Ashutosh Wechalekar:

Hello. I’m Ashutosh Wechalekar. I’m a hematologist from the National Amyloidosis Center at University College London. And it’s my pleasure to be here this evening with Professor Sanchorawala who leads the Amyloidosis Center at Boston University. Vaishali, welcome. It’s an interesting ASH for us to talk about what’s happening in the world of amyloidosis.

Vaishali Sanchorawala:

Yes, absolutely. I think this ASH really has captured a lot of stuff on AL amyloidosis, including treatments, diagnosis, anti-fibril agents. I think this is a very, very exciting meeting for us.

Ashutosh Wechalekar:

Can we start with diagnosis then? There is a very exciting oral representation to come on a brand new test, which may tell us which light chains may be amyloid forming or amyloidogenic. What do you think of that?

Vaishali Sanchorawala:

I think this is a transformative diagnostic test that can be used for clinical utility because of screening for monoclonal gammopathy of unkown significance patients as well as for prognostication and risk stratification of patients with AL amyloidosis.

It is an immunoassay that has been developed by a small biotech company that looks at the dimeric light chain constant domain on the lambda amyloidogenic light chains. And what they found was that in a quantitative analysis or quantitative assay that patients with AL amyloidosis had very high levels of this dimeric light chain constant domain compared to normal individuals, compared to patients with multiple myeloma and compared to patients with monoclonal gammopathy of unknown significance. I think if this test gets validated and if it works, it’ll be really transformative in patients with lambda AL amyloidosis.

Ashutosh Wechalekar:

I completely agree with you. I think not only will it be transformative in amyloid, but it’ll also be give us a tool to figure out which patients with MGUS, smoldering myeloma and myeloma should we follow-up more closely for the development of amyloid. It is one of those tests that we’ve been waiting for the last 20 years, and if this test is validated, it’ll certainly be a sea change in amyloid diagnosis.

Vaishali Sanchorawala:

Absolutely.

Ashutosh Wechalekar:

What else was interesting for you in this meeting?

Vaishali Sanchorawala:

I think that the other thing that is interesting is there’s a lot of data also coming out on plasma cell-directed therapies. And I think that you have a poster here on belantamab mafodotin with your updated data. I think that is also very, very interesting. It is not available in the United States because of FDA withdrawal of the medication, but it’s available in UK. Can you tell us a little bit more about it?

Ashutosh Wechalekar:

Yeah. Belantamab is a monoclonal antibody BCMA-targeted conjugated with a toxin. And we have certainly used it in patients with relapsed/refractory amyloidosis. We have now treated about 35 patients with this. And certainly in our hands we find it’s extremely well tolerated, very few adverse events. There is of course the problem with ocular toxicity, but in amyloidosis where we have to use it less frequently with lower doses, we find that that’s a very manageable side effect.

Vaishali Sanchorawala:

And how do you dose it, Ashu?

Ashutosh Wechalekar:

We tend to dose it as full dose as per the recommendation to begin with, but then we proactively dose reduced by 25% or 50% even before the patients develop eye toxicity that allows us to give the drug to majority of the patients.

Vaishali Sanchorawala:

And do you increase the time interval between the doses?

Ashutosh Wechalekar:

The time interval in the SPC is every three weeks, but we tend to give it between every four and six weeks depending on the tolerance, which makes a big difference to this patient population. I think it is a drug which at least in amyloidosis needs further study even though at the moment it is still under review for what’s going to happen with it in multiple myeloma. You had an interesting presentation, Vaishali, on anti-fibril antibodies with safety data from the large prospective studies that were done by Prothena on birtamimab.

Vaishali Sanchorawala:

That is a poster presentation of birtamimab, its safety and tolerability in patients with AL amyloidosis. And 302 patients were included in this analysis who participated on Phase I and II trials open-label extension, PRONTO trial, VITAL trial and also PRONTO crossover open-label extension. And the median duration of birtamimab exposure in 302 patients was 12.2 months.

