Hello, everyone. In this first section, I will talk about the patient's journey to diagnosis.

[00:06:44]

Light Chain (AL) Amyloidosis

Light chain amyloidosis is the type of amyloidosis where the problem starts, typically, in the bone marrow, with clonal plasma cell proliferation. These clonal plasma cells often harbor chromosomal translocations, which confer to them the ability to produce impaired immunoglobulin and free light chain overproduction. These free light chains come out in the circulation, misfold to produce amyloid fibrils, which then deposit as insoluble deposits in various organs. Now there are many different types of amyloid diseases in humans, and light chain amyloidosis is one of those types.

[00:07:32]

Light Chain Amyloidosis Is a Rare Disease in the US

If we look at the epidemiology of light chain amyloidosis, this is still a very rare disease. It is indeed an ultra-rare disease based on the incidence and prevalence. Now, I have to point out that the incidence is going up. 15 years ago, the incidence was typically described as under 10 cases per million person-years. This is slowly going up, I think, more related to increased recognition and improved diagnosis. In more recent studies, this has gone even over 15 cases per million person years now. In keeping with this, the prevalence has also gone up. In most recent epidemiologic studies, the prevalence of this disease is a little over 48 cases per million population. The disease is a little more common in men than women.

[00:08:30]

Global Epidemiology of AL Amyloidosis

Globally, from countries where we do have data on the incidence and prevalence overall, the number of incident cases per year is around 15,000. In the United States, every year, 3,000 to 4,000 patients are diagnosed with AL amyloidosis.

[00:08:52]

A Disease of Delayed Diagnosis

Now, this is a disease of delayed diagnosis. These are data that were done by the Amyloidosis Research Consortium in an online survey of over 500 participants, the majority of whom had AL amyloidosis. What patients told us is that they have many different symptoms and they have symptoms for a long time, as well, many months to sometimes more than two years. They often seek health care with multiple specialists. On average, patients with AL amyloidosis see four different specialists before the diagnosis is made.

[00:09:34]

Many Pre-AL Diagnostic Signs and Symptoms

Similarly, if we look at the electronic health record data of these patients, in the time preceding the AL diagnosis, sometimes two years, sometimes three years, we can identify multiple symptoms and signs as diagnosis. What that tells me is that physicians, healthcare providers are identifying various symptoms and signs as ICD diagnoses in these patients. It still takes a long time to put this all together, all these red flag diagnoses, into that unified diagnosis of AL amyloidosis. When we have looked at EHR data of patients, we have found various red flag symptoms and signs, including clonal diseases like monoclonal gammopathy of undetermined significance or smoldering myeloma, various cardiac diagnoses, renal diagnoses, neurologic diagnoses, and so on.

[00:10:37]

Patients with Precursor Diagnoses Before AL Amyloidosis Diagnosis

Two years before patients are diagnosed with AL, if we count the number of these red flag diagnoses, we find a median of two. In the six months before AL is diagnosed, this goes up to four different red flag diagnoses encompassing three different organ systems. At the time of AL diagnosis, oftentimes patients have up to six and encompassing at least four organ systems. All these data, what they suggest to us is that we should perhaps be able to diagnose these patients at least six months before the current diagnosis paradigm, but even as early as two years before, because they are being seen, they are being diagnosed with various red flag conditions.

[00:11:30]

Impact of Delayed Diagnosis on Patient Outcomes

Why is this important? Because delayed diagnosis has a direct association with patient outcomes. Patients who are diagnosed in early stage have better overall survival. Once patients develop advanced cardiac amyloidosis, once they have stage IIIa or IIIb, which means they have heart failure or increased cardiac biomarkers, the risk of early mortality really goes up in the first 6 to 12 months after diagnosis. This is something that we all have to do better at being able to recognize those red flag symptoms and signs, and getting patients to a diagnosis of AL amyloidosis earlier.

[00:12:22]

Shifting Symptom Profiles and Accelerated Diagnosis, 2022-2024

I want to end this section on a positive note. It does appear that in the more recent years, we are doing a better job. These are newer data that were just reported at ASH last month from the Amyloidosis Research Consortium that now show that our median time to diagnosis is indeed going down from 2.7 years in 2022, down to about 1.4 years in 2024.

[00:12:50]

AL Amyloidosis Recognition and Diagnosis

How do we recognize AL amyloidosis, and what is that multidisciplinary pathway to making a diagnosis of AL amyloidosis?

