Smilow Shares with Primary Care: Gammopathies

Transcript

• 00:00Get started. Welcome to SmiloShares
• 00:03with Primary Care.
• 00:05Just an introduction
• 00:06to this series.
• 00:08Smilo Shares with Primary Care
• 00:10is a collaboration
• 00:11between primary care and oncology
• 00:14here at Yale. I'm Karen
• 00:16Brown, a primary care internist,
• 00:17and I work with Anne
• 00:19Chang, an oncologist
• 00:20and the associate cancer center
• 00:22director for clinical initiatives.
• 00:24We are happy to present
• 00:25today's topic, which is gammopathies.
• 00:29Our perspective
• 00:30in cancer care is distinct
• 00:32in primary care. We're constantly
• 00:34providing advice to prevent cancer,
• 00:37testing to screen for cancer,
• 00:38testing for cancer, and fortunately,
• 00:41far less often, actually finding
• 00:43new cancer.
• 00:44Diagnosing a new cancer, whether
• 00:46by screening or due to
• 00:48a patient complaint, is a
• 00:49time where we want to
• 00:49be as efficient as possible
• 00:51to get our patients to
• 00:52the treatment they need. We
• 00:53are delighted that doctor Chang
• 00:55and our oncology colleagues are
• 00:56interested
• 00:57and willing to explore this
• 00:59interface of care with us
• 01:00in this series.
• 01:02During the talk, please feel
• 01:03free to enter your questions
• 01:05into the chat,
• 01:07and we will,
• 01:09look at those at at
• 01:10the end of the talk.
• 01:11We'll we'll try to save
• 01:12some time.
• 01:14I'd like to introduce my
• 01:16primary care colleague, doctor Drew
• 01:18Cutney.
• 01:19Doctor Cutney is board certified
• 01:21in internal medicine and pediatrics
• 01:23and a very valuable member
• 01:25of our Northeast Medical Group
• 01:27primary care community.
• 01:29My own first memory of
• 01:30him is he knew how
• 01:31to use Epic better than
• 01:33anybody else,
• 01:34before anybody else did.
• 01:37He practices,
• 01:38he's been with us since
• 01:40two thousand and eight and
• 01:41primary care in Trumbull, Connecticut
• 01:43at the Park
• 01:45Avenue Medical Center. And I'll
• 01:47turn it over to you
• 01:48and to introduce our other
• 01:49panelists.
• 01:51Great. Thanks so much for
• 01:52joining us tonight and for
• 01:54continuing to access this series
• 01:56online.
• 01:59And, I have the honor
• 02:00of introducing the hematologists
• 02:03tonight that are joining us,
• 02:04doctor,
• 02:05Sabrina
• 02:06Browning.
• 02:07That's on the right. She
• 02:08is assistant professor of medicine
• 02:11in hematology, and she received
• 02:13her medical degree from Yukon.
• 02:16And then her internship and
• 02:17residency completed at Yale New
• 02:19Haven
• 02:20Hospital. After residency, she served
• 02:22as an amyloid fellow
• 02:24at the internationally
• 02:25recognized,
• 02:26amyloidis
• 02:27amyloidosis
• 02:29center at BU,
• 02:31in Boston Medical Center. And
• 02:33then she returned to Yale
• 02:34New Haven Hospital to complete
• 02:36her her fellowship
• 02:38in medical oncology and hematology.
• 02:41She's a physician in the
• 02:42Smiling Multiple Myeloma and Gammopathies
• 02:45program, and her clinical and
• 02:46research interests
• 02:48include evaluating new treatments for
• 02:50multiple myeloma,
• 02:52amyloidosis,
• 02:53and other hematologic
• 02:54diseases.
• 02:57Also, I would like to
• 02:58introduce doctor Nofar Bahr, who's
• 02:59an assistant professor of medicine
• 03:01and hematology
• 03:02at the Yale School of
• 03:04Medicine. She completed her internship
• 03:06and residency
• 03:07at the, at the Mount
• 03:09Sinai hospital and her fellowship
• 03:10at Yale,
• 03:12and received her medical degree
• 03:14from the American medical program
• 03:15at Tel Aviv university in
• 03:17New York. She's a member
• 03:18of ASCO, the American Society
• 03:20of Hematology,
• 03:21the International Myeloma Society,
• 03:24and her research is focused
• 03:25on multiple myeloma
• 03:27and other plasma cell disorders.
• 03:30And she specializes in all
• 03:32treatment modalities for myeloma, including
• 03:34CAR T
• 03:35cell therapy and stem cell
• 03:37transplant. She'll talk a little
• 03:38bit about those as, well
• 03:40tonight. So we've got a
• 03:42great program,
• 03:44for you tonight.
• 03:46Save up your questions.
• 03:48You always have some excellent
• 03:50ones, and I will now
• 03:52turn it over to doctor
• 03:54Barr to sort of set
• 03:55us up with, what we're
• 03:56gonna do tonight. Thank you.
• 03:59Thank you, Anne.
• 04:01And thank you for having
• 04:02us.
• 04:03Today,
• 04:04some of the key points
• 04:05I wanna highlight
• 04:07is reviewing the reference ranges
• 04:09for,
• 04:10serum free light chains, and
• 04:12this could be, affected by
• 04:13age and renal dysfunction.
• 04:15Second, discuss some of the
• 04:16differences between IgA, IG,
• 04:19sorry, IgG, IgA versus IgM
• 04:22monoclonal gammopathies.
• 04:24Define low risk MGUS and
• 04:25discuss how this could be
• 04:27managed by the primary care
• 04:28physician.
• 04:29Discuss some red flags,
• 04:31that warrant more urgent referral
• 04:34to hematology.
• 04:35And also review this, EPIC
• 04:37monoclonal gammopathy
• 04:39pathway we've developed recently
• 04:41and provide,
• 04:42hopefully, you can provide us
• 04:43some feedback over time.
• 04:46So to begin, I wanna
• 04:47start with some background.
• 04:49And monoclonal gammopathies on for
• 04:51the most part, are driven
• 04:53by clonal or abnormal plasma
• 04:56cells within the bone marrow,
• 04:57and they secrete a monoclonal
• 04:59protein called an m spike
• 05:01or m protein
• 05:03as I show you here.
• 05:04And this is a picture
• 05:05of, either an IgG or
• 05:07an IgA.
• 05:08And you can see that
• 05:09a part of the whole
• 05:10antibody
• 05:11is also the the light
• 05:13genes, which is important.
• 05:16I'm I mentioned that most
• 05:17gammopathies are from plasma cells.
• 05:19There are several gammopathies that
• 05:20originate from b cells, clonal
• 05:22b cells, but for the
• 05:23most part, plasma cells.
• 05:26Now when you're thinking about
• 05:28a monoclonal gammopathy,
• 05:30this is the pair protein,
• 05:31evaluation.
• 05:33We do a serum protein
• 05:34electrophoresis,
• 05:35and I show you here
• 05:36what would be normal on
• 05:37the left and on the
• 05:39right, an abnormal spike in
• 05:40the gamma region.
• 05:42There is some differences with
• 05:44gammopathies. For example, IGAs often
• 05:47come in the beta region
• 05:48over here if you see
• 05:49this. And you see the
• 05:51two spikes that actually makes
• 05:52it a little bit more
• 05:53difficult,
• 05:54and often underrepresents
• 05:57IgA gammopathy, so just some
• 05:58key points there.
• 06:00The immunofixation
• 06:02below
• 06:03identifies
• 06:03the clone. Okay? So the
• 06:05SBAP quantifies it. The immunofixation
• 06:08identifies for example, here we
• 06:09see an IgG kappa.
• 06:11In addition to this, we
• 06:12also need to have a
• 06:13serum free,
• 06:15light chains.
• 06:16We do not check urine
• 06:17free light chains anymore.
• 06:19And,
• 06:20the importance of this one,
• 06:21it helps us with, some
• 06:23risk stratification diagnosis myeloma, but,
• 06:26also, there's a few patients,
• 06:28about twenty percent of myeloma,
• 06:30that
• 06:31presents only with light chain
• 06:33secretions.
• 06:34So you might miss a
• 06:35diagnosis of a if you're
• 06:37not checking the light chains.
• 06:39Additionally, it's important to note,
• 06:41and this is kind of
• 06:42not something you think about,
• 06:43but different labs have different
• 06:46ranges of,
• 06:48abnormalities
• 06:49be because the the
• 06:51units are different. So for
• 06:53example, Yale uses milligrams per
• 06:55deciliter, but Quest, which some
• 06:57of our our patients use,
• 06:59uses milligrams per liter.
• 07:01So, like, sixty
• 07:02at Quest is six at
• 07:04Yale. So that's important to
• 07:06recognize, and some patients will
• 07:07say, oh my god. Eighty.
• 07:08But it's really eight.
• 07:10So it's important to compare
• 07:13apples and apples and not
• 07:14apples and oranges.
• 07:17The definition of abnormal light
• 07:20chain ratio depends on age.
• 07:22And here is some information
• 07:24from a recent analysis
• 07:26in Iceland
• 07:27where they are testing everyone
• 07:29for monoclonal gammopathy,
• 07:31and they saw that patients
• 07:32who are older tend to
• 07:34have a higher light chain
• 07:35ratio. As you can see
• 07:36here, the higher end is
• 07:38two point five and is
• 07:39a reference range of what's
• 07:41normal in our lab is
• 07:42one point six five.
• 07:45Additionally,
• 07:46creatinine clearance affects light chain
• 07:48ratios. You can see with
• 07:49that lower creatinine clearance or
• 07:52worse renal function, the ratio
• 07:55gets higher at three point
• 07:57three. So when you have
• 07:58someone
• 08:00with, normal IFE and a
• 08:01light chain ratio of two
• 08:03point five, well, it is
• 08:05abnormal in our lab.
