DR MIKHAEL: So a lot of data was presented about AL amyloidosis at ASH this past year both using the agents that we currently have but also looking forward to newer agents that we are hoping to have in the near future.

I think one of the important abstracts that reflects the practice of what we have in North America was the European study that had compared patients receiving melphalan and dexamethasone versus bortezomib/melphalan/dexamethasone. This was a large Phase III trial. For so many years, we’ve been using melphalan-based therapies for patients with AL amyloidosis. But over the last 4 to 5 years, we’ve been able to demonstrate that using bortezomib up front yields a rapid response and a deeper response than melphalan.

In AL amyloidosis, the rapidity of response is critical, perhaps even more so than in multiple myeloma, because the longer those light chains are in the peripheral blood, the more likely they are to get into the organs, like the kidney and the heart and cause long-term, if not irreversible, damage, especially because once they’re deposited, we can’t really empty those deposits.

And so I think this study was really important. They did a large Phase III study comparing the standard of care of melphalan/dexamethasone to bortezomib/melphalan/dexamethasone. And that was a study that was primarily done in Europe, but there were sites here in the US. And the bottom line is that the hematological response and the organ response was significantly higher when bortezomib was added to that combination of melphalan and dexamethasone.

Furthermore, it’s really well tolerated even in patients with cardiac and renal involvement. We always have to be a bit careful using bortezomib in patients who have preexisting neuropathy and amyloidosis, but I’d take the take-home message here that bortezomib up front for AL amyloidosis is definitely the new standard of care. Here in the US, we don’t always combine it with melphalan up front. Often we combine it with cyclophosphamide up front in the CyBorD protocol.

I had the privilege of leading the first CyBorD protocol published on this subject. And those patients can do very well in the short term. Often, those patients who would not have been transplant eligible can become transplant eligible when treated with CyBorD up front.

DR LOVE: What about other proteasome inhibitors, particularly ixazomib, and also even carfilzomib?

DR MIKHAEL: Mm-hmm. So we’re now starting to see proteasome inhibitors as a whole class being used in AL amyloidosis, not quite in Phase III trials yet. But ixazomib is particularly attractive because of its lack of neuropathy in general, compared to bortezomib. And so we are doing some up-front studies and relapse studies with ixazomib. And again, it may not have the same rapidity of response that we see with bortezomib, but, in particular, in older and more frail patients, it’s very feasible to use and very effective.

And then carfilzomib, carfilzomib is perhaps the most potent proteasome inhibitor currently. And we’ve seen some very dramatic responses in AL amyloidosis. There is a small subset of people who can have challenges with cardiac issues with carfilzomib. And so starting it in patients with significant cardiac amyloid has not been done very aggressively. We’ve been a bit more cautious in that group. But in particular, those amyloid patients who have a high proliferative rate of light chains, large, high volume of burden of disease, if you will, then carfilzomib is definitely an option now and one that we’re studying to understand more fully in the future.

Up-front management of newly diagnosed multiple myeloma (MM)

Management of relapsed/refractory MM

Smoldering myeloma and primary amyloidosis

Non-Hodgkin lymphomas

Hodgkin lymphoma

Chronic lymphocytic leukemia

Acute myeloid leukemia (AML)

Myelodysplastic syndromes (MDS)

Myelofibrosis