Smilow Shares: AL Amyloidosis

September 14, 2023

September 12, 2023

Presentations from Sabring Browning, MD; Edward J. Miller, MD, PhD; Randy Luciano, MD, PhD, Sacha Zivkovic, MD, PhD; and Terri Parker, MD.

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00:00Welcome everyone again.
00:02Thank you for joining us this evening.
00:05I think we can get started.
00:08Thanks again for joining for the
00:10SMILO Shares program on Light
00:11Chain or Ale and Lodoises tonight.
00:13My name is Sabrina Browning.
00:15I am an assistant Professor of
00:16Medicine in the section of Hematology
00:18here at ALE and a physician in
00:20the Smilo Multiple Myeloma and
00:22Gamopathies program and program.
00:23And I'm honored to be joined
00:26tonight by my expert colleagues
00:27who all really serve critical
00:29roles in the multidisciplinary
00:30care of our patients with with a L
00:33amyloid and have helped create us,
00:35helped us to create a comprehensive
00:37discussion for you all tonight.
00:39So during our session,
00:41I will begin by providing some
00:43background on amyloidosis and
00:45we'll then talk about soft tissue
00:46as well as gastrointestinal and
00:48liver involvement of a L amyloid.
00:50Dr.
00:50Ed Miller,
00:51who is an Associate Professor of
00:53Medicine and Radiology and serves as
00:55Vice Chief of Cardiovascular Medicine,
00:56Education Director of the Cardiology
00:59Fellowship Program and Director of
01:01the Clinical Nuclear Cardiology
01:03Laboratory here at Yale will then give
01:05us a summary on cardiac AL amyloid.
01:08Doctor Randy Luciano will follow.
01:10Doctor Luciano is an Associate
01:11Professor of Medicine in the
01:13section of Nephrology and Associate
01:15Program Director of the Nephrology
01:16Fellowship and will discuss for
01:18us renal or kidney ale amyloid.
01:20And then Dr.
01:21Zipkovic is a professor in the
01:24Department of of Neurology and is
01:26actually out of the the country currently,
01:29but has kindly shared his expertise on
01:32nervous system involvement of ALE amyloid.
01:35And then lastly,
01:35doctor Terry Parker,
01:36an Assistant Professor of Medicine
01:38in the section of Hematology
01:40and Assistant Medical Director
01:41at our Smylo Care Hospital,
01:43North Haven location,
01:44where all of our amyloid
01:45patients received their care,
01:47will speak to us about the treatment
01:49and management of ALE amyloidosis.
01:53So
01:57our respective disclosures are all
01:59outlined here on this slide and I
02:02encourage all of you to submit any
02:04questions that you may have in either
02:06the question and answer or the chat
02:08sections during our our discussion.
02:10So to begin, amyloidosis is a group
02:12of diverse diseases that are all
02:15characterized by abnormal folding
02:16of proteins within the body,
02:18and these proteins then aggregate
02:20aggregate to form insoluble amyloid
02:22fibrils and what is referred to as
02:24a beta pleated sheet confirmation.
02:26And to date there have been 36
02:28different precursor proteins
02:30identified that can form amyloid
02:31fibrils and lead to amyloidosis.
02:33Amyloid fibrils then deposit
02:35extracellularly into organs and tissues,
02:38resulting in impaired function
02:39and progressive organ damage.
02:41And amyloid fibrils,
02:42which are depicted in the figure
02:43here on the right,
02:44have a unique appearance on electron
02:47microscopy where they are rigid
02:49nonbranching fibrils and typically
02:50measure 8 to 12 nanometers in diameter.
02:53Additionally,
02:53the structure of amyloid fibrils
02:55leads to positive staining with
02:57Congo red dye and tissues and an
02:59applegreen biforinge instead is
03:01observed when amyloid is viewed
03:02with polarized light microscopy,
03:04and this is illustrated in the bottom
03:07panel of the figure here on the right.
03:10Today our focus is on light chain
03:12or what was previously referred
03:14to as primary amyloidosis,
03:16where the amyloidogenic proteins
03:17are Kappa or Lambda light chains,
03:19which are produced from a clonal population
03:21of B cells located in the bone marrow.
03:24Lambda light chain is more common
03:25than Kappa in ALE amyloidosis,
03:27and in the majority of cases there
03:29will be a clonal plasma cell
03:31population in the bone marrow,
03:32although in ALE amyloid this
03:34clone can be quite small,
03:35and occasionally ALE amyloidosis
03:36can occur in association with a
03:39lymphoma or a clonal lymphocyte
03:40population in the bone marrow.
03:42ALE amyloidosis can be localized in nature,
03:45but more commonly will be systemic
03:47where the amyloid fibrils deposit in
03:49several distinct tissues and organs,
03:51causing significant impairment and function.
03:53And we will discuss specific organ
03:55involvement with ALE amyloid in more
03:57detail throughout the remainder of this talk.
03:59ALE amyloid is a rare disorder
04:02with an incidence reported as 5
04:03to 12 persons per million per year
04:05and it can be quite aggressive
04:07and therefore early diagnosis and
04:09treatment is really vital
04:13given the known delay in
04:14diagnosis with AL Amyloidosis,
04:16the importance of early treatment to
04:18help prevent progressive organ disease.
04:20It's incredibly important to have
04:21a high level of of suspicion for
04:23this disorder in patients with with
04:26concerning symptoms which again we will
04:27review while covering the different
04:29organ systems and notably in patients
04:31with a known monoclonal gameopathy.
04:33And this is really a driving factor in
04:35our group's goal to increase education
04:37and discussion about ALE amyloidosis
04:39including with all of all of you tonight.
04:41The diagnostic work up of ALE amyloidosis
04:44will generally include if not already
04:46already completed monoclonal gameopathy
04:48labs and a bone marrow biopsy.
04:50And and regarding these gameopathy labs,
04:52it's important to obtain all those
04:54that I've listed here on this slide,
04:56given that as mentioned,
04:57sometimes the monoclonal protein and
04:59ale amyloidosis can be quite low level
05:01or there may be an abnormality only
05:03detected on the serum free light chain assay.
05:06Amyloid should also then be
05:08documented on tissue biopsy,
05:10again using Congo red stain.
05:12And this can occur in the bone marrow
05:14on bone marrow biopsy or with an
05:17abdominal fat pad aspirate or less
05:19commonly A salivary gland biopsy.
05:21And the sensitivity of of abdominal
05:23fat pad aspiration when combined
05:25with bone marrow evaluation has
05:27been reported to be as high as 85%.
05:29The figures here on the right show
05:31an abdominal fat pad aspirate sample
05:34from a patient of mine where Congo
05:36red positivity is seen on the top,
05:38and then green biforingents displayed when
05:42when exposed to polarized light microscopy.
05:45And lastly,
05:46A biopsy of a suspected involved organ
05:48may be required to confirm the diagnosis
05:51of AL Amyloidosis if the previously
05:53discussed workup is is not diagnostic.
05:57And as you recall, I mentioned there
05:59are up to 36 different amyloid
06:01proteins that have been identified
06:03and therefore after confirmation of
06:05the presence of amyloid and tissue,
06:06it's crucial to complete what
06:08we refer to as amyloid typing.
06:10Amyloid typing has been prefer performed
06:13previously with immunohistochemistry,
06:15although this technique is thought
06:17to be unreliable in AL amyloidosis
06:19as well as with immunofluorescent
06:21such as in kidney biopsies and
06:23immunoelectron microscopy or immuno Gold.
06:25However, really our gold standard
06:27for amyloid typing is with liquid
06:29liquid chromatography, excuse me,
06:31liquid chromatography tandem
06:33mass spectrometry,
06:34which is a procedure where the amyloid
06:36deposits are micro dissected and
06:38then proteins are sequenced by mass
06:40spec and compared with libraries
06:42of proteins for identification.
06:44And at our institution,
06:45we send out our specimens to the Mayo
06:47Clinic for amyloid typing by mass mass spec,
06:49again as a gold standard.
06:52And importantly,
06:53accurate time typing as mentioned
06:54of the amyloid protein is really
06:57essential to determine appropriate
06:59treatment for amyloidosis given
07:00that different types of amyloidosis
07:03can have differ significantly
07:04differing treatment regimens.
07:08And this figure summarizes the pathogenesis
07:11of ALE amyloidosis which we have discussed.
07:14Again, an underlying B cell clone in
07:16the bone marrow produces excess or
07:18abundant serum free light chains which
07:20are abnormal and therefore misfold
07:22and form aggregates which can be
07:24directly toxic to to the organs and
07:26in particular in particular the heart.
07:29And these aggregates then form
07:31amyloid fibrils which then deposit
07:32into organs and tissues,
07:34some of which are depicted here
07:37and cause significant damage.
07:39And while this is a bit of a busy figure,
07:42it outlines the tissues and organs
07:44that can be affected by AL amyloidosis.
07:46So again, after a confirmation of
07:48of amyloid by Congo red and tissue,
07:51followed by typing,
07:52it's unimportant to determine organ
07:54involvement and we will discuss
07:56several of these in more detail.
07:57As mentioned,
07:58patients with ALE amyloid can
08:00also present with nonspecific
08:02symptoms including fatigue and
08:04unintentional weight loss,
08:05and can have bleeding or easy
08:07bruising for a number of reasons,
08:09including acquired deficiency in factor 10,
08:12which is a clotting protein that can be
08:15absorbed and eliminated by amyloid fibrils.
08:17Importantly,
08:18ALE amyloidosis does not affect the
08:20brain in the central nervous system.
08:26So moving on to soft tissue
08:28involvement of amyloid, this affects
08:30approximately 10% of our patients.
08:33Macroglossia or enlarged tongue and
08:35periorbital purpura or bruising around the
08:37eyes are classic features of ALE amyloidosis,
08:39but really are found in only a
08:42small proportion of our patients.
08:43On exam, macroglossia may present with
08:45dental indentations on the lower tongue,
08:47which we refer to as scalloping,
08:50as well as a a firm or stiff
08:51tongue on palpation,
08:52and the figure here on the right
08:54provides an example of these findings.
08:56Macroglossia can lead to a variety of
08:59things including obstructive sleep apnea,
09:01altered taste with difficulty eating
09:03and swallowing, and dry mouth.
09:05And unfortunately,
09:06there are no specific therapies for
09:08macroglossia outside of monitoring for
09:11organ response as a result of administration
09:13of systemic antiplasma cell therapy,
09:15which we'll hear more about
09:17later from Doctor Parker.
09:19Although some patients with severe
09:21macroglossia may need a feeding tube
09:24for adequate nutritional intake.
09:26And the periorbital purpura that you
09:27see here on the right results from
09:30vascular fragility due to amyloid
09:31deposition in the soft tissues and
09:33vessels that are located around the eyes.
