Morie Gertz:
Hello, and thank you for joining us for this ASH review on amyloidosis, brought to you by Video Journal of HemOnc. We’re very fortunate today because we’ve brought together some of the global thought leaders in amyloidosis that are responsible for a lot of the research output in this disease. I’m Morie Gertz from the Mayo Clinic. And we’re welcoming this evening Vaishali Sanchorawala, the director of the amyloidosis unit at the Boston University Medical Center, Professor Ashutosh Wechalekar from the National Amyloidosis Center in the United Kingdom, and Professor Raymond Comenzo, who directs the center at Tufts New England Medical Center. We’re very grateful for your time today.

Morie Gertz:
We’re going to start right off in discussing, I think, one of the most important presentations of the ASH meeting, and that was the ANDROMEDA study for newly diagnosed, AL light chain amyloidosis. All three of our guest panelists, Dr. Sanchorawala, Sorry about that Vaishalli, Professor Wechalekar, and Professor Comenzo all made important contributions. I think we’ll all have important points to make, but Dr. Comenzo was the presenting author and we’re going to start with him. And so Professor Comenzo, could you discuss please the ANDROMEDA study, the updated efficacy and safety data. What does it mean for hematologists in the community that see a newly diagnosed patient with AL amyloidosis?

Raymond Comenzo:
Thank you. Dr. Gertz. ANDROMEDA was a Phase III randomized clinical trial, it was not blinded, in which patients who are newly diagnosed with light chain amyloid. They could have a stage three cardiac amyloid, for example, but it had to be 3A, their NT-proBNP had to be less than 8,500. And with randomization, they were treated with either the combination chemotherapy, bortezomib, cyclophosphamide, dexamethazone, which goes by two acronyms, CyBorD or VCd. Or that standard chemotherapy plus daratumumab.

Raymond Comenzo:
The schedule of treatment was six months with VCd in both arms, VCd was given weekly. In the daratumumab arm, daratumumab was given a weekly for eight weeks and then every two weeks for four months. And then 18 months of monthly daratumumab was given to those who were randomized to VCd plus daratumumab. The primary endpoint of the trial was a complete response defined as negative immuno fixations and the involved free light chain in the normal range or below normal. The light chain ratio was not used as a criterion of response.

Raymond Comenzo:
In addition, there was a novel secondary endpoint called major organ deterioration progression-free survival. That secondary endpoint was a way to capture the deterioration in particular heart disease that can occur in patients with light chain amyloid. And that endpoint was defined as progression to heart transplant, left ventricular assist device, or intra-aortic balloon pump with respect to cardiac disease progression to end-stage renal disease requiring dialysis or renal transplant. In addition, death was also a criterion for major organ deterioration progression-free survival, as well as progression of the hematologic disease.

Raymond Comenzo:
The data that was presented, was presented with a median follow-up of about 16 months. And the reason that time point occurred was that the statisticians had to wait until every patient on the study had completed six months of therapy before they could assess outcomes with respect to complete response and major organ deteriorations progression-free survival. Overall, the two arms were well-balanced. There were about 70% in stage two and three cardiac patients in both groups.

Raymond Comenzo:
And the percentage of patients who had stage two or three renal involvement was very similar between the two groups. It was about 40%, as I recall. The treatments in both groups were well tolerated and the safety signal was what you would expect. The outcomes were quite interesting as Dr. Gertz indicated. The importance of the trial is contained in the difference between the VCd and dara VCd arms, with respect to complete response rates. The VCd arm had a complete response rate of 18%. The dara VCd arm had a complete response rate of 53%.

Raymond Comenzo:
I think that the statistics were very, very well assessed and there was clearly a difference in the major organ deterioration PFS not only between those and both groups who achieved complete responses, but particularly between those who were in the dara VCd group and the VCd group. That difference translated to hazard ratio of over 40% reduction in risk of major organ deterioration progression free survival in those who received dara VCd. In the first couple of months of the study, there were 13 deaths in each arm.

Raymond Comenzo:
Overall, there were 27 deaths at the time the data was cut in the dara VCd arm and 29 deaths in the VCd arm. The deaths were very, very significantly related to cardiac involvement. They were cardiac deaths. The trials data is still being analyzed. You will hear, I think, from Dr. Sanchorawala about quality of life data. We’ll hear from Dr. Wechalekar about the impact of complete responses on cardiac responses. And I think the overall survival data will mature as time passes. Although there was a significant cohort who received daratumumab in second line among the VCd patients. So we’ll see how that plays out as the data matures.