[00:13:02]

AL Amyloidosis: Clinical Presentation and Early Symptoms

Once again, we ask our patients what were their commonly reported initial symptoms. You can see here from patient interviews and surveys that patients often have these nonspecific multi-organ system symptoms, including fatigue, malaise, shortness of breath, edema, sometimes dizziness on standing. Very nonspecific symptoms. Now, purpura, enlarged tongue of amyloidosis, these are more classic textbook symptoms of the disease.

I have shown the images of what macroglossia can look like on physical exam, or the classic “raccoon eye” sign with the bilateral periorbital purpura. Even when patients present with these symptoms and signs, we sometimes do not recognize it because we are not thinking of the diagnosis. Really, in the clinic, if we do not suspect the disease, we will not diagnose it. Once we suspect, we have to take a stepwise approach to screening for the monoclonal process, demonstrating on tissue that amyloid is present, and then finally confirming the protein of origin.

[00:14:25]

Patterns and Co-occurrence of Symptoms/Signs

In data coming from large amyloid centers, the majority of patients with systemic AL amyloidosis have cardiac involvement. More than 75% of patients have some degree of cardiac involvement, including left ventricular hypertrophy, elevated cardiac biomarkers NT-proBNP and troponin T. Oftentimes, the pattern seen on echocardiogram is diastolic dysfunction with preserved ejection fraction.

The next organ that is commonly involved is the kidney. More than 60% of amyloid patients have renal involvement, which often presents with proteinuria, less often an elevated creatinine.

Other organ systems include neuropathy, peripheral neuropathy, autonomic neuropathy as well as impingement neuropathy. What we recognize as carpal tunnel syndrome. Less than 20% of patients have macroglossia and periorbital purpura.

Additionally, I think what is more important is not looking at these organ systems on their own, but when they co-occur, when more than one organ system is present, it makes the likelihood of having AL amyloidosis higher.

[00:15:51]

Patterns of Organ Involvement

The majority of patients with AL amyloidosis, as I just mentioned, have more than one organ involvement.

[00:15:58]

High-Risk Populations for Delayed AL Amyloidosis Diagnosis

What are our high-risk populations that you should think of where AL amyloidosis should be kept higher in the differential? Older adults, Black race. Both of these conditions have a higher association with monoclonal gammopathies, either MGUS or smoldering myeloma. These are the typical groups where you should think we are very good when we are seeing patients with MGUS to make sure we are not missing multiple myeloma, remember that these patients are also at a risk to develop systemic AL. There are data from Europe that show that in a patient with MGUS, if you check their NT-proBNP, check a urine protein creatinine ratio, and alkaline phosphatase, just these three biomarkers, you will be able to identify if that patient is now developing AL amyloidosis.

Additionally, other clonal disorders such as CLL, SLL, or marginal zone lymphoma, Waldenström macroglobulinemia are also associated with a small but real risk of developing AL amyloidosis. The data on this slide show that when we compare patients who have a diagnosis of AL and look at racial differences, Black patients have a higher likelihood of having both delayed diagnosis as well as underdiagnosis.

[00:17:33]

Diagnostic Testing That May Be Helpful

When you are suspecting amyloidosis in a patient in your clinic, what are the diagnostic tests that may be helpful? When it comes to the heart, think of the cardiac biomarkers. Both the serum NT-proBNP as well as troponin. An EKG can provide important clues, such as low voltage, QRS complexes, the pseudoinfarct pattern. Sometimes you will see arrhythmias on the EKG.

Then, in terms of imaging, the echocardiogram, particularly when obtained with strain imaging, can show multiple signs of amyloidosis. These include diastolic dysfunction. Typically, the ejection fraction is preserved till late. The abnormal strain pattern with the cherry on top appearance, thickened interventricular septum, concentric left ventricular hypertrophy.

An MRI, especially done with contrast, can show multiple clues, including elevated ECV, a higher T1 score, as well as the classic delayed gadolinium enhancement pattern. Then, finally, the technetium pyrophosphate scan, or PYP scan, is increasingly used to identify ATTR amyloidosis, but remember that some patients with AL amyloidosis can have a positive PYP scan as well.

In terms of other organs, for the kidneys you are screening patients for albuminuria. Elevated creatinine can be seen, but it is less common.

With the liver, an elevated alkaline phosphatase, sometimes an elevated bilirubin. Typically, these patients do not have elevations in transaminases. On physical exam, the liver may be enlarged.