09:36Patients can also get things
09:38like nail abnormalities,
09:40joint pain and swelling as a result
09:42of amyloid deposition in the joints,
09:44as well as claudication or pain
09:46with ambulation or use in the jaw,
09:49buttocks or or calf,
09:52and this is due to amyloid deposition
09:54in the in the small vessels.
09:58Emily Deposition in the GI track
10:00can result in several symptoms,
10:02including nausea, vomiting,
10:04dyspepsia or indigestion,
10:06abdominal bloating or pain, diarrhea,
10:09Constipation, malabsorption,
10:10or symptoms of gastroparesis.
10:12And it can sometimes be difficult or
10:15challenging to differentiate these
10:17findings from those we see where
10:19amyloid infiltrates the autonomic
10:21nervous system that controls the bowel.
10:23Patients with GI amyloids can also have
10:26complications that can include GI bleeds,
10:28obstructions,
10:28intestinal perforation or gastric.
10:31Gastric outflow obstruction and GI
10:33amyloid can also be localized in nature.
10:36And therefore it is important important
10:39for patients who have Congo red
10:41positivity on a GI biopsy to complete
10:43a comprehensive evaluation with to
10:45determine the presence of amyloid
10:47involvement in other organs which
10:49would indicate systemic disease.
10:51And close collaboration with our
10:53GI colleagues is very important
10:56both for monitoring and symptom
10:57management for these patients.
10:58And the figure here on the right
11:01included on the slide shows amyloid
11:03in the stomach and small intestines
11:05as seen in biopsied during an
11:07endoscopic upper endoscopic procedure.
11:13And then lastly, liver involvement of ALE,
11:15amyloid generally presents with
11:17enlargement of the liver or an increase
11:19in alkaline phosphatase level.
11:21Liver involvement is seen actually more
11:23commonly with Kappall H8 amyloid and is often
11:27seen concomitant with kidney involvement.
11:29In the presence of symptomatic liver
11:31involvement or synthetic liver dysfunction
11:33or liver failure is quite uncommon.
11:35And so when this is seen,
11:37it likely indicates more advanced or late
11:40stage disease in regards to the amyloid,
11:42given the potential for other
11:44disorders to cause enlarged liver or
11:47hepatomegaly and abnormal liver enzymes,
11:49liver biopsy is sometimes needed
11:50for a definitive diagnosis.
11:52And again incorporating our
11:54hepatology colleagues into the
11:56multidisciplinary care of our patients
11:58with AL amyloid is definitely very,
12:01very beneficial.
12:03So I will stop sharing my screen
12:06and invite Doctor Miller to discuss
12:10with us about cardiac amyloid.
12:17All right, thanks, Sabrina.
12:18Nice to see virtually everyone
12:21happy to be here tonight to
12:23talk about cardiac amyloidosis.
12:26How does this look?
12:27Does this look OK, Sabrina?
12:29All right. So again,
12:31so I focus on cardiac Amyloidosis and and
12:35I'm going to talk about AL Amyloidosis,
12:38but I'm also going to talk on the
12:40other type of cardiac amyloidosis
12:42as well called TTR Amyloidal a bit
12:45because I frequently get questions
12:47about both types of amyloidosis.
12:50So I don't want to gross people
12:51out on the on the on the column
12:53and I have a medical background,
12:54but I think this is a really
12:57illustrative slide.
12:58So with what happens in amyloidosis is
13:03as as Doctor Browning was mentioning
13:04is that you have amyloid fibers that
13:06deposit in organs and it causes
13:08those organs not to work well and
13:10it makes those organs really stiff.
13:11And what we're seeing here is a
13:14heart of a patient who underwent
13:16a heart transplant.
13:17So this is the heart that's been
13:19taken out of the patient and
13:20they've received a new heart and
13:21they're doing very well.
13:22But when you take,
13:24when you take a heart out of out of somebody,
13:27what should happen after the blood
13:28goes out of it is that it should
13:31collapse on itself because there's
13:32nothing to hold it open anymore.
13:34But you can see here these they
13:36can see chambers that are normally
13:38filled with blood that are held open
13:40by these amyloid fibers that are
13:42deposited in between the cells of the heart.
13:44And so this really shows you the
13:47stiffness and the architectural
13:49change that that under that patients
13:52who have amyloidosis undergo.
13:54When when the surgeons put a I
13:57think this is a couple liter bottle
13:58of fluid on top of the heart,
14:00you see doesn't collapse which is
14:02which is again is showing how the the
14:06physical changes that are occurring
14:08when amyloid deposits in the heart,
14:09it doesn't really depend,
14:10doesn't really matter what
14:11type of amyloid it is.
14:13The same type of changes generally
14:16occur as Doctor Browning was mentioning.
14:18It's really important particularly
14:19in the heart to understand the type
14:22of amyloidosis that one might have.
14:25And I always caution my patients
14:27not to Google a cardiac amyloidosis
14:29or look it up because it's such
14:32a complex
14:34disease and there are a
14:36lot of subtleties to it.
14:37And one could quickly become both
14:39confused and and disturbed by one
14:42what what one reads on on the Internet
14:44and according to doctor Google,
14:46but in general in the heart there are
14:49two types of amyloidosis that occur.
14:52The first is the type that we're
14:55focusing on tonight which is light
14:58chain amyloidosis from the bone marrow
15:00cancer type process Doctor Browning
15:03was describing in that in that disease
15:07light chains or parts of antibodies
15:09deposit in the heart and other organs.
15:12But it's also important to realize
15:14that much more commonly the type of
15:17amyloidosis that people will have that
15:19I see animals be seen by cardiologists
15:21is from a completely different disease
15:24called transthoretin or TTR amyloidosis.
15:27So even though they're both
15:29called cardiac amyloidosis,
15:30they're much different in
15:31how they're treated,
15:32how they're and what their prognosis is.
15:35And so we have to differentiate
15:37those two types of amyloid if we're
15:39going to treat patients effectively.
15:43So here's a nice graphical cartoon of what
15:48light chain amyloidosis, what happens.
15:51As Doctor Browning mentioned,
15:52there's a there's a problem with cells
15:55in the bone marrow where they where
15:57plasma cells of these cells that
15:59produce antibodies kick out proteins.
16:01Those proteins circulate through our blood
16:04and the the the proteins that are that
16:07are circulating are called light chains.
16:09Those light chains stop folding correctly.
16:12When they stop folding correctly,
16:14they come out of solution in our blood
16:17and then deposit into different organs.
16:19When they deposit,
16:21they organize together to make these
16:23sheets of of of of sticky material
16:27that cause the organs not to work well.
16:30Those are called amyloid fibrils
16:32and they can deposit an organ such
16:34as the heart or other tissues and
16:37instead of having the protein come
16:40from the bone marrow and the other
16:42type of cardiac amyloidosis,
16:44TTR proteins coming out of the liver.
16:46It's a protein that we all have all
16:48around our that circulate through our
16:50through our bodies throughout our
16:52entire life called TTR that circulates.
16:54And as we get older or if we have genetic
16:57mutations again amyloid fibers can form.
17:00But those amyloid fibers are from
17:01a completely different protein in
17:03a completely different process.
17:04They also cause similar heart problems.
17:09So it so if you're looking
17:12for cardiac amyloidosis,
17:13you have to understand whether somebody
17:16has systemic amyloidosis or amyloidosis
17:18involves other organs besides the heart.
17:20Personally, I think there's no other
17:22organ besides the heart doctor.
17:23Lisciano might disagree but but but
17:27nonetheless A cardiac amyloidosis is
17:30something that we can usually look
17:32at to to help figure out whether
17:35cardiac amyloidosis may be present by
17:37looking at what we call noninvasive
17:39testing or imaging of the heart.
17:42So this can include things
17:44like an echocardiogram,
17:45ultrasound of the heart.
17:47It can look at MRI scans of the
17:49heart or other nuclear imaging
17:51studies that help us to differentiate
17:54and look for amyloidosis that is,
17:56that's affecting the heart.
17:59Patients with amyloidosis of the heart,
18:01whether it's a TTR type or a L type,
18:05have some common features.
18:07The heart gets thick or what we
18:09call ventricular hypertrophy.
18:10And when the heart gets thick it,
18:13it doesn't relax well.
18:15We call diastolic dysfunction and so
18:17the heart is restricted in its movement.
18:20We get problems with the EKG
18:21and we can get arrhythmias.
18:23Most patients present to my clinic with
18:26symptoms of what we call heart failure,
18:28which means generally speaking
18:31edema or swelling that involves the
18:35the legs and it and into the lungs
18:38for a number of different reasons.
18:39People can get lightheaded and have low
18:41blood pressures when they stand up.
18:42That's called orthostasis.
18:45As Doctor Browning was alluding to.
18:46People can get the classic anginal
18:49symptoms or chest pain and have
18:51trouble with with passing out.
18:53It's called syncope but it but
18:55the prognosis and the treatment
18:57for patients is very different.
18:59So AL cardiac cardiac involvement
19:03it is is something that I talked
19:05to the the people on this call very
19:08often about it is an emergency and
19:10we have to see if it's present and
19:14treated aggressively and early in
19:16order to prevent further progression.
19:18TTR amyloid on the other hand takes a more,
19:21a much slower course and even
19:23if we don't treat it,
19:25the survival can be years and decades.
19:29When we're talking about
19:32amyloidosis, we can in the heart,
19:36we can stage people,
19:37meaning we can tell them what
19:39how severe their amyloidosis is.
19:42And we can use things like measurements
19:45of common blood tests such as troponin
19:48or another test called a BNP test.
19:50And those look at things related
19:52to cardiac function.
19:53And generally speaking,
19:55the the more abnormal those things are,
19:58the worse the prognosis
19:59might be for somebody.
20:01And we treat patients more
20:03aggressively or in different ways
20:05based on those staging systems.
20:08Because I get a lot of questions about TTR,
20:10I'm going to talk about some of
20:12the aspects of that as well.
20:13So it has similar features and how it
20:15presents to a L amyloidosis of the heart.
20:18But there's some specifically
20:20different features in,
20:21in particular those relating to neuropathy
20:24as doctors of Kovich will talk about,
20:26as well as things like carpal
20:28tunnel syndrome and at orthostatic
20:30low blood pressure syndrome,
20:32what we call autonomic dysfunction.
20:35These things, including aspects of age,
20:39sex, weight and race,
20:41will will cause us to screen
20:44different types of patients
20:46for different types of amyloid.
20:49I should also mention that
20:51with respect to TTR amyloid,
20:53there is a genetic
20:57variant of this disorder where it's passed
20:59down from parent to child in many cases
21:04should also mention that A L amyloidosis
21:07as opposed to TTR amyloidosis does
21:10not have a genetic component to it.
21:13So people always ask me why I had my brother
21:16had AL Amyloidosis or my sister or uncle.
21:18Am I likely to get it?
21:20The answer to that is no.
21:23With regards to amyloidosis,
21:24she would be screening patients
21:26with heart failure for amyloidosis
21:27in particular for the TTR type.