Morie Gertz:
Thank you very much. Dr. Sanchorawala, is this the new standard of care for newly diagnosed amyloid?

Vaishali Sanchorawala:
I think, as Dr. Comenzo mentioned, that we need to wait for the final analysis as well as a longer follow-up time. However, the hematologic complete responses do look extremely promising and unprecedented. They are very, very high. And if we believe that hematologic complete responses are surrogate for overall survival and organ responses, then I think that this potentially could become the new standard of care and could be a game changer in patients with AL amyloidosis. I do want to mention about health-related quality of life, which was also analyzed and presented at this meeting as a poster session. And again, that the median time to improvement in some of the quality of life related domains was shorter for patients treated with dara VCd and median time to improve worsening was longer for those who were with dara VCd compared to VCd alone. So I think that yes, there is also patient-reported outcome data suggesting that dara VCd is well tolerated.

Morie Gertz:
Thank you. Professor Wechalekar, when we’re talking about hematologic responses, when you’re seeing a patient, what is the goal of therapy that you’re seeking?

Ashutosh Wechalekar:
I think the goal of therapy is achieving not only a complete response, but also a deep light chain response. I think data that we’ve all analyzed from you’ve got some data coming out of your center where you’ve looked at light chains of less than 20 milligrams per liter. Professor Comenzo has reported light chain at less than 10. And we reported the difference between the involved and the uninvolved light chain of less than 10 as has a Professor Sanchorawala. And while we find the complete responses are important, it is really the light chain which is the driver of the disease.

Ashutosh Wechalekar:
And achieving a deep reduction in light chains translates into both organ responses and survival. And we did see this in the ANDROMEDA study where 70% of the patients achieve these deep light chain responses. And when the responses were analyzed based on whether you looked at a dFLC response of less than 10, or an iFLC response of less than 20, or just a complete hem response, all of these seem to translate into improved MOD-PFS, which was the newly defined endpoint in this study. So CR is the new goal of treatment and a really deep light chain response is probably your next goal of treatment. And then we had an abstract about MRD. And I guess our final goal is going to be MRD-negative CRs in this group of patients.

Morie Gertz:
So I’m hearing from talking about the involved free light chain or the difference between the involved and uninvolved. No one’s talking about the light chain ratio in this disease. Could you clarify that Dr. Wechalekar?

Ashutosh Wechalekar:
I think it’s fair to say that the light chain ratio is dead. It is hugely affected by the uninvolved light chain in amyloidosis, and it varies massively depending on what happens to the uninvolved light chain. So there is a role for light chain ratio, but I think we are now moving away from the light chain ratio because we can see massive fluctuations in the light chain ratio, particularly when the light chains dropped down to a very low level. And then we find in the ANDROMEDA study that if the light chains are below the normal range, the light chain ratio goes from abnormal to normal to abnormal again, and by definition, your patient will fall out of a complete response and that’s not what is happening to the patient.

Morie Gertz:
Professor Sanchorawala, before we move on to the next topic, this is an important aspect. Most oncologists and hematologists deal with progression-free survival and hematologic malignancies. Now we’ve got this composite endpoint of modified progression-free survival where it’s not just the blood test we monitor, but it’s your heart, then it’s your kidneys. Is this going to be incorporated into future trials ongoing as a endpoint for therapy efficacy?

Vaishali Sanchorawala:
So again, this is a novel endpoint, which was designed for this particular trial with major organ deterioration defined as either death or hematologic progression or organ failure. So whichever occurred or whichever came first, and this obviously has not been yet kind of accepted as the standard endpoint, but these novel endpoints, which would incorporate hematologic progression as well as organ deterioration, I think does make sense. And it has shown in this trial that yes, dara VCd did improve major organ deterioration progression-free survival, significantly compared to the control arm.

Morie Gertz:
Thank you. Dr. Sanchorawala, you had some data at the meeting regarding the use of isatuximab in the management of relapsed AL amyloid, could you comment on that please?