• 08:07If they're older or have
• 08:08renal dysfunction, it might actually
• 08:09be normal.
• 08:11So this is, the most
• 08:13this is the spectrum of
• 08:14monoclonal gammopathies.
• 08:16It's not all inclusive, but
• 08:17it's representing the most common
• 08:19gammopathies.
• 08:20You can see here at
• 08:21the end,
• 08:23multiple myeloma, which is the
• 08:24cancer.
• 08:25But on
• 08:27the the right is the
• 08:28mono the first or initial
• 08:30precursor state of what we
• 08:32call MGUS, monoclonal gammopathy of
• 08:35undetermined significance.
• 08:37And then it goes through
• 08:38an intermediary
• 08:39stage of smoldering myeloma,
• 08:41with both of these, MGUS
• 08:43and smoldering, another name for
• 08:44smoldering, asymptomatic
• 08:46myeloma, these are precursor states
• 08:48and are not representing cancer
• 08:50and do not need to
• 08:51be treated. And these do
• 08:52not have CRAP criteria, which
• 08:54we'll talk about soon.
• 08:57The major difference when you're
• 08:58evaluating the bone marrow in
• 08:59these patients and part of
• 09:01the diagnosis
• 09:02is that there are less
• 09:04clonal plasma cells with MGUS
• 09:05and more clonal plasma cells
• 09:07with smoldering,
• 09:08less than ten or more
• 09:10than ten percent. And what's
• 09:11relevant for the patient is
• 09:13the risk for progression.
• 09:15One percent with MGUS,
• 09:16ten percent
• 09:17on average per year with
• 09:19smoldering.
• 09:21So I think most of
• 09:23you know that the definition
• 09:25of myeloma
• 09:26requires a clonal plasma cell
• 09:27clone of, clonal plasma cells
• 09:29on the bone marrow of
• 09:30more than ten percent in
• 09:32addition to
• 09:33one or more of the
• 09:35CRAP criteria, including
• 09:36high calcium level, renal insufficiency,
• 09:39anemia, and bony disease.
• 09:41However, about a decade ago
• 09:43now, the definition of myeloma
• 09:45actually changed,
• 09:47And now we have what's
• 09:48called the slim crab.
• 09:50So for those of you
• 09:51who don't know what the
• 09:51slim crab criteria is, I
• 09:53like to go backwards to
• 09:55review the spectrum of gammopathies
• 09:57to really understand where the
• 09:59slim crab came from.
• 10:00And here you can see
• 10:02that the clonal the the
• 10:04smoldering myeloma is actually a
• 10:05very heterogeneous group of patients.
• 10:08While on average, ten percent
• 10:10progressed to myeloma. There are
• 10:12some patients that behave like
• 10:14MGUS and will never progress,
• 10:16and some patients progress within
• 10:18one to two years and
• 10:19probably should be diagnosed as
• 10:21myeloma. And that is exactly
• 10:23where the slim criteria came
• 10:24from. Researchers identified
• 10:26factors
• 10:28that led to a risk
• 10:29of progression of myeloma
• 10:31at two years at eighty
• 10:34percent.
• 10:35And they said, we are
• 10:36this is unacceptable,
• 10:37and patients should be treated
• 10:38for myeloma. And this is
• 10:40sixty percent clonal plasma cells
• 10:42in the bone marrow or
• 10:43more, a light chain ratio
• 10:45over a hundred,
• 10:46and having
• 10:47more than one bony lesion
• 10:49on advanced imaging, like whole
• 10:51body MRI, PET scan.
• 10:55So with that,
• 10:57we will
• 10:58move forward to our cases.
• 11:02Thanks, Nafoor.
• 11:04So before we get into
• 11:05this case, just wanna give
• 11:07a brief,
• 11:10context of the four case
• 11:11that I'm gonna bring in,
• 11:12and and these are all
• 11:13cases from a panel.
• 11:16They're relatively fresh, which means
• 11:17that they they're they're either
• 11:18a new diagnosis of of
• 11:20monoclonal,
• 11:21gammopathy or it's a new
• 11:23patient to me that I
• 11:24had to get to know
• 11:26or it it's either
• 11:29a change in the clinical
• 11:30status that,
• 11:32has happened recently.
• 11:34And the one thing I
• 11:36just wanna,
• 11:37have you pay attention to
• 11:38is, you know, pay attention
• 11:39to crab cure crab criterias.
• 11:41We go through go through
• 11:42the cases,
• 11:44but, also,
• 11:45they don't fit a hundred
• 11:46percent by the book,
• 11:48necessarily. And I think that
• 11:50goes along with a lot
• 11:51of patients that we see.
• 11:52We're we're always, trying to,
• 11:57figure out
• 11:59what's going on from noise.
• 12:02And,
• 12:03their diseases vary,
• 12:04and don't go go by
• 12:06our
• 12:08strict criteria a hundred percent
• 12:10all the time. And but
• 12:11they do represent key points
• 12:12and pearls. So what that's
• 12:14what, with that, we'll jump
• 12:16into our first case. And,
• 12:18this is a fifty year
• 12:19old Hispanic female that was
• 12:21new to me in in
• 12:22twenty twenty one. And for
• 12:24the most part, she was,
• 12:26it was well known that
• 12:27she had MS,
• 12:28that was diagnosed in twenty
• 12:29nineteen,
• 12:31and we talked about that
• 12:32quite a bit.
• 12:33She had presented with incapacitating
• 12:35migraines at that point with
• 12:37vertigo, which prompted the MRI
• 12:40and,
• 12:41confirmed a diagnosis. And she
• 12:42started on Ocrevus,
• 12:46which is, for therapy every
• 12:47six months and had no
• 12:49disease progression and it was
• 12:50otherwise stable.
• 12:52Her her history, otherwise, is
• 12:54noncontributory.
• 12:55She had a cervical fusion,
• 12:58in twenty seventeen,
• 13:00and she had a c
• 13:01section nineteen ninety four.
• 13:03Her family history
• 13:05was notable just for hypertension,
• 13:07hyperlipidemia,
• 13:08heart disease, and substance
• 13:10addiction,
• 13:11and she herself was married.
• 13:14She had a son.
• 13:16She worked in an office
• 13:17setting. She, had a ten
• 13:19pack year tobacco history, but
• 13:21had quit in twenty eleven,
• 13:23and she's locally,
• 13:25born and raised.
• 13:27Next slide.
• 13:29And so in the fall
• 13:31last fall in twenty twenty
• 13:32four, she came to me
• 13:34with six months of a
• 13:36chronic cough
• 13:37and this persistent,
• 13:41you know, frequent, really recurrent,
• 13:43bilateral
• 13:44otitis externa where her ears
• 13:46or her external ears were
• 13:47just swollen closed,
• 13:49very tender,
• 13:51really hurting. And she was
• 13:53at her wit's end,
• 13:54not only from the ears,
• 13:55but she had this cough
• 13:56that was relentless. A lot
• 13:57of abdominal pain, couldn't sleep,
• 13:59this dry cough, you know,
• 14:04just
• 14:05unmitigating.
• 14:06And she had seen neurology,
• 14:08ear, nose, and throat and
• 14:10immunology for these things.
• 14:13And, when she was coming
• 14:14to me, she was asking
• 14:15me a lot of questions
• 14:16about that workup. So the
• 14:18SAR, we looked at the
• 14:19cough, looked like a it
• 14:21turned out to be a
• 14:21really strong GERD trigger,
• 14:24and
• 14:26some allergic postnasal drip. So
• 14:28we addressed that. And then
• 14:29the the recurrent otitis through
• 14:31some Pseudomonas and,
• 14:34you know, sensitive staph oxycelin
• 14:36sensitive staph, and we just
• 14:38treated those
• 14:39accordingly. We got the cough
• 14:41under, control. In the years,
• 14:43we we had a regimen
• 14:44that that
• 14:45settled down.
• 14:47But during the subspecialty evaluation,
• 14:50she was found to have,
• 14:52so, suppressed b cell
• 14:54presence under flow cytometry,
• 14:57and she had a low
• 14:58I g g two subclass.
• 15:02And then, they they challenged
• 15:03that with a
• 15:05pneumococcal
• 15:06conjugate
• 15:08vaccine and it and it
• 15:10and and no antibody responded.
• 15:13So the the theory was
• 15:15that this was from her
• 15:16ocrevus,
• 15:17the suppressing her b cell
• 15:18colonies, and that in turn
• 15:20was
• 15:22causing return
• 15:23recurrent otitis externus.
• 15:26The interesting thing here is
• 15:28that on her SPEP and
• 15:29her immunofixation,
• 15:32she had an IgA kappa
• 15:35monoclonal protein. So next slide.
• 15:39And, you know, the key
• 15:41points to eval is that
• 15:42she had she's not anemic.
• 15:44She had good new, renal
• 15:45function. She had noble calcium
• 15:47levels.
• 15:47There are no discrete monoclonal
• 15:49bands identified on the SPEP.
• 15:52But
• 15:53on the immunofixation,
• 15:55there were,
• 15:56there was IgA cap identified
• 15:58in three monoclonal components in
• 16:00that beta region that doctor
• 16:02Barr had mentioned earlier.
• 16:04And she had low immunoglobulin
• 16:06levels, IgA and IgG two,
• 16:10and she had elevated
• 16:11kappa
• 16:12light chain with an elevated
• 16:14ratio of three point nine
• 16:15five.
