Therapy Selection for Congestive Heart Failure

John L. Berk, MD: Dr Witteles, your hematology colleague comes to you needing some advice. A patient has cardiac AL [light-chain amyloidosis], is going to undergo chemotherapy, and there are a variety of options. There are alkylating agents, there are immune-modulating agents, there are proteasome inhibitors. How do you help guide the selection of therapy? Which ones actually aggravate the congestive heart failure?

Ronald Witteles, MD: Thanks. So, first I’d make the point that I’d briefly mentioned before, the importance of patients with AL cardiac amyloidosis being seen at a big referral center, if at all possible. I believe that for transthyretin amyloidosis, we really need to democratize the diagnosis and treatment, which is quite straightforward and it’s a common disease. AL amyloidosis is much less common and much more complex in terms of the treatment. And it’s really important that these patients be seen by people who are experienced with treating in the disease and not just the cardiologists, but perhaps even more importantly, a hematologist who has a great deal of experience with AL amyloidosis.

Myeloma, which is of course, is related to AL amyloidosis, also arises from a malignant plasma cell and is something that is really “bread and butter” for hematologists. But the treatment targets are very different in patients with myeloma than AL amyloidosis, particularly cardiac AL amyloidosis where you really don’t want to accept any residual pathologic light chain, if at all possible. Whereas in myeloma if you get pretty good control, you’ll often back off the therapy and say that that is pretty good. It’s very important for patients, if at all possible, to be seen at a big referral center.

In terms of agents of choice, the standard of care most of the time is for people to get started on a regimen called CyBorD, with the alkylator cyclophosphamide, the proteasome inhibitor bortezomib, and then the steroid dexamethasone—although that I suspect may change in the coming months to a small number of years.

CyBorD is overall associated with quite good response rates. It doesn’t tend to be magical in everybody, or many people at all where they get started on it and within a cycle or 2 they normalize. But most people do have a response and some people have excellent responses, and a smaller number, but still not insignificant, have what we call complete hematologic response where their light chains and their electrophoreses completely normalize.

The key though, is being ready, willing, and able to deftly move to other therapies if the treatment that was chosen is either inadequate—you’re not having a good enough response, or intolerable from a adverse event standpoint. And so, particularly for patients with significant cardiac involvement, if they’re in a cycle or 2 and their light chains haven’t come down very much, this is not somebody that you want to give another 6 months and see what happens. It’s time to make a change. And the beauty with AL amyloidosis is that we now have so many different options.

We have multiple classes of chemoimmunotherapy, and we have multiple agents within each class. So, somebody might not respond, for example, to lenalidomide but might respond to pomalidomide. They might not respond to bortezomib, but they might respond to carfilzomib. And then, an agent that has, I would say, really revolutionized the treatment for many, which is the monoclonal antibody daratumumab, which is actually currently being studied in a clinical trial called ANDROMEDA where people with cardiac amyloidosis are randomized upfront to therapy with either the CyBorD chemotherapy I was just mentioning, or, a combination of CyBorD plus daratumumab. The results haven’t come out yet. I would be utterly shocked if daratumumab does not add significant extra control for light chains, because we’ve so obviously seen it in patients who have gotten to daratumumab after failing other treatment.

Now, for the question of the cardiac adverse events of these agents. So fortunately, most of them are actually well tolerated from a specific cardiovascular standpoint. Steroids, of course, can cause salt and water retention as I’m sure all cardiologists are dealing with.

The agent that has the most evidence for causing true cardiac toxicity is carfilzomib, one of the proteasome inhibitors. The toxicity of carfilzomib does not tend to cause systolic heart failure. The clearest toxicities are hypertension, increased rates with thrombosis, and diastolic heart failure, the last being the most challenging because obviously with these patients, that’s what they tend to have is diastolic heart failure.

I certainly would not go so far as to say you cannot use carfilzomib in patients with cardiac amyloidosis. And we certainly found this to be helpful in patients who have failed treatment with bortezomib and have had good responses on carfilzomib. But you’ve got to be very careful with it and know that cardiotoxicity can be a real issue with that drug. In terms of the so-called IMiD things like lenalidomide, pomalidomide, thrombosis is the biggest risk. It’s important to know that and in some cases to prophylax.

So when you read about hematologic therapy for patients with amyloidosis, a lot of the algorithms will point to upfront saying, is the patient a stem-cell transplant candidate, and will having that be a divergent point? I could not disagree with this strategy more. That stem cell transplant—we’re talking about an auto stem cell transplant, not an allotransplant. So we’re not getting any graph versus tumor affect.

All an auto [autologous] stem cell transplant is in this disease is a way to give a higher dose than you could otherwise give of single class of chemotherapy, namely an alkylator agent. And then you rescue by giving the patient their own marrow back. This arose because the initial treatments of AL amyloidosis, the options for therapy were very limited—namely melphalan and prednisone, later melphalan and dexamethasone.

And so the idea was, well if we give a higher dosage to patients, that should be better. And there was a number of retrospective studies that said, “Yes, patients who got stem cell transplant did seem to do better than the patients who didn’t.” But of course, they were hopelessly confounded because there’s a reason why those patients had gone on and gotten stem cell transplants and the others hadn’t.

There’s only a single randomized trial that ever compared the 2, and importantly, that’s how it was done in an era when standard chemotherapy was nothing like it is today. It was melphalan and dexamethasone. And yet, in that clinical trial there were actually better outcomes, including better survival, in the patients who received the standard chemotherapy then the auto stem cell transplant.

When you think about in today’s world where we have so many better options, I would say stem cell transplant in my mind should be a potential option for patients, particularly if they fail others, but should not be what the goal is that you’re trying to get to.

John L. Berk, MD: We have a lot to talk about in terms of TTR [transthyretin] therapies and there have been some really monumental publications that have occurred.