For neurologic symptoms, electromyography and nerve conduction velocity studies can be helpful. Then remember that patients who have a lot of bruising, the periorbital purpura, screen these patients for factor 10 deficiency because patients with AL amyloidosis can develop an acquired factor X deficiency.

[00:19:56]

Detecting and Typing Amyloid Protein

Once you have gotten these tests done, imaging studies, or blood or urine tests, the next step is to biopsy a site. We often start with an abdominal fat pad, along with a bone marrow biopsy combined. This can identify amyloidosis with about a 90% sensitivity. If this is negative and your suspicion is high, I often go straight to the target organ, the organ where you think there is amyloid involvement, such as the kidneys or the heart, or the liver. After biopsy, the tissue needs special stains with Congo red or thioflavin T or S.

If the stain is positive, it tells us there is amyloid, but it does not tell us what type it is, and so determining that amyloid type is a very important step after you get a positive amyloid stain. At the current time, we have many different techniques to determine the amyloid type. I often go with mass spectrometry. It is a send-out test at my institution with a turnaround time of one to two weeks, but it is able to tell me what is the dominant protein in the biopsy sometimes. We are increasingly seeing these situations. There is more than one type. You will see AL and ATTR together, and so the mass spectrometry is a very helpful test to determine the amyloid type.

[00:21:32]

Systemic Amyloidosis: Diagnostic Approach

Let us put this all together in our diagnostic approach.

[00:21:36]

Multidisciplinary Diagnostic Approach to Systemic Amyloidosis

You have a patient with cardiac-specific signs, and as reviewed earlier, these could be diastolic dysfunction, infiltrative cardiomyopathy, elevated NT-proBNP, or heart failure with preserved ejection fraction. The first two steps to screen for amyloidosis is getting a comprehensive monoclonal protein study. This should include the serum protein electrophoresis with immunofixation and the free light chain assay. The complete monoclonal workup ideally should also include a 24-hour urine protein electrophoresis with immunofixation, and along with this, the PYP scan.

If the patient has no monoclonal immunoglobulin and the PYP scan shows grade 2 or grade 3 cardiac uptake, this is one setting where we do not need tissue diagnosis. This is consistent with ATTR amyloidosis. In this setting, the next step then is to determine whether the TTR gene is wild type or variant and, accordingly, start treatment.

However, if the patient has a monoclonal immunoglobulin or abnormal free light chains, it does not matter what the PYP scan shows. In this setting, we cannot rule out AL amyloidosis. In this setting, when AL amyloidosis is possible, we do need to obtain tissue diagnostics, starting with a fat aspirate or salivary gland biopsy along with the bone marrow biopsy. If it is positive, type the deposits and confirm it is AL type. If it is negative in the right clinical suspicion, proceed with an endomyocardial biopsy. If it is positive, type, if it is negative, you have ruled out cardiac amyloidosis.

In the presence of non-cardiac specific signs such as proteinuria, neuropathy, or elevated alkaline phosphatase, again, start with the same process, screen for the monoclonal protein, and go down the same pathway if there is an M protein or abnormal free light chains.

[00:23:52]

Approach to Amyloidosis Consults

To summarize this section, to approach patients who you are suspecting could have amyloidosis, really it starts with having that suspicion of amyloidosis and putting it together from the history and physical exam findings. Remember your high-risk populations: older adults, Black patients, those who have a clonal disease such as MGUS or smoldering myeloma. Then employing a systematic approach to work up a patient when amyloidosis is suspected, including laboratory testing, imaging, screening for a plasma cell disorder. The one setting, ATTR, where a tissue diagnosis may not be needed. Then, after diagnosing amyloidosis, really making sure you have typed the amyloid deposits.

With that, I will hand over the next part of the presentation to Dr. Zonder.

[00:24:53]

Initial AL Amyloidosis Treatment: Current Therapies

Dr. Jeffrey Zonder (Wayne State University): Thank you so much for that overview of the recognition and diagnosis of AL amyloidosis. I am going to talk about initial treatment.

[00:25:05]

ANDROMEDA: Daratumumab + VCd vs VCd Alone in Newly Diagnosed AL Amyloidosis

The one initial treatment that is probably most important for you to remember is daratumumab plus VCd. That is bortezomib, cyclophosphamide, and dexamethasone. A lot of us call that CyBorD. I am going to refer to it as Dara plus CyBorD for the remainder of my talk. We have data from a very well-conducted randomized study, the ANDROMEDA study, that demonstrates the utility of this regimen. This builds on a historical usage of CyBorD, or a similar regimen that was used overseas melphalan, bortezomib, and dexamethasone.

