Vaishali Sanchorawala:
So I’m Vaishali Sanchorawala, Professor of Medicine and Director of Amyloidosis Center at Boston University and Boston Medical Center. I’m delighted to be here at the 66th Annual American Society of Hematology meeting in San Diego and I’m delighted to be here with VJHemOnc and discussing with my colleague here about AL amyloidosis.

Ashutosh Wechalekar:
I’m Ashutosh Wechalekar. I’m a Professor of Medicine and Hematology at University College London. And it’s also my pleasure to be here with Vaishali at this ASH meeting and VJHemOnc to talk about the exciting advances that we are seeing in AL amyloidosis presented at this meeting. So Vaishali, if I may start. We’ll start with the one treatment regimen which has been game-changing for amyloidosis, the ANDROMEDA trial and the daratumumab-VCD. We are getting an update on the results of the trials. Would you like to tell us about that?

Vaishali Sanchorawala:
Yes, absolutely. So this is the most exciting news of this meeting, which is the updated analysis of an updated and final analysis of ANDROMEDA clinical trial. As a reminder to the audience, ANDROMEDA clinical trial led to approval of daratumumab-VCD in the treatment of AL amyloidosis for newly diagnosed patients. It enrolled 388 patients with newly diagnosed AL amyloidosis, and they were randomized to receive either daratumumab-VCD or VCD alone. And in this updated analysis, overall survival and major organ deterioration progression-free survival are being presented. The median follow-up time was 61 months, close to five years and hematologic CR was achieved by 59% of patients treated with dara-VCD compared to 19% of patients treated with VCD alone. Median duration of hematologic CR was not reached and the major organ deterioration, progression-free survival and overall survival were better in favor of dara-VCD treated patients and also the complete cardiac response was achieved by 40% of patients who were treated with dara-VCD. So I think this is going to be the new standard of care for all patients who are newly diagnosed with AL amyloidosis.

Ashutosh Wechalekar:
Indeed, it’s really exciting to see that the deep hematologic responses that we have seen and known about for some time are translating not only into organ responses, but into improved survival, which is really our goal in patients with systemic AL amyloidosis.

Vaishali Sanchorawala:
I think this is going to replace autologous stem cell transplant completely because this is a very well tolerated treatment and is also improving overall survival. Now, let me ask you about your data on the risk stratification and stage IIIb with incorporation of echocardiographic parameters in patients with AL amyloidosis?

Ashutosh Wechalekar:
That is something which is very important. I think one of the key things in systemic amyloidosis is that we have to risk stratify our patients at representation. For the last 20 years, led by Angela Dispenzieri, NT-proBNP and Troponin-T or Troponin-I have been underlying our staging system for amyloidosis. We refined this staging system with a European modification in 2012 by adding an additional category of NT-proBNP over 8,500, which at that time defined a subgroup of patients who had a median survival of about four or five months. But what we’ve realized over the years is that as our treatments have improved, and data-CyBorD is one of them, that patients are surviving better and better. The 8,500 cutoff still identifies a group of patients who have got poor-risk disease, but the median survival of these patients is now well over a year. So we are not able to truly capture the patients who have got the highest risk disease who may need a very different treatment approach. And we looked at various things within our patient cohort of just over a thousand patients recruited within our ALchemy study. And what we realized was that serum-free light chains, the difference between the involved and the uninvolved free light chain, dFLC, which was a very important prognostic factor in one of the staging systems, is probably not as important in defining early prognosis. We had also said that systolic blood pressure, which was a very important factor in telling which patients would do badly, also does not remain as important. In amyloidosis, when the protein deposits in the heart, the longitudinal, the vertical function of the heart is affected first. And when we looked at longitudinal strain, which is a marker of this vertical function, we find that it remains an independent predictor of prognosis. But when we add it to the 2012 staging system with the NT-proBNP cutoff of 8,500, we define an ultra-poor risk group of patients who have a median survival of just over four months. In the same cohort of patients, if we look at patients who are IIIb, who have an NT-proBNP of 8,500 and an abnormal troponin, but have a global longitudinal strain which is greater than 9.5, so over 9.10, 11, 12. We find that these patients have a median survival of nearly 24 months. And there is a stark difference. And we hope that we will be able to define clinical trials using this new strategy. Now, I know there are some challenges. This has been done in a single center. We need to validate this data across multiple centers. There are also some challenges in the way the strain is measured because different machines measure strain differently. So we need to validate it across different methodologies of measuring strain. But I do hope that this will underpin a new way of risk stratifying patients with AL amyloidosis.