21:29We think so because a lot of patients
21:32have TTR amyloidosis as they get
21:35older and in various conditions in
21:38in various racial and ethnic groups.
21:41So I'll finish with it.
21:42There's some slides on the
21:44treatment for cardiac amyloidosis,
21:45not in the chemotherapy but then the but the,
21:48you know, the simple stuff that I do,
21:49not the complex stuff that oncologists do.
21:52So some general principles
21:55about cardiac involvement.
21:56We want to take away people's fluid,
21:59meaning their edema,
22:00their their their swelling in
22:02their legs and their ankles,
22:03and another in their lungs.
22:05We want to keep them in normal rhythm.
22:07And in many cases,
22:08because patients have been
22:09told they have a heart problem,
22:11they've been put on medications that are
22:13commonly used for heart problems that
22:15actually make cardiac amyloidosis worse.
22:17So things like medications that are
22:19commonly used for heart failure,
22:21things like beta blockers or other
22:23medications that don't have a
22:25benefit in patients with amyloidosis
22:27and make them feel much worse in
22:29patients who have low blood pressure.
22:30And Doctor Luciano will probably
22:32talk a little bit about this.
22:33We can use medications that support the
22:35blood pressure such as might adrene.
22:36We can use blood thinners because
22:38of a risk of stroke in some cases,
22:41putting things like a defibrillator
22:43to protect from arrhythmias.
22:45I'll say 1 slide on TTR therapies,
22:48which have come a tremendous way since 2019.
22:51There are many different options
22:53in this in this space,
22:54including pill forms and injection forms
22:57to reduce the amyloid burden that's
23:00circulating or prevented from depositing.
23:03We're excited to be part of a
23:05gene editing study which will be
23:07enrolling for patients that risk
23:09for TTR amyloidosis as well.
23:14Lastly, we are involved in a
23:16number of multicenter trials
23:18here at Yale that include for TTR
23:20amyloidosis and other amyloidosis,
23:22including one focused on screening minority
23:25populations for cardiac amyloidosis
23:27because of a genetic predisposition
23:28in patients of West African heritage.
23:31If anybody's interested,
23:32please reach out to me and I'm
23:35happy to discuss this further.
23:37So thanks for the opportunity to talk
23:38and I'm looking forward to further
23:40discussion answering questions.
23:41This is all my team and collaborators
23:43around the country as well as at Yale.
23:45So thank you very much.
23:56Thank you Doctor Miller and Doctor Luciano.
23:57If you're all set, you can
24:00proceed with your discussion.
24:18Sorry, just having an issue with Sharon.
25:26I apologize.
25:29I
25:50would just add while we're
25:51waiting for the next presentation,
25:52thank you for those who have submitted
25:54questions in the Q&amp;A and the chat portion.
25:57We will try to save the questions
25:58for the question and answer session
26:00at the end, but please continue
26:02to submit those questions.
26:13OK. Sorry about that.
26:24Is that visible?
26:29It is. It's just in presenter view. OK.
26:53I will get this
27:26still the same that
27:46better.
27:50OK. Sorry, I was dealing with two
27:52screens and I'm not used to this.
27:54So at this computer. OK.
27:56So hi, thank you, Sabrina,
27:58Doctor Browning for inviting me to
28:00talk about Amyloidosis in the kidney.
28:03So I am the kidney doctor and I
28:05will talk about what we call renal
28:07amyloidosis or amyloidosis in the kidney.
28:09In the kidney world, we have a lot
28:11of different terms for the kidneys.
28:12So when you hear renal,
28:14it's synonymous with the kidney
28:15for the most part.
28:16And there's some other terms
28:16which will go over.
28:18So if you don't have a medical background,
28:20I'm going to go into the kidney,
28:22what it is and why it becomes disease and
28:25how it becomes disease and amyloidosis.
28:27So kidneys are organs that filter
28:29and clean the blood.
28:30Most people have two kidneys
28:31that kind of sit in our back.
28:33They're kind of higher up
28:35than most of us think,
28:36just a little bit below
28:38the posterior rib cage.
28:39And what they do is at any given
28:42time they're receiving about 25% of
28:44the total blood volume and they're
28:46filtering this blood in the kidney.
28:48There are these small little
28:50filters called glomeruli,
28:51which are these beautiful
28:52collection of cells, collagen,
28:54and it's the interface between
28:55the blood and the urine,
28:57more or less.
28:58So as blood is filtered,
29:00what happens is blood passes
29:04through more or less these filtering
29:07units and it creates urine.
29:10Function of the kidney can be
29:11checked by looking at blood work.
29:13In blood work we check something
29:15called the creatinine.
29:15Creatinine will tell us how well
29:17the kidneys are doing their job,
29:18which is cleaning the blood.
29:20Creatinine is checked at, you know,
29:22with with basic metabolic,
29:24with a basic metabolic panel.
29:26It's something that your provider
29:28would check with routine blood work.
29:30For example for a physical this
29:32creatinine level can tell us how well
29:34the kidney is doing its job or working.
29:36Now the other thing which we
29:37look at is we look to see whether
29:38or not there's anything in the
29:39urine that should not be there.
29:41Two of the more in two of the more
29:43revealing things could be blood in
29:44the urine and or protein in the urine.
29:46If you find either,
29:47it could tell you that there's
29:49damage to the kidney,
29:50which is causing blood and or
29:51protein to leak from the blood
29:53into the urinary space.
29:55And we'll get that into a second.
29:57We'll get,
29:57we'll get into how that happens in a second.
29:59Now many different diseases can
30:01cause damage to the kidneys,
30:03the most common being diabetes.
30:05High blood pressure is probably
30:07the second most common disease
30:08process that can affect the kidneys.
30:10And then there's a lot of other
30:12things including infections, cancers.
30:13Certain medications can harm
30:15or damage the kidney,
30:17leading to impaired kidney function.
30:21So again, the kidney is a filter,
30:23blood is filtered through the
30:25glomerulus and the byproduct of
30:26this filtration more or less is
30:28urine. That's a very simplistic
30:29way of looking at the kidney.
30:30And if we look on the right hand
30:32side of the screen here, we have a
30:34very simplistic view of this filter.
30:36And it's important to kind of
30:38understand this process because it will
30:40give us clues as to how a specific
30:42disease is affecting kidney function.
30:44And it'll also give us clues
30:45as to how we can treat it,
30:46but more importantly what we expect
30:48in terms of recovery of the of of
30:51kidney and the kidney function.
30:52So blood is filtered through this filter,
30:55which is called the glomerular
30:57basement membrane,
30:57which is essentially a collection
30:59of collagen.
31:00In so doing,
31:01everything that our body doesn't
31:03need kind of passes through.
31:05We have the passage of all these toxins
31:08that go through this membrane and we
31:11also have passage of certain electrolytes,
31:13sodium, potassium,
31:14magnesium, calcium,
31:15which then fall into these collection
31:18tubules demonstrated right here.
31:20And that's essentially the beginnings
31:22of the byproduct of filtration,
31:24which is which more or less
31:26becomes urine that we excrete.
31:28As this liquid travels through
31:30these tubes in the kidney,
31:33we have reabsorption of certain substances
31:35that allows our kidney to modulate
31:37not only the electrolytes in our body,
31:39but also the amount of fluid.
31:41This filter is very selective.
31:43Blood will stay in the blood,
31:45cells will stay in the blood and
31:46protein should also stay in the blood.
31:48Protein should not cross this
31:50glomerular basement membrane
31:51and actually go into the urine.
31:53So if we see blood and or
31:55protein in the urine,
31:56it could tell us that this membrane
31:59or this filter is in some way damaged.
32:04Albumin is a is one of the most
32:07abundant proteins in the body.
32:08It exists in the blood vessels.
32:11We can measure that with with
32:14routine blood tests or more
32:16or less routine blood tests.
32:17And the presence of album,
32:19which we'll get into in second,
32:20is very important for the blood itself.
32:22If albumin, a protein,
32:24leaks into the urine,
32:25we can pick that up in urinary
32:27tests and it can tell us that
32:29there's something wrong with
32:30the membrane because albumin
32:31normally should not leak across
32:33the membrane into the urine.
32:36If albumin does leak across the
32:38membrane and goes into the urine,
32:40it tells us that there's some
32:41defect in the membrane and
32:42that defect can be varied.
32:47OK, so how do we notice kidney damage?
32:49Again, we notice this in two ways.
32:51If the kidney is not filtering well,
32:53we can see that the creatinine level
32:56will be significantly increased.
32:57Creatinine is a substance made by
33:00muscle that circulates in the blood
33:02and it's filtered through this
33:04membrane and excreted in the urine.
33:06Now if the membrane is
33:08not working effectively,
33:09what will happen is the creatinine will
33:12increase because the kidney is unable
33:14to filter all of that creatinine out
33:16of the body which is a bi or which is
33:18a surrogate for filtration in general.
33:21So a higher creatinine indicates that
33:23the kidney is not filtering well.
33:25Now the other way to see whether
33:26or not the kidney is working well
33:28is to look at albumin in the urine.
33:30If we start seeing albumin in the urine,
33:32it tells us that this membrane has
33:34some damage and it's leaking and
33:36it's allowing the leaking of this
33:38albumin from the blood into the urine.
33:40Now, a filtration may not be impaired
33:43if albumin is leaking to the urine.
33:45So you can have a normal filtering
33:47kidney with the leakage of albumin,
33:50and there's a lot of subtleties as
33:52to what causes one versus the other,
33:54but the presence of either indicates
33:56or both indicate that the kidney
33:58has sustained some damage.
34:02Now taking a step back,
34:03because this is going to be important when
34:05we talk about amyloidosis in the kidney,
34:07So what is the importance of this albumin
34:09and what happens when it leaks out of
34:11blood vessels and is excruted in the urine?
34:14Now albumin is a protein that
34:15exists in the blood, blood vessels.
34:18This is an example of a blood vessel
34:20with red blood cells and albumin.
34:22There's other components there too,
34:24but these are the two substances
34:25we're going to focus on,
34:27the cellular component,
34:28the red blood cells and the protein,
34:29the albumin.
34:30So one of the functions of albumin is
34:33to actually serve as a substance that
34:35allows the fluid portion of blood to
34:38actually stay in the vessels itself.
34:40So if albumin is present at a relatively
34:43normal or high level in the blood cells,
34:45it's going to allow that
34:47fluid component of blood.
34:48Blood is fluid plus red blood cells to
34:51actually stay in the blood vessels.
34:53Now if albumin is decreased in the
34:57blood vessels and one way for this to
34:59occur is through the leakage of protein
35:02of albumin from the blood vessel into
35:05the urine and we can lose albumin that way.
35:08What's going to happen is the
35:10blood vessels or the blood,
35:12the blood vessels cannot hold
35:14on to that liquid component.
35:16The albumin is there to kind of in a sense
35:18keep that liquid in the blood vessels.
35:20If albumin is gone,
35:22what happens is the liquid or aqueous
35:24component of the blood can then
35:26leak out of the blood vessels and
35:28be deposited elsewhere in the body,
35:30and this is often seen with edema.
