the individual right.
12:30So these drugs have toxicities have
12:32side effects we want to make sure that
12:35the patient the individual can tolerate it.
12:37So just to give you an example
12:39from someone with kidney disease
12:41which you can have with my Loma
12:43doesn't tolerate limit very well.
12:45So in this case we might use cytoxan instead.
12:48You know some folks you know four
12:50or even three drug books might be.
12:52Too difficult,
12:53and in that situation we use two drugs,
12:56so the bottom line is we want a
12:59very effective treatment that will
13:00be well tolerated,
13:01and that's how we choose
13:03our induction treatment.
13:06Initial therapy doesn't stop with induction,
13:08as many of you know,
13:10we have several cycles of induction,
13:12but then we move on to different treatments.
13:14So for some folks we do recommend high doses
13:16of chemotherapy and stem cell transplant,
13:18and that's again to deepen the responses
13:21and prolong the time you stay in response.
13:23But this is.
13:26Cancer treatment with significant
13:27side effects and that recovery time
13:30so it's not meant for everyone.
13:32It is something to decide
13:34on individual basis.
13:36Regardless, if you get a transplant or not,
13:38after induction you move onto to
13:41maintenance and maintenance is
13:42really you know what it stands for.
13:44It's meant to maintain the the disease and
13:47are good levels so it doesn't come up,
13:50but meant to be well tolerated so
13:52you can continue this for years.
13:54So often we use one drug or maybe
13:572 for some situations,
13:58or the disease might behave a little
14:02bit more aggressively and we continue
14:04this for as long as as we can.
14:07As I mentioned,
14:08at some point the disease does
14:10come back and we do need to think
14:13about different treatments.
14:14So how do we decide treatment at relapse?
14:17Well, we choose a different combination.
14:19Again,
14:19we'd like to choose combinations
14:21from different classes of drugs here,
14:23so I added a few to my list to
14:26my treatment menu.
14:27Here we have palm list,
14:29which is the 2nd generation of the relevant.
14:32That meant we also have other other
14:34monoclonal antibodies, like below,
14:36and we basically choose something
14:38you have not had before.
14:39Often we use pomalidomide as the
14:41second it you include pummel,
14:43admired in the combination.
14:45Second treatment, and then if you
14:47need a third or fourth treatment,
14:49we're very lucky that our treatment
14:51menu is growing and is continuing to grow.
14:54So we have selling X or we have a blunt wrap.
14:58We have now male flap.
15:01And most recently, the cartee avec ma.
15:04And least, but not.
15:06Sorry,
15:07last but not least clinical trials,
15:09so we have an assortment of clinical
15:12trials where it gives opportunity to try new,
15:15very possibly very effective
15:17treatment for myeloma.
15:18So with that I'd like to conclude
15:20my section of the talk and move
15:23on to doctor Sabrina Browning.
15:25He will talk about the details
15:28of these newer agents that we
15:30have for to treat myeloma.
15:47Great, OK, so good evening everyone
15:49and thank you again for joining us.
15:52Come again. My name is Sabrina
15:54Browning as Doctor Barr stated.
15:56I am one of the doctors in our multiple
15:59myeloma gammopathy program here at Yale.
16:01So in this next part of our discussion
16:04I will review recent advances in the
16:06treatment of multiple myeloma and
16:08specifically will focus on the newly
16:11approved medications for patients.
16:12Either that have relapsed so with
16:15recurrence of their disease or refractory.
16:17They're not responding to
16:18their current treatment.
16:24And I have no disclosures to report.
16:28So fortunately, as a result of the
16:31introduction of new medications and
16:33combinations of my Loma agents,
16:35as stated by Doctor Bar
16:36over the last few decades,
16:38there has been significant improvement
16:40both in prognosis and quality of life.
16:43For those letter living with
16:44multiple myeloma, the major classes
16:46of medications used in myeloma,
16:48as touched upon by Doctor Bar,
16:50which may be familiar to you or listed here,
16:53and they include the immunomodulatory
16:55agents or imids proteasome inhibitors,
16:57or Pi monoclonal antibodies.
16:58Alkylating agents and the histone
17:00DSS release inhibitor referred
17:02to as put in a panobinostat.
17:04These medications have been or are
17:07currently being studied as a part of.
17:10Combination regimens and many
17:11are targeting earlier in disease
17:13course as Doctor Barr mentioned,
17:15our treatment going myeloma is really
17:17to achieve what we refer to as deep or
17:19maximum responses to therapy that are
17:22prolonged without disease progression.
17:24And while we won't review this
17:26agent in detail today,
17:27I've signaled Isatuximab in the chart
17:29here as a more recently approved
17:31antibody that targets a protein known
17:33as CD 38 found on immune cells and
17:36myeloma cells and isatuximab is now
17:39approved for use in combination with.
17:41Both pomalidomide and dexamethasone,
17:42as well as with carfilzomib
17:44and dexamethasone,
17:45and is being studied further
17:47in additional clinical trials.
17:50So what has remained a challenge
17:52and an area where improvements
17:54are essential is the treatment of
17:56individuals with myeloma who have
17:58received multiple lines of therapy,
18:00particularly those who are no
18:01longer showing response to the
18:03P eyes or proteasome inhibitors.
18:05The imids immunomodulatory agents
18:06or the monoclonal antibodies and
18:08this is referred to as a triple,
18:10reclass refractory disease,
18:11and as you can see here,
18:13in addition to isatuximab,
18:14there have been four other agents
18:17approved over the last two years for
18:19the treatment of individuals with.
18:21Relapsed or refractory myeloma and this
18:23really presents great opportunities
18:24and promise for our myeloma patients.
18:26And so we'll review each of these
18:28medications and in more detail,
18:29and we'll have time at the end of our
18:33discussion for any questions that come up.
18:36So firstly is selinexor which is a
18:38small molecule that binds and blocks
18:40exportin one and export and one is a
18:43protein that's found on myeloma cells
18:45that can promote the growth of tumor
18:47by removing proteins from the myeloma
18:50cells that are meant to suppress the tumor.
18:52However,
18:53if you see here in the in the
18:55figure on the right when selinexor,
18:57which is also referred to as selective
19:00inhibitor of nuclear export or sign,
19:02is bound to this exportin.
19:03One.
19:04The tumor suppressors can accumulate
19:05in the nucleus of the cell and the
19:08body then can eliminate tumor cells
19:10while preserving normal cells.
19:12Selinexor is the first drug in this
19:14class of medications and is being
19:16studied in other blood cancers as well.
19:18In multiple myeloma,
19:19selinexor is approved as an oral
19:22pill at a dose of 80 milligrams,
19:24taken twice per week with the steroid
19:26dexamethasone and this is for
19:28individuals with relapsed or refractory
19:30myeloma who have received at least
19:32four prior lines of therapy and are
19:34no longer responding to at least two
19:36of the pies previously discussed.
