ASH 2020 | Addressing unmet needs in the treatment of amyloidosis

Earlier this year a trial was published, the ANDROMEDA trial, that really demonstrated an increased response depth and increased organ response when daratumumab was added to bortezomib, cyclophosphamide and dexamethasone. And this was subcutaneous daratumumab so it’s increasingly likely that patients who receive daratumumab are going to do better. There were a number of very important presentations at ASH this year. One was a trial of an antibody CAEL-101 and it deals with one of the major unmet needs in amyloid. One of the issues that we find in amyloid is that over 40 years, the frequency of early death remains approximately 30% at one year. This usually represents late diagnosis of cardiac amyloid. And even though we have very effective anti-plasma cell therapies to reduce production of amyloid in these patients. None of it addresses the fact what do you do about the established amyloid deposits. Those deposits that are already in tissues, the resident amyloid. Because stopping production doesn’t really address the fact that what about all the amyloid that’s already there?

So the C-A-E-L-101 or CAEL-101 antibody is an antibody that’s actually designed to bind to amyloid deposits, activate macrophages and in vitro and in mouse model reduce the actual burden of amyloid in tissues. So it addresses the unmet need of late diagnosis and what to do about existing amyloid. And in this study there were 13 patients, seven cardiac, three renal and three that were both cardiac and renal, that were enrolled in a three by three dose escalation study, and came up with the recommended Phase II dose that will be used in Phase III trials which will be double-blind studies of bortezomib-cyclophosphamide-dex compared with bortezomib-cyclophosphamide-dex and CAEL-101 antibodies. So far we know that the antibody will not reduce the hematologic response rate to bortezomib-cyclophosphamide-dexamethasone, and we’re hopeful that all the responses will occur early in the course over time. And so the development of antibodies to digest amyloid deposit is a major unmet need. Second unmet need are those patients who have what are called Mayo Stage 3B amyloidosis.

Patients with very advanced congestive heart failure, patients who have an NT-proBNP over 8,500. To date there has been no therapy that is demonstrated to improve outcome for these patients. And when I talked about the ANDROMEDA trial, looking at daratumumab-bortezomib-cyclophosphamide-dexamethasone, patients with an NT-proBNP over 8,500 were excluded from participation in those trials. So we don’t actually know whether daratumumab improves outcomes. So a key unmet need is what can we do for those patients who have Stage 3B disease? And although no trials have been activated as yet, there is no question that patients who have very advanced heart failure have not as yet been favorably impacted by any of the available therapies.

There was a SWOG trial that was presented looking at the anti-CD38 antibody isatuximab in patients with relapsed/refractory amyloidosis and of 35 patients that were treated and available for response, complete response was seen in one patient, a very good partial response in 19 patients and a partial response in seven patients. So that comes up to a 77% response rate using isatuximab in previously treated amyloidosis. In addition, isatuximab had a very good safety profile and it has simple administration where it’s given weekly during the first 28-day cycle followed by every other week cycles two through 24, a maximum of 24 cycles or 24 months of therapy. So isatuximab is another important regimen for the treatment of amyloidosis.

Another part that was abstract that was presented in amyloidosis was one that tried to evaluate the correlation between light chain values and outcomes, and it turns out that the light chain ratio is not a very good measure to predict outcomes in light chain amyloidosis, and the light chain ratio involved to uninvolved should actually not be used. What was really the key were the reduction in the absolute involved free light chain, so just one light chain, or the difference between the involved and uninvolved light chain were major predictors of progression-free survival and organ decline, organ deterioration. And so it’s important for practitioners that don’t see a lot of amyloid to not use the light chain ratio in assessing patients for response. And that hematologic response should look at the involved, only change or the involved minus the uninvolved change. And these also did reaffirm the value of daratumumab in the amyloidosis population.

There was a trial from the European Myeloma Network that actually looked at over 2000 patients with amyloidosis and demonstrated that over the years, between 2004 and 2010 outcomes, 2011 to 2018, really improved, likely due to the introduction of bortezomib for the treatment of patients with amyloidosis. After 2010 in the European Union, the predominant therapy for patients with amyloidosis was cyclophosphamide-bortezomib-dexamethasone. And that resulted in the proportion of patients not achieving a response was reduced by 23% and a trend toward improvement of overall survival for Stage 3A disease, but not Stage 3B disease.

And I think those are some of the really key findings for patients with light chain amyloidosis – still doesn’t change the fact that these patients are not being diagnosed early enough. Hematologists continued to monitor patients with MGUS and smoldering myeloma for the development of myeloma, forgetting the fact that these patients may develop light chain amyloidosis. And if there’s a signal also for cardiologists and nephrologists, that they’re continuing to look at other causes that without considering light chain amyloidosis in their practice.