• 16:17She was seeing and this
• 16:18was this was kinda known
• 16:19to me, and then she
• 16:20was unprocessed going to hematology,
• 16:22went to hematology, got the
• 16:23bone marrow biopsy,
• 16:25and that came back with
• 16:26a less than ten percent
• 16:27clonal plasma cell.
• 16:29And,
• 16:31for further discussion, we have
• 16:33doctor Browning. Great. Thank you
• 16:35very much. So, you know,
• 16:37I think this is a
• 16:38a great case.
• 16:39You know, I think with
• 16:40this, patient
• 16:42appropriately in the setting of
• 16:43hypogammaglobulinemia
• 16:44and increased frequency of infections,
• 16:47both of which can occur,
• 16:48across the spectrum of monoclonal
• 16:50gammopathy. She had this pair
• 16:51of protein identified.
• 16:53And if you can advance
• 16:54the slide.
• 16:55So importantly,
• 16:56what we wanna talk through
• 16:58is what the patient's diagnosis
• 16:59is, and we'll go through
• 17:01the spectrum of monoclonal gammopathy.
• 17:03Again, she had a bone
• 17:04marrow biopsy showing less than
• 17:05ten percent clonal plasma cells,
• 17:07which in the absence of
• 17:08end organ damage is consistent
• 17:10with MGUS.
• 17:11So she had an IgA
• 17:12kappa MGUS. And we'll talk
• 17:13a little bit about
• 17:14when we think about doing
• 17:15a bone marrow and skeletal
• 17:17imaging and what type of
• 17:18skeletal imaging we are choosing
• 17:19now for our patients with
• 17:20MGUS.
• 17:21As already mentioned,
• 17:23IgA gamopathies
• 17:25are unique
• 17:27in a couple of different
• 17:28ways.
• 17:29The first being where we
• 17:30see the band migrating on
• 17:32the SPEP,
• 17:33in the beta region as
• 17:34opposed to the gamma region,
• 17:36which is where we see,
• 17:37the majority of our monoclonal
• 17:38gamopathies or monoclonal proteins.
• 17:41And this may underestimate
• 17:43the, burden of,
• 17:45clonal plasma cells in the
• 17:46bone marrow. And so,
• 17:48with an IgA MGUS, it's
• 17:49important to remember, and we'll
• 17:50talk through why, you know,
• 17:52we never really refer to
• 17:53an IgA MGUS or an
• 17:54IgA gammopathy as low risk.
• 17:59So this scheme, again, you've
• 18:00seen,
• 18:02illustrates the spectrum of monoclonal
• 18:04gammopathy
• 18:04importantly,
• 18:05in our patient's case. If
• 18:07you can advance,
• 18:09Nofar, she had less than
• 18:10ten percent clonal plasma cells
• 18:12consistent with an MGUS with
• 18:14a one percent risk per
• 18:15year of progressing to myeloma.
• 18:17We could go to the
• 18:17next slide.
• 18:19So this table outlines,
• 18:20in further detail the definition
• 18:22of MGUS.
• 18:23Importantly, with non IgM MGUS
• 18:26and light chain MGUS,
• 18:27the risk of progression is
• 18:29to multiple myeloma or, light
• 18:31chain or AL amyloidosis.
• 18:32And this is as,
• 18:34indifferent from an IgM MGUS
• 18:37where if patients progress,
• 18:39the majority of the time,
• 18:40they progress to a a
• 18:41lymphoplasmacytic
• 18:42lymphoma or what we refer
• 18:43to as Waldenstrom macroglobulinemia
• 18:46with an IGM
• 18:47IGM myeloma being very rare.
• 18:50And, as you can see
• 18:51across all three of these,
• 18:53importantly,
• 18:54the clonal,
• 18:55bone marrow cells are less
• 18:56than ten percent.
• 18:58With non IgM MGUS and
• 19:00IgM MGUS serum m protein
• 19:01is less than three grams.
• 19:03And with light chain MGUS,
• 19:04we see an abnormal light
• 19:05chain ratio and a urine
• 19:07monoclonal protein less than five
• 19:08hundred milligrams on a twenty
• 19:09four hour urine.
• 19:11And, as you can see
• 19:12here on the table with
• 19:13IgM MGUS, there may at
• 19:14least initially be a slightly
• 19:16higher risk of progression,
• 19:18compared to the non IgM
• 19:19MGUS and the light chain,
• 19:20a little bit lower.
• 19:22And we could go to
• 19:22the next slide.
• 19:24So historically, the prevalence of
• 19:27MGUS in individuals over the
• 19:28age of fifty has been
• 19:30reported at three
• 19:31percent. Doctor Barr mentioned that
• 19:33there's a large population,
• 19:36population screening study that was
• 19:38performed in Iceland where approximately
• 19:40seventy five thousand, individuals were
• 19:42screened for monoclonal gammopathy.
• 19:44And the prevalence that came
• 19:45out of that study was
• 19:46a bit higher at five
• 19:47percent of individuals over the
• 19:48age of fifty. And that
• 19:49was that was called the
• 19:50I ISTOP, my study, which
• 19:53occurred in Iceland.
• 19:55Importantly, MGUS can occur up
• 19:57to four times more,
• 19:59is four times more common
• 20:00in black or African American
• 20:02individuals, and the prevalence may
• 20:03be high in that population.
• 20:05And then we talked about
• 20:06the uniqueness of IgA
• 20:08type gammopathy.
• 20:10It it has been shown
• 20:11in studies to potentially rise
• 20:13more slowly through the prevalence
• 20:15of it rising more slowly
• 20:16with age,
• 20:17although it's thought to be
• 20:18associated with more rapid progression.
• 20:20And in that same
• 20:21large,
• 20:22population screening study, the iStop
• 20:24M study,
• 20:26the investigators
• 20:27looked at, patients with IgA
• 20:29MGUS and compared to them
• 20:30to IgG MGUS and found
• 20:32that those with IgA
• 20:33had a a higher frequency
• 20:35of detecting clonal or abnormal
• 20:37plasma cells in the bone
• 20:38marrow.
• 20:40And so, again, we talked
• 20:41about how with IgA,
• 20:43the m protein may not
• 20:44be a true reflection of
• 20:46the disease burden. And so
• 20:47it's really important to look
• 20:48at IgA levels, serum free
• 20:50light chains, and we'll talk
• 20:51about further workup for our
• 20:52IgA gamopathies.
• 20:54So important when we're considering,
• 20:57the need for additional workup
• 20:59for MGUS,
• 21:01is,
• 21:02risk stratifying. And so we
• 21:03do that,
• 21:04with these three, different factors.
• 21:07Individuals who have an IgG
• 21:09type monoclonal gammopathy, a serum
• 21:11and protein in the, in
• 21:13the serum less than one
• 21:14point five grams in normal
• 21:15light chain,
• 21:16meet the criteria for low
• 21:18risk MGUS. And generally in
• 21:19these patients, we, in the
• 21:21absence of any evidence of
• 21:23the slim crab criteria or
• 21:24end organ damage, we are
• 21:26able to, withhold bone marrow
• 21:27biopsy aspiration and skeletal imaging.
• 21:29And there has been studies
• 21:31looking at this
• 21:32and show in those that
• 21:33meet all three criteria,
• 21:35if we do do not
• 21:36do a bone marrow, we
• 21:37miss less than one percent
• 21:39of patients that could have
• 21:40clinical or active myeloma. And
• 21:42this,
• 21:43show it has shown in
• 21:44studies also that this population
• 21:46has an absolute risk of
• 21:47progression at twenty years. It's
• 21:49very low at two percent.
• 21:51Now all those that don't
• 21:52meet these criteria, we refer
• 21:53to as non risk, gammopathy.
• 21:55And these are patients where,
• 21:57we definitely want to at
• 21:59least see them in the
• 21:59hematology clinic to discuss
• 22:01whether or not they warrant
• 22:02a bone marrow biopsy,
• 22:04and skeletal image. And and
• 22:05historically for MGUS,
• 22:07for many years, we had
• 22:08been using skeletal surveys, which
• 22:09we know now have very
• 22:10poor sensitivity and specificity. And
• 22:12so guideline recommendations is is
• 22:14instead to use a low
• 22:15dose whole body CT, which
• 22:17we now have available,
• 22:19at the York Street campus
• 22:20for our patients.
• 22:22So in summary, in individuals
• 22:23who have a confirmed MGUS,
• 22:25whether that's a low risk
• 22:26MGUS,
• 22:27who don't warrant any further
• 22:29workup or patients who have
• 22:31a bone marrow biopsy and
• 22:32are found to have less
• 22:33than ten percent clonal plasma
• 22:34cells,
• 22:35our management,
• 22:36is observation and clinical,
• 22:38laboratory follow-up every six months
• 22:40initially in those patients who
• 22:42may be more stable
• 22:43over a longer period of
• 22:44time. We sometimes extend that
• 22:46out, to annual follow-up.
• 22:50So before we move to
• 22:51the next case, I wanted
• 22:51to introduce our SMILO multiple
• 22:53myeloma and gammopathies program,
• 22:55which,
• 22:56includes, in addition to doctor
• 22:58Barr and myself, doctor Natalia
• 22:59Neparizzi, doctor Terry Parker, and
• 23:01doctor Elaine Gorshine,
• 23:03who sees patients in at
• 23:04our SMILO North Haven location
• 23:06and Smilo Guilford.