19:39At least two images and an anti CD.
19:4138 monoclonal antibody selinexor
19:43is also approved at a dose of
19:45100 milligrams once per week with
19:47Bortezomib and dexamethasone.
19:48For patients,
19:49again with three lobster refractory myeloma.
19:51But this time,
19:52those who have received only at least
19:55one prior line of therapy and these
19:57approvals are based on the storm and
19:59Boston clinical trials, respectively,
20:01which we'll talk more about.
20:04So the storm clinical trial evaluated
20:07122 patients in the US in Europe
20:10who had this triple refractory
20:12multiple myeloma that I mentioned
20:14and had received a median of seven
20:16lines of prior treatment.
20:18These individuals were given oral selinexor,
20:2180 milligrams and dexamethasone 20
20:23milligrams, both twice twice a week,
20:26and 26% of these patients achieved
20:28what doctor bar defined as a partial
20:31response or more than 50% improvement
20:34in their monoclonal protein.
20:36And while 30 and end of this group,
20:3939% of patients had at least a
20:41minimal response and responses
20:42overtime in those patients who did
20:44have at least a partial response or
20:47seen in the figure here at the left,
20:49the median duration of the response
20:51or the
20:52median time that the response
20:54lasted was about 4.4 months.
20:56And then the second trial with Selinexor is
20:59the multicenter phase three Boston trial,
21:01which looked at 402 myeloma patients.
21:05That were treated with one to
21:07three prior lines of therapy,
21:08and these patients were randomly assigned
21:10to get either selling X or 100 milligrams
21:13once per week combined with Bortezomib.
21:15The proteasome inhibitor and dexamethasone.
21:17The steroid or Bortezomib and
21:19dexamethasone alone and what's shown
21:21here in the figure on the right is that
21:23the patients who received selinexor,
21:25so they sell an extra group,
21:27had a longer time without disease.
21:29Progression at a median of 13.9 months
21:31when compared to the group who only
21:34got Bortezomib and dexamethasone.
21:36Where the progression at the time
21:38without progression was about 9.5 months.
21:41The more common side effects observed
21:43with selinexor in both of these clinical
21:46trials and in practice include fatigue.
21:49Gastrointestinal symptoms such as nausea,
21:51infections, and low blood counts.
21:54Thrombocytopenia or low platelet
21:55count in particular,
21:57was seen in 73% of patients and storm,
21:59although in the Boston trial,
22:01even though patients had low platelet counts,
22:04they did not have significant bleeding
22:06events or complications with bleeding.
22:08Notably,
22:09the use of anti nausea medication,
22:11so medications to try to prevent
22:13nausha is really important with
22:15selinexor and one specific approach
22:17that has been used by our group
22:19and others is to give a medication
22:22called olanzapine or Zyprexa daily.
22:23With treatment to try and prevent
22:26the onset of significant nausha.
22:28Side effects from selinexor do
22:30appear to improve as after initial
22:32treatment or as treatment continues
22:34and they can be well managed with
22:37supportive care and are reversible.
22:39If this selinexor is stopped.
22:44The next agent will discuss is
22:46Bill Lanthanum Alpha Dowtin,
22:47which is a medication made up of an
22:50antibody that's attached to a drug that's
22:53toxic or can kill myeloma cells and as
22:56seen in the figure here on the right,
22:58it binds what's referred to as B
23:01cell maturation antigen ORB may,
23:02which is a protein on the surface of
23:05myeloma cells that overexpressed.
23:07So there's more than than in normal cells,
23:10and this allows for delivery
23:11of mpid open into the cells.
23:14Resulting in interruption or stopping
23:16of cell division and myeloma cell death.
23:18Blanton on methadone and also
23:21improves or enhances the body's own
23:23immune spot response are the immunes
23:25ability to fight off myeloma cells.
23:28Blanton AB is approved as a single agent,
23:31a single medication at a dose
23:33of 2.5 milligrams per kilogram,
23:36which is administered through
23:37intravenous infusion.
23:38Once every three weeks,
23:39and this again is approved for
23:42patients with relapsed or refractory.
23:44Hi Wilma,
23:45who have received at least four
23:47prior therapies including Apiai,
23:49Imid and an anti CD.
23:5138 monoclonal antibody and this
23:53is based off effectiveness that
23:55was shown in the dream two study.
24:01So the dream two trial evaluated
24:04this first anti BCMA antibody drug
24:06conjugate in 196 patients with
24:08relapsed or refractory myeloma who
24:11had received at least three lines of
24:14treatment prior and were refractory
24:16or were no longer responding to the.
24:19Again, the three categories of medications
24:21we talked about frequently, the P,
24:24imid or immunomodulatory agent and an
24:26anti CD 38 monoclonal antibody and these
24:30patients studies were rent studied.
24:32End of my story.
24:33See if either a 2.5 milligram
24:35per kilogram dose of Balanta map
24:38or 3.4 milligrams per kilogram,
24:40and this was given intravenous,
24:42intravenously or through through
24:43an Ivy every three weeks.
24:45The overall response rate in
24:47the dose that's recommended,
24:49which is the 2.5 milligrams per kilogram,
24:51was 31%,
24:52and 60% of these patients who responded
24:55had at least a very good partial response,
24:58which is a improvement in the
25:00monoclonal protein of more than.
25:0290%.
25:03Overall response rate was also
25:0638.5% in the the population of
25:09patients who had higher risk
25:11genetic features to their myeloma.
25:14And in this population is
25:16often a harder to treat,
25:18and the median time to response
25:20for Balanta map was 1.4 months,
25:22with 73% of those patients
25:24who achieved a response.
25:25Having it maintained at least
25:27for six months at the time that
25:30this clinical trial was reported.
25:32A major category of side effects
25:35with with Balanta map or the eye
25:37disorders that are listed here
25:39and observed in 77% of patients
25:41in this clinical trial and mainly
25:43the the side effects in regards
25:45to eye symptoms are related to
25:47changes that happen in the cornea,
25:49which is the very front part of
25:51our I and these changes are known
25:54as keratopathy and the reported
25:56frequently within mostly the first two
25:58treatment cycles and they may require either.
26:01A reduction in dose or
26:03holding of the treatment.
26:05Learning about these eye symptoms
26:07has prompted a requirement for
26:09patients with angle antiknock ticket.
26:12Regular eye exams for close monitoring
26:14and also it's recommended that
26:16individuals on this medication
26:18use a lubricant.
26:19Eye drops regularly and avoid contact lenses.
26:23Other potential side effects associated
26:25with Blanton Mabor listed here.
26:27They include allergic,
26:29type or infusion related reactions,
26:31infections, and low blood cell counts.
26:37So Next up is melphalan Fluphenazine
26:39mid or malfouf in and this again
26:42is a first in class medication.
