Dr Kastritis Discusses Adding Daratumumab to Standard Therapy in AL Amyloidosis
Efstathios Kastritis, MD, Associate Professor of Clinical Therapeutics/Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Greece, shares updated results from the phase 3 ANDROMEDA study of subcutaneous daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in patients with newly-diagnosed light chain (AL) amyloidosis, the data of which are being presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.
Hello, my name is Dr Kastritis, and I'm working in the National and Kapodistrian University of Athens in Greece.
As you know, AL amyloidosis is a rare disease which is caused by plasma cells which produce light chains. These light chains from amyloid fibers deposit in the organs, like the heart and the kidneys, and this causes organ failure.
The treatment of this disease depends on killing the plasma cells that produce these toxic light chains. What we need is very active treatments that can fast kill these cells and reduce the amount of the toxic light chains. We need safe and very effective therapies that can allow to achieve the hematologic response—the reduction of free light chains—very fast.
We have some treatments coming from myeloma based on bortezomib, mostly. However, we definitely need more effective therapies. Daratumumab and anti‑CD38 monoclonal antibodies has shown to be extremely active in myeloma and in other studies of amyloidosis. Combining these two therapies is probably the best way to overcome the disease.
ANDROMEDA is the largest prospective, randomized, phase III study in AL amyloidosis. In this study, we enrolled patients with newly diagnosed AL amyloidosis. The patients were randomized to receive either the standard of care, which is the combination of bortezomib, cyclophosphamide, and dexamethasone, for 8 cycles or the same combination with the addition of subcutaneous daratumumab for 8 cycles and therefore, after 24 cycles, monotherapy with daratumumab as maintenance.
The primary endpoint of this study is the complete hematologic response rate, which means the elimination of the toxic light chains that caused the amyloid fibers. In this study, we found that the combination of bortezomib, cyclophosphamide, dexamethasone, and subcutaneous daratumumab substantially improved the complete hematologic response rate.
In the previous presentation 1 year ago, the complete hematologic response rate was 53 percent for the combination with daratumumab versus 18 percent for the standard therapy. The updated results I will present in ASCO, this is now 59 percent versus 90 percent.
First of all, we have a substantial improvement in the complete hematologic response rate. The second very important finding was that this improvement was consistent across all the subgroups of patients, including patients with stage 3 cardiac disease. The study actually included stage 3A patients. Also, across patients with specific translocations, such as the translocation t(11;14).
Importantly, at 6 and at 12 months, we have seen a doubling of the organ response rate, which means the improvement in renal responses and cardiac responses. The combination of subcutaneous daratumumab with VCd is the first therapy that has been approved for the treatment of patients with AL amyloidosis.
The real‑world application is that finally we have an approved therapy for this rare disease. The second is that both VCd and daratumumab are available for myeloma, so this is a therapy that we have extensive experience in myeloma, and now we have also experience in AL amyloidosis. It's a therapy that can be easily administered in patients with AL amyloidosis.
It is also important that in our study, we didn't find any new unexpected toxicities in patients with AL amyloidosis. The toxicity of this combination is more or less what we expected for patients with AL amyloidosis or myeloma. It is a relatively safe and very, very effective therapy.
The ANDROMEDA study still is running, and patients are receiving therapy with daratumumab maintenance. The first thing that we want to evaluate is, after a little bit longer follow‑up, the role of maintenance with daratumumab in patients who receive this therapy. We will need to evaluate further the organ responses. We need to evaluate further the major organ deterioration rate, progression‑free survival, which is also a new endpoint relevant to major organ dysfunction because of AL amyloidosis, or death, or hematologic progression. We also want to evaluate the rates of minimal residual disease negativity in patients who receive this therapy.
In the near future, given the activity of daratumumab, we need to explore new combinations based on daratumumab and perhaps new therapies that may not include, let's say, chemotherapy or even bortezomib.
I think that it is very important that finally we have an approved therapy for AL amyloidosis. It is clear that this therapy substantially improves the major outcomes in this disease, including complete hematologic response rate and, importantly, organ response rates. We expect that this therapy will further improve the survival of these patients, although we still do not have enough follow‑up to prove this.
Building on the results of ANDROMEDA, we may be able to substantially improve the outcomes also of patients with more advanced cardiac amyloidosis. We expect that we will have even better outcomes in patients that are diagnosed earlier in the course of the disease rather than later because the major issue with amyloidosis is the late diagnosis, which is associated with worse outcomes.
Building on this study, we will learn a lot about this therapy, about the disease, and we will be able to build more active therapies, more safe therapies in the near future.