Treatment Efficacy of Daratumumab in Newly Diagnosed AL Amyloidosis

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My name is Efstathios Kastritis. I'm a professor of medical oncology in the National and Kapodistrian University of Athens in Greece. I have been participating as an investigator in the ANDROMEDA study along with other investigators from several other countries. The ANDROMEDA study is a phase 3 randomized study in patients with newly diagnosed AL amyloidosis.

What existing data led you and your coinvestigators to conduct this research?

AL amyloidosis is a rare disease, which is caused by plasma cells that produce light chains. The light chains form amyloid fibrils. These amyloid fibrils are deposited in various organs such as the heart and the kidneys, and they cause organ dysfunction and failure.

The treatment of this disease is based on the elimination of the plasma cells that produce the light chains, resulting in a reduction of the toxic light chains. The treatment is based mainly on treatments that have been derived from myeloma with dose modifications and adjustments.

However, we do need more effective therapies and also more safe therapies that can eliminate this light change fast and also with minimal toxicity, since patients with AL amyloidosis are sensitive to the toxicity of the various therapies. We have data indicating that bortezomib is very active, and actually most regiments are based on bortezomib.

Daratumumab is a monoclonal anti-CD38 antibody, which has been extremely efficacious in myeloma but also in amyloidosis as a monotherapy.

Combining the current standard of care, which is a combination of bortezomib-cyclophosphamide and dexamethasone, with daratumumab seems to be a very promising approach to treat patients with AL amyloidosis by inducing higher rates of hematologic responses, also with an acceptable safety profile.

This is the concept behind the ANDROMEDA study: to compare a new combination therapy with the old standard and see whether we can really improve the outcomes of our patients with AL amyloidosis.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

The ANDROMEDA study is the largest prospective randomized study in AL amyloidosis. In this study, patients were randomized to receive either the standard of care which is bortezomib-cyclophosphamide with dexamethasone, also called BCD, versus the standard of care, BCD, plus subcutaneous daratumumab for 6 cycles, followed with maintenance with daratumumab monotherapy for up to 24 cycles.

The study enrolled patients with newly diagnosed AL amyloidosis who are stage 1, 2, or 3A cardiac disease. The primary endpoint of the study is complete hematological response rates. There are of course important secondary endpoints.

One year ago, we presented the first interim analysis of the study which showed that the addition of daratumumab to BCD substantially improved the complete hematologic response rates and was 53% for dara-BCD versus 18% for BCD alone.

This year, after an additional 9 months of follow-up, the complete hematologic response rate has improved further for dara-BCD arm to 59% versus 19% for the BCD arm.

An important observation is also that this substantial improvement in complete hematologic response rate was consistent across several different subgroups of patients, such as patients with more advanced cardiac disease or patients with t(11;14) translocation.

Importantly, at 6 months, there was a doubling of the organ response rates concerning cardiac responses and renal responses. With the additional follow-up in that 12 months landmark, we saw that the cardiac response rates further improved and increased from 42% to 57% in the dara-BCD arm.

We have a fairly significant improvement in cardiac response rates. These were also improved in the BCD arm from 22 to 28%, but it was smaller. This increase was smaller. Also, renal responses at 6 and 12 months were doubled with the addition of daratumumab to BCD.

Overall, we were very happy to see that this combination of BCD with daratumumab substantially improved the two major endpoints of outcomes of our patients, meaning complete hematologic response rates and vital organ responses.

What are the possible real-world applications of these findings in clinical practice?

The combination of daratumumab with BCD became the first therapy that has been officially approved for the treatment of patients with AL amyloidosis. This is a very important step forward for the treatment of this disease and for the treatment of our patients with AL amyloidosis.

It is very important that we can achieve so high complete hematologic response rates with this therapy, which is applicable to most of our patients with AL amyloidosis. It is also important that the toxicity of this combination is manageable. We didn't see any additional or new toxicities associated with the addition of daratumumab in patients with newly diagnosed AL amyloidosis or in combination with the BCD.

Also, this therapy substantially improved organ response rates. This is very important, given that for many therapies, we will not be able to see significant improvement in the organ response rate. Now, we have a treatment that importantly improves cardiac function and also renal responses.

Do you and your coinvestigators intend to expand on this research?

The ANDROMEDA study is an ongoing study, so many patients that still receive maintenance with daratumumab. We need to further evaluate the additional responses in complete hematologic response rates and organ responses with the completion of full maintenance.

Further, we need to evaluate whether this therapy has further improved depth of response by evaluating the rates of minimal residual disease negativity. The very positive results that we have seen also are important to build new regiments and new combinations in the future based on daratumumab, which is very effective in this disease and has also shown very favorable safety profile.

Is there anything else pertaining to your research and findings that you would like to add?

Since we finally have an approved therapy for AL amyloidosis, we can expect that we can improve the outcomes of our patients with AL amyloidosis across all stages of the disease. We have also studies running in patients with more advanced cardiac disease such as those with stage 3B disease based on daratumumab, which we'll present in the EHA 2020.

I think in the near future we will be able to build on combinations that may be not requiring bortezomib or chemotherapy, be safer and more effective. The ANDROMEDA study is a large study and will also provide us with a lot of data about this disease and how to best manage our patients with AL amyloidosis.