26:44It's a peptide which is a short chain
26:47of amino acids and it's combined
26:49with or conjugated to an alkyl
26:52later drug similar to the melphalan
26:54that we had discussed previously.
26:56And what happens is this medication
26:59can rapidly enter and be released
27:01into myeloma cells,
27:02causing irreversible damage
27:03to the DNA of the tumor.
27:05That's important for two.
27:07Or growth and this therefore
27:09leads to cell death.
27:10Melphalan Fofana Mid is approved
27:12at a dose of 40 milligrams.
27:14It it two is given by intravenous infusion,
27:17but once every four weeks and it's
27:19combined with the steroid dexamethasone,
27:22which is administered weekly for patients.
27:24And again this this approval is
27:26for patients with relapsed or
27:28refractory multiple myeloma who
27:29have received at least four prior
27:32therapies and are no longer responding
27:34to a PPI image and an anti CD.
27:3738 monoclonal.
27:37Antibody and this is based off the
27:40horizon study melphalan fluphenazine.
27:42I'd is a bit unique in that it does
27:45require a central catheter for infusion,
27:48such as a port or a pick line.
27:53So the horizon study was a multicenter
27:55trial of a total of 157 patients
27:58with relapsed or refractory myeloma.
28:00Though the approval was really based on
28:02a smaller group of patients in the study
28:05who had received at least four prior
28:08lines of treatment and were considered
28:10or triple class refractory refractory.
28:12In this group, the overall response
28:14rate was 26% and 9.3% of patients
28:17achieved a very good partial response
28:19or improvement of more than 90%
28:21in their monoclonal protein.
28:23The the median time to response
28:26was 2.1 months,
28:27so it took about 2.1 months for most
28:29patients to see a response and the duration
28:32of response was about 4.2 response.
28:34But 4.2 months there was a
28:3615% overall response rate.
28:38In patients with what's referred to as
28:40extramedullary disease or myeloma disease
28:42involving tissues and or organs that
28:45are outside the bone or bone marrow,
28:47which typically is a high
28:49risk feature for myeloma.
28:50Side effects observed with melphalan flu.
28:53Fenamad included primarily low grade low
28:55blood cell counts which were managed
28:57appropriately with either reduction
28:59in doses of the medication or other
29:02supportive care given by providers.
29:04Fatigue,
29:04swelling,
29:04and bone and joint inks also occurred.
29:07GI symptoms such as nausea and vomiting,
29:10were not severe in the clinical
29:12trial and there was no hair loss or
29:16neuropathy or numbness and tingling
29:18in the extremities or legs or arms.
29:20That were reported with the use of
29:22melphalan flu femmed in this trial.
29:27The last therapy we will discuss
29:29is the one most recently approved
29:31and this is the chimeric antigen
29:34receptor T cell or what is known
29:36as CAR T cell therapy idake.
29:40Excuse me, I to sell or idake.
29:44I do sell Vic Loosle ore Ida Salandit,
29:47the brand name forward is referred
29:49to as a Beckman.
29:51And the way that the car T and
29:53this product in particular works
29:55is that a patient's own T cell,
29:58a type of immune or white blood cell,
30:00is genetically modified by adding
30:02the chimeric antigen receptor or
30:04car that can then bind to the BCMA
30:07antigen present on myeloma cells.
30:09As previously discussed,
30:10there is activation and growth of
30:12these reprogrammed T cells which
30:13are then able to find and kill
30:16myeloma cells through various
30:17mechanisms through a variety of ways
30:19including release of cytokines.
30:21Which are small proteins?
30:22Importantly,
30:23which are important in inflammatory
30:25responses and signaling to cells.
30:26Ida Cell is the first car T
30:28approved in patients with relapsed
30:30or refractory multiple myeloma,
30:32and these patients who are eligible
30:34to receive it have received at
30:37least four prior lines of therapy,
30:39which again include AP and image and
30:41anti CD 38 monoclonal antibody and.
30:44This was based off what is known
30:46as the Karma trial and with car
30:49T cell therapy there are more.
30:51Multiple steps which are required
30:53including with Ida cell treatment
30:55and this includes blood collection
30:57or removal of these T cells through
30:59a process called a pheresis.
31:01This is followed by the manufacturing
31:04or the production of the car T cell
31:07product and this usually takes about
31:09a four week period and patients
31:11receive a low dose chemotherapy
31:13before I do cell infusion,
31:15usually over three days.
31:16And I do cells then administered as an
31:20infusion over 30 minutes per infusion bag.
31:22Importantly,
31:23there is a period of close monitoring
31:25after receiving Ida sell as well.
31:31So the Karma trial was a multi
31:33center phase two trial that included
31:35patients who had received at least
31:37three prior therapies including Apiai,
31:40Imid and an anti CD 38 antibody.
31:43Patients received I to sell at
31:45different dosages and of the 128
31:47patients who received this therapy,
31:4973% of them had a response with 33%
31:52having achieved a complete response or
31:55normalization of their myeloma studies
31:57in the blood or urine or better,
31:59the responses observed at the various
32:01dose levels and in the total group
32:04are seen in the figure here with the
32:07approved dose for Ida cell now being 300
32:10to 450 * 10 to the six Carty positive.
32:13Cells the majority of patients who
32:16received the approved dose were free
32:18of disease progression for 11.1 months
32:20and this increased to 20.2 months in
32:23those who had achieved what's known
32:25as a stringent complete response.
32:27With where there's disappearance
32:28of the myeloma protein in the blood
32:31in urine and no evidence of myeloma
32:33and the bone marrow,
32:34the most common side effects of
32:36this treatment were low blood cell
32:38counts and what's referred to as
32:40cytokine release syndrome,
32:42or the body's response to
32:43this uncontrolled and.
32:44Really excessive release of these
32:47proinflammatory cytokines that we
32:49discuss and this can lead to fever,
32:51low blood pressure,
32:52fast heart rate and low oxygen levels,
32:55among other symptoms.
32:56Cytokine release syndrome occurred
32:58to some degree in 84% of patients at
33:01a median of one day after infusion.
33:03Those severe events were not very common,
33:06and cytokine release syndrome
33:07was quickly identified due to the
33:09close monitoring and appropriately
33:11managed depending on its severity.
33:13Neurologic side effects occurred
33:15less frequently in this study than
33:17with other card T agents.
33:21So in addition to these newly approved
33:23agents, treatment options for patients
33:25with multiple myeloma continue to expand,
33:27and this is really through the study
33:29of new medications and combinations.
33:31On this slide, I've outlined a sampling
33:33of our available clinical trials here
33:35at Smilow and Yale Cancer Center,
33:37which, as you can see,
33:39are fortunately available for all time
33:41points in the myeloma disease course.