35:32So that fluid will leave the blood vessels
35:34and kind of sit elsewhere in the body.
35:37One place where we can definitely
35:38see this on a physical exam
35:40is in the lower extremities,
35:42and this is just a picture of
35:44edema in the lower extremities.
35:46So normally when you push it on your foot,
35:48you may notice a little indentation.
35:50But in patients who have a very
35:52low amount of albumin in the blood,
35:55who've lost albumin in the urine,
35:58patients that I see in my kidney
36:00or nephrology clinic,
36:01they will have a significant amount of edema.
36:03And if you push in on lower extremities
36:05or even other parts of the body,
36:07you'll get a pretty significant
36:08indentation that will last for
36:10a significant amount of time.
36:11This indicates that that fluid which
36:13is normally in the blood vessels
36:15has leaked elsewhere and one of
36:17the culprits can be the loss of
36:19this albumin in the in the urine.
36:23So how does so?
36:24So as I stated, there's damage to
36:27the glomerular basement membrane.
36:29So if you remember back to Doctor
36:31Browning and Doctor Miller,
36:32they talked about these
36:34abnormally folded proteins.
36:35So these abnormally folded proteins,
36:38these amyloid protein or this amyloid
36:41substance actually gets filtered
36:42through the kidney and it can actually
36:45deposit in the membrane itself.
36:47When it deposits in the
36:49glomerular basement membrane,
36:50it actually disrupts the
36:52integrity of this membrane.
36:53When that membrane integrity is compromised,
36:57protein or albumin can no longer
36:58stay in the blood vessel.
37:00It actually leaks or seeps
37:02through into the urinary space,
37:04and you can lose a lot of albumin
37:06over a given period of time.
37:08At any given time,
37:09the kidneys filtering 25%
37:10of the total blood volume,
37:12it filters blood at a rate of
37:15roughly 150 mils per minute.
37:16So you can definitely lose a lot of
37:19albumin in a very short amount of time.
37:21And this can actually lead
37:23to pretty explosive,
37:24what we call protein or albumin
37:25area and the presence of and
37:27and subsequently the development
37:29of the demon in a very short,
37:31short amount of time.
37:34So this is actually a sample of a
37:38kidney filter or this glomerulus
37:40on the left hand side.
37:42This is a normal filter.
37:43I don't expect anybody to actually
37:45understand these pictures,
37:46but hopefully you can see the
37:48striking difference between the two.
37:49So this right here is a normal filter.
37:52It has a collection of membranes
37:54and cells that allow for blood
37:57to pass through and create and
37:59create urine more or less.
38:01Now on the right hand side you
38:03you can see that these are,
38:04these are the two exact same structures
38:06from two different patients.
38:07Of course one is a very normal looking
38:10one and one is a very abnormal looking one.
38:12So I don't expect any to know anyone
38:14to know anything about pathology,
38:16but hopefully you can appreciate the
38:18difference between these two figures.
38:19On the left hand side you have
38:20a very normal looking one,
38:21on the right hand side you have a very
38:24abnormal looking one and hopefully
38:26the abnormality can preach is this
38:28very intense pink substance that is there.
38:30That pink substance is albumin,
38:32which is basically flooded,
38:34this whole filter and in so doing
38:36disrupts the integrity of the
38:38filter and causes a spillage of
38:40protein or album into the urine.
38:42When we kind of blow this
38:44up in a larger scale.
38:46So we use a special microscope
38:47called the electron microscope.
38:49We have a normal filter here
38:51and this is that membrane.
38:53On one side you have blood,
38:54on the other side you have the urinary space.
38:56Blood crosses this way,
38:58blood is filtered.
38:59This when you have the general
39:01or the production of urine here.
39:04Now this filter is a very normal
39:05looking filter on this side.
39:07This is a filter that is completely
39:09filled with this amyloid protein.
39:11And if you blow this up,
39:13you see these small little fibrils that
39:15are just jammed into this filter space.
39:17When that happens,
39:18it disrupts the integrity of this filter.
39:21These amyloid proteins allow for the
39:23leakage of albumin across the filter
39:26from the blood side into the urine side.
39:28And this is essentially what
39:30we're dealing with.
39:31This is a beautiful picture of
39:33these abnormal unfolded proteins
39:35that's that's basically leading to
39:36pure disease in the kidney itself
39:39and that's the main problem that's
39:41occurring in kidney disease in in
39:44amyloid related kidney disease.
39:46There's some other minor disease
39:48processes that can occur,
39:49but this is perhaps the most
39:51significant one and the one that
39:53causes the most distress with patients.
39:55So how do we diagnose this?
39:56So if we know that the creatinine
39:59is abnormal,
39:59if we know that there's protein in the urine,
40:01we then want to figure out whether
40:03or not there's kidney involvement.
40:04Sometimes we're actually seeing
40:06patients before we identify amyloid.
40:08Oftentimes I see patients who have
40:10new onset swelling or edema and or new
40:12onset protein and we quite haven't
40:14figured out that they have amyloid yet.
40:16So in those patients or in patients
40:18who have amyloid and we want to
40:20see if there's kidney involvement,
40:21we can do a kidney biopsy.
40:23A kidney biopsy is a minimally invasive.
40:26Procedure whereby you use an ultrasound
40:29in a biopsy needle device to take two
40:33to three small samples from the kidney.
40:35The kidneys sit in the back.
40:37They're actually somewhat close
40:38to the surface,
40:39only about 5 to 10 centimeters deep.
40:46You do this under ultrasound guidance.
40:47This is actually the needle going
40:49into the butting, the kidney.
40:50You just press a little button on
40:52this device and the needle injects
40:53into the kidney, new pull out.
40:55The whole process itself takes
40:57roughly 5 to 10 minutes with the
40:59majority of that being set up.
41:01And what this yields is these
41:03small little kidney pieces,
41:04these this piece is less than an inch
41:06long and although this is blown up,
41:08it's about the thickness of
41:09a piece of dental floss.
41:10You take two or three of these samples,
41:12you send them to pathology and they
41:14process them with special stains,
41:16immunofluorescence and electron microscopy,
41:17which gives us the images that
41:20I just presented before of these
41:21filters that are either normal or
41:23have some form of disease in them.
41:25We can easily pick amyloid up
41:28in a sample that is that small.
41:29And again, this sample is very small
41:32and it'll give us roughly 20 to,
41:34you know, 30 filters.
41:36And if amyloids involved in the kidney,
41:38all of those filters will have
41:41evidence of amyloid in them.
41:43Again,
41:43this is another picture of what we obtained.
41:45You have this filter with this very
41:48abnormal protein in it or this very
41:51intense to amyloid protein in it.
41:53Now we're talking about AL amyloid.
41:54But as Doctor Miller talked,
41:56there are other forms of amyloid
41:57that can affect different organs,
41:58the kidneys though different.
41:59We have different forms of amyloid,
42:01which I'm not going to get into.
42:02We have an infection,
42:03mediated amyloid and then rarer
42:05forms of amyloid that are due
42:07to abnormally folded proteins.
42:08And we also have hereditary forms
42:10of amyloid that affect the kidney.
42:12But perhaps the most significant
42:14one is a L amyloidosis,
42:16the one that Doctor Browning,
42:18Doctor Miller were both talking about
42:20and the one we're focusing on tonight,
42:24upwards of depending on what study you see,
42:26anywhere between 75 to 85% of
42:29patients with amyloidosis may have
42:31some form of kidney involvement.
42:33Now kidney involvement can be varied.
42:35You can have minor protein,
42:36urea or protein or albumin in the urine.
42:39You can have massive amounts
42:41of albumin in the urine.
42:42To put things in perspective,
42:43the normal amount of albumin in urine
42:45in a patient who has normal kidney
42:48function with no significant diseases,
42:49roughly 30 milligrams,
42:51which is a very, very small amount.
42:54Now in patients who have amyloidosis,
42:56this can go upwards of 20,000 milligrams.
43:00So or you know or 20 grams of
43:03protein and that's a tremendous
43:05amount of protein that's spilling
43:06from the blood into the urine.
43:08A patient can be losing a lot of protein
43:11in patients who have very severe
43:13amyloid involvement in the kidneys.
43:14Again, it can also be minor,
43:16but in a lot of cases and those who present,
43:18they're presenting with very severe
43:21forms of amyloid in the kidney with
43:23a lot of protein in the urine.
43:26So what happens when the kidney
43:28loses A tremendous amount of protein?
43:30Well, the first,
43:31the first thing they're the most
43:32noticeable thing is that the patient
43:34will develop edema or swelling,
43:35as I had previously mentioned.
43:37Other things that happen is a kidney
43:39can have filter less effectively
43:41and this can lead to an elevation
43:43in the creatinine.
43:44So this protein there can inhibit
43:46the ability of the kidney to get rid
43:49of all the toxins and in so doing
43:51your creatinine will be higher and
43:52the patient develops some degree
43:54of sickness from that.
43:55Usually the edema comes on 1st and you
43:58notice that before the kidneys starts
44:01getting into significant the kidney
44:03function becomes significantly impaired.
44:04Your cholesterol numbers can also increase
44:07as protein is being lost into the urine.
44:09The liver will compensate for that and
44:11try to build up the pressure in the blood
44:14so it'll actually increase cholesterol.
44:16And patients with normal cholesterol
44:18easily can get cholesterol numbers
44:20into the three to 400 range.
44:22In diseases where you're losing
44:24a significant amount of protein
44:26when you're also losing protein,
44:28you not only lose albumin,
44:29you can also lose other proteins that
44:32have other functions in the body.
44:33And one set of proteins that you
44:35can lose are proteins that are
44:37involved in the clotting cascade.
44:38Specifically,
44:39you you lose proteins that help
44:41the body prevent clotting.
44:43So if that happens,
44:44you're shifting the body from a
44:46neutral clotting state because
44:48you're losing proteins that prevent
44:50clotting to a proclotting phase,
44:52and patients are at a higher risk
44:54of clotting.
44:55This is somewhat correlated with the
44:57amount of protein that's lost in
44:59patients who are losing more protein
45:00have a higher risk of forming blood clots.
45:03And also you can lose proteins
45:05that are responsible for infection
45:07or controlling infection,
45:08and you have a slightly increased
45:10risk of infection when you lose
45:12a significant amount of protein.
45:14So lastly, how do we treat
45:16amyloid in the kidney? So first,
45:18to actually treat the disease itself,
45:20which I'm not going to get into,
45:21you actually treat the
45:22underlying amyloid disease,
45:23and I know there'll be some talk
45:25about that a little later on.
45:27Rarely am I doing this myself,
45:29Actually, I'm never doing it myself.
45:30I'm usually doing it in conjunction
45:32with an oncologist and we're
45:34coming up with a therapy plan that
45:37is safe for the patient and will
45:40not in any way harm or further
45:43disrupt the function of the kidney.