With CyBorD, historically, we expect about a 60% hematologic response rate. About two-thirds of those, 40% should be a very good partial response rate or better. Only about 20% of patients historically get to a complete hematologic response. Very good hematologic response, remember, the definition of that is getting the difference between the involved free light chain and the uninvolved free light chain down to 4 mg per deciliter or less. At some centers, that will be reported as 40 mg/l or less.

A complete hematologic response is defined as getting the involved free light chain down into the normal range or lower, and also disappearance of any M protein that is coexisting.

Now, in this study, 388 patients were randomized between CyBorD for six cycles or CyBorD plus subcutaneous daratumumab administered concurrently. Then, in that arm, the daratumumab-treated patients went on to get another 18 months of daratumumab maintenance therapy.

The primary endpoint of this study was achievement of complete hematologic response. And secondary endpoints, the key ones include progression-free survival, a composite PFS endpoint called major organ deterioration PFS, or MOD-PFS. Just so that you understand what this is, this is the usual PFS censoring points of hematologic progression or death, plus some fairly catastrophic organ-related events such as the need for a heart or renal transplant, the initiation of dialysis, or things like a ventricular assist device. Overall survival was also a key secondary endpoint, and we will go through all of these now.

[00:27:57]

ANDROMEDA: Subcutaneous Dara+ VCd plus SC in AL Amyloidosis

What we see here in the left panel, far left, we see that the primary endpoint for the entire patient group was far superior for the daratumumab-treated arm. We see that the CyBorD arm performed exactly like we would have expected, just shy of 20% complete hematologic responses, and we had about three times that rate of complete hematologic response in the Dara arm. When we look across FISH and cytogenetic subsets, high-risk groups that we are used to hearing about in AL amyloidosis, but more importantly maybe in multiple myeloma, the rate of complete hematologic response was the same in 11;14 patients. It was also the same in patients with a gain of 1q.

Other groups have shown that the likelihood of achieving a complete hematologic response might be lower in that latter group, the gain of 1q patients, so the jury is out on that. In ANDROMEDA, there was no obvious cytogenetic subgroup risk that had a lower incidence of complete hematologic response.

If we look at the right panel, this is the MOD-PFS, and we see that after the first six months, there was a significant separation of MOD-PFS. Remember, it is a composite endpoint. When we break that down, this was not driven at all by the organ-related events, because those hardly happened at all on the study. It was also not driven by actual overall survival differences, because at the time of this initial report in the New England Journal of Medicine, there was no difference in the mortality rate in the first 60 days or at the time of the publication. They were identical in each arm.

Really, this difference was driven completely by hematologic progression. The likelihood of having hematologic progression was three times as high in the CyBorD arm, and the likelihood of switching therapy, either because of progression or because of inadequate heme response, was four times as high in the CyBorD arm. That was entirely what drove this MOD-PFS result.

At the time of this initial report in the New England Journal of Medicine, there was no difference in survival reported because of the duration of follow-up. At ASH in 2024, we did get a long-term follow-up, and there is now an overall survival benefit that has emerged later in the Dara-treated group, which is not surprising at all. What that analysis essentially is is a landmark analysis. We had an equal number of patients in each group get to about the six-month mark. The difference in those groups is that one group continued to get anti-plasma cell therapy with daratumumab maintenance, and also going into that post-induction period, three times as many of them had a complete hematologic response. We already knew from our colleagues in Italy in a previous landmark analysis that patients who had higher degrees of hematologic response had improved survival compared to patients that did not. I really would have been surprised if there had not been a survival difference.

[00:31:30]

Daratumumab: Update for November 19, 2025

I am going to come back to survival in a second after I just acknowledge briefly that subcutaneous daratumumab received full approval in combination with CyBorD as induction therapy in AL amyloidosis based on this extended survival benefit.

[00:31:52]

Daratumumab (Dara-CyBorD) as 1L in AL Amyloidosis vs CyBorD)

We have a real-world retrospective analysis that was published by Mayo Clinic. They looked at all of their AL patients who were treated with initial therapy between 2018 and 2022, and about 370 of them were treated with either CyBorD or Dara-CyBorD. A slight excess with CyBorD.