33:43So we have a study available
33:45for patients with smoldering or
33:47asymptomatic multiple myeloma that
33:49assesses or evaluates the benefit
33:51of adding Derek to map the anti CD
33:5338 monoclonal antibody to previously
33:55studied Lenalidomide for patients
33:57with newly diagnosed multiple myeloma.
33:58We we do have an investigator initiated
34:01trial led by Doctor Never Eats that is
34:04evaluating a more complete assessment
34:06of response in myeloma by looking
34:08both in the bone marrow and data
34:11myeloma bone lesions before and after.
34:13Therapy with carfilzomib,
34:15Lenalidomide and dexamethasone.
34:18And for those patients who are to
34:20receive maintenance therapy after
34:22undergoing a stem cell transplant
34:24but still have evidence of a low
34:27level of residual or remaining
34:28myeloma disease in the bone marrow,
34:31or what Doctor Barr defined
34:32as minimal residual disease,
34:34we do have a study looking at outcomes
34:37of adding again daratumumab to
34:39our standard maintenance regimen.
34:41For many patients, which is Lenalidomide.
34:43And lastly,
34:44we have multiple trials for patients
34:46with relapsed or refractory myeloma.
34:49Including an investigator initiated
34:50trial looking at quality of life
34:52for patients on daratumumab and
34:54trials with new medications,
34:55including those that use our patient's
34:57own immune system to fight off the
35:00myeloma and so at the conclusion of our talk,
35:03we'd be happy to share more information
35:05to help answer any questions you
35:07may have about our clinical trials.
35:09And thank you again for your time.
35:12I will now turn it over to Tara Anderson.
35:22Alright. One second, see.
35:40OK. Thank you Sabrina. So I'm Tara Anderson.
35:44I'm a physician assistant with the myeloma
35:47group here and I've been here since
35:492015 and started doing myeloma in 2005
35:52and I'm going to talk about the common
35:55side effects with the myeloma therapies.
35:57The main therapy since the doctor Browning
36:00touched on all of the recent approved
36:02drugs and all of those side effects.
36:05So I'm going to talk about the
36:07main classes of medications that
36:09Doctor Barr discussed and.
36:11The general side effects from each class.
36:16Alright, so the different classes of
36:18treatment as Doctor Barr discussed
36:20in her presentation and then we
36:23usually combine as she mentioned,
36:25three drugs, or potentially now
36:27for drugs and one from each class.
36:30So produce some inhibitors,
36:32immune modulatory drugs,
36:33monoclonal antibodies,
36:34and most of our therapies
36:36include dexamethasone.
36:39So the general side effects that are
36:41included in all of our treatments,
36:44I just don't want to have to put it
36:46in all the slides, so you can always
36:49refer back to this slide is fatigue.
36:52All of them are transgenic.
36:54We know with the imids we always do the
36:57Rams program, but all of them should
37:00require 2 forms of contraception and.
37:03They're all class D for pregnancy,
37:06so and all of the medications
37:08that we use can cause rashes.
37:11So what we typically would do for
37:13a rash is use a steroid cream.
37:16Or, depending on the how much
37:18the rash covers of the body or
37:20the symptoms from the rash.
37:22Sometimes we'll just do an Anna
37:24histamine prior to taking the medication,
37:26and if the rash is more severe
37:28than we will hold the medication
37:31and potentially reduce the dopes.
37:33And then all of the treatments
37:35also cause decreased blood counts.
37:37So with each treatment when you
37:39come in for treatment,
37:40we check your blood counts to make sure
37:43it's safe to go ahead with treatment.
37:45And if it's not,
37:46sometimes we have to hold the medication,
37:49and occasionally we have to reduce the dose.
37:51And I and sometimes will also
37:53use growth factors like NEUPOGEN
37:55to stimulate the bone marrow to
37:58help reduce some of those cells.
38:00And with the reduced blood counts
38:02you can see,
38:03I mean a suppression and with all
38:05of the treatments that can happen.
38:07So we want to make sure you call
38:10for any fevers you know.
38:12There's always somebody here,
38:13so a temperature is considered
38:15100.4 or higher,
38:16and then if you get frequent infections
38:18or hospitalized for several infections,
38:20sometimes will talk to you about giving
38:22an Ivy called IVIG which is immuno globulin.
38:25Which gives you some of the immunoglobulins
38:27that you don't normally produce.
38:29To help protect you.
38:31From getting infections,
38:32and we usually do that once a month,
38:34so these are the general side effects
38:37from all those classes of drugs.
38:39And then specifically for the produce
38:41some inhibitors which are listed below.
38:43I will talk about someone
38:44specific just for those,
38:45and you can see the dates when
38:47these drugs were approved.
38:48So I started doing my element 2005 and I
38:51can tell you when we started doing it.
38:53When I started doing it.
38:55The drugs that we use weren't
38:56as good as the ones we have now.
38:59We saw a lot more side effects and most
39:01of these drugs are pretty well tolerated.
39:03At least we want them to be.
39:05So if you're not tolerating them well then
39:08definitely reach out to us so we can.
39:10Make it easier for you to tolerate it,
39:12because once you're started on treatment,
39:15we tend to keep you on therapy for
39:17life and want to make sure we can
39:19keep the disease under control while
39:21maintaining good quality of life.
39:26So proteasome inhibitors in general can
39:28cause gastrointestinal side effects mildly.
39:31Sometimes we hear nausea,
39:32vomiting, not commonly,
39:34but it can some more than others,
39:37as I'll get two with the oral proteasome
39:40inhibitor and they all have a risk of
39:43reactivating herpes zoster or shingles,
39:46so all patients should be on
39:49acyclovir as a prophylaxis.
39:52And again, referring to the first slide,
39:54all those apply as well.
39:57And then both them up or VELCADE.
39:59One of the most common side effects we
40:00see with that is peripheral neuropathy.
40:03We would see it a lot more when we
40:05did give Velcade Ivy and we used to
40:07give allocate twice a week and now
40:09that we give it in a subcutaneous
40:11form and typically we give it weekly.
40:13We see a lot less neuropathy,
40:15but we still see it.
40:16So the key is to get a baseline
40:18assessment to see if anybody has any
40:20numbness or tingling in their hands
40:22and feet is typically where we see
40:24it at baseline and then to monitor
40:26to make sure it's not getting.
40:28Worse,
40:28we want to make sure it's not painful
40:30and it's not interfering with daily
40:32functioning like buttoning buttons
40:34or holding on to a coffee cup,
40:36or those types of things.
40:38And if it does then we may have to
40:41hold it or lower the dose and most of
40:44the time in 70% of patients it's reversible,
40:46so the key is to communicate with us
40:49when you have the neuropathy so we can,
40:51you know,
40:52make it better,
40:53and then we can also use these medications.
40:56Gabapentin,
40:56Lyrica or Cymbalta which sometimes.
40:58Help with neuropathy?