45:45But mostly when this happens,
45:46the disease is relatively systemic or
45:50systemic and therefore we're referring
45:53to oncology and the oncologist
45:55is coming up with a treatment
45:57plan and treating the patient.
45:59We do however want to treat some of
46:02the adjunct processes that occur.
46:04So with the swelling,
46:06what you want to do is treat with diuretics.
46:10Depending on the degree of swelling
46:11and the blood pressure,
46:12you may also want to add medicines
46:15that can help modulate urine
46:17flow and decrease protein.
46:19That becomes somewhat tricky because in
46:21a lot of amyloid patients blood pressure
46:23can become very low due to several things,
46:26autonomic or nervous system dysfunction,
46:29also the loss of what we call this
46:33oncotic pressure among other things.
46:35And if there's you know cardiac involvement,
46:37you would not necessarily want
46:39to use these medications.
46:40But in patients who have low levels of
46:43protein loss and or isolated kidney function,
46:45we will try to use some of these
46:48medications that can that can prevent
46:50the loss of protein in the urine
46:52by modulating flow to the kidney
46:54with what we call ACE inhibitors,
46:56RBS or mineral corticoid receptor antagonist.
46:59As far as acute kidney injury.
47:01So when the kidney is losing a lot of
47:03protein and we're trying to die a Reese,
47:05the kidney is very prone to injury.
47:07So we want to be very mindful of
47:09blood pressure and not push the
47:10blood pressure too low,
47:11which can become somewhat difficult
47:13when you're trying to die a Reese
47:15or get fluid off of these patients.
47:17And you also want to make sure you're
47:19not providing the patient with other
47:21medications that can adversely affect
47:23kidney function such as your NSAIDs,
47:25which are ibuprofen, Advil,
47:26Motrin or Aleve.
47:28And you want to be careful with
47:29herbal supplements,
47:30which can have significant impact
47:33on kidney function.
47:34With increased cholesterol,
47:35you want to place the patients on statins,
47:38amyloid can take a while to treat,
47:40and the kidney problem itself can
47:43actually take much longer than
47:45treating the underlying amyloid itself,
47:47because it takes a while for the
47:49kidney to repair itself.
47:50So even if you treat amyloid,
47:52you may still be losing protein for
47:54a while after you've successfully
47:56treated amyloid with certain blood
47:58parameters being achieved.
48:00So you probably want to put these
48:02patients on statins,
48:02assuming there's no other contraindication
48:04to help lower the cholesterol.
48:07To address the increased risk of blood clots,
48:10we put patients on aspirin if
48:11they have a minimal amount
48:13of protein loss or stronger,
48:15stronger anticoagulants if they
48:16have more significant protein loss.
48:20Blood clots are significant and they
48:22can lead to significant morbidity
48:24including pulmonary embolus or
48:26stroke in certain patients and
48:28for increased risk of infection.
48:29We actually don't give any
48:32antibiotic prophylaxis specifically,
48:33but we recommend vaccinations
48:35before starting treatment,
48:36avoidance of avoidance of ill of
48:41people who are ill around the patient
48:44and just vigilance going forward.
48:48And I believe that is it. And I will
48:52then turn it over. Doctor Brennan,
48:58thank you very much.
48:59And we're now going to share
49:00a video from Doctor Ziffkovic.
49:18Well, I say you're muted.
49:19We just have to unmute.
49:30I'm Sasha Zepary.
49:32I'm a neuromuscular neurologist
49:33and I will be talking to you about
49:36nerves and light chain amyloidosis.
49:40Amyloidosis can be associated
49:42with peripheral neuropathy.
49:43So what is neuropathy?
49:45The term itself refers to various
49:47conditions that affect the function
49:49of peripheral nerves that send
49:51and receive the signals between
49:53the brain and the spinal cord.
49:55In other organs and parts of the body,
49:58peripheral nerves control the function of
50:01muscles and different types of sensations.
50:05Typical symptoms of neuropathy
50:07include numbness or lack of sensation,
50:11and different types of abnormal
50:13sensations like tigling.
50:15Some patients may also experience
50:18neuropathic pain, loss of strength,
50:21or loss of coordination.
50:23Symptoms of neuropathy are often
50:25worse or they start in the feet
50:27where we find the farthest nerve
50:30endings which are farthest from
50:32the central nervous system.
50:34In general,
50:35population 2 to 3% of all people
50:38have neuropathy and it becomes
50:40much more common as we age.
50:43It has been estimated that around
50:468 to 10% of people after the age
50:49of 55 will develop neuropathy.
50:52In the western world,
50:53the most common cause of neuropathy
50:56is diabetes,
50:57which affects more than half
50:59of all diabetics.
51:0210% of all patients with neuropathy
51:05with unknown cause will also have
51:09monoclonal protein in their blood and
51:12this condition is usually not associated
51:16with any hematologic disorders and
51:19is that caused volplogramopathy of
51:22unknown significance in patients
51:25with light chain amyloidosis.
51:27It has been estimated that 1/3 to 1/7 of
51:33all patients with light chain amyloidosis
51:36will have peripheral neuropathy.
51:39So why do patients with the light
51:43chain amyloidosis get neuropathy?
51:45Neuropathy may develop as a result of the
51:48position of amyloid peripheral nerves.
51:51We can also have the position of
51:54amyloid in connective tissue and
51:56muscle tendons that may compress the
51:59nerves and lead to nerve entrapment.
52:02Most common is carpal tunnel syndrome
52:06where the nerve is entrapped at the rest,
52:09leading to hand numbness,
52:12weakness and discomfort.
52:13Some of the medications can also
52:15cause some rapidity.
52:19Patients with light chain and diabetes
52:21may develop diabetic neuropathy
52:23and we can also have neuropathy
52:25associated with different types of
52:28nutritional deficiencies and with
52:30different type of autoimmune disorders.
52:33Neuropathy may also be the first sign
52:36of light chain amyloidosis or it can
52:38present later in the course of this.
52:41Some of the early signs of neuropathy
52:43in light chain amyloidosis include loss
52:46of sensation which is present in five
52:49out of six patients with amyloid nerve.
52:52But the early on some of the patients
52:55will develop loss of strength and weakness
52:58and some may display abnormal function
53:02of autonomic nervous system manifesting
53:05with various symptoms like vomiting,
53:09diarrhea, Constipation,
53:12partial hypotension and this is a
53:16condition when the blood blood pressure
53:18drops steadily upon the change of but
53:21position typically when patients stand up.
53:23Patients may also have decreased
53:26sweating and overall amyloid
53:29neuropathies are often painful,
53:31but it can be painless as well and sometimes
53:35they can present with this autonomia.
53:39But this autonomia is not present in
53:42every patient with amyloid neuropathy.
53:46So how is neuropathy diagnosed?
53:49In amyloid patients?
53:52Evaluation starts with neurologic
53:56consultation with different types of
53:59lab tests that look at alternative
54:03causes of neuropathy
54:08and many patients will also
54:11undergo electromyography with
54:13nerve conduction studies.
54:15And we can also pursue nerve
54:17and muscle biopsy to look for
54:19the position of amyloids in
54:21peripheral nerves and muscles.
54:25As the signs and symptoms of amyloid
54:29neuropathy are not specific for light
54:32chain and pletosis that nurses is often
54:35delayed up to 2 1/2 years or even longer
54:41once patient is diagnosed with neuropathy.
54:46We can try to treat the symptoms
54:50of neuropathy but the priority is
54:53the treatment of the underlying
54:55disease of light chain amyloidosis.
55:00Treatment of light chain amyloidosis
55:02may also lead to improvement of neuro
55:06and supportive and symptomatic
55:10treatment of neuropathy may include
55:13physical and occupational therapy,
55:15treatment of nerve band pain,
55:17and removing other factors that can
55:20potentially worsen the neuropathy.
55:25To summarize everything,
55:26the peripheral nerves are often
55:28affected in light chain amyloidosis
55:30and peripheral neuropathy may be the
55:33first sign of amyloid deposition.
55:36Some of signs and symptoms of
55:39neuropathy include loss of sensation,
55:42lack of coordination and unsteadiness,
55:45weakness, neuropathic pain
55:46or just static hypertension,
55:48abnormal sweating and loss of bowel control.
55:56You can also find a lot of
55:59helpful information on Internet.
56:01At the website of Amyloidosis Support Group
56:05you can find the wealth of information
56:08on different types of amyloidosis,
56:11all kinds of aspects of amyloidosis
56:14that can affect your daily lives,
56:19and all kinds of information
56:21on amyloid neuropathy.
56:23At the website of National Issues of Health,
56:28you can look at the web page
56:31on peripheral neuropathy and it
56:35will provide you on information
56:37what is peripheral neuropathy,
56:40what kind of symptoms are associated with
56:43neuropathy and what can be done about them.
56:47And on YouTube you can find a
56:50very helpful video What to expect
56:55during Electro diagnostic testing.
56:58Once again,
56:59I want to thank you for your attention
57:02and I want to thank the organizers
57:05for inviting me to present you this
57:09information on nerves and amyloidosis.
57:11Thank you,
57:26Okay.
57:31And last, we are going to be talking
57:33about the treatment of AL Amyloidosis.
57:37So when we talk about treatment,
57:39our goal is really to treat the underlying
57:43plasma cell disorder with the goals
57:46of decreasing amyloid production,
57:47limiting further organ damage and allowing
57:50for regression of tissue amyloid deposits.
57:54Hopefully you have all heard tonight the
57:57management is truly multidisciplinary
57:59across several disciplines.
58:02All patients with systemic AL amyloidosis
58:05require treatment at the time of diagnosis.
58:07However, treatment is not
58:09necessary with localized forms.
58:11Therefore, as previously mentioned,
58:13it's important to determine if a patient
58:15has localized our systemic ale amyloidosis.
58:20As ALE amyloidosis is a rare disease,
58:23we previously did not have published
58:25treatment guidelines until 2022,
58:27and then the European Hematology
58:30Association in conjunction with the
58:32International Society of Amyloidosis
58:34published a set of guidelines.
58:37As part of these guidelines,
58:38the first question was whether or
58:41not an individual was eligible for
58:43autologous stem cell transplant.
58:46Eligibility is key as careful patient
58:50selection will avoid early mortality
58:53or what we would call increased risks.
58:56Overall, the hematological overall
58:58response rate for autologous stem
59:01cell transplant in AL amyloidosis
59:03has been shown to be about 84%.
59:07And so as part of this checklist,
59:09they have different inclusion and
59:11exclusion criteria and evaluation for
59:13again autologous stem cell transplant.
59:15These include items such as age,
59:18performance status,
59:19which is how functional an individual is,
59:23blood pressure and evaluation of their heart,
59:26liver, kidney and respiratory function.
59:30Some items that would exclude patients
59:32from proceeding to autologous
59:34stem cell transplant include
59:35refractory orthostatic hypotension,
59:37meaning low blood pressure,
59:39refractory arrhythmias,
59:41or abnormal heart rhythms,
59:43decompensated heart failure,
59:45a refractory pleural effusions
59:47which is fluid in the lung or
59:50an increased risk of bleeding.