[00:32:18]

Hematological Response: 1L Dara-CyBorD vs CyBorD

We saw, as we did in the ANDROMEDA study – and we are seeing this in the top panels, probably best appreciated in the second panel from the left – that there was at the six month mark a significant difference in the likelihood of achieving a complete hematologic response. It was strongly, statistically-significantly different than CyBorD alone, but it was not quite as high as what we saw in ANDROMEDA. In ANDROMEDA, we hit about a 55% complete response rate. Here in the Mayo series, it was about a 40% complete response rate.

This group had about 10% to 15% stage IIIb patients, which are patients with more advanced heart involvement than what was included in ANDROMEDA, and so it showed that it is possible to give this therapy to those patients. We actually knew that also from a 19-patient series from Columbia University of IIIb patients treated with Dara-CyBorD.

In the Columbia experience, with modification of bortezomib, with more modification of dexamethasone, we could give this regimen. The overall hematologic response rates were quite high, over 90%. In that series, two-thirds of the patients were alive at one year. Now that suggests that there was the potential to have a huge impact on survival using this regimen in advanced cardiac patients.

[00:34:01]

Survival Outcomes by Treatment: Dara-CyBorD vs CyBorD

The Mayo series that I am showing you here, even though we did see evidence of a higher likelihood of cardiac response and an overall survival benefit favoring the Dara and CyBorD group, when they did a subanalysis this survival benefit shown in the top right was almost entirely driven by cardiac stage II patients. When you look at the advanced cardiac patients, there really was not any overall survival difference whether they got daratumumab upfront or not.

I want to just leave you just by talking about the very bottom panel here, and basically, the three curves we are seeing here are patients treated with Dara-CyBorD, patients treated with CyBorD who had access to daratumumab later, and patients who never ended up having access to daratumumab, and that is the lowest survival curve. You can look at this in different ways, but the way I look at it, to drive home a point Dr. D'Souza made, is that improved survival is dependent on getting fast hematologic response rates. Really, what we are seeing, these two dotted lines basically just show that there is a lower likelihood of achieving a good hematologic response with CyBorD induction therapy. Some patients who do achieve that have very good initial outcomes that are similar to the initial outcomes with the superior regimen, but you also have a subgroup of patients who are nonresponders, and you have drop off because they basically do not live to get second-line therapy or are not in shape to get that.

Anyway, this is a summary of the available data about initial therapy with Dara-CyBorD, and I would say that I would consider it the standard of care for not just patients with stage I through IIIa disease, but also can cautiously be used for patients with IIIb disease.

[00:36:09]

Making It Personal: Approaches for Personalized Care for Relapsed AL Amyloidosis

I am going to turn it back over to Dr. D'Souza, who is going to talk about personalized care for relapsed AL amyloidosis.

Dr. D'Souza: Thank you, Dr. Zonder.

[00:36:19]

Understanding Treatment Options in Second Line and Beyond

When we look at treatments in second line and beyond, we do not have any FDA-approved therapies in this setting. However, we have a lot of effective therapies targeting plasma cell disorders that are approved in multiple myeloma, and so we take from the myeloma literature, drugs that are effective against plasma cells and use them in the relapsed AL setting.

Starting from Dara-CyBorD, we have the option of reusing them at the time of relapse. There are other monoclonal antibodies, such as isatuximab or elotuzumab, other proteasome inhibitors like ixazomib, carfilzomib, although noting that patients who have advanced cardiac AL may not tolerate cardiotoxic drugs such as carfilzomib. We have alkylators, high-dose melphalan, bendamustine. The IMiDs, remembering that with IMiDs, there is this class effect of having an increase in cardiac biomarkers. What we see in practice is even as their free light chains are improving, their NT-proBNP and troponin can go up, so recognizing that this is an effect, not cardiotoxicity, but just an expected effect of IMiD therapy.

Then we have BCL-2 inhibitors, which work really well in patients with translocation 11;14, which is really to our advantage in AL amyloidosis, because 40% to 60% of AL patients can harbor translocation 11;14. Then we have several BCMA-directed therapies, what I call the ABC, the antibody drug conjugate, bispecific antibodies, and CAR T-cell therapies. I will pick a few of these in the next few slides to discuss in more detail.