41:01We can also lower blood pressure,
41:03so if you're on blood pressure
41:05medication sometimes will have
41:07to hold it during the time when
41:08you're getting the VELCADE,
41:10and this isn't really a side effect
41:12but just kind of a note that if
41:14we take them in C supplements,
41:16we should hold it because there
41:18is data showing that vitamin C can
41:20interfere with the efficacy of alkane.
41:25Carfilzomib so the main thing
41:26with carfilzomib is the cardiac
41:28toxicities and the key here is also
41:30getting a baseline assessment.
41:31So if you have hypertension to get
41:34it controlled before we get started
41:36with the treatment and then to
41:38monitor it throughout and then we
41:40also want to make sure the hearts
41:42functioning OK so we'll do an echo.
41:44So an ultrasound of the heart prior to
41:47starting typically and we usually do an
41:49EKG and then a BNP as a as a blood draw.
41:52The lab that looks at the.
41:55Nonspecific marker of the
41:56stress on the heart.
41:58So we monitor that monthly.
41:59And then we want you to watch out for
42:02any kind of swelling in your legs,
42:05shortness of breath.
42:06Abdominal distention, because some of
42:08those could indicate that the heart isn't
42:11pumping as effectively as it should,
42:13so we watch for those.
42:15It's a low percentage,
42:17but it does happen so.
42:19We monitor those monthly as well.
42:22And because it's given Ivy,
42:24we sometimes see inflammation of
42:25the vein or thrombophlebitis,
42:27and you can use ice and that
42:29should help Tylenol.
42:31But if it keeps happening sometimes we
42:33recommend to use support and occasionally
42:35we can see pulmonary hypertension.
42:37So sometimes the shortness of
42:39breath may not be due to the.
42:42The heart,
42:43but it may be more due to the lungs,
42:45so we can usually pick that up on an echo.
42:48Or if we can't figure out
42:49what's going on with the heart,
42:51sometimes will refer to a pulmonary doctor.
42:55And then examine or narrow is the
42:57last produce I'm going to have better
43:00that was approved and it's oral.
43:01So because it's oral we see a lot
43:04more GI side effects or in the data.
43:06And in all the trials they see
43:08a lot more jet GI side effects.
43:10I think in practice we don't see as many,
43:13but we usually tell you to have Zofran
43:15or Imodium on hand just in case,
43:17and then obviously if you were to
43:20vomit after taking the pill we won't
43:22want you to reach, you know take the
43:24pill again 'cause we don't know.
43:26How much was absorbed?
43:28And also reach out to us if
43:30that was to happen.
43:32You can also see lower extremity
43:34swelling with this one.
43:36We recommend compression stockings,
43:38elevating your legs and sometimes
43:40will give you a water pill or lay 6.
43:46OK, and the second class of medications
43:48that we use in combination or the
43:51immunomodulatory drugs or image.
43:53So the first one that was
43:55approved was the Little Mide
43:57and that was approved in 2006,
44:00but we were using it earlier
44:02and kind of off label,
44:04and we don't use it as much because it
44:07has more toxicities and the other two.
44:10So now we typically start with
44:13Lenalidomide or REVLIMID and
44:14then after relapse, use POMALYST.
44:19So in general, that emits are
44:21putting patients at higher
44:22risk of venous thromboembolism.
44:24So we don't want so blood clot.
44:26So we want you to let us know if you
44:29had any swelling in your legs or pain
44:32and your legs or shortness of breath.
44:35And we put you on an aspirin
44:37as prophylaxis, typically.
44:38Or if you if you're at high risk
44:41or have had a thought before,
44:43we usually place you on an
44:45oral anticoagulant now.
44:46In the past we use Lovenox or Coumadin.
44:49And now we have the newer agents which
44:52are easier to use the oral anticoagulants.
44:55And then I know I brought up the terror
44:58that regeneca effects in general,
45:00but with this one we have to do the
45:03Rams paperwork and you have to do the
45:06phone surveys and so just a reminder
45:08with that way back in the 50s and
45:1160s the limit was used as a sleeping
45:13pill for pregnant women and then
45:15they had babies that were had deformity.
45:18So that's why the REMS program
45:20is in place with that drug.
45:25So Speaking of full time,
45:26I'd the main side effects that we
45:29see are fatigue, Constipation,
45:30numbness and tingling.
45:31So those are the top three and then also
45:35we can see a slowed heart rate with it,
45:37which may be causing some other fatigue.
45:41We typically used it at lower
45:42doses when I was using this,
45:44when there wasn't much else to use,
45:46we would use much higher doses and it was
45:49very difficult to tolerate at that time.
45:51But with the lower doses we can usually.
45:55Use it with minimal side effects and
45:57some of these medications to help so
45:59the same with them with the numbness
46:01and tingling in the gabapentin,
46:03Lyrica, and Cymbalta.
46:05And the typical things we we want
46:08you to do if you're constipated,
46:10so Senate police increased water fiber.
46:13Those types of things.
46:17And then learn a little made one of them
46:19are common side effects as diarrhea,
46:22especially the longer you're on.
46:23It tends to be more of a cumulative
46:26effect and we do different things.
46:28First, we want to make sure that
46:30you're not having diarrhea from a,
46:32you know a different cause like infection.
46:35Or, you know, is it you know,
46:37did you develop an intolerance to
46:39lactose or something like that?
46:41Or high fat foods?
46:42So sometimes will alter the diet.
46:44Try Imodium,
46:45and if those don't work,
46:46sometimes will add a medication called
46:48full listed which helps with the
46:50diarrhea associated with Lenalidomide.
46:52And then I put trash in here,
46:54even though we already talked about it,
46:56because it's fairly common with Lenalidomide,
46:58and again,
46:59a lot of times we have to hold and reduce the
47:02dose if the creams and the Anna histamines.
47:05Aren't controlling the rash?
47:08And then if you second primary
47:10malignancies can happen,
47:12this is because people are living
47:14longer and doing better with myeloma.
47:16On this for a long time.
47:19And they've seen second primary malignancies.
47:22So just a reminder to follow up with
47:25your primary care for routine screenings.
47:27Definitely the the benefits of the
47:30Lenalidomide Lenalidomide outweigh the
47:31risk of these second primary malignancies,
47:33but it's still something to be cautious
47:36of and follow up with your primary care.
47:40And then the last images,
47:42comma,
47:42little mid and again rash is
47:44fairly common with this one and the
47:46only other one we see peripheral
47:48neuropathy occasionally with this
47:50not as much as with the little mine,
47:52but otherwise it's fairly well tolerated.
47:54We don't usually see as many GI side effects.
47:57We tend to see a little bit more
48:00cytopenia or low blood counts.
48:02Mainly because it's used later in therapy.
48:07OK, and then the last class of
48:10medications or the monoclonal antibodies.
48:13So there's three.