Vaishali Sanchorawala:
So isatuximab was used as a second-line treatment or as a treatment for relapsed/refractory AL amyloidosis after one prior line of therapy in a multicenter cooperative group trial, which was led by Southwest Oncology Group. And this was presented as an oral presentation by my co-investigator, Dr. Terry Parker. And in that clinical trial, it was a Phase II clinical trial, 36 patients with relapsed Al amyloidosis were enrolled. The eligibility criteria required at least one prior line of therapy.

Vaishali Sanchorawala:
And the difference between involved and uninvolved light chain of greater than 45 milligrams per liter and NT-proBNP of less than 8,500 micrograms per ml. The hematologic responses, which was the primary endpoint of this clinical trial were achieved by 77% of the patients and the hematologic complete response and very good partial response were achieved in about 57% of the patients.

Vaishali Sanchorawala:
This isatuximab was well tolerated with no major side effects except for infusion-related reactions, which majority of them were grade one and two and occured in about 50% of the patients. There were some grade one and two upper respiratory infections and pneumonias. And the median time to hematologic response was one month, and one year duration of response was about 89%. So similar to daratumumab, this treatment was quite effective in patients with Al amyloidosis in the second line of treatment and safety profile and tolerability data were quite compatible as well.

Morie Gertz:
Thank you. Professor Wechalekar, as we move away from the studies, the studies of course are not a reflection of real-world experience. These patients couldn’t be cardiac stage 3B with an NT-proBNP over 8,500. They had to have a GFR over 20, had they have a measurable light chain greater than five milligrams per deciliter, dFLC. You reported on a European consortium, over 5,000 patients who are treated. Can you give us some insights on outcomes for patients in the real-world? How it’s changed over time, please?

Ashutosh Wechalekar:
Yeah. So this was a effort spearheaded by the European Myeloma Network, where data was collected from most of the European centers. And the data presented at ASH included just about 2,700 patients with the hope that we will add another maybe 1500 patients as a UK being out of the European Union was not a part of the current data collection center. And hopefully we’ll have that data in time to come. And the data was analyzed in two different groups. Patients diagnosed between 2004 to 2010 and then 2011 to 2018, mainly because there was a change in therapy.

Ashutosh Wechalekar:
About a third of the patients were in the earlier period and then two thirds of the patients were in the later period, there was a switch in therapy from alkylator based treatment in the earlier period to proteasome inhibitor-based, bortezomib-based treatment in the later period. And what we find is that a number of patients present with advanced disease. So at about 35% of patients have stage two disease and another, nearly 38 to 40% of patients have stage three of which about 20% have the very advanced sort of European stage 3B with very high NT-proBNPs.

Ashutosh Wechalekar:
With the treatment, we find that in the real-world the complete response rates remain fairly low and less than a fifth of all patients will achieve a complete response. Within this cohort about 16 to 20% of the patients had an autologous stem cell transplant as their frontline treatment. And of all the treatments that seem to give the best VGPR or complete response rate followed by a bortezomib-based treatment. The survival data was quite disappointing that we still see a very high mortality in the cardiac patients, both 3A and 3B.

Ashutosh Wechalekar:
The survival of the patients with 3A has improved in that two time periods that we have seen, but the survival of the very advanced 3B patients still remains to about three or four months with about 40 to 50% of patients dying within the first few months of diagnosis. The overall survival of the stage one patients is very good with the medians now going up to eight to nine years, irrespective of the type of treatment used. So in the real-world, we are still seeing disappointing responses. We are still seeing very high, early mortality. We are seeing some improvement in the response rates, but despite this long time period and a very large patient number, the improvement in outcomes is not as dramatic as one would have expected it to be. And the unmet medical need of the patients with advanced disease, I think is very open to reflected in this very large dataset.

Morie Gertz:
Are you able to make any comments? Because early on melphalan dexamethazone was a dominant therapy and then it was replaced by bortezomib-containing regimens. About relative efficacy, what would be considered, forgetting about the daratumumab right now, starting out therapy for amyloid patients?