[00:38:24]

Role of Autologous Stem Cell Transplantation in AL Amyloidosis

Starting with what is the role of stem cell transplant in 2026 in AL amyloidosis? Given the deep and complete hematologic responses to Dara-CyBorD, we now do not know what, if any, the role of upfront stem cell transplant is. Now, remember that only 15% to 20% of newly diagnosed AL amyloidosis were even eligible for transplant. There is an ongoing SWOG trial, the SWOG 2213, which randomizes patients who have started Dara-CyBorD induction to either receiving autologous stem cell transplant or continuing Dara-CyBorD.

If we do not transplant in the upfront setting, we may have the option of doing transplant at relapse. There are data from the National Amyloidosis Centre showing that patients who defer stem cell transplant to first relapse also have excellent outcomes if they are transplant eligible. Indeed, there are data from CIBMTR, which show that even doing a second transplant in some select patients who had an upfront auto and are still transplant eligible may still derive benefit from a second autologous stem cell transplant.

[00:39:46]

BCL2 Inhibitor Venetoclax in t(11;14) AL Amyloidosis

Let us go into more detail with the BCL2 inhibitor venetoclax. There are now multiple retrospective series from single centers, and actually, I think the first one is a multicenter study, which showed that in patients who have had multiple prior lines of therapy, we are seeing response rates above 80% to 90% with the use of venetoclax in translocation 11;14 AL amyloidosis. When this drug works, we are seeing median progression-free survival of upwards of two years and corresponding improved overall survival as well. We had an update, which Dr. Zonder will go over, of venetoclax in a clinical trial in this setting from ASH.

[00:40:39]

BCMA-Directed Therapies: ADC Belantamab Mafodotin

In terms of BCMA-directed therapies with belantamab mafodotin, there are multiple retrospective series, again suggesting high response rates. There is also the EMN27 phase 2 trial from Europe, which tested belantamab mafodotin as monotherapy in relapsed AL. We see high response rates. However, there is increased toxicity, especially with keratopathy, and a lot of patients need dose interruptions and dose modifications.

[00:41:19]

BCMA-Directed Therapies: Bispecific Antibodies Teclistamab and Elranatamab

Bispecific antibodies show incredible response rates, an overall response rate of almost 100% across the board. I do want to again point out that while response rates are high, these drugs have unique toxicities. The CRS ICANS, while manageable in this setting, most CRS with bispecific antibodies in AL have been grade 1, perhaps because of the lower tumor burden at the time of relapse in many of our patients. There are deaths. There are deaths from infections in the elranatamab series that was reported recently. Out of the nine treated patients, there were two deaths from multi-organ failure.

The other part is that a lot of these series, the median follow-up has been very short. While these drugs are very promising, I think they need to be studied in the prospective clinical trial setting. Again, at ASH, we were fortunate to have some data on bispecific antibodies in AL.

[00:42:31]

BCMA-Directed Therapies: CAR T-Cell Therapies

Finally, with the last of the BCMA-directed therapies, CAR T-cell therapies are also potential options for AL patients. The first two columns in this table are academic CARs. The first one, the ARI0002h from Spain, and the second one, HBI0101 from Israel, which is now developed as NXC‑201, showed that it is feasible to use CAR T in amyloidosis patients. Then the final two series, the Tarn et al and Goel et al., are retrospective series from the US using approved CAR Ts from myeloma in AL setting.

[00:43:18]

Fibril-Directed Therapies

Finally, I want to end with fibril-directed therapies. What is the current state of the science on this in AL? This has been a somewhat disappointing journey for patients, clinicians, scientists, pharmaceutical companies. We had birtamimab, which targeted misfolded light chain fibrils. After many clinical trials, the final confirmatory study, AFFIRM-AL, was reported to be negative last year, and this drug has now been discontinued from further development. We had the Anti-SAP antibody along with CPHPC, which was aimed at amyloid clearance, and the early trials were again halted due to some safety concerns.

[00:44:05]

Cardiac Amyloid Reaching for Extended Survival (CARES) Anselamimab in AL Amyloidosis Study Design

Then, finally, a little bit of promising results from the CARES studies. This was using CAEL-101 or anselamimab in AL amyloidosis. There were two trials, the 301 and 302, studying this drug in stage IIIa and IIIb patients who were treatment naive, and while the primary endpoint was not met, there was a pre-specified subgroup of AL kappa patients that had a meaningful improvement in time to all-cause mortality and frequency of cardiovascular hospitalizations. More to come on this, and I think we should be hearing or reading more about this study in the near future. With that, I will hand it back to Dr. Zonder.