48:14There are two memebr and ilities
48:17map were both approved in 2015 and
48:20then just last year daratumumab was
48:23approved subcutaneously and then.
48:26It's a text map,
48:27is just approved last year,
48:29so these have made a big
48:31difference and treatment,
48:32and they're fairly well tolerated.
48:34And now that we have
48:35daratumumab subcutaneous,
48:36it's made a big difference and some
48:38other patients that have had Ivy
48:40know that the first time we give it.
48:43It's like an all day infusion and
48:45then the next is like half a day.
48:47So it was a long.
48:49There are long days and now that
48:51we can give it subcutaneously,
48:53it's a lot shorter.
48:54It's about a 10 minute injection.
48:57And you only have to stay for a few
48:59hours after the first injection.
49:01So our main concern with these
49:04medications are the infusion
49:05related reactions and we typically
49:08would only see a reaction with the
49:11first injection or first infusion.
49:13But as you can see the the reactions
49:16are fairly common marso with Dara.
49:19I've eaten subq, it's 34 to 48%.
49:23Well,
49:23at last with the subcu and then it's a text.
49:27Matt is similar to the Dara and
49:29the E Lo is only about 10%.
49:32So to prevent these infusion
49:34reactions we premedicate with Tylenol,
49:36Benadryl and dexamethasone and
49:37with the first infusion we also
49:39give singular for Dara.
49:41And we give Pepcid for acid attacks in men.
49:45And this and we give this with
49:47each infusion the singular we
49:48only do with the first infusion,
49:49and this tends to reduce the rate.
49:52And most of the infusion reactions
49:55are very mild. We just stopped.
49:57Infusion treat the reaction and
49:59then we started at a lower dose.
50:02So we just want to make sure you
50:04let the nurse know if you notice
50:06anything like scratchy throat,
50:08cold,
50:08nauseous to let the nurse know
50:10right away so we can stop the
50:13infusion and treat the reaction.
50:15And then we also see shingles
50:17with monoclonal antibodies.
50:18So you need to be on prophylaxis with
50:21acyclovir with this one as well,
50:23and then the studies that are
50:25increased risk rates of an
50:27upper respiratory infections.
50:30And then the fast, the last one is steroids.
50:34Everyones favorite dexamethasone.
50:35So this one is probably the hardest to
50:38tolerate just because of you know the weight.
50:40Gain the irritability.
50:41All these things that
50:43happened and trouble sleeping.
50:44So sometimes will give melatonin or
50:46atterax which is a older generation
50:49antihistamine and we may have to reduce
50:51the dose if there's lots of side effects,
50:54and then you should be following up with an
50:57eye doctor 'cause it can cause cataracts.
51:00And primary care under friend
51:03'cause you can see steroid
51:05induced steroid induced diabetes.
51:08Excuse me
51:11alright. So in summary,
51:13treatment for myeloma is generally
51:16well tolerated now with a lot a lot
51:19better and the like since 2005.
51:21Prior to 2005. I think it was,
51:24you know, more of the traditional
51:26chemotherapy with hair loss, nausea,
51:28vomiting, a lot of a lot more toxicity.
51:31So with the newer generation of all
51:34the different classes we have now,
51:37that treatment should be
51:38pretty well tolerated.
51:40So the key is communication.
51:42Make sure you let us know if
51:44you're having any side effects
51:45so we can adjust it and get the
51:48best treatment to help improve.
51:50The disease and also we want to
51:52get a good baseline assessment
51:54to make sure the side effects
51:57are coming from the medication.
52:00And not something else.
52:03So I need a good doctor patient team.
52:07Relationship. OK, and then these are just
52:10resources for you to look up different
52:12side effects and different information.
52:15So MRF is a good website and then the
52:17multiple myeloma support group meets
52:19every the last Tuesday of every month.
52:22And then I just put in their
52:25their phone number and.
52:26The contact information if
52:27anybody's interested in.
52:28I know it's zoom now because because
52:30of kovit I don't know if they're
52:33planning to go back to in person, but.
52:37That is another place.
52:39And that's it, I think.
53:01So thank you to Doctor Barr and
53:04Doctor Browning and Terra for this.
53:06Great talks and presentations.
53:07Very educational.
53:08I think we have a few questions
53:11in both the chat and the Q&A.
53:14And. I believe, UM, the.
53:17There's a few actually discussing whether
53:20or not these slides would be made available,
53:23and the video of presentation will be
53:25posted at the yalecancercenter.org website,
53:28and a copy of the slides can be requested
53:31by emailing cancer answers at yale.edu,
53:34Her Emily, which we can hopefully if
53:37Emily maybe you could put that in
53:40the chat box for everyone if they
53:43were interested in obtaining a copy.
53:46I think that answers to our questions on
53:49our chat and one of the first questions
53:52that we had and that maybe Doctor
53:55Barkin answer was regarding where a
53:58Lam Lloyd fit on the spectrum of EM guys,
54:02to my Lomax, sure.
54:03So
54:04that's a very good question.
54:07It can fit on any of that spectrum actually.
54:11So anytime you have, UM,
54:12a cell or plasma cell,
54:14even the B cell conflicts of lymphomas.
54:17So creating these proteins
54:19specifically these light chains
54:20they can deposit into organs,
54:22and there's no way to predict which which
54:25patient or which condition will lead amyloid.
54:28It's something about the nature
54:30of this protein that leads to the
54:32deposition into different organs,
54:34and that's what Emily is right?
54:36So you can get it.
54:38With us you can get a smoldering
54:40and you can get it in the same
54:43time that you have myeloma,
54:44so this is something we as
54:46physicians I think about and UM,
54:48no ask you questions that make us,
54:51UM, you to screen for these things.
54:53Ask you questions that if if it
54:55is positive that makes us think we
54:57should I look deeper into whether
54:59there is amyloid deposition.
55:00So it's a good question.
55:08OK, uh, thanks no Friday.
55:10I do believe Emily posted in the
55:13chat now where the slides could be
55:16obtained if he would like her copy.
55:19And we had a few questions.
55:21Then over in the Q&A that
55:24whoever wants to tag,
55:25take a stab at them regarding the
55:28effectiveness of the COVID vaccine
55:30for our multiple myeloma patients,
55:32and what precautions should someone
55:34still be taking either around other
55:37vaccinated or unvaccinated individuals?
55:39So I don't know who wants
55:41to brave the COVID world.
55:43I can answer that one, so I think it's
55:46obviously a very important question,
55:48and I think you know we're learning more
55:52about it as time goes on, you know,
55:55I think studies have suggested that
55:57patients myeloma patients on a treatment,
55:59and patients with other blood
56:01disorders may have less of a response
56:04to our available COVID vaccines.
56:06You know. Fortunately,
56:07the COVID vaccine start at a high level,
56:10very high level of effectiveness,
56:12and so our recommendation
56:14to our myeloma patients.
