Raymond Comenzo, MD, Tufts Medical Center, Boston, Massachusetts, discusses updated results from the ANDROMEDA study, which evaluated the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone (VCd) for patients with light-chain (AL