• 23:08Many of you may be
• 23:09familiar,
• 23:09through Yale Medicine with the
• 23:11hematology eConsult program,
• 23:13that I think may be
• 23:15a good option specifically for
• 23:16patients who who have low
• 23:18risk MGUS or a question
• 23:19of light chain abnormality
• 23:21either due to age or
• 23:22CKD or a question of
• 23:24polyclonal gammopathy, which we didn't
• 23:26talk much about, but can
• 23:27be associated with, liver disease
• 23:29or chronic infection, connective tissue
• 23:31disorders, and importantly does not
• 23:32have any risk of progression
• 23:34to myeloma or other plasma
• 23:36cell dyscrasias.
• 23:37And then we also hold
• 23:38an MGUS clinic monthly,
• 23:40at our Smilow North Haven
• 23:41location, and, patients,
• 23:44in that clinic,
• 23:45usually are low risk MGUS
• 23:47or kind of less complicated
• 23:48MGUS patients, and the referral
• 23:49to that clinic is through
• 23:50the same referral process to
• 23:52our, gamopathies program.
• 23:55And so I'll turn it
• 23:56back over to doctor Kuttney.
• 23:58Great.
• 23:59Thank you, Sabrina. I think,
• 24:01those are some good pearls
• 24:03there. I love them.
• 24:04So this next case will,
• 24:07look at a sixty nine
• 24:09year old,
• 24:10male,
• 24:11with who came to me
• 24:12in the fall of last
• 24:14year as well,
• 24:16with per like, a progressive
• 24:18distal neuropathy,
• 24:20at least, over the you
• 24:22know,
• 24:23described as pins and needles
• 24:25in the feet and the
• 24:26hands.
• 24:27He described it as being
• 24:28his feet more than his
• 24:29hands and his left foot
• 24:30more than his right foot.
• 24:31And it was particularly worse
• 24:33in the evening with walking,
• 24:35and,
• 24:36there's absolutely no weakness,
• 24:39and you couldn't really identify,
• 24:41you know,
• 24:42exactly when or or how
• 24:43it had emerged. It was
• 24:44just something that just kind
• 24:46of slowly developed.
• 24:48And
• 24:49this past medical history is
• 24:51significant for a p c
• 24:52PBC induced cardiomyopathy,
• 24:56diagnosed in two thousand five,
• 24:58which progressed to, you know,
• 25:00paroxysmal,
• 25:01and atrial fibrillation in in
• 25:03twenty fourteen.
• 25:04They thought that was due
• 25:05to his, he he was
• 25:07a very high volume runner
• 25:09at the time. And,
• 25:11he was successfully ablated,
• 25:14and wanted to it's held
• 25:16in sinus
• 25:17rhythm since.
• 25:18His ulcer he did get
• 25:20diagnosed in twenty eleven with
• 25:21ulcerative colitis,
• 25:23and he was being managed
• 25:25with, Lialda four point eight
• 25:26grams per,
• 25:28deciliter
• 25:29sorry. Per day. I'm sorry.
• 25:32Yeah. He was a frequent
• 25:34sport shooter with the
• 25:36lead exposure,
• 25:37from intending
• 25:38the indoor shooting range,
• 25:40and, his serum level lead
• 25:42level,
• 25:43was on baseline,
• 25:45twenty to twenty five,
• 25:47since we started checking it.
• 25:49He stopped attending that indoor
• 25:50range in twenty nineteen.
• 25:52And he was also
• 25:54at the time when I,
• 25:55you know, saw him for
• 25:56this neuropathy symptoms, he was
• 25:57taking a lot of zinc
• 25:58for his ulcerative
• 26:00colitis for whatever reason.
• 26:02Next slide.
• 26:06Other comorbid included
• 26:07some,
• 26:08BPH,
• 26:09you know, prostatic
• 26:11hyperplasia,
• 26:12and some tinnitus.
• 26:14He had,
• 26:15a couple of meniscus surgeries
• 26:17in the two thousands. I
• 26:19think both knees were affected.
• 26:21And, he's a software developer.
• 26:23He played the electric guitar,
• 26:24hence his tinnitus and, a
• 26:26little social alcohol, no elicits.
• 26:29He's married, three kids,
• 26:31distant smoking history, small amount,
• 26:34seven pack years. Spent a
• 26:35lot of time out
• 26:37outdoors.
• 26:38On the note on the
• 26:39family history,
• 26:41Crohn's disease and dementia, his
• 26:42mother and his father had
• 26:43type two diabetes, and his
• 26:45brother had Crohn's disease. And
• 26:47his sister,
• 26:48was suspected to have a
• 26:49non Hodgkin's lymphoma. I can
• 26:51really confirm
• 26:53the the details on that.
• 26:54And then we did an
• 26:55evaluation
• 26:56for his neuropathy.
• 26:59And
• 27:01the
• 27:02the
• 27:03notables are, like, you know,
• 27:05no anemia, normal creatinine, normal
• 27:07calcium.
• 27:08He had no no monoclonal
• 27:10bands on the SPEP.
• 27:12He had an IgA Lambda,
• 27:15that presented on the immunopixation
• 27:18and normal immunoglobulins,
• 27:21and then his,
• 27:23light chain,
• 27:26his lambda light chain of
• 27:27sixty one point two with
• 27:29a,
• 27:30a significantly decreased ratio
• 27:33of zero point zero three
• 27:35was there. And then end
• 27:36of note two, he had
• 27:37this Lyme antibody that was
• 27:40quite high at four point
• 27:42zero.
• 27:44I treated him for Lyme
• 27:46disease.
• 27:47Symptoms didn't change,
• 27:48so I repeated the,
• 27:50the serum free limed,
• 27:52light chains again because, hey,
• 27:54maybe they they got better,
• 27:55but they didn't.
• 27:58And,
• 27:59it referred them on to
• 28:00hematology.
• 28:02And he, you really he
• 28:03went on and got a
• 28:04bone marrow biopsy, and you
• 28:05had ten percent plasma cells
• 28:07with the
• 28:08lambda restriction.
• 28:10And
• 28:12we have a you know,
• 28:15and for discussion, we'll go
• 28:16back to doctor Browning. Great.
• 28:18Thank you. So I think
• 28:19what
• 28:20the difference we're seeing here
• 28:21compared to the first case
• 28:23is that this patient does
• 28:24have ten percent, clonal plasma
• 28:26cells in the bone marrow,
• 28:28which qualifies for at least
• 28:29smoldering myeloma.
• 28:31Looks like he had a
• 28:32PET scan that didn't show
• 28:33any bone lesions. So importantly,
• 28:35with smoldering myeloma, what we're
• 28:37looking to do again is
• 28:38to exclude the slim CRAB
• 28:40criteria.
• 28:42So no evidence of bone
• 28:43lesions. The light chain ratio
• 28:44was less than,
• 28:46a hundred.
• 28:47And so, you know, he
• 28:48meets criteria for a smoldering
• 28:50or asymptomatic myeloma, which I
• 28:52think what I think is
• 28:53complicated or challenging is the
• 28:55addition of the the neuropathy
• 28:57and question of cardiac
• 28:59cardio cardiac disease, which certainly
• 29:01raises concern,
• 29:03specifically for late chain or
• 29:04AL amyloidosis,
• 29:05which can be seen
• 29:06more frequently in lambda tympic
• 29:08gammopathies.
• 29:10So I think we can
• 29:10go on to the next
• 29:11slide.
• 29:13So again in this case,
• 29:14the patient has,
• 29:15ten percent clonal plasma cells,
• 29:18significant for a smoldering myeloma.
• 29:20We've excluded
• 29:21CRAB criteria, and then he
• 29:23has no evidence of the
• 29:24slim criteria either.
• 29:27And so this figure here
• 29:29shows the difference in the
• 29:30risk of progression as you
• 29:31can see, compared to a
• 29:33one percent risk per per
• 29:34year initially with MGUS.
• 29:36In smoldering myeloma, we see
• 29:37at least initially about a
• 29:39ten percent risk per year
• 29:40of progression.
• 29:41As you can see, the
• 29:42line flattens out with the
• 29:44smoldering and asymptomatic
• 29:45myeloma. As doctor Barr mentioned,
• 29:46smoldering myeloma is very heterogeneous.
• 29:49And those patients who don't
• 29:50progress, you know, over time
• 29:52start to behave more like
• 29:53MGUS. And, you know, I
• 29:55think we often will alter
• 29:56our management to to fit
• 29:58that.
• 30:00So, the definition for the
• 30:02international
• 30:03myeloma working group for smoldering
• 30:05myeloma, again, we've gone over
• 30:06this, but a a a
• 30:07clonal plasma cell percentage
• 30:09of ten percent to sixty
• 30:11percent, over sixty percent being
• 30:13consistent with clinical or active
• 30:14myeloma,
• 30:15a monoclonal m protein greater
• 30:16than three, and a urinary
• 30:18m protein greater than five
• 30:19hundred. This is on a
• 30:20twenty four hour urine. Again,
• 30:21importantly, in our asymptomatic or
• 30:23smoldering myeloma patients, we're excluding
• 30:25the presence of slim crab
• 30:26or amyloid,
• 30:28and in particular,
• 30:29ensuring that there is no
• 30:31evidence of bone lesions. And
• 30:32we do that via advanced
• 30:34imaging either with a PET
• 30:35scan or a whole body
• 30:36MRI, both of which we
• 30:37have available here at Yale.