56:16Is still to get the vaccine,
56:18but I think it is important to know that
56:21that maintaining preventative measures like.
56:25Mask wearing and good hand
56:26washing and avoiding sick people.
56:28It's probably more important
56:29in our in our myeloma patients
56:31and the general population,
56:33so I would recommend that all my lower
56:35patients get the vaccine as soon as possible.
56:38If they have not already,
56:39but continue to practice
56:41measures to try to avoid COVID.
56:46And and I
56:47would add to that that there were
56:48a couple of recent publications
56:50about myeloma patients and their
56:52response to the vaccinations.
56:54And yes, it is evident that the
56:57antibody production may be lower,
56:58like 50% of what you might
57:01get in healthier population.
57:02But there are also very significant
57:04cell responses in their immune cells,
57:06T cells and some of the T cells
57:09and B cell responses and.
57:11And that's what provides protection to
57:13model of patients after vaccination.
57:18Yeah, I think to follow
57:20up on that and the group
57:22at Mount Sinai published some
57:24of their findings just recently.
57:26Actually, on the 28th of this month
57:29and they had looked at 320 individuals
57:31who had had the COVID vaccine,
57:34260 of them received either the Pfizer,
57:37the Moderna, so the two dose and
57:39what they had shown was about 16%.
57:42Fifteen point.
57:438% of patients did not mount any detectable
57:46antibodies compared to the other 84.
57:48Your dad, but that response was
57:50very variable and they did find
57:53that patients who had had COVID
57:55prior to being vaccinated had
57:57a higher immune response.
57:58Tattoo that.
58:01OK, and we have some other questions.
58:04I think 2 regarding acyclovir are
58:06and whether or not an individual
58:07could stop acyclovir if they had
58:09received the shingles vaccine.
58:11So I don't know if Terra if you want
58:13to address that under side effects.
58:16Yeah sure I meant
58:17to say that actually no.
58:19I mean, if you had the shingles vaccine,
58:22you still need to stay on acyclovir.
58:24If you're getting a monoclonal
58:26antibody or producing inhibitor,
58:27sometimes we will stop the if you're
58:29just on an image for maintenance.
58:31You can you can stop the acyclovir,
58:33but otherwise you need to stay
58:35on it regardless of the vaccine.
58:44OK. Uh, we have a few questions coming
58:47in and about Carty and transplants.
58:51And so maybe Doctor Power
58:53you can handle some of these.
58:55Someone is asking whether or not there's
58:58hospitalization involved with Carty,
59:00and if So what is that duration? Yes,
59:05so there is hospitalization
59:06involved with car T therapy,
59:08and that's really to
59:10follow on the side effect.
59:11Expected side effects,
59:12which are this side that kind of lease
59:15which majority of patients do get
59:17and then potentially even neurotoxicity.
59:20So at least seven days but sometimes
59:23longer really depends on how you do.
59:28OK, great and another question
59:30that's coming in regarding on stem
59:32cell transplant and side effects.
59:34As a questioning at about the
59:37malignancies that we should be
59:39looking out for following a stem
59:41cell transplant and use of REVLIMID
59:44maintenance so I don't know if
59:46either Natalia know first Sabrina
59:48would like to answer one of that.
59:52I can respond to that.
59:55I can respond to that Terry.
59:57So in the studies with REVLIMID
59:59or Lenalidomide maintenance,
01:00:01there was a slight increase in the absolute
01:00:04risk of developing second primary cancers,
01:00:07and there was approximately
01:00:083% absolute increase risk,
01:00:10so the risk is very small,
01:00:12and the types of cancers that were
01:00:15observed or mostly another blood related
01:00:17malignancy or bone marrow malignancy.
01:00:20There were a few cases of non
01:00:23Hodgkin lymphoma, leukemia,
01:00:24myelodysplastic syndrome.
01:00:25These were.
01:00:26Types of bone marrow cancers that
01:00:28developed overtime in among those
01:00:30observed on the trials there.
01:00:32But there were also several
01:00:34solid tumors as well,
01:00:35and this is what we see in our practice.
01:00:39So the conclusion is that
01:00:41majority of the second primary
01:00:43cancers would be blood related,
01:00:45but overall absolute increased
01:00:47risk of secondary cancers is
01:00:49on the order of two to 3%,
01:00:51so the risk is small and the benefits
01:00:54certainly outweighs benefits a benefit.
01:00:56A problem in prolonging
01:00:57survival awhile and maintenance
01:00:59therapy outweighs that risk.
01:01:04Great thank you Natalia. Does anyone
01:01:06have anything else to add on that?
01:01:10And if not, we'll move on
01:01:13to another question is,
01:01:14as far as if an individual has a medical
01:01:17officer of undetermined significance
01:01:19for an extended period of time,
01:01:21what is the likelihood to remain at that?
01:01:24I'm guess level versus risk
01:01:26of transformation to myeloma.
01:01:30I can answer that so you know,
01:01:32come with them guys. As I mentioned,
01:01:35the risk of progression is 1% per year,
01:01:37but this is an average and there's
01:01:39actually other markers we look
01:01:41at to assess the risk of M gusts.
01:01:43These are things like elevated light chains.
01:01:46UM, the amount of protein,
01:01:47the monoclonal protein, and I'd say yes,
01:01:50time does give us some information, right?
01:01:52If someone said M ghosts and everything
01:01:54is completely stable for five years,
01:01:56that is informative.
01:01:57And in in actually smaller in world,
01:01:59we know as we.
01:02:00Go, you know,
01:02:02as we follow patients overtime that 10%
01:02:04risk does go down after five years or so.
01:02:07If there is no progression.
01:02:09So so yes, time is important,
01:02:11but it gives us information about
01:02:14the behavior for disease.
01:02:17Great so I love that line of questions.
01:02:20We did have some questions that had
01:02:22come in before the presentations
01:02:24and those were dealing with
01:02:26smoldering myeloma specifically.
01:02:28If there's anything in individual can
01:02:30do to help prevent the progression
01:02:32of smoldering to multiple myeloma?
01:02:34If So what does that look like
01:02:36and what treatments are available
01:02:38for small joint individual?
01:02:40I know Doctor Browning you had
01:02:42mentioned that there are some trials,
01:02:44so would you mind enlightening
01:02:46us on smoldering myeloma?
01:02:48Sure, absolutely.
01:02:49So similar to our approach with an M Gus.
01:02:52When we look at somebody
01:02:54with smoldering myeloma,
01:02:55we want to understand their risk
01:02:57and you know, we we do that by
01:03:00looking at a couple of things.
01:03:02The percentage of a plasma cells
01:03:04that are in the bone marrow as
01:03:07well as the size of the protein
01:03:10in the blood and the size of or
01:03:12the amount of free light chains
01:03:14that we see in the blood as well.