[00:45:00]

Where Are We Heading? Emerging Therapies

Dr. Zonder: What a great overview of personalized options and some emerging data about BCMA targeted therapy.

[00:45:09]

AL Amyloidosis: Therapeutic Landscape 2026

I am going to drill down on some newer BCMA-targeted options and even trispecific antibodies. I am going to also talk about a different anti-fibril agent at the very end of my talk.

[00:45:29]

Phase I/II Venetoclax-Dexamethasone in R/R AL Amyloidosis

As promised, there was some updated data about venetoclax with dexamethasone presented by Dr. Chakraborty at ASH this year. This is a prospective trial of venetoclax and dexamethasone in patients who, on the whole, are in an earlier stage of their treatment than many of the retrospective series. These are patients who, on average, had only one prior line of therapy. All of the patients on this study had to have had an anti-CD38 antibody and a proteasome inhibitor, and they all had to be 11;14 positive.

At the time of his presentation, he reported on 12 patients from the Phase I portion of the study. It was a Bayesian optimal interval approach, which means at the very lowest dosing levels, only one patient was treated at each dosing level, and if there was no DLT then at the higher dosing levels, it was a more typical Phase I design. Of these first 12 patients, the overall response rate was 92%. Half of them achieved a complete hematologic response. Probably the most promising things were that the best response happened on average within one cycle of starting treatment. In contrast to the experience we had in myeloma, where a higher dose of venetoclax was tested in combination with a proteasome inhibitor, infections really have not, so far at least, been a major issue on this study. There was one patient who had a grade 3 COVID infection, and otherwise, infections were lesser severity and quite manageable.

More to come with this. The recommended Phase II dose from this presentation is a dose of 400 mg of venetoclax daily, along with 20 mg of dexamethasone weekly.

[00:47:46]

Selected BCMA-Targeted Therapies

We already heard a little bit about data from the currently approved BCMA-targeted agents. I am going to focus on newer ones.

[00:47:59]

AL Bone Marrow Plasma Cells Express BCMA

Just to remind everybody, BCMA is a very established target in plasma cell dyscrasias, and it may be a particularly great target in AL amyloidosis. We know from myeloma that soluble BCMA in the blood correlates with bone marrow plasma cell burden. This was shown by Dr. Godara, who is at Salt Lake City now doing amyloidosis research. We showed that this relationship holds true in AL amyloidosis as well, and that, on average, the soluble BCMA level is quite low in AL amyloidosis. It reflects a low plasma cell burden. There is an indolent plasma cell biology, and the soluble BCMA, which can serve as an interfering decoy molecule for immune-directed therapies, is low in these patients. These are patients who are probably primed for success with BCMA-targeted agents.

[00:48:55]

Belantamab Mafodotin for AL Amyloidosis: Active!

I do not need to go over this data because Dr. D'Souza already did about belantamab.

[00:49:00]

BCMA x CD3 Bispecific Antibodies in AL Amyloidosis

Also, the case reports and case series of BCMA-targeted bispecific antibodies that have been reported up to this point. We do not have to go into that so much either.

[00:49:12]

Bispecific T-Cell Engagers in Relapsed AL Amyloidosis: Baseline Characteristics

I will just highlight one case series. The reason I want to bring this bispecific case series up is because these are pretty heavily pretreated patients.

[00:49:28]

T-Cell Engagers in Relapsed AL Amyloidosis: Treatment Response

Many of them have advanced cardiac involvement, but probably most importantly, a handful of them actually got other bispecific antibodies that do not target BCMA, but four of the patients in this series actually got talquetamab GPRC5D-targeting bispecific antibody, also commercially available for relapsed multiple myeloma. I am not going to try and point you to the specific lanes on this swimmers' plot graph, but two out of the four patients treated with talquetamab had responses, including one VGPR and one CR.

[00:50:09]

Etentamig Dose Escalation in R/R AL Amyloidosis

I want to move on to etentamig. This was presented at ASH. This is a second-generation or next-generation bispecific BCMA targeting antibody. It has bivalent targeting of BCMA, also targets CD3 but with lower affinity, and it has a modified FC tail to give it a longer half-life. It permits monthly dosing. In this dose escalation phase I, II study, and we heard about the phase I results so far, with 34 patients, monthly IV dosing was used. Step-up dosing was used in the 40 mg and 60 mg cohorts.