• 30:40Similar to MGUS,
• 30:42we, in smoldering myeloma, once
• 30:44a definition once a a
• 30:45diagnosis is confirmed, we look
• 30:46to risk stratify our patients
• 30:48and most commonly do that
• 30:49with the IMWG
• 30:51two twenty twenty rule,
• 30:53with,
• 30:54high risk criteria being patients
• 30:56who have an m protein
• 30:57or a monoclonal protein in
• 30:59the serum being greater than
• 31:00two grams per deciliter,
• 31:02having twenty percent or more
• 31:03clonal plasma cells in the
• 31:05bone marrow, and having an
• 31:06involved or uninvolved
• 31:08involved over uninvolved,
• 31:10serum free lysine ratio of
• 31:11greater than twenty. So,
• 31:13in patients who have a
• 31:14a kappa,
• 31:16gamopathy, that's the kappa over
• 31:17lambda
• 31:18ratio. If in lambda, it's
• 31:20a reverse. And so having
• 31:21that above twenty is a
• 31:22high risk criteria. And then
• 31:23there's a a four,
• 31:25criteria
• 31:26model
• 31:27that includes cytogenetics
• 31:28that are high risk from
• 31:29the bone marrow, which are
• 31:30outlined here. So translocation fourteen
• 31:32before fourteen, fourteen sixteen,
• 31:35having
• 31:36a
• 31:37gain of one q or
• 31:37a deletion of thirteen q.
• 31:38And you can see here
• 31:39in the table,
• 31:40in particular, patients with high
• 31:42risk,
• 31:43smoldering myeloma, which, is three
• 31:45to four of these criteria,
• 31:48have a high risk of
• 31:49progression at two years to
• 31:50clinical or active myeloma with
• 31:52end organ damage of sixty
• 31:53three percent.
• 31:57So to touch very briefly
• 31:58on management of smoldering myeloma
• 32:00which is really evolving,
• 32:03with our low or intermediate
• 32:04risk, smoldering myeloma patients,
• 32:07we are routinely observing them.
• 32:09We do this a bit
• 32:10more frequently than we do
• 32:11at least initially with our
• 32:13MGUS patients. So we're seeing
• 32:14them and doing laboratory evaluation
• 32:16every three months. And then
• 32:18again, to exclude any presence
• 32:20or development of bone lesions,
• 32:21we get annual, advanced imaging
• 32:23usually with a whole body
• 32:24MRI or a PET scan.
• 32:26Again, the frequency of these
• 32:28evaluations
• 32:29may change over time if
• 32:30patients remain stable.
• 32:32In high risk,
• 32:34smoldering myeloma patients,
• 32:35this is where I think,
• 32:37you know, the field is
• 32:38continuing to evolve,
• 32:40and there are differing opinions,
• 32:42I think, within the field.
• 32:43But in patients with high
• 32:45risk, smoldering myeloma, especially younger
• 32:47patients, I think, you know,
• 32:48we really consider clinical trials,
• 32:50pretty pretty highly.
• 32:52We do have some data
• 32:53about potential benefit,
• 32:55progression free survival benefit with
• 32:57our immunomodulatory
• 32:58agent lenalidomide,
• 33:00and more recently have a
• 33:01study, a phase three study
• 33:02that was published looking at
• 33:04the anti CD thirty eight
• 33:05monoclonal antibody daratumumab,
• 33:08where there was evidence in
• 33:09high risk, smoldering myeloma of
• 33:11progression free survival benefit and
• 33:13a small overall survival benefit.
• 33:15And then there still is
• 33:16an option, you know, with
• 33:17these patients to observe them
• 33:19closely.
• 33:20You know, I think there
• 33:21there is some thought, again,
• 33:23with the heterogeneity that some
• 33:24patients will progress very quickly.
• 33:26I think in younger patients,
• 33:28doctor Barr will talk about
• 33:29our, therapy, which often includes
• 33:32four drugs. And so treating
• 33:33these high risk myeloma patients,
• 33:35especially young patients with one
• 33:36drug, there is some concern
• 33:38that we could be potentially
• 33:39undertreating them. And then I
• 33:40think importantly,
• 33:42is that patients with smoldering
• 33:44or asymptomatic
• 33:45myeloma, although they may be
• 33:46without symptoms, can have some
• 33:48increased risk of other
• 33:50associated,
• 33:51complications like infections, osteoporosis,
• 33:54thromboembolism, and the risk of
• 33:55secondary malignancies.
• 33:59So I think in conclusion
• 34:00with smoldering myeloma,
• 34:01it is a very heterogeneous
• 34:03disorder. We see some individuals
• 34:04that progress quickly and others
• 34:06who never progress and act
• 34:07more like MGUS, and we
• 34:09tailor our management,
• 34:10to that.
• 34:12And with patients that are
• 34:14behaving more like a low
• 34:15risk MGUS over time, there
• 34:17is a possibility,
• 34:18you know, to have them
• 34:19referred back to their primary
• 34:20care clinician, with close monitoring.
• 34:24Again, in this case, I
• 34:25think what's
• 34:26complicated is the concomitant peripheral
• 34:28neuropathy in the setting of
• 34:30monoclonal gammopathy, which I think
• 34:31also often will warrant a
• 34:33referral so that we can
• 34:34evaluate for more rare plasma
• 34:36cell dyscrasias or other neuropathic
• 34:38symptoms,
• 34:39specifically light chain or AL
• 34:40amyloidosis,
• 34:42POEM syndrome, cryoglobulinemia.
• 34:43And with IgM monoclonal gamopathies,
• 34:46again, we can see rare
• 34:47anti MAG neuropathies and Kanamad
• 34:49syndrome as well.
• 34:51So it is, I think,
• 34:52very reasonable in patients with
• 34:54unexplained
• 34:54new or progressive peripheral neuropathy
• 34:56to consider gammopathy panels. And
• 34:58then,
• 34:59you know, if there is
• 35:00a monoclonal monoclonal protein, refer
• 35:02them to our hematology clinic
• 35:03and our neurology colleagues as
• 35:05well for further evaluation.
• 35:09And I will turn it
• 35:10back over for case three.
• 35:12Great.
• 35:14Okay. So we've had two
• 35:15cases of IgA
• 35:17monoclonals,
• 35:18and we're gonna
• 35:20we're gonna give you an
• 35:21a a different one now.
• 35:22So this is an eighty
• 35:24five year old male,
• 35:26very active, very cognitively sharp.
• 35:29New patient to me in
• 35:30October of twenty twenty.
• 35:34He came to me with
• 35:35a history of hyperlipidemia,
• 35:37hypothyroidism,
• 35:38and some mild,
• 35:40aortic valve stenosis.
• 35:42He had a right shoulder
• 35:44and left hip replacement with
• 35:46the which with a subsequent
• 35:48right total shoulder
• 35:49in twenty twenty three.
• 35:53Never smoker,
• 35:54married with two kids. He's
• 35:55a retired salesman for industrial
• 35:57cable manufacturer.
• 35:59His mom died in her
• 36:00late thirties
• 36:01from postpartum complications.
• 36:04His father and oldest sister
• 36:05died from lung cancer.
• 36:07His older brother died from
• 36:09salivary gland tumor and his
• 36:11second brother of an unknown
• 36:12cause.
• 36:14Prior to coming to me
• 36:16in twenty eleven,
• 36:19more significantly, he developed a
• 36:21mild,
• 36:22macrocytic
• 36:23anemia,
• 36:24with a hemoglobin of thirteen
• 36:26point two, MCV of ninety
• 36:28eight. His SPEP
• 36:29at the time during the
• 36:31eval,
• 36:32showed a monoclonal band,
• 36:35consistent with IgM kappa at
• 36:37zero point eight milligrams per
• 36:38deciliter.
• 36:41Because the IgM
• 36:44monoclonal
• 36:45protein,
• 36:46he went on to bone
• 36:47marrow biopsy, which revealed a
• 36:49twenty to thirty percent low
• 36:50grade
• 36:51b cell,
• 36:52lymphoproliferative
• 36:54disorder
• 36:55with plasma cell differentiation,
• 36:58kappa restriction.
• 36:59And,
• 37:01we think about Waldenstroms
• 37:03with the IgM,
• 37:05chemotherapy.
• 37:06He didn't meet criteria for
• 37:08treatment at that time.
• 37:11So, he had his SPEP
• 37:13done every year. And
• 37:16it from
• 37:17twenty eleven through twenty nineteen,
• 37:19he was very stable at
• 37:20that zero point eight milligram
• 37:21per deciliter
• 37:23level.
• 37:25In twenty nineteen
• 37:27and twenty one, the level
• 37:29rose to one point zero.
• 37:31And then in twenty two,
• 37:32it went up again to
• 37:33one point four. And then
• 37:35in twenty twenty three,
• 37:36it rose to one point
• 37:38seven.
• 37:39His hemoglobin
• 37:40dropped from eleven to eight
• 37:41point four,
• 37:43and he does developing fatigue.
• 37:45So he's becoming symptomatic. He
• 37:46had no other causes for
• 37:48the anemia to explain the
• 37:49drop.
• 37:50His his,
• 37:51kappa light chain was three
• 37:53point eight, and his IgM
• 37:56antibodies were in the mid,
• 37:58two thousand six hundred twenty
• 38:00two. Excuse me. And at
• 38:02that point, decision was made
• 38:04to treat with rituximab,
• 38:06and we want to,
• 38:09pass over to doctor Barr
• 38:10to talk about
• 38:12IgM disease here.
• 38:14Yes. So
• 38:16you can see here that
• 38:17the spectrum of IgM gammopathies,
• 38:20are very similar to the
• 38:21IgG and IgAs where you
• 38:23have the MGUS and you
• 38:24have this middle stage of
• 38:26asymptomatic
• 38:26or smoldering,
• 38:28Waldenstrom's
• 38:29and then symptomatic
• 38:30Waldenstrom's
• 38:31that needs therapy.