01:03:17And patients who fall.
01:03:19Uh, into the intermediate or higher
01:03:22risk category for smoldering myeloma.
01:03:24There has been evidence that earlier
01:03:27treatment with the medication,
01:03:29Lenalidomide has been helpful now,
01:03:32as occurred.
01:03:33Doctor Parker stated,
01:03:34there are more trials looking at
01:03:37either additions to Lenalidomide
01:03:39or other combinations of therapies
01:03:42and their effectiveness in
01:03:45preventing progression too.
01:03:47End organ dysfunction in patients
01:03:48who have smoldering myeloma.
01:03:49So to answer the first question,
01:03:51you know,
01:03:52I don't think there's anything
01:03:54in particular that individuals
01:03:55can can do you know?
01:03:56I think when we get this question,
01:03:59you know maintaining a healthy diet
01:04:00and physical activity is important.
01:04:02But but really,
01:04:03it depends on kind of the the
01:04:05risk of the smoldering myeloma
01:04:07and how it progresses overtime.
01:04:12I think there was
01:04:13a question on the generic Lenalidomide.
01:04:17Yeah, and I think there's none that
01:04:20are currently available for the
01:04:22United States as an approved use.
01:04:24As you know, the REVLIMID slash
01:04:26Lenalidomide produced by Celgene is
01:04:28currently off the label of the patent,
01:04:31meaning the patent has expired,
01:04:33but unfortunately,
01:04:33the price of the drug has not been reduced
01:04:37across the world in Europe and Asia.
01:04:39There are several similar drugs
01:04:41you may call them biosimilars,
01:04:43or the generics of these emit medications.
01:04:46Lenalidomide or pomalidomide,
01:04:47and these are produced in various
01:04:50parts of Europe and Asia.
01:04:52So, for instance,
01:04:53you may hear people using Indian when a
01:04:56little mind and similar drugs and and
01:04:59they appear to be just as effective.
01:05:01I think there there were some of the
01:05:04studies coming out of Asia that that
01:05:07showed efficacy that's kind of equivalent,
01:05:10so. But uhm.
01:05:13I'm not aware of the approved US use.
01:05:21OK, and then one more that's in the chat
01:05:24and then we can go to another one that
01:05:27was submitted ahead of time is do the
01:05:30panelists recommend patients having their
01:05:33cells sequenced or and next generation
01:05:35sequencing done to look for targeted
01:05:37treatment or for personalized medicine?
01:05:39And so maybe we can go around having having
01:05:42each of the panelists answer that question.
01:05:48Sorry, I think that's a very interesting
01:05:50question and under you know, uh, the right?
01:05:53UM study where you can use this
01:05:55information to guide treatment.
01:05:57I think it's very useful. It's not,
01:06:00it's not something that's routinely done.
01:06:02It's not an FDA approved, UM.
01:06:05A way to do things,
01:06:07but I think it's in the research world.
01:06:09I would recommend it.
01:06:13Yeah, I would agree with that I.
01:06:16I think it's not a part
01:06:18of our standard practice,
01:06:19but I think there's a lot to learn
01:06:21from that and and I agree that no
01:06:24incorporation of that into clinical
01:06:26trials moving forward is important
01:06:28and I think will be enlightening and
01:06:30how to best guide our our treatments.
01:06:33As you saw, for patients who have
01:06:35relapsed or refractory disease,
01:06:36we now have a whole number of treatments,
01:06:39but understanding the sequencing of what
01:06:41to use first you know is is a challenge.
01:06:44And I think understanding more about
01:06:47you know the specifics of each patient.
01:06:49My Loma may help that.
01:06:55I don't have money.
01:06:56I don't have much to add to
01:06:58that. I mean, I think it's been
01:07:00it's been around for awhile.
01:07:01Just having it has not been approved but
01:07:03it would be great if we could do that.
01:07:05'cause there's so many different
01:07:07presentations of myeloma.
01:07:07If we could know how to target different,
01:07:09you know, specific patients that
01:07:11have different mutations and things,
01:07:12but I don't know how far they
01:07:14are like getting this approved.
01:07:21Great, so it sounds like more to come
01:07:23and then again one last question that
01:07:26was submitted ahead of time which was
01:07:29dealing with solitary plasmacytomas
01:07:31and specifically what is the risk
01:07:34of progression to multiple myeloma
01:07:36with the solitary plasmacytoma?
01:07:39And and so I don't know if Doctor Bar you
01:07:42wanna take that or doctor Pepper eats.
01:07:50I'm sorry, can you rephrase the question?
01:07:53Yes, so the question that was submitted
01:07:55was regarding solitary plasma cytoma's
01:07:57and risk factors for progression to
01:08:00multiple myeloma. So
01:08:01in the in some of the largest cohorts
01:08:04out of US and European experience says
01:08:07it was observed that patients who had
01:08:10solitary plasmacytomas either in the
01:08:11bone or in other tissues within the
01:08:14subsequent follow up after initial
01:08:16treatment for the plasmacytoma.
01:08:18Approximately 50% of patients did.
01:08:20Evolved to develop multiple myeloma in the
01:08:23subsequent three to five years of follow up.
01:08:26So I think the close follow-up is
01:08:29recommended with periodic imaging as to what?
01:08:32What are the factors that
01:08:34promote that progression?
01:08:35I think the Nordic Group had looked at
01:08:38some of the angiogenesis risk factors and
01:08:41they did not identify many risk factors,
01:08:44but there one of them was the badger,
01:08:47which is the endothelial blood vessel.
01:08:50Type of.
01:08:51Inflammatory or angiogenesis mediator,
01:08:53but it's not something that
01:08:55we routinely test,
01:08:57and there's no other easy ways
01:08:59of making that prediction,
01:09:01and so they the mainstay of monitoring
01:09:03would be just periodic surveillance
01:09:05initially at every three months,
01:09:08and subsequently at every six month
01:09:11interval with updated blood work,
01:09:13urine tests all of the usual
01:09:15myeloma lab tests,
01:09:16which includes certain protein
01:09:18electrophoresis like chains and urine,
01:09:20protein electrophoresis and
01:09:22and at least an annual.
01:09:24I think nowadays that will be with one
01:09:26of the advanced imaging modalities,
01:09:29like either a PET scan or low dose CT scan,
01:09:33or alternatively MRI of the
01:09:35body where it's available.
01:09:41Great, thank you.
01:09:42So those were all of our pre
01:09:44submitted questions and I don't see
01:09:46any additional ones in the QA or chat.
01:09:49So if anyone has any last minute
01:09:51questions please submit those now.
01:09:53If not but we can wipe things as down
01:09:56and thank you all for your attention
01:09:58and thank you to all the panelists.
01:10:03Thank you very much everybody.
01:10:05Great talks everyone.
01:10:09Thanks for joining. Bye.