Ashutosh Wechalekar:
So the deeper responses, we certainly see a big switch in treatment. What we are seeing is that there is clear improvement in survival with bortezomib based treatments in patients with stage 2A and stage 3A disease. With the stage one patients we’re really not seeing such a dramatic difference in outcomes, whether they were treated with an inocular based treatment or with a melphalan based treatment, clearly suggesting there more time, and these patients may be able to access other therapies for improving the deeper responses. And patients with 3B disease, we really don’t see a huge difference in respect of what kind of treatment was used. Although with an IFoA, there is probably a slightly better tale of survival for the bortezomib treated patients. So-

Morie Gertz:
I’m sorry. I apologize.
Ashutosh Wechalekar:
No, please go ahead.

Morie Gertz:
We’re going to be talking about unmet needs, but could you just comment about the three-month mortality for this very large cohort?

Ashutosh Wechalekar:
So the three month mortality for the 3A patients was about 25 to 30%. And the 3B patients would have been about 40% plus.

Morie Gertz:
Thank you.

Ashutosh Wechalekar:
I can’t remember if they redid our entire overall survival. I don’t recall seeing them in the presentation.

Morie Gertz:
Thank you. Dr. Comenzo we’re still seeing a lot of early mortality and patients dying before any form of therapeutic intervention could possibly be beneficial. And of course, all of our therapies have been targeted towards the production of amyloid in the bone marrow but doesn’t really deal with resident amyloid in the tissues at the time of diagnosis. There was a very small trial of the CAEL-101 antibody. Could you overview for us what the thought process is about anti-amyloid antibodies and kind of what the future holds as we begin to investigate these?

Raymond Comenzo:
Yeah. Thank you Dr. Gertz. I do think it’s important to start with the fact that AL amyloid and amyloid overall, except for a ATTR amyloid, which can be diagnosed with a scan in patients who don’t have monoclonal myopathies, but AL really does require a tissue diagnosis. And indeed at the point when amyloid can be appreciated in the fat or in the gingiva or in the rectal fat, patients have a large burden of amyloid. And I think that the delays in diagnosis, in addition to the fact that we base our diagnostic process on a congo red stain that was implemented for this purpose 80 years ago, puts patients at a disadvantage to start with.

Raymond Comenzo:
That is to say that delayed diagnosis seems to be built in to the diagnostic process in AL. We definitely need better tools for diagnosis and for early diagnosis. That having been said about five years ago, it became a very, very interesting experimental effort on the part of several companies to develop ways to resorb amyloid from the body’s tissues. The work of Mark Pepys, who’s now retired, the work of Alan Solomon, who’s now retired, bore fruit in three clinical trials. One clinical trial, which was advanced by, I believe by GSK, involved the use of two different agents that clearly could help to mobilize amyloid from the tissues based on a small Phase I data, Phase I trial that was described five years ago in the New England Journal.

Raymond Comenzo:
However, that trial was just a signup of hopefulness, I think. And as the attempt was made to bring amyloid resorbing agents into the clinic, there were unintended consequences and unexpected adverse reactions, and that trial was suspended. That agent is no longer in development by GSK. A second effort was by Prothena using a monoclonal antibody called NEOD001. That monoclonal had a great deal of promise and seemed to work pretty effectively, particularly in patients with renal involvement. However, when it was brought into the clinic, the registration trial was based upon a bio-marker NT-proBNP that has its own vagaries in this disease.

Raymond Comenzo:
And that registration trial when analyzed did not meet its primary endpoint and that trial was closed, and the other several trials with NEOD001 were closed in April of 2018. That left us with the KO 101 monoclonal and the data from the Phase I trial that was conducted in Columbia and the dose-finding problem that Jason Allen presented this week are very interesting. The Columbia data are very interesting because it’s the monoclonal antibody that goes after amyloid fibrils, and there does appear to be some change in the global longitudinal strain, a measure of how well the heart is contracting in patients who received KO 101 in the Columbia trial.

Raymond Comenzo:
In the trial conducted at Cleveland clinic, the dose finding trial, what was most interesting to me was how the renal patients responded. It did appear to have the same kind of a promise that NEOD001 had early on with respect to renal AL. There are two trials open now. The trials are being sponsored by Alexion. Both are for cardiac amyloid, a trial for stage 3A, a trial for stage 3B. Both involve them a two to one randomization. Patients who are randomized to receive CAEL-101 are in that two thirds group. Both involved the use of CyBorD as initial chemotherapy for these newly diagnosed cardiac patients. And soon we will be able to use dara CyBorD I expect in the stage 3A trial because we expect our CyBorD to be approved.