• 38:33So what defines
• 38:34needing therapy,
• 38:36is different in myeloma and
• 38:38the lymphoma. For example,
• 38:40for lymphomas, we look at
• 38:41b symptoms, like
• 38:43constitutional
• 38:44symptoms, weight law unexplained
• 38:46weight loss,
• 38:47fevers, night sweats, things like
• 38:50that, feeling just generally very
• 38:52poorly.
• 38:53We look at symptomatic
• 38:54cytopenias, which are mainly from
• 38:57crowding of, the bone marrow
• 38:59from the lymphoma
• 39:01or from hepatosplenomegaly,
• 39:03which can also cause cytopenias.
• 39:05Obviously, hyperviscosity
• 39:07is very concerning. It should
• 39:08be treated right away.
• 39:11Also, if you have progressive
• 39:13bulky lymphadenopathy,
• 39:14that would be criteria for
• 39:16treatment
• 39:16for glabalinemia
• 39:18called,
• 39:19agglutin disease
• 39:20and significant neuropathy.
• 39:22It's important to to also
• 39:24know that not all neuropathy
• 39:26would warrant therapy. Sometimes people
• 39:28have very mild,
• 39:30case and they're fully functional
• 39:32and we just kind of
• 39:33watch them because, again, you
• 39:34have to assess the risk
• 39:35and benefit. Waldenstrom is also
• 39:37not it it's not a
• 39:39curable,
• 39:40cancer.
• 39:42So when you assess someone
• 39:43with IgM gumopathy,
• 39:45your your questioning and what
• 39:47you're looking for is quite
• 39:48different from when you're assessing
• 39:50someone with non IgM gumopathy.
• 39:58Good.
• 40:01And then, you know, to
• 40:03to take,
• 40:05to move on from an
• 40:06IGM,
• 40:08discussion,
• 40:10We have, this next case,
• 40:11which was a fifty two
• 40:13year old gentleman from Ecuador,
• 40:17who's new to me,
• 40:19really this past December. But
• 40:21in
• 40:23June of twenty two
• 40:25twenty twenty
• 40:26two, he went to his
• 40:27PCP, had a urologic symptom,
• 40:29but on the side said,
• 40:31oh, by the way, my
• 40:32neck pain my neck hurts,
• 40:33you know, for last week.
• 40:35And I, you know, just
• 40:36changed my mattress. You know?
• 40:37What do I do?
• 40:39And,
• 40:40the,
• 40:41you know, looked in you
• 40:42know, looked into it, said
• 40:44no no red flags on
• 40:46discussion exam, etcetera.
• 40:47He,
• 40:48looked over his chart. He
• 40:49had no past medical history,
• 40:51no surgeries.
• 40:53Social wise, he was married
• 40:55with two kids, immigrated in,
• 40:57two thousand five, and he
• 40:58works as a graphic artist.
• 41:01So,
• 41:02you know, you know, conservative
• 41:03care was instructions were provided,
• 41:06and he was advised to
• 41:07come back to the clinic
• 41:08and and,
• 41:10if if things improve.
• 41:12But four weeks later
• 41:14in July,
• 41:16he went to the emergency
• 41:17room at Bridgeport Hospital with
• 41:18worsening neck pain
• 41:20and right,
• 41:22ear numbness
• 41:23and right arm pain.
• 41:26He had a subjective fever.
• 41:27He had cough. He had
• 41:28congestion. So he was tested
• 41:30for COVID. He was positive.
• 41:32He was discharged
• 41:33with molnupiravir
• 41:34and, PCP follow-up.
• 41:37The next day, he had
• 41:38a phone call, video visit
• 41:39with his primary care doc,
• 41:42mentioned the neck pain again.
• 41:43She ordered an X-ray,
• 41:46but the patient didn't get
• 41:47it done for whatever reason.
• 41:49And,
• 41:51he went back to his
• 41:52primary care doc saying, hey.
• 41:53I have this neck pain.
• 41:54It's still here.
• 41:56And I think she said,
• 41:57well, where's the X-ray? He
• 41:58said I didn't get it
• 41:59done. So he and then
• 42:00he went and got it
• 42:01done. And he had a
• 42:03c three h, indeterminate,
• 42:05you know, compression fracture,
• 42:09and an MRI was ordered,
• 42:11for follow-up. And, two weeks
• 42:13later, he got that done.
• 42:14And,
• 42:15you see here at the
• 42:16c three level,
• 42:18under the red circle, he's
• 42:20got a
• 42:21pathologic fracture.
• 42:23It's a burst fracture. It's,
• 42:25you know, moving posteriorly and
• 42:27then pinching the cervical
• 42:29spinal cord.
• 42:32Yeah.
• 42:33He had multiple lesions throughout
• 42:34his vertebrae,
• 42:36a rib and a humeral
• 42:37head, and, no other signs
• 42:39of a of a alternative,
• 42:41you know, cancer identified.
• 42:44And then he had,
• 42:45he had
• 42:46a mild you know, he
• 42:47had anemia, normalcytic anemia of
• 42:49twelve point eight, normal calcium,
• 42:51normal creatinine.
• 42:53He had a, he had
• 42:54a identifiable monoclonal protein on
• 42:56the s PEP that was
• 42:57IgG kappa on immunofixation,
• 43:00elevated kappa light chain, elevated
• 43:02kappa light chain ratio.
• 43:04One six eight, he had
• 43:05elevated IgG immunoglobulins,
• 43:07and he had some pain
• 43:09proteins on the urine,
• 43:11electrophoresis.
• 43:12But,
• 43:14clinical course, he went through
• 43:15a c three corpectomy
• 43:17and,
• 43:18with an interview vertebral,
• 43:20device placement.
• 43:22Well, you know, a few
• 43:23days later by posterior cervical
• 43:25fixation,
• 43:27tissue,
• 43:28pathology from the burst fracture
• 43:29showed sheets of plasma cells,
• 43:31you know, CD one thirty
• 43:32eight, you know, capilloid chain
• 43:34restriction.
• 43:36And then
• 43:37few days later, had his
• 43:38bone marrow,
• 43:39biopsy done and, twenty percent
• 43:42kappa,
• 43:43plasma cells identified.
• 43:45And back to doctor Barr.
• 43:49Sorry. I was so excited
• 43:50to talk about myeloma that
• 43:52I speeded ahead.
• 43:54So so this patient does
• 43:55have a diagnosis of multiple
• 43:57myeloma. He has,
• 43:59definitely bony lesions. It has
• 44:00some anemia. And, actually, in
• 44:02fact, the most common
• 44:03presenting, CRB criteria is bony
• 44:05lesions and anemia.
• 44:07I think the key features
• 44:08here is this kind of
• 44:10persistent progressive bony pains that
• 44:12in a young patient, someone
• 44:15might not think is is
• 44:16that,
• 44:17you know, concerning, especially we
• 44:19see a lot of patients
• 44:19who are shoveling snow and
• 44:21have some back pain, but
• 44:22that does not go away.
• 44:23You know? So it's like
• 44:25something that continues, something that
• 44:26needs to be evaluated for
• 44:28sure with more, imaging.
• 44:30So myeloma is not curable,
• 44:32and, of course, that's devastating
• 44:33for patients,
• 44:35to hear.
• 44:36And as I show you
• 44:38here, it's categorized by multiple
• 44:40relapses.
• 44:41The first
• 44:43remission
• 44:44or response to therapy
• 44:46is often the longest one.
• 44:48And you don't really have,
• 44:50numbers here, but on average,
• 44:52these patients
• 44:53have a first duration of
• 44:55response of about five years.
• 44:56So it's quite good.
• 44:59And then once they relapse,
• 45:00they get another therapy, and
• 45:01then each with each relapse,
• 45:03it shortens.
• 45:04We do,
• 45:05kind of classify as early
• 45:07relapse and late relapse mainly
• 45:09for kind of treatments
• 45:11different treatments that are approved
• 45:12for these particular situations,
• 45:16and a little bit relevant
• 45:17for a few slides from
• 45:18now. So in terms of
• 45:20epidemiology,
• 45:21it's definitely not the most
• 45:22common cancer, so fourteenth most
• 45:24common cancer.
• 45:26It's usually seen in the
• 45:27elderly, median age of sixty
• 45:29nine,
• 45:30more commonly seen in individual
• 45:31of African American descent.
• 45:33The median survival, I can
• 45:35see here in the,
• 45:37green
• 45:39graph here, has
• 45:40steadily
• 45:42improved
• 45:42for the last two decades.
• 45:44Okay?
• 45:46And it it it does
• 45:47depend on risk. And right
• 45:49now, we're looking here,
• 45:51or we don't we don't
• 45:52actually have twenty twenty five
• 45:54with the most recent evaluation
• 45:56from the SEER database
• 45:58is twenty twenty one,
• 46:00showing you that at five
• 46:01years, if you were diagnosed
• 46:02in twenty twenty one, the
• 46:04chance
• 46:04of being alive at five
• 46:06years is sixty two percent.
• 46:07But I can tell you
• 46:08this is very much an
• 46:10underrepresentation
• 46:11of our survival in our
• 46:13patients,
• 46:13and this is probably more
• 46:15close to seventy five to
• 46:16eighty percent.
• 46:18High risk patients
• 46:20probably,
• 46:22do die within the first
• 46:23five years, but if you're
• 46:24not high risk, you do
• 46:25have that benefit of of
• 46:27longer duration of survival.
• 46:30Majority of the reason why
• 46:32our patients are living longer
• 46:33is because of new therapies.
• 46:36So the initial therapy for
• 46:38myeloma,
• 46:39can be quite cumbersome. So
• 46:41it actually involves three different
• 46:43parts. The first is induction.
• 46:45We use several drugs together.
• 46:48And after you get
• 46:50here, you see burden of
• 46:51disease,
• 46:53and then it goes down
• 46:54with induction.
