Recently, the FDA approved subcutaneous daratumumab in combination with bortezomib/cyclophosphamide/dexamethasone (VCd) for the treatment of patients with newly diagnosed amyloid light chain (AL) amyloidosis. In this interview, Efstathios Kastritis, MD, Associate Professor of Clinical Therapeutics at the National and Kapodistrian University of Athens and senior author of ANDROMEDA (NCT03201965), the study on which the approval was based, discusses the challenges of treating patients with AL amyloidosis, the significance of the approval, and the future of treatment for patients with this disease.
What are some of the most challenging aspects of treating patients with newly diagnosed AL amyloidosis?
Efstathios Kastritis, MD: The most challenging aspect of treating patients with AL amyloidosis is identifying them early. We need to make an early diagnosis and start the appropriate treatment before the disease causes end organ damage—for example, before the disease destroys the heart, the kidneys, or the liver. The second challenge is the fact that because these patients have multisystem involvement with cardiac, renal, or liver dysfunction, the classical treatments that we use in similar diseases such as myeloma may not be well tolerated. It is very crucial to identify these patients and treat them on an individual basis with the most appropriate therapy, trying to avoid excess toxicity.
The third challenge is that we have to be very fast in achieving responses. It is very critical to achieve a rapid hematologic response to reduce the burden of the light chain that forms the amyloid in order to salvage the organs. There is a lot of data indicating that we have to be very swift in achieving this deep hematologic response, ideally within the first two or three months. To do this, we need to have an effective therapy which will induce a rapid response, but at the same time, this therapy needs to have limited toxicity. All of these factors together really make the management of these patients very challenging.
What is the significance of the approval of subcutaneous daratumumab in combination with VCd for this patient population?
Dr. Kastritis: The approval of daratumumab with VCd is a great moment in the history of amyloidosis management because this is actually the first official approval of any treatment for AL amyloidosis. Today we treat AL amyloidosis based on the fact that there is a plasma cell clone, and it may look like myeloma. However, it is a very different disease, and it's significant that we now have an officially approved therapy. What is most important, though, is that this therapy is extremely active. For example, this combination substantially improves complete hematologic response rates and also doubles organ response rates at six months. This means that we now have a significantly effective and rapidly active approved therapy for AL amyloidosis. The combination is also associated with a manageable toxicity, as is expected with each drug individually. The approval of daratumumab is a very important step forward in the treatment of amyloidosis and the management of patients with this disease.
How do you foresee the treatment of AL amyloidosis evolving in the coming years?
Dr. Kastritis: First of all, I think that combinations with daratumumab will become the standard of care for amyloidosis across the world. Next steps will include the addition of other agents to the backbone of daratumumab, perhaps with the omission of cyclophosphamide or even bortezomib; we will probably be able to have non-chemotherapy combinations for this disease.
Second, there are new targeted therapies that may also move forward. For example, drugs such as venetoclax, which targets the t(11;14) translocation, may be quite effective in patients with AL amyloidosis who have this translocation, which is about 50% of patients.
The next step, although we are still far from it, is the development of therapies that target amyloid deposits. There is an ongoing clinical study that is evaluating monoclonal antibodies that may absorb the amyloid from the organ. This will be another important step forward if the study shows that these drugs are effective.
Do you have any words of advice for members of the cancer care team treating patients with AL amyloidosis?
Dr. Kastritis: I think that it is very important for all physicians who treat patients with plasma cell malignancies to remember that AL amyloidosis is not such a rare disease and that patients may go undiagnosed. Always suspect and look for AL amyloidosis. Second, you have to remember that AL amyloidosis is not just myeloma with less tumor burden; it's a different disease requiring special care, especially for patients with severe cardiac and renal involvement. Be very careful with the treatment and management of these patients, and always remember to aim for a rapid hematologic response in order to improve the outcomes of patients with AL amyloidosis.
About Dr. Kastritis
Efstathios Kastritis, MD, is an Associate Professor of Clinical Therapeutics and Medical Oncology at the National and Kapodistrian University of Athens School of Medicine in Athens, Greece. He specializes in the treatment of patients with plasma cell dyscrasias, including multiple myeloma, Waldenstrom macroglobulinemia, and amyloidosis. Dr. Kastritis' research focuses on the identification of prognostic factors, the management of disease complications, and the development of novel therapeutics for patients with plasma cell malignancies. He has authored or coauthored more than 300 publications in peer-reviewed journals.
For More Information
Wechalekar AD, Palladini G, Merlini G, et al (2020). Rapid and deep hematologic responses are associated with improved major organ deterioration progression-free survival in newly diagnosed AL amyloidosis: results from ANDROMEDA. Blood (ASH Annual Meeting Abstracts), 136(suppl_1):6-7. Abstract 2305. DOI:10.1182/blood-2020-140514
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.