And the most reported side effects with birtamimab were very, very minimal of fatigue, constipation, nausea and dyspnea. And what they also show is that there was all cause adverse events and treatment related adverse events were no different than placebo control, placebo arm on VITAL and PRONTO, which were the placebo controlled randomized trials. I think this is also an ongoing AFFIRM AL trial, which is a confirmatory trial for efficacy as well as safety of patients in Mayo stage IV, 2012 staging system AL amyloidosis.

Ashutosh Wechalekar:

One of the concerns with these anti-fibril antibodies has always been that they will cause macrophage activation to help amyloid clearance. Was there anything in the safety data to suggest that there was any adverse event related to that?

Vaishali Sanchorawala:

Right. Not for this particular antibody. It was very well tolerated, no suggestion of any fever, macrophage activation, increase in inflammatory markers or anything like that. And there’s also another oral presentation happening on the Phase II data of CAEL-101 trial, which is also an amyloid busting agent or amyloid anti-fibril agent. Can you expand on that, Ashu?

Ashutosh Wechalekar:

There are two presentations actually on the CAEL-101, which is another anti-fibril strategy. One is a poster which is looking at the mechanism of action of CAEL-101 of which we haven’t heard very much over the last few years. What it shows is that CAEL-101 is a monoclonal antibody which not only binds to the amyloid fibrils but also binds to the pre-fibrillar aggregates. And therefore, it may have a dual mechanism of action reducing the toxicity, but also helping to clear the amyloid fibrils.

The Phase II study was a small study which is not completed. It’s final data lock as yet. But what it shows is that in this small Phase II study when CAEL-101 was given with standard of care chemotherapy, mostly Dara CyBorD, we did see a substantial number of patients showing renal responses and a number of patients showing cardiac responses.

Now of course this is small data, but we’ve got two very large Phase III studies, the CAEL-101, 301 and 302 studies looking at patients with moderately advanced and very advanced cardiac amyloidosis which have now fully recruited. And I think it is exciting times in the next year where we should see data maturing from these two clinical trials. The same is true for the Prothena antibody where we have the AFFIRM trial, which will also complete recruitment in AL patients hopefully this year.

Vaishali Sanchorawala:

And then, can you tell me a little bit about the staging system, Mayo 2004 versus Mayo 2012 staging system? Because both these clinical trials of anti-fibril agents are using different staging systems for their enrollment into the clinical trial.

Ashutosh Wechalekar:

As you know, the basis for every patient before we treat is to risk stratify them. We use the cardiac staging system based on biomarkers, which was reported initially by the Mayo Clinic, then further updated using free light chains and then we further updated it in Europe using NT-proBNP.

When we were looking at our patient outcomes recently, we realized that our treatments have become more effective and therefore the impact of the light chains on outcomes may not be as important. And therefore when we reanalyze data using the Mayo 2012 staging system, which uses NT-proBNP, troponin T and a dFLC of more than 180, we realized that the very adverse risk stage IV group is actually doing a lot better than what had been originally reported.

And the difference between the stage III and the stage IV is still significant, but no longer as significant as it used to be. And therefore we think that in the modern era of treatments, we do need to look at all the staging systems again because we are also seeing something very similar with the European modified NT-proBNP, troponin staging system where the difference between the stage II and stage III is not as significant.

Most of our patients weren’t treated with daratumumab up front. I think there is a poster from the group in Columbia, which is also looking at a small number of patients using the same staging systems. And they find that the difference even between stage I and II is much less when you use dara-based treatments. I do believe we need to redefine staging now that we have got these highly effective modern treatments for amyloidosis.

Vaishali Sanchorawala:

Absolutely. I think in conclusion, I think the future for AL amyloidosis is very bright. I think we are attacking different targets in pathogenesis of fibrillogenesis of AL amyloidosis. And I think that the outlook for patients with AL amyloidosis is very, very improved since you and I started working in this field.

Ashutosh Wechalekar:

I think I completely agree with that. I think it’s an exciting few years to come with treatments targeting the clone treatments, targeting the fibrils themselves, and we may have ways of diagnosing the disease much, much earlier. It’s been great talking to you about amyloidosis at this meeting, Vaishali.

Vaishali Sanchorawala:

Same here. Same here, Ashu. Thank you.