Raymond Comenzo:
Overall, however, I think this is still a work in progress. And the most trenchant question that was asked of Dr. Valley this week was how do we expect a monoclonal antibody to work against a solid deposit with tissues. And the mouse data, which is certainly a stretch for me, these little amyloid tumors and slice of mice suggest that neutrophils and macrophages are brought into the deposits and help to resorb the deposits. Well, an amyloid dome in the flank of a mouse is not the same as cardiac amyloid. It’s not the same as hepatic amyloid. It’s not the same as renal amyloid. So the jury is still out on this whole approach. And my money actually is on better imaging, earlier diagnosis, and the pursuit of complete responses with therapies like dara CyBorD or isatuximab.

Morie Gertz:
Thank you very much. We’re going to have some time I think just for some brief summary statement. I’d like to start with Dr. Sanchorawala. Two minutes maybe on what you see are the unmet needs for this patient population and where the field is going.

Ashutosh Wechalekar:
I think in my opinion, the most unmet need for systemic AL amyloidosis is earlier diagnosis. Earlier diagnosis will lead to early stage diseases, stage 3B as shown by the EMN group remains an unmet need with median survivals of less than six months or six months. And that has not changed in the last two to three decades. So I think that earlier diagnosis, increasing awareness in the community that this disease exists specifically in patients with nephrotic syndrome, cardiomyopathy, constellation of syndromes that need to be placed in one bucket. And I think the other unmet need, in my opinion, is organ failure, end stage renal disease, because most of these clinical trials exclude patients with end stage renal disease. Furthermore, I think the other third unmet need is also severe autonomic neuropathy associated with systemic AL amyloidosis because patients who have systolic blood pressures of less than 90 millimeters of mercury are not eligible to participate from any of these clinical trials.

Morie Gertz:
Thank you. Professor Wechalekar, unmet needs, where we’re going?

Ashutosh Wechalekar:
So unmet need. I think two areas, education awareness and early diagnosis. We still miss these patients, two thirds of the patients have advanced stage cardiac disease. We still don’t have drugs which are proven to remove amyloid protein deposits and all the things that Professor Sanchorawala has said, we need something we should actually improve the end organ dysfunction. Where we are going. I think the monoclonal antibodies are exciting, they’re interesting, we’re seeing deep responses, but we have to remember we’re using them in combination with chemotherapy, which is still toxic. And having a regimen where we are able to avoid toxic chemotherapy high-dose steroids, maybe combinations of monoclonals, may be something that we need to be going towards in the future to achieve deep responses and clearly long lasting responses because with every relapse we see worsening of organ function.

Morie Gertz:
Thank you. Professor Comenzo, this discussion about less toxic regimens, there was a presentation at the meeting on an all oral regimen of ixazomib, cyclophosphamide and dexamethazone. Is this going to go anywhere?

Raymond Comenzo:
I sure hope so for some patients. But the ixazomib story is quite complicated and it was dealt another blow, I think, by the presentation by […] with the addition of ixazomib to Revlimid and dex. I really wonder whether or not insurers are going to permit ixazomib to be used in AL, accepted instances when bortezomib-related adverse events have occurred. And even then you’ve got to do peer-to-peer and argue for it. So it’s a great combination, I think, in terms of starting patients, perhaps with dara ixazomib Dex, but I’m not optimistic that ixazomib will be widely available for AL patients going forward.

Morie Gertz:
Thank you. We’re drawing close to our time. I’d like to just summarize some of the things I think I’ve heard as key points for our listeners. One I heard was that daratumumab has the potential to increase substantially the frequency of very deep responses and prevent organ deterioration, but that when you translate trial results into the real-world, they don’t always, because of the nature of participants in trials, translate. And there’s still a major problem with early mortality in these patients. I heard that the light chain ratio fundamentally should not be used in the monitoring of these patients and that our hematologists need to really be aware of this diagnosis, particularly in the patients they’re monitoring with MGUS and smoldering myeloma to be alert for the development of light chain amyloidosis. And that clearly the development of anti-amyloid antibodies that might act beyond the simple production of amyloid has a lot of potential. I wanted to thank our three speakers and very grateful for your attendance to this conference.