• 46:55Some patients get a high
• 46:57dose chemotherapy and stem cell
• 46:59transplant if they're eligible,
• 47:01and then everyone goes on
• 47:03to getting maintenance. And we
• 47:04continue therapy for myeloma
• 47:07ongoing
• 47:07forever, which now as patients
• 47:09are living longer,
• 47:10is creating more problems. And
• 47:12we're trying to,
• 47:14figure this out who we
• 47:15can stop therapy,
• 47:17for.
• 47:19We know that achieving
• 47:20deep responses
• 47:22as we can
• 47:24measure by minimal residual disease
• 47:26negativity
• 47:28achieves good duration response and
• 47:32overall outcomes of survival.
• 47:34And with our newer therapies
• 47:35that we're using in induction
• 47:38and even in maintenance, we're
• 47:39achieving higher rates of MRG
• 47:41negativity, and this is why
• 47:42our our patients are overall
• 47:44doing much better.
• 47:46However, unfortunately, again, it is
• 47:48not curable, so patients do
• 47:50progress.
• 47:51And patients who progress several
• 47:53times
• 47:55historically
• 47:56have horrible prognosis, and this
• 47:58is historically
• 48:00four years ago. Okay?
• 48:02This is showing you patients
• 48:03who have had three late
• 48:05relapses.
• 48:06The chance of them
• 48:08responding to the next line
• 48:10of therapy
• 48:11is only thirty percent.
• 48:13And even if they do
• 48:14respond, they tend to progress
• 48:16with within several months, usually
• 48:19less than six months,
• 48:20and they often die within
• 48:22a year.
• 48:24What do we have today?
• 48:25This is quite different.
• 48:27We are now in the
• 48:28era of T cell redirection
• 48:30therapies, which is a type
• 48:31of immunotherapy
• 48:33that
• 48:34engages the T cells or
• 48:36uses T cells
• 48:37to identify
• 48:39the cancer, myeloma,
• 48:41through an antigen,
• 48:42which is a cell,
• 48:43a marker on the cell
• 48:45surface of the myeloma,
• 48:47identifies it,
• 48:48attacks it, kills it.
• 48:50So this is done through
• 48:52two different ways. One is
• 48:54called a bispecific
• 48:55T cell engager,
• 48:57which is basically an antibody,
• 48:58as you can see, shaped
• 48:59like a myeloma,
• 49:02monoclonal protein,
• 49:03which one of the arms
• 49:05binds to the T cell
• 49:06and the other one binds
• 49:07to the myeloma cell.
• 49:09The other T cell redirection
• 49:11therapy is a CAR T
• 49:12cell, which is basically a
• 49:14T cell that's engineered
• 49:16to
• 49:17have a receptor that recognizes
• 49:19the myeloma and kills it.
• 49:21And the T cells are
• 49:21kind of superstar T cells
• 49:23because they have
• 49:25costimulatory
• 49:26molecules once they get stimulated.
• 49:30So why are we so
• 49:31excited about these t cell
• 49:33redirection therapies? Again, historically,
• 49:36these patients
• 49:37who received these therapies on
• 49:39clinical trials would have had
• 49:41a thirty percent chance of
• 49:42response. And indeed, a lot
• 49:43of the treatments we use
• 49:44now upfront, they got approved
• 49:46by the FDA because of
• 49:47a thirty percent response rate,
• 49:49and we were excited about
• 49:50that.
• 49:51And, again, these patients who've
• 49:53progressed three times,
• 49:54they usually, even if they
• 49:56respond,
• 49:57progress within a few months.
• 49:59So this is a busy
• 50:00slide, but I want you
• 50:01to focus on two things.
• 50:02The first is in the
• 50:04orange box, the percent of
• 50:05page patients responding.
• 50:08First, I show you here
• 50:10three different types of bispecific
• 50:12T cell engagers,
• 50:13and in the second box
• 50:14is the two types of
• 50:16CAR T cell therapy products.
• 50:18And you can see on
• 50:19the bottom in gray,
• 50:21the chance of patients responding
• 50:22is more than double
• 50:24in the bispecific t cell
• 50:25engagers
• 50:27and even close to a
• 50:28hundred
• 50:29in the in this CAR
• 50:31T cell product, ciltasil,
• 50:32ninety seven percent. Only one
• 50:34of the patients did not
• 50:35respond in this clinical trial.
• 50:37So this is great.
• 50:39Unprecedented.
• 50:40Now in blue, our bar
• 50:42is showing you
• 50:44the number of months
• 50:46where fifty percent of the
• 50:47population
• 50:49progressed or in the other,
• 50:52the half the the cup
• 50:53half full, half empty,
• 50:55fifty percent did not progress
• 50:57at this time point. And
• 50:59comparing to the six months
• 51:01or less historically,
• 51:03you can see these agents
• 51:04are doing far superiorly
• 51:07with celtacel
• 51:08going on about three years.
• 51:10So on average,
• 51:11patients have a duration of
• 51:13response of three years.
• 51:14Again, unbelievable in these patients.
• 51:17And because these are so
• 51:19useful and efficacious in this
• 51:21late relapse,
• 51:23They've been tested earlier and
• 51:24were approved in early relapse
• 51:26and are now being tested
• 51:28in frontline therapy
• 51:30and even,
• 51:32testing against transplant.
• 51:35We'll we'll know more in
• 51:36maybe five to ten years.
• 51:39So CAR T is a
• 51:40little bit different than other
• 51:42therapies we use because,
• 51:44it requires
• 51:45manufacturing.
• 51:46So I just wanted to
• 51:47show you what this entails,
• 51:48what patients have to go
• 51:49through. First, we have to
• 51:50collect the T cells from
• 51:51the patients through apheresis, then
• 51:53they get shipped off to
• 51:54the manufacturer.
• 51:56They separate,
• 51:57the T cells. They they
• 51:59genetically
• 51:59modify them to express
• 52:02the chimeric T cell receptor,
• 52:04then they grow, and then
• 52:05they get
• 52:06brought back to the patient
• 52:08and infused
• 52:09like a regular blood transfusion
• 52:10similar to that.
• 52:13This here show you a
• 52:14highlight of what this CAR
• 52:16T,
• 52:16what what the receptor looks
• 52:18like. So there's a binding
• 52:19domain. Again, this is to
• 52:20a protein
• 52:22called BCMA.
• 52:23IDACel has two binding domains
• 52:25and I and, sorry, cilta
• 52:27cell has two binding domains
• 52:28and IDACel has one.
• 52:32Now a major difference between
• 52:34CAR T and the bispecific
• 52:36T cell engagers also is
• 52:38how you administer it, which
• 52:40is relevant for patients. So
• 52:42bispecifics,
• 52:43we don't stop therapy. We
• 52:44give it every week or
• 52:45every two weeks and sometimes
• 52:46every four weeks depending on
• 52:48the product. But CAR T
• 52:49is a one time treatment,
• 52:51which is really,
• 52:53nice for patients who've been
• 52:54treated for many, many years
• 52:55continuously.
• 52:58So just to close on
• 53:00the myeloma
• 53:02category, you know, a lot
• 53:03of patient care happens with
• 53:05us, so you don't,
• 53:06see it as much, but
• 53:07you do see them once
• 53:08in a while. And there
• 53:09are some comorbidities
• 53:11that,
• 53:12can be exacerbated by our
• 53:14treatment. Steroids are often used
• 53:16in many of our regimens,
• 53:17so this could worsen hypertension,
• 53:19diabetes. I mean, we might
• 53:21need more support from you
• 53:22guys to help manage that.
• 53:24Carfizumab,
• 53:25which is the second generation
• 53:26proteasome inhibitor, could also,
• 53:29lead to hypertension
• 53:30and heart failure.
• 53:32And many of our treatments
• 53:33increase the risk for infections,
• 53:36often not opportunistic.
• 53:38But now with the t
• 53:39cell redirection therapies, we are
• 53:41seeing some more opportunistic
• 53:43infections. So it's important to,
• 53:46to recognize that. And with
• 53:47an infection, let us know
• 53:49what's going on so we
• 53:50can further assess.
• 53:52And lastly,
• 53:53I wanna end by showing
• 53:55you the gammopathy pathway that
• 53:56is in EPIC.
• 53:58And,
• 53:59it's a busy slide, but
• 54:00I want you to know
• 54:01it's there
• 54:02As
• 54:03and you can see that
• 54:05it guides you through if
• 54:06you have a monoclonal protein
• 54:07on SBEP or not.
• 54:10And showing you the monoclonal
• 54:11gammopathy,
• 54:13screen panel here, which makes
• 54:15sure you're ordering all the
• 54:16pair protein evaluation that we
• 54:18need
• 54:19and also some key information
• 54:21about when to refer urgently,
• 54:24when to not refer urgently,
• 54:25when to repeat labs, and
• 54:27reassess.
• 54:30So to close our,
• 54:33talk today,
• 54:34these are just some summary
• 54:36points that we wanna highlight.
• 54:38First, we showed you how
• 54:39it's important to recognize whether
• 54:41it's normal light chain ratio,
• 54:43how, how age and, renal
• 54:45dysfunction
• 54:46can affect these.
• 54:47We showed you what low
• 54:49risk MGUS is, what is
• 54:51the definition,
• 54:53and that this often can
• 54:55be managed by primary care
• 54:56doctors
• 54:57if
• 54:58or co managed with us.
• 55:01When to urgently refer patient,
• 55:02CRAB criteria,
• 55:04certainly,
• 55:06things that make it in
• 55:07IgM, gammopathies,
• 55:09things that kind of, are
• 55:11red flags is new progressive
• 55:13neuropathy or
• 55:15other symptoms
• 55:16diagnose,
• 55:17diagnosing Waldenstrom.