[00:50:56]

Phase I/II Etentamig: Safety

This actually resulted in an extremely low rate of cytokine release. Really, only one patient had cytokine release, so 9% of the patients total reported on this study, and it was grade 1. There was hardly any cytokine release seen. In terms of other toxicities, we had a fairly low incidence of infections, a fairly low incidence of treatment-emergent hematologic problems, and we have an extremely high efficacy rate.

[00:51:34]

Phase I/II Etentamig: Efficacy

This slide is actually, the colors, the key is backwards. The response rate reported was 100%, 82% of the patients achieved a hematologic CR, and the others had VGPR. It was 100% VGPR or better, and most of those patients were complete hematologic responses. Many of these responses happened quite quickly, so extremely promising data.

[00:52:04]

JNJ-79635322 (Ramantamig) in R/R AL Amyloidosis

Now, there is also an ongoing study of JNJ‑79635322, called ramantamig. This is a trispecific antibody that co-targets BCMA and GPRC5D along with CD3. This is a subcutaneously administered antibody. This is in an ongoing trial right now in relapsed refractory AL amyloidosis. This builds off of some success we have seen in multiple myeloma. There was just a publication in the New England Journal of Medicine about using teclistamab and talquetamab together to co-target each of these plasma cell antigens, and with very high response rates. So I think all of us are very excited to see how this ends up working in AL amyloidosis. We should remember that GPRC5D has on-target off-tumor effects, and so we are going to need to be on the lookout for skin, nail, taste, tongue, GI side effects that we sometimes see with GPRC5D targeted therapy. We will look forward to that.

[00:53:21]

NEXICART-2: NXC-201 CAR-T in R/R AL Amyloidosis

I am going to move into investigational CAR T therapy. We have had two updates now on a clinical trial in relapsed, refractory AL amyloidosis using NXC-201. At ASCO in 2025, we heard about 15 patients, and this was updated at ASH to 20 patients. Of those 20 patients, 19 out of 20 have had a hematologic response and the vast majority of them, almost all of them, are complete hematologic responses. 16 patients have been tested for MRD, and of those 16, 14 of them were MRD negative by day 25. Cytokine release was seen in the majority of patients, which is no surprise in a CAR T trial, but almost all of these were grade 1, and no ICANS events have been seen so far.

[00:54:10]

ALACRITY: CAR T-Cell Therapy Targeting CD19 and BCMA

There is also an ongoing study of an investigational CAR T, AZD0120, previously called GC012F, and this is a CAR T that targets BCMA and CD19, and it is in an ongoing clinical trial right now, currently in the phase I components.

[00:54:36]

AT-02 (Zamubafusp Alfa): Antibody-Peptide Fusion

I am going to close with just one slide about a newer antifibril directed therapy, AT-02. It is also called zamubafusp alfa. I think I am going to just call it AT-02 as we talk about it. This is an antibody peptide fusion. There is a pan-amyloid binding peptide attached to the antibody. It binds hypersulfated heparan sulfate, which is present in all amyloid fibrils. It has pan-amyloid potential. You can see in the bottom panel binding of this antibody peptide fusion across AL, ALECT2, and ATTR biopsies. At ASH this year, Dr. Masri gave us a presentation on 14 patients who had either renal or cardiac involvement by amyloid or both after getting initial therapy. Basically, what he was able to show us in this very early study is that some patients had a modest improvement in GFR, one patient had a marked reduction in proteinuria, and several patients had improvements in NT-proBNP. As Dr. D'Souza pointed out, we are going to need randomized studies to really understand the full extent of any benefit that might be realized from this, because it has been an unpredictable course with these antifibril therapies.

[00:56:03]

AL Together Now: A Multidisciplinary Approach for AL Amyloidosis Care

I am going to just move into a closing comment for all of us as questions start to filter in.

[00:56:11]

Supportive Care and Complications Management

I just want everybody to remember that multidisciplinary care is of the utmost importance in the management of these patients. These patients are often frail, not because of huge plasma cell burden, but because of huge organ-related symptom burden, and initial management. We are now entering an era where we can get the vast majority of patients, maybe nearly all patients, into a hematologic CR. But we are going to rely on our colleagues to help us manage the cardiac, GI, renal, and other toxicities that these patients have because those symptoms may persist for quite a bit longer, even after we have obtained a complete hematologic response.