Subcutaneous Daratumumab Plus CyBorD Improves Outcomes in AL Amyloidosis

Transcript

My name is Ray Comenzo. I'm a hematologist. I work at Tufts Medical Center in Boston. I have a longstanding interest in plasma cell diseases, multiple myeloma, and light chain amyloidosis, particularly.

The difference between those 2 diseases is that multiple myeloma does its damage by plasma cells that are malignant proliferating in a large number, causing bone damage as well as low blood counts and other organ damage.

Light chain amyloidosis, on the other hand, is a disease in which the product produced by, sometimes, very small numbers of malignant plasma cells deposits in the body's tissues as a substance called amyloid. Those deposits classically go to the heart, the kidneys, the liver and GI tract, and the peripheral nervous system, causing immense damage to those organs.

The way both diseases are treated is to eliminate the malignant cells. In the case of multiple myeloma, we have experienced a tremendous growth of the number of drugs that have been approved to treat multiple myeloma patients at many stages of their disease.

In the case of light chain amyloidosis, in contrast, there are no approved drugs for treatment. Light chain amyloidosis, historically, therefore has been a poor cousin of multiple myeloma, dependent on the ability to get effective therapy as a result of clinical trials conducted in multiple myeloma over the past several decades.

I'm here today to talk with you about a very, very important phase 3 trial whose results were just presented on June 14th at EHA 25, a virtual conference in Europe. The trial, as you may guess based on the image behind me, was the ANDROMEDA trial.

It's a phase 3 trial in newly diagnosed patients with light chain amyloidosis. Without exaggerating, it's likely the most important phase 3 trial ever conducted in light chain amyloidosis.

It's a trial that took in about 350 patients around the world and randomized these newly diagnosed patients to receive what recently has become a standard therapy, a combination of 3 medicines, cyclophosphamide, bortezomib (Velcade), and dexamethasone, colloquially called CyBorD, or CyBorD plus daratumumab, the monoclonal antibody that attacks CD38 proteins on the outside of plasma cells.

The unique difference in this trial is that the preparation of daratumumab was administered subcutaneously. A very, very exciting advance not only for patients with plasma cell diseases but also and especially for patients with light chain amyloid, whose hearts are damaged by the disease process itself and, should they get IV fluids, might go into heart failure.

Intravenous daratumumab given in volumes of 500 or 1,000 cc's might be a challenge for the sickest patients with light chain amyloid and cardiac involvement. Subcutaneous daratumumab, however, in a volume about the size of a tablespoon, 15 mls, administered over 5 minutes or so under the skin of the abdomen is a huge advantage for patients with light chain amyloidosis.

What's most interesting about the trial is how much more effective the combination of CyBorD and daratumumab was compared to the standard therapy of CyBorD.

Over 50% of the patients who received daratumumab subcutaneously and CyBorD achieved complete hematologic responses compared to about 20% of those who received CyBorD alone. The overall response rate with the daratumumab addition to CyBorD was over 90% compared to over 70% for patients who received CyBorD.

What's critical about this is that the ability to control the light chain that causes light chain amyloid, and to do it quickly, translates into improved organ function. The heart can get better, the kidneys can get better, the liver and GI tract can get better, and the peripheral nervous system can get better.

In addition, by overall improving the frequency of organ responses, patients who received daratumumab/CyBorD had a much lower rate of organ damage over the course of the trial compared to those who got CyBorD alone.

It is likely that in the next year this combination of medicines will be the first approved therapy for newly diagnosed patients with light chain amyloidosis ‑‑ a tremendous step forward for the patients around the world who are going to be diagnosed with this disease in the future.

Where does the field go now? Good question. One of the important answers that we'll get over the next decade is how effective Dara/CyBorD is at keeping the disease away.

That is to say, what fraction of patients who had such deep responses to Dara/CyBorD on this trial will effectively be cured five years from now. Also, what will the response be in the future if patients need to receive daratumumab and CyBorD a second time? Those are very important questions that time will provide answers to, I hope.

The structure of the trial is important to pay attention to, because daratumumab was administered with CyBorD for six months. CyBorD, in the CyBorD arm, was administered for six months. Both groups had a very, very good tolerance of these therapies.

In addition, daratumumab was continued for another 18 months in the group of patients who got daratumumab/CyBorD, and was extremely well‑tolerated over the total of two years in which daratumumab was given. The ANDROMEDA trial is without a doubt the most important Phase 3 study that has ever been performed in light chain amyloidosis.

It will change clinical practice very, very quickly once the combination is approved, and once medical centers and hospital pharmacies approve the use of subcutaneous daratumumab—a preparation that can be given over just a few minutes as opposed to patients getting intravenous daratumumab for hours.

An important side effect that's largely avoided with subcutaneous daratumumab is the occasional first‑dose side effect of a wheezing and a coughing that can occur in patients who have underlying lung disease. Subcutaneous daratumumab in all likelihood is safer for those patients as well.

Thank you for your attention and your interest in light chain amyloidosis, and thank you for listening to my presentation about the ANDROMEDA trial.