• 55:18And lastly,
• 55:20it would be,
• 55:21wonderful if you can look
• 55:22at the gammopathy pathway if
• 55:24you have a positive,
• 55:26finding and tell us if
• 55:27it was helpful or unhelpful.
• 55:30How can we, improve this
• 55:32pathway? And, also, there is
• 55:33some education material
• 55:34for MGUS
• 55:35to bring to the patient
• 55:37to reduce anxiety.
• 55:41That was terrific. A real,
• 55:44everything you know need to
• 55:45know from a to z
• 55:46or maybe a to IGG.
• 55:48I I don't know. IGM.
• 55:50We have a couple of
• 55:52questions, and we are
• 55:54getting near the end of
• 55:55the hour. One is the
• 55:57usual, is there a CME
• 55:59code? And and, Renee, if
• 56:00you can just type in,
• 56:02that I I I think
• 56:03what we found before is
• 56:04if you're if you're here,
• 56:06we end up getting you
• 56:07credit,
• 56:08as long as your name
• 56:09shows.
• 56:10But one question from doctor
• 56:12Zarku Power is, is there
• 56:14is there robust research to
• 56:16link the risk of multiple
• 56:18myeloma to pesticides,
• 56:20agent orange, or other chemicals?
• 56:22There are sets of two
• 56:24patients in her panel who,
• 56:27have asked her opinion on
• 56:29that, pertaining to themselves and
• 56:31relatives. And if there's no
• 56:32robust research, why not?
• 56:39So, I'll say agent orange,
• 56:41definitely.
• 56:43That's a definite risk
• 56:45factor. Pesticides?
• 56:48I don't think so.
• 56:49I'm not I'm not familiar
• 56:51either with pesticides. One one
• 56:52thing I did wanna add
• 56:54is there is emerging evidence
• 56:55looking at connections, associations with
• 56:58components of metabolic syndrome, specifically
• 57:00obesity and diabetes, and both
• 57:02development and progression of monoclonal
• 57:04gammopathy and,
• 57:06you know, some studies looking
• 57:07at the potential for preventative
• 57:09interventions,
• 57:10because they you know, I
• 57:11think
• 57:12the thought is just kind
• 57:13of the the level of
• 57:14inflammation, but I think we
• 57:15we don't know exactly what
• 57:16the connection is.
• 57:24Drew, do you have any
• 57:25other questions for our panelists?
• 57:27You've been knee deep in
• 57:28this, and and you have
• 57:29an internist opportunity
• 57:31to be face to face.
• 57:33Any additional ones?
• 57:36I think I think I
• 57:37had a couple of of
• 57:39I guess I guess the
• 57:40IGA,
• 57:41like, we had two cases
• 57:42here with IGA. We had,
• 57:44you know, nothing detected on
• 57:45the SPEP. We know that
• 57:47the IGA migrates,
• 57:48you know, through the,
• 57:51into the beta,
• 57:55you know, the beta we
• 57:56we went blank on my
• 57:57knee on the term here.
• 57:59The beta region.
• 58:01Is there
• 58:02I guess the question is,
• 58:04like,
• 58:07the it it I
• 58:09guess, if it's high it's
• 58:10high risk. Right? So
• 58:12how do you
• 58:14when you're going by IGA
• 58:15levels
• 58:16and light chain levels to
• 58:18see if there's any progression
• 58:20of the disease,
• 58:22Is that always a hundred
• 58:23percent reliable?
• 58:26It does so does does
• 58:28I know there there when
• 58:29you do a bone marrow
• 58:30biopsy, you're more likely to
• 58:31see, like,
• 58:33more plasma cells in IgA,
• 58:37right, relative to IgG. So
• 58:39do do you see a
• 58:40direct correlation between the IgA,
• 58:43protein or the or the
• 58:45or
• 58:46the free light chain,
• 58:48quantification
• 58:49and,
• 58:51cell you know, like,
• 58:53progression of disease. Is that
• 58:55is that reliable?
• 58:57That that's that's a very
• 58:58good question. I mean, generally,
• 58:59we we look at everything.
• 59:02In
• 59:03when patients progress, even if
• 59:05they have myeloma or if
• 59:06they're MGUS and they're going
• 59:07up, the IgA typically goes
• 59:09up first.
• 59:10And then the m spike
• 59:11will rise later, several months
• 59:13later. So that's why we
• 59:15look at both.
• 59:17The again, the trend holds
• 59:18true for the most part.
• 59:20When the there's more clonal
• 59:21plasma cells, there's gonna be
• 59:23more clonal,
• 59:24protein or or IGA or
• 59:26or light chains.
• 59:27But it might not be,
• 59:29like, a a one to
• 59:30one representation,
• 59:32but the trends hold true.
• 59:34Okay.
• 59:35That helps.
• 59:39I think
• 59:40I think it's really important
• 59:41for, like, primary care docs
• 59:43to
• 59:44recognize
• 59:45that low risk category. You
• 59:47know, the three criteria where
• 59:48it's the IgG,
• 59:50m protein, the less than
• 59:51one point five
• 59:53milligrams on the SPEP,
• 59:54and then the the normal
• 59:56serum prelate chain ratio. So
• 59:58I think,
• 59:59you know, we see something
• 01:00:00like this and we're like,
• 01:00:01oh my gosh.
• 01:00:02I don't want this to
• 01:00:04be my own, you know,
• 01:00:06monitoring, you know, responsibility.
• 01:00:08But,
• 01:00:10I think that's a key
• 01:00:11nugget for me,
• 01:00:12looking at this talk and
• 01:00:14going through this talk.
• 01:00:16The difference you know, the
• 01:00:17IGM,
• 01:00:18you have to think Waldenstrom's,
• 01:00:20you know, and then the
• 01:00:21IGA not the is always
• 01:00:22a low risk, needs a
• 01:00:24needs that biopsy. I think
• 01:00:25those are key take homes
• 01:00:26from my,
• 01:00:28standpoint.
• 01:00:32I guess the question going
• 01:00:34back to the toxins too,
• 01:00:36which
• 01:00:38and and the,
• 01:00:39monoclonal the the monoclonal proteins.
• 01:00:41But can
• 01:00:43they get the gentleman in
• 01:00:44this case who developed the,
• 01:00:47IgA Lambda
• 01:00:48and with the false positive
• 01:00:49Lyme, etcetera,
• 01:00:52he blames things on his
• 01:00:54COVID vaccine. Right? So,
• 01:00:56yeah, COVID vaccine, he developed
• 01:00:58this neuropathy, and we found
• 01:01:00this this issue.
• 01:01:02He developed ulcerative colitis after
• 01:01:04his COVID vaccine. So he's
• 01:01:05a he's he's moving towards
• 01:01:07that realm. I'm not saying
• 01:01:09anything is
• 01:01:11is is you know, I'm
• 01:01:11not I'm not buying that
• 01:01:13story a whole lot, but
• 01:01:14at all. But, you you
• 01:01:15know, thinking of,
• 01:01:17yeah, I know, thinking of,
• 01:01:21antibody like, is there a
• 01:01:22correlation between
• 01:01:23any autoimmune syndrome or kind
• 01:01:25of stimulation of b cells
• 01:01:26in some way and increase
• 01:01:28risk of of of these
• 01:01:30disorders?
• 01:01:32Like, you know, COVID vaccine,
• 01:01:33we're stimulating,
• 01:01:35you know,
• 01:01:37antibody production,
• 01:01:39but not saying causation. But
• 01:01:40is there any
• 01:01:41is there any discussion of
• 01:01:43that, or is there any
• 01:01:47similar concerns being brought to
• 01:01:49your
• 01:01:50attention.
• 01:01:51Yeah. I I think these
• 01:01:52are questions we get as
• 01:01:53well. I mean, I think
• 01:01:54there is
• 01:01:55thought to be association with
• 01:01:56autoimmune
• 01:01:58inflammatory disorders where there's kind
• 01:01:59of constant stimulation of b
• 01:02:01cells like like you're saying.
• 01:02:03You know, I'm not aware.
• 01:02:04I I there was,
• 01:02:06a small study presented as
• 01:02:07an abstract looking at change
• 01:02:09in monoclonal protein after COVID
• 01:02:11vaccines, and there was none.
• 01:02:12No evidence of progression. So,
• 01:02:14I'm not aware of anything
• 01:02:15kinda larger than that, but
• 01:02:17that's a question that comes
• 01:02:18up a lot from our
• 01:02:19patients. But, you know, that
• 01:02:20and from that small information,
• 01:02:21I don't think we think
• 01:02:22there's connection. At least in
• 01:02:24patients that have have MGUS,
• 01:02:25you know, don't progress to
• 01:02:26to something more.
• 01:02:28Yeah. I mean, that's that's
• 01:02:29good. Just, cut us off
• 01:02:31because we passed our hour.
• 01:02:33Yeah. And I so appreciate
• 01:02:36all of the preparation
• 01:02:37that you all did to
• 01:02:38bring us
• 01:02:39all of this information. This
• 01:02:41is really helpful. And, if
• 01:02:43there are others who you
• 01:02:43think may be interested, please
• 01:02:45feel free,
• 01:02:46to share the link, to
• 01:02:47watch afterwards. We thank you
• 01:02:49for attending,
• 01:02:51and we'll see you next
• 01:02:53month when we have colorectal
• 01:02:54cancer prevention and screening as
• 01:02:56our hot topic.
• 01:02:59Thanks, everyone. Bye bye. Very
• 01:03:00much.