59:54So if we evaluate our patient and we
59:56determine that they would be eligible
59:59for an autologous stem cell transplant.
01:00:01The next step is often induction
01:00:05chemotherapy or chemo immunotherapy,
01:00:07typically giving 2 to 4 cycles.
01:00:09The current recommendation is for
01:00:12a combination of daratumumab which
01:00:14is a CD38 monoclonal antibody in
01:00:18conjunction with cycloblosamide
01:00:20abortasmen and dexamethasone often
01:00:23abbreviated as Cyber D Typically
01:00:26induction therapy is recommended for
01:00:28any individual who has a bone marrow
01:00:30plasma citosis meaning involvement of
01:00:32their marrow by over 10% plasma cells.
01:00:34However, more often than not,
01:00:37we are proceeding with two to
01:00:39four cycles of induction prior to
01:00:41autologous stem cell transplant.
01:00:43As patients obtain A hematological
01:00:46complete response with induction,
01:00:48autologous stem cell transplant may be
01:00:51deferred by starting induction therapy.
01:00:53It also allows as a faster time to
01:00:57potential organ response as well.
01:00:59If a patient has an advanced single organ
01:01:02dysfunction due to AL amyloid doses,
01:01:04it is possible to perform a solid
01:01:07organ transplantation such as a
01:01:09heart or a kidney transplant prior
01:01:11to autologous stem cell transplant.
01:01:13For those patients undergoing
01:01:15autologous stem cell transplant,
01:01:17Methlin,
01:01:17which is a type of chemotherapy is
01:01:19used as our conditioning regimen.
01:01:22This can be just reduced if an
01:01:24individual does have renal dysfunction
01:01:26after atalicus stem cell transplant,
01:01:29we would assess the response and
01:01:31if an individual has achieved a
01:01:33very good partial response then
01:01:35they would go on to observation.
01:01:37There's currently no maintenance
01:01:39therapy for ALE amyloidosis.
01:01:41However,
01:01:41if an individual has a concomitant
01:01:44multiple myeloma diagnosis then
01:01:46maintenance therapy may be indicated.
01:01:49So for those not familiar with
01:01:52Atalicus stem cell transplant,
01:01:53we use a patient's own stem cells.
01:01:56Mobilization of those stem cells
01:01:58is achieved using a subcutaneous
01:02:01injection called a granulosite
01:02:03colony stimulating factor.
01:02:05These cells are then leucophrised off.
01:02:08During this period, fluid shifts can occur.
01:02:10So it's really important that we monitor
01:02:13a patient's fluid status at closely.
01:02:16These stem cells are then can
01:02:19be frozen for use at a later
01:02:22date or used almost immediately.
01:02:24If patients are proceeding directly
01:02:26to autologous stem cell transplant,
01:02:28they would then be given high dose
01:02:30chemotherapy which is where the
01:02:31Methaline comes into play prior to
01:02:33having their own stem cells reinfused.
01:02:38Now unfortunately not all of our patients
01:02:41are considered to be transplant eligible.
01:02:43Again, a lot of this is
01:02:46due to organ dysfunction,
01:02:47advanced age, patient preference.
01:02:50And so if an individual is
01:02:53not a transplant eligible,
01:02:56our next step is to relate to ask for
01:02:58any contraindications to pertitasimeb,
01:03:00which is a chemotherapeutic agent Austin,
01:03:03known as Velcade.
01:03:04The most common reason for our
01:03:06patients to have a contraindication to
01:03:09Vertazimeb is peripheral neuropathy,
01:03:11which as just mentioned can be
01:03:12seen in up to 15% of our patients.
01:03:15And this is because one of the
01:03:17side effects of vertismeb can be
01:03:20peripheral neuropathy if bortazimab
01:03:22is not a contraindication.
01:03:24And then we look at our staging
01:03:27and for stage 1 to 3A and the
01:03:31staging system is the European
01:03:33modified Mayo 2004 staging system,
01:03:35We would use what was mentioned previously,
01:03:38a combination of daratumumab,
01:03:40a CD38 monoclonal antibody with
01:03:43cyclophosmide bortazimab which
01:03:44is VELCADE and dexamethasone for
01:03:47those patients who are at stage 3B.
01:03:50And again,
01:03:51our staging is largely based on
01:03:53cardiac involvement utilizing
01:03:54a probium pean and troponin.
01:03:56We would also use the combination
01:03:58of daratumumab, cyclophosphamide,
01:03:59fortasmid and dexamethasone.
01:04:01However,
01:04:02we would do suggest specifically
01:04:04the dose of dexamethasone would
01:04:07be adjusted down to 20 milligrams
01:04:09maximum and often times we have to
01:04:11go lower and the dose of fortasmid
01:04:14would be suggested down to the
01:04:16lowest dose possible,
01:04:17which is 0.7 Migs per meter square.
01:04:19And that can always be just
01:04:22escalated depending on tolerability.
01:04:23So you're in an area where Dara
01:04:25to my mob is not available,
01:04:27which could be parts of the world
01:04:29not here in the United States.
01:04:32Then we could utilize induction
01:04:34regiments such as cyclophosphonide,
01:04:36Britasom of dexamethasone without the
01:04:38Dara or Britasom of methyl and dexamethasone.
01:04:43So we mentioned the combination
01:04:45of deritumimab, cyclophospamide,
01:04:47Britasmab and dexamethasone.
01:04:48So this is a relatively recent
01:04:51recommendation and it comes from
01:04:53a clinical trial that's often
01:04:55called the Andromeda trial.
01:04:57This was published in the New
01:04:59England Journal Medicine in 2001.
01:05:01This was a randomized phase three trial
01:05:04in treatment that you've patients,
01:05:06so individuals who have never seen therapy.
01:05:09There was a total of 388 patients who
01:05:13were randomized to receive either
01:05:16the combination of cytoxin for tasmid
01:05:19dexamethasone versus daratumumab,
01:05:21cytoxin for tasmid dexamethasone for
01:05:25six months followed by 18 months
01:05:28of daratumumumab maintenance.
01:05:30The primary endpoint of this trial
01:05:33was the hematological complete
01:05:35response rates and what they showed
01:05:37was that there were higher rates of
01:05:39a hematological complete response
01:05:41at 53.3% and those individuals in
01:05:44the daratumumab group compared to
01:05:4718.1% and they had the median time
01:05:51to hematological CR or complete
01:05:53response of 60 days.
01:05:55They also showed cardiac and munal
01:05:58responses were improved in the
01:06:00individuals who received daratumumab
01:06:01at the six month mark,
01:06:0341.5 versus 22.2% and 53% versus 23.9%.
01:06:10The deratuma MAP group was favored
01:06:14across all cytogenetic subgroups and
01:06:17this trial led to deratuma MAP in
01:06:19combination with cyber D becoming the
01:06:21first drug approved by the FDA in
01:06:24February of 2021 for ALE amyloidosis.
01:06:28So there's a few caveats here
01:06:30to induction gap.
01:06:31One is if an individual has an IGM
01:06:34producing clone as this accounts
01:06:36or can be seen in up to 5% of all
01:06:39AL amyloidosis patients.
01:06:41And in that case the current
01:06:43guidelines recommend the use of
01:06:45retuxime and bedded mustine which
01:06:47is a chemotherapeutic agent and
01:06:49an immunomodular and a anti CD28
01:06:53monoclonal antibody.
01:06:54The hematological response rates
01:06:56with this combination is 60% if
01:06:59you send a genetic considerations.
01:07:01If an individual has a translocation 11/14,
01:07:03which is the most common cetogenetic
01:07:06abnormality BC and AL amyloidosis patients
01:07:11with a rate of occurrence between 40 and 60%,
01:07:16This translocation has been associated
01:07:18with a lower response rate and
01:07:21poorer survival in individuals who
01:07:23are treated with cyber D However,
01:07:25this risk can be overcome with the
01:07:28additions of DERA Tumor MAP and Oramoflin.
01:07:31And then we have amplification of 1 Q 21,
01:07:34which is seen in up to 20% of
01:07:36ALE amyloidistic patients.
01:07:38Individuals with an amplification
01:07:40of 1 Q 21 have a lower response
01:07:43rate and shorter survival if they're
01:07:45treated with Oralmoflin.
01:07:47And more recently data has come
01:07:48out about a lower response rate and
01:07:51survival and these individuals who
01:07:52receive Derek tumor mouth.
01:07:53But this data is mainly in the
01:07:56relapsed or refractory setting as
01:07:58the rate and depth of hematological
01:08:00response in the Andromeda trial were
01:08:03not affected by amplification one Q 21.
01:08:08And so I think the important thing
01:08:10as we talk about treatment is we also
01:08:12have to be making sure our patients
01:08:14are responding to therapy And so we
01:08:16would talk about response to treatment.
01:08:18There's two things that we talk about.
01:08:20The 1st is hematological response.
01:08:23We define a hematological complete
01:08:25response as normalization of the serum
01:08:27free light chain levels and ratio,
01:08:29and a negative serum and urine IFE
01:08:32or immuno fixation Electro recess.
01:08:35A very good partial response is defined
01:08:37as reduction in the difference between
01:08:39the involved to uninvolved free light
01:08:42chain of less than 4 milligrams per
01:08:44deciliter and a partial response as a
01:08:46greater than 50% reduction again and
01:08:48the difference between the involved
01:08:51to uninvolved free light chain organ
01:08:53responses lag behind hematological responses.
01:08:57Organ responses can be seen at best up
01:08:59to three months after starting therapy,
01:09:02but often times it's not seen until
01:09:04a year goes by.
01:09:08And in looking at specifically
01:09:10heart and kidney as that's what
01:09:12we talked about here today.
01:09:13Cardiac responses are based on a
01:09:15reduction in the NT pro BMP as
01:09:17a decrease of greater than 30%
01:09:19compared to baseline for example.
01:09:22And in kidney it's based on a
01:09:24reduction in the 24 hour protein.
01:09:26Unfortunately,
01:09:2730 to 4030 to 40% of patients who
01:09:31do obtain A hematological complete
01:09:33response do not have an organ response.
01:09:38And so we do have certain milestones
01:09:41that we ideally would like to meet when
01:09:45we're treating individual patients.
01:09:46So during the induction therapy,
01:09:48our goal is to have a
01:09:50hematological partial response.
01:09:51So again at 50% and the difference
01:09:54between the involved and uninvolved
01:09:56free light chain after the first cycle
01:09:58that increases the two cycles of
01:10:01daratumumumab is not used up front.
01:10:03And then after two cycles of
01:10:05a Dara cyber decombination,
01:10:06we would really expect to have at least a
01:10:09very good partial response at any time.
01:10:12We do not achieve these milestones.
01:10:14We should be thinking about an alternative
01:10:17second line or rescue therapies if you will.