Vaishali Sanchorawala:
Wonderful. And do you feel that in your ALchemy database, it was mature, like all patients were treated with CyBorD or VCD, that dara-VCD is going to change this median survival from four months to a little bit higher?

Ashutosh Wechalekar:
I’m very hopeful that we’ll see less of a mortality with dara-CyBorD, but this new staging system needs to be validated in patients treated with dara-CyborD. Since you bring up dara-CyborD, I’ve got a question to ask you. You said that in the ANDROMEDA dataset, there was a very high proportion of patients who achieved a complete response. What about minimal residual disease? And what do you think about the data that’s going to be presented on minimal residual disease and its impact on outcomes in patients with amyloidosis?

Vaishali Sanchorawala:
Sure. So there is an abstract that is being presented at this meeting from the European collaboration between multiple centers, which is looking at assessment of measurable residual disease by next-generation flow cytometry in patients with suspected hematologic complete response following treatment in AL amyloidosis. I think 320, 315 patients were part of this retrospective study. And what was shown was that patients who had achieved hematologic complete response, only 43% of patients had MRD negativity based on this assessment. And the progression-free survival as well as time to next treatment were better for those who achieved MRD negativity based on this technique versus those who had MRD positivity. And I think that this potentially could, and I think the other important thing was that there was, the MRD negativity held its prognostic value despite the type of treatment that led to MRD negativity. So I think MRD negativity could become a therapeutic endpoint in prospective clinical trials, even larger data sets and larger cohort of patients. So I think it is going to be a, you know, a new way of kind of telling us that hematologic CR is, you know, can be deepened with MRD assessment and outcome of patients could be better. And obviously, the free light chain mass spectrometry, the data that you presented last year, also, again, you know, is another way of deepening the hematologic responses. And then, you know, I think that the other exciting abstract that I thought was very, very interesting at this meeting was the CAR-T from the Israeli group, which is a novel academic HBI0101. What do you think of that abstract?

Ashutosh Wechalekar:
I think that’s a really exciting advance. I mean, we are all hearing about immunotherapy in multiple myeloma, both using CAR T-cells and bispecific antibodies. We also heard from Vaishali that in the ANDROMEDA clinical trial, we are seeing complete responses in 50% or 60%. But if I flip that data out to the other side, 40% of patients actually not responding to dara-CyBorD. And when we look at minimal residual disease assessment, we are finding that maybe 60% of patients continue to have minimal residual disease positivity. So we do need other treatments which are even more active than what we are doing to be able to eliminate the clone to a deeper degree. Now in myeloma we have seen excellent responses with immunotherapy but we have always been concerned in amyloidosis because these patients have end organ damage. How would immunotherapy be tolerated by patients with amyloidosis and what responses would we see with immunotherapy? And this is an exciting study done by an academic group from Israel who have developed a BCMA targeted CAR T-cell and what they’ve shown in their data set is that a) this can be delivered to patients, it can be delivered to patients who may have advanced disease, we can get very deep responses with this CAR T-cell in a very high proportion of patients who are treated with this immunotherapy and patients are able to tolerate this treatment. There were some patients who unfortunately died after the CAR T-cell and we need to understand that a bit better as to whether this was related to the therapy or whether it was related to patient selection. But there are a number of other molecules and number of other CAR T-cell products that are out there. And I think it is an unmet need in amyloidosis for patients who don’t get MRD negativity to reach that next level. And I do believe that CAR T-cells would be one of the ways of treating these patients. I also feel that we are treating patients who have a very low level gammopathy. And therefore, with CAR T-cell treatment, we may achieve the very long duration responses that you have demonstrated in the past with stem cell transplantation, maybe with a lower toxicity and say that these patients may be functionally cured by an active immunotherapy approach. So I do believe this has a long future in amyloidosis.

Vaishali Sanchorawala:
And I think that in this particular abstract, at least, you know, that the median prior lines of therapies were four, ranging from three to 10. So if we can really select patients better for CAR-T therapy, I think the outcomes are going to be much better.

Ashutosh Wechalekar:
Totally. And then the other exciting, since you bought the CAR-T topic, is data which is going on in the lab at Columbia, where they are trying to develop a macrophage, which is engineered to clear amyloid deposits. We have got monoclonal antibody-based trials which can accelerate the removal of amyloid deposits. But what these antibodies do is they essentially attract the macrophages onto the amyloid deposit and then clear the amyloid. But if we can actually have a macrophage which is directly targeting the amyloid deposit, that may be completely transformative in this disease. I think there’s a lot of preclinical science that still needs to go into this, but having this as an exciting new and a completely different avenue to target and treat our patients will be very, very exciting in the years to come.

Vaishali Sanchorawala:
I totally agree. And we look forward to more excitement in 2025.