01:10:20Similarly,
01:10:20when we talk about monitoring of disease,
01:10:23if an individual has a satisfactory response,
01:10:26it defined as a complete hematological or
01:10:28very good partial hematological response,
01:10:31US organ response.
01:10:32We would continue monitoring for
01:10:34a deepening of organ response.
01:10:35About any time we do not achieve the
01:10:38desired response or we have relapse disease,
01:10:41we would talk about a second line
01:10:44or an alternative therapy.
01:10:45So really when we talk about relapse or
01:10:48refractory patients with AL amyloid doses,
01:10:51our treatment is really based
01:10:52on our prior therapy.
01:10:53We have to take into account
01:10:56still their organ function,
01:10:57how fit they are to receive treatment
01:11:01but also what have they seen previously.
01:11:04So the first question we'll often ask
01:11:06is whether or not an individual received
01:11:08a CD38 monoclonal antibody such as
01:11:11Dera tumor mob and or Esotexamab which
01:11:15is an alternative CD38 monoclonal antibody.
01:11:18If an individual is not CD38 monoclonal
01:11:22refractory monoclonal antibody refractory,
01:11:24often times we will proceed with single
01:11:27agent dera tumor MOB and there have
01:11:29been two prospective trials looking at
01:11:31this or isotuximab and there has been
01:11:34one prospective trial through the SW
01:11:36oncology group looking at this as well.
01:11:38If someone is considered to be
01:11:40refractory to a CD38 monoclonal
01:11:42antibodies such as deratuma mob,
01:11:44then when we talk about whether or
01:11:46not they are pertussimid refractory,
01:11:49if an individual is not pertussimid
01:11:51refractory,
01:11:51we can utilize some of the injection
01:11:55therapies such as cyclophosmide,
01:11:58bartasamide, dexamethasone or bartassamide,
01:12:00methyl and dexamethasone.
01:12:02The double combination of bartassum of
01:12:05dexamethasone and exassom of dexamethasone,
01:12:07which is an oral proteasome inhibitor
01:12:09have also been evaluated with similar
01:12:12overall hematological response
01:12:13rates of 68 and 63%.
01:12:17If someone is refractory to vertazimeb
01:12:19and then our next line of therapy is
01:12:22often an immunomodulatory agent which
01:12:24could be either linalidomide or pomalidomide,
01:12:26which are both oral pills that can
01:12:29be combined with dexamethasone.
01:12:31However, as we mentioned,
01:12:33a lot of our patients do develop
01:12:36relapsed retractory disease or
01:12:37do not have organ response.
01:12:39So additional therapies are needed.
01:12:41So what's on the horizon?
01:12:43So these agents are currently
01:12:45under investigation.
01:12:46The 1st is the Lantomat Mat that
01:12:49Delton which is an antibody drug
01:12:51conjugate targeting the B cell
01:12:53maturation antigen on the plasma cell.
01:12:56There have been two very small
01:12:58retrospective analysis published.
01:13:00The first which is shown here
01:13:02at included eleven patients
01:13:04and they had an overall hematological
01:13:06response rate of 64% and another study
01:13:09only had six patients but had a reported
01:13:12hematological response rate of 83%,
01:13:14which is encouraging.
01:13:15So there's a prospective phase two
01:13:18trial which is ongoing in Europe and
01:13:20they're looking at the drug given every
01:13:22six weeks for a maximum of eight doses.
01:13:25And there's a planned phase one,
01:13:27two study here in the United States
01:13:29that will evaluate different doses
01:13:31and different schedules of the drug.
01:13:36The next drug that's currently under
01:13:38investigation is the Neti clocks and many
01:13:40of you of you may have heard about this drug
01:13:44as it is currently FDA approved in other
01:13:47hematological disorders such as CLL&amp;AML.
01:13:50So the Netoclax is a BC L2 inhibitor and
01:13:53there is a retrospective meaning looking
01:13:56at patients who were already treated study
01:13:59of 43 patients across 14 institutions.
01:14:02The dosing of the Netoclax was varied,
01:14:06but 30 patients did have a
01:14:09translocation 11/14 and in these
01:14:11patients which is seen in graph C,
01:14:13the overall hematological
01:14:15response rate was 81%.
01:14:16So this has led to various studies
01:14:20that are currently ongoing or in their
01:14:25works looking at the combination of the
01:14:28Netoclaxin dexamethasone or the Netoclaxin
01:14:30combination with exassive or Darituminum.
01:14:33And again these are all in patients
01:14:34who have an 1114 translocation
01:14:39and the other agents that are
01:14:42currently under investigation
01:14:43including anti amyloid antibodies.
01:14:45So these are antibodies designed
01:14:47to bind to epitopes on the amyloid
01:14:49fibril that would lead to macrophage
01:14:52activation and fibril dissolution.
01:14:55So there are currently
01:14:56two drugs in development.
01:14:57One is for Tamimab.
01:14:58This is being done through the AFFIRM
01:15:01AL study which is a phase three
01:15:04double-blind placebo-controlled trial.
01:15:05This is for newly diagnosed untreated
01:15:08AL amyloid patients that have cardiac
01:15:11involvement or who are also known as Mayo.
01:15:13Stage 4 patients will be randomized
01:15:16and meaning they're randomly
01:15:18chosen to either receive the Ivy,
01:15:20Britaminab or standard of
01:15:22care which would be Dara,
01:15:23cyber D or placebo plus
01:15:26the standard chemotherapy.
01:15:27This trial is actually
01:15:29currently open here at Yale.
01:15:31The other anti amyloid antibody that's
01:15:34being studied is known as Cal 101.
01:15:37There was a published Phase 1A
01:15:39B study of 27 patients which
01:15:41was mainly looking at safety,
01:15:44but they did not see any dose limiting
01:15:47toxicities and 63% of the patients
01:15:49had what the authors considered
01:15:51to be a therapeutic response based
01:15:53on biomarker and or imaging.
01:15:55So there are two ongoing phase three
01:15:58trials for specifically for Mayo stage
01:16:003A and 3B AL amyloidosis patients.
01:16:02And again both of these trials are
01:16:05double-blind randomized phase three
01:16:07studies combining the antiamyloid fibril
01:16:09Cal 101 with standard of care which
01:16:12would be the combination of daratumumab,
01:16:14cyclothroxamide prettisum and dexamethasone.
01:16:18Well,
01:16:19that's a lot of information
01:16:21which is not easy to parse down.
01:16:24But in conclusion,
01:16:25we really need to individualize our
01:16:27amyloid dosage treatments based upon an
01:16:30individual staging performance status,
01:16:32organ involvement and comorbidities.
01:16:34In addition,
01:16:35those with Relapsure refractory disease,
01:16:37we need to really look about their prior
01:16:39therapies in choosing the next line.
01:16:41Our aim is for a rapid reduction
01:16:44in light chain burden.
01:16:45However,
01:16:45novel therapies are needed for those
01:16:48with relapse refractory disease and
01:16:50in order to improve organ responses.
01:16:52Therefore,
01:16:52clinical trials are necessary in order
01:16:55to advance care in this rare disease
01:16:57and for this patient population.
01:16:59So I'm happy to take questions
01:17:03for myself for the group in
01:17:06the last 15 minutes or so.
01:17:13Great, Thank you, Doctor Parker.
01:17:15I I think Doctor Miller kindly
01:17:16answered a number of the questions,
01:17:18but I'm just seeing if Dr.
01:17:22Luciano is still with us.
01:17:25There was a question about any
01:17:28data connecting chronic uric acid,
01:17:31kidney stones and renal amyloidosis
01:17:36to my knowledge. No,
01:17:40no.
01:17:41OK, great. Yeah,
01:17:43I'm not familiar with any either.
01:17:46Another attendee asked or shared
01:17:49that she is of a family of Hispanic
01:17:52origin and her mother died of amyloid
01:17:56before ELECT 2 was identified.
01:17:59Are there any updated?
01:18:02Is there any updated research on
01:18:05kidney involvement with ELECT 2
01:18:06which I know you mentioned as
01:18:08kind of a rare type of amyloid
01:18:10and it is a rare formula we're we're
01:18:13just in the stages of recently being
01:18:15able to identify it more readily.
01:18:18But as far as treatment specific,
01:18:21you know, as far as specific therapies
01:18:23targeting luck to unfortunately there's
01:18:25there's nothing out there that's close
01:18:28to close to trial at this point.
01:18:31It's one of those very rare forms.
01:18:33So therefore although it is
01:18:36being studied by isolated labs,
01:18:38it's not to the point where it's you know
01:18:40offered on a trial basis at this point.
01:18:43Great, Thank you.
01:18:44And maybe I can answer a question and
01:18:47then turn it over to to Doctor Parker.
01:18:49But one question was what do we
01:18:51see for the future of ALE amyloid,
01:18:52which I think is a great question.
01:18:55You know, I think Doctor Parker did a
01:18:57great job of going through our current
01:19:00data on induction therapy which with
01:19:02their Cybor D and the Andromeda trial.
01:19:04I think a majority of our patients
01:19:07are achieving quick and pretty
01:19:09significant hematologic responses.
01:19:10But I think the challenge is still
01:19:12the organ response which can be
01:19:14quite delayed and a number of our
01:19:17patients can unfortunately have
01:19:18complications of their organ disease
01:19:20despite having hematologic response.
01:19:22So I think I I think the data
01:19:26on antiamyloid fibrils are quite
01:19:27promising in hopes to kind of
01:19:30improve organ function as we're
01:19:32achieving hematologic response.
01:19:34And then hopefully some of the more
01:19:36novel agents that Doctor Parker
01:19:37mentioned can be helpful in patients
01:19:39with relapse refractory disease,
01:19:41which I think is still a
01:19:42really challenging population.
01:19:44Don't know Doctor Parker,
01:19:46if you have anything to add to that,
01:19:51Sure. Just looking at through
01:19:52a few of the other questions,
01:19:55one of the things about cardiac stage 4,
01:19:57I think the biggest thing when we
01:20:00talk about individuals who do have
01:20:02advanced stage amyloidosis, Stage 4,
01:20:05stage 3B is we really have to be
01:20:07mindful of the doses of drugs that
01:20:09we're giving these individuals
01:20:11and that comes across in the most
01:20:13recently published guidelines.
01:20:14For individuals who have stage
01:20:163B disease and that's again based
01:20:19on the European modified Mayo
01:20:212004 criteria is what they use in
01:20:24the current ISA EHA guidelines.
01:20:27They really make a point of
01:20:28it's just the same treatment,
01:20:29the Dara ISA toxin and
01:20:32daratumumumab dexamethasone.
01:20:33But the doses of the dexamethasone and
01:20:35the delicate are being just modified.
01:20:37And a lot of that has to do with fluid
01:20:39retention and fluid shifts and that
01:20:41we can actually make some of these
01:20:44individuals with significant cardiac
01:20:45involvement symptomatically worse.
01:20:47And therefore,
01:20:47we have to be mindful of those
01:20:49doses and really work together
01:20:51with our cardiology and nephrology
01:20:54colleagues on supportive care
01:20:55and other symptom management,
01:20:57which both Doctor Miller and
01:20:59Doctor Luciano attached upon
01:21:07great. So I think there's a
01:21:09question about a patient,
01:21:10if a patient underwent a bone marrow
01:21:12and autologous stem cell transplant,
01:21:13should they be on medications as well,
01:21:16which I think is maybe referring to
01:21:18maintenance therapy which is common
01:21:20in our patients with multiple myeloma.
01:21:22So in patients who have achieved A
01:21:25hematologic complete response or a good
01:21:28hematologic response post transplant,
01:21:29we really don't have data at least at this
01:21:32time for continued maintenance therapy.
01:21:34So you know we are definitely monitoring
01:21:37these patients very closely for worsening
01:21:39of their light chains or other protein
01:21:42amyloid markers and also for any
01:21:44evidence of progressive organ disease.
01:21:46But if there is a good hematologic response,
01:21:49again generally we are not
01:21:50using maintenance therapy.
01:22:04I think one of the other questions
01:22:06is can you reach hematological
01:22:08response and have worsening organ
01:22:11damage or new issues related to
01:22:14amyloidosis such as nine years and
01:22:17suddenly develop carpal tunnel.
01:22:19So I think the first part of that
01:22:22question unfortunately we know that
01:22:23individuals can achieve A hematological
01:22:25response and have worsening organ
01:22:27damage as 30 to 40% of our patients
01:22:30do not have an organ response.
01:22:33And so some of the thoughts about why
01:22:35that can be is that patients can have
01:22:38very end stage organ disease when
01:22:40they're diagnosed as I think several
01:22:42of our presenters mentioned that
01:22:44it can take several years sometimes
01:22:45or there can be delay in diagnosis.
01:22:47So really these patients present
01:22:49with end stage organ disease.
01:22:51Another area of ongoing active research
01:22:53is looking at the real minimal
01:22:55residual disease plays and one thought
01:22:57is that an individual could have a
01:22:59hematological complete response.
01:23:01However still have MRD in that MRD is
01:23:04what's driving ongoing organ dysfunction
01:23:07like again an area of ongoing a study,
01:23:17right. And I think another
01:23:18question was about autonomic
01:23:20nervous system involvement of of
01:23:23amyloid leading to dysautonomia,
01:23:26which certainly we can see with
01:23:27AL amyloid and also I think with
01:23:30transthyree and TTR amyloid.
01:23:31So I think those are really the
01:23:32two main types we think about.
01:23:41And I think we do have a question
01:23:43for Doctor Luciano about treating a
01:23:46patient who was amyloid in a I'm not
01:23:48sure if they you asked about either
01:23:50transplanting a kidney or obtaining a
01:23:52kidney transplant and they said yes.
01:23:54So I don't know if you want
01:23:55to tackle one or both.
01:23:56Yeah. So I'm not sure either what that
01:23:59question refers to in general, but so both.
01:24:01So treating amyloid in a transplanted kidney,
01:24:06so that's complicated because the
01:24:09immunosuppression involved is necessary for
01:24:13maintaining the the life of that kidney.
01:24:17It it does happen, it does occur.
01:24:20But in a sense,
01:24:21treating the amyloid is, you know,
01:24:25priority as opposed to saving the kidney.
01:24:28So you would treat accordingly and if
01:24:32you have to modify the immunosuppression,
01:24:34you would do that.
01:24:37Unfortunately,
01:24:37I'm not a transplant nephrologist,
01:24:39so a lot of my colleagues will
01:24:42be treating those patients,
01:24:43but it does happen in transplanted kidneys.
01:24:45Now as far as obtaining A transplant
01:24:47after you've received amyloid,
01:24:49that differs from center to center,
01:24:52transplant center to transplant center.
01:24:54So if you have kidney disease after amyloid
01:25:00and oftentimes a patient and Doctor Parker,
01:25:02this is what you kind of alluded to,
01:25:03the residual disease damage that
01:25:05can occur in specific organs,
01:25:07the kidney is very susceptible to that.
01:25:09When you have a lot of protein in the
01:25:11kidney and that protein is spilling,
01:25:13it takes well over 6 to 12 months to
01:25:16actually achieve a response in the kidney.
01:25:19And oftentimes you don't have
01:25:21complete response and you'll
01:25:22have residual proteinuria.
01:25:23Now it's not because amyloid
01:25:25is still in the kidney.
01:25:26In my mind it does take a while for
01:25:28amyloid to clear up in the kidney.
01:25:29But it's because all of that amyloid
01:25:31and or the treatment that we're using
01:25:34to control the amyloid and or the
01:25:36diuretics that we're using or the
01:25:38low blood pressure that ensues does
01:25:40create ischemia or damage in the
01:25:43kidney and that leads to scarring.
01:25:45And that scarring will therefore
01:25:47lead to permanent proteinuria.
01:25:49So they'll never actually clear
01:25:50the protein urine,
01:25:51they always have a little residual protein.
01:25:53It's often dependent on scar and
01:25:57oftentimes I biopsied patients post
01:25:59treatment response to see if there
01:26:01is a significant degree of scarring
01:26:03or some residual amyloid left over.
01:26:05And more often than not,
01:26:06it is scarring that's there and not
01:26:08actually amyloid itself or some other
01:26:10disease process secondary to treatment.
01:26:14Now if that patient does develop
01:26:17more advanced kidney disease,
01:26:18it's very dependent on how long
01:26:20after you've had a complete response
01:26:22that you can then undergo a kidney
01:26:25transplant and that's very dependent
01:26:27from center to center.
01:26:28Some centers are more aggressive,
01:26:29other centers are very conservative
01:26:31and it and some centers don't offer
01:26:34transplant after the diagnosis of amyloid.
01:26:36So it is very dependent on which
01:26:38center you go to and what their
01:26:40specific criteria for transplantation
01:26:42after amyloidosis.
01:26:46Great, thank you.
01:26:47And I think Doctor Miller,
01:26:48there is also a question in
01:26:50the chat about recommendations
01:26:51for heart transplants in
01:26:53patients with cardiac amyloid.
01:26:56Yeah, so that's a complicated scenario.
01:26:59In general, there are heart transplants
01:27:01as as I said on my you saw my talk
01:27:04offered for patients with both AL and TTR
01:27:07amyloid bending on the severity in the
01:27:11age of the patient and the likelihood
01:27:13that the disease particularly in a L can
01:27:16be controlled and other comorbidities.
01:27:18But our center has done a number of
01:27:20transplants for both types of amyloid,
01:27:22amyloid in the heart.
01:27:26In the kind of the short answer
01:27:30there was another question,
01:27:31I think it's it's one that I
01:27:33actually interested in hearing
01:27:35from from Terry or the group.
01:27:37The KL101 study is focused
01:27:39on a L monoclonal antibody
01:27:42therapy for removal AL protein.
01:27:44I'm not aware of any monoclonal treat
01:27:47and by treatments for TTR amyloid
01:27:51that are that are in clinical trials.
01:27:54Are you aware of any?
01:27:57I'm not, you know, right now the
01:28:01only available trials with the anti
01:28:04amyloid fibrils are an AL amyloid
01:28:07and they're specific to that,
01:28:08the light chain fibril,
01:28:09because they're finding to an
01:28:11epitope on that specific fibroid,
01:28:14right. I'm not aware of it either.
01:28:16Couple other questions.
01:28:17Carpal tunnel syndrome tends to
01:28:19be more common than TTR amyloid.
01:28:22It's very early on and TTR amyloid
01:28:25that predates the diagnosis,
01:28:27but somebody's like 5 or more years.
01:28:29So surgery can be very helpful.
01:28:31And if you have amyloid or
01:28:33considering having amyloid,
01:28:34having carpal tunnel surgery,
01:28:37let your hand surgeon know because
01:28:38they can sometimes take a biopsy of
01:28:40the nerve sheet to see if it's there.
01:28:45And I think to answer the
01:28:46other part of that question,
01:28:48to look for amyloid in the GI tract,
01:28:51often patients will have endoscopy or
01:28:54colonoscopies and have biopsies where
01:28:56the biopsy can be stained with Congo
01:28:58Red to look for amyloid deposits.
01:29:00That's generally how that will be diagnosed.
01:29:07I think there's another
01:29:08question we kind of answer that,
01:29:10but if the individual seeing
01:29:12cardiac involvement but
01:29:13doesn't know their type yet,
01:29:15just diagnosed, is it likely AL
01:29:17or is ATTR still a possibility?
01:29:21Yeah, both are possible.
01:29:24It's a involves us looking at the imaging,
01:29:28looking at the bone marrow,
01:29:30looking at other organs that may
01:29:31be involved looking in the blood.
01:29:33Sometimes we have to do a heart biopsy
01:29:35which is not as bad as it sounds.
01:29:36It's a it's a outpatient procedure
01:29:38done through a catheter.
01:29:40Patients tolerate very,
01:29:43very well and and and go home
01:29:45that day to figure it out.
01:29:47In fact, we've had patients who had both
01:29:51AL&amp;ATTR because they're as I mentioned,
01:29:52they're separate diseases.
01:29:55So, so it can be quite complicated,
01:30:1020 years old, my neuropathy very hands
01:30:16where you make this question about.
01:30:18So it's interesting, obviously,
01:30:21sorry, you've had a complicated
01:30:23course of V one 43122 Y,
01:30:26which is a common TTR
01:30:30mutation without 20 years old.
01:30:32I'm sure you've been heard this before,
01:30:34would be an extremely young age
01:30:37to be diagnosed with neuropathy
01:30:40from B1B122I or B142ITT R So.
01:30:43So I I hear all the problems and
01:30:46understand all the issues that you're
01:30:48going through and I'm sorry to hear that.
01:30:51It's obviously be a complicated case
01:30:53that would require a lot of personalized
01:30:55discussion to try to figure out if
01:30:56there's another process going on.
01:30:57But it seems likely that there would be,
01:31:00based on what we know about
01:31:01that particular disease.
01:31:13We do have a question about
01:31:14whether or not this recording
01:31:16will be shared or accessible.
01:31:17I'm not sure if Eliza is
01:31:19able to answer that question.
01:31:28Yes, this is being recorded.
01:31:30It will be shared
01:31:31to our YouTube channel and I
01:31:33will be emailing the link out to
01:31:35all panelists and participants.
01:31:37So please stand by for that
01:31:39within the next few days.
01:31:48And I we may have a few opportunity
01:31:49questions still out there,
01:31:50but I think that's probably a good
01:31:52place to end on as we are three
01:31:55minutes past our time at 8:30.
01:31:56So I just want to thank all of our
01:31:59panelists and speakers for joining.
01:32:01It's I've been great to hear
01:32:03about updates And AL Amyloid,
01:32:08thank you everyone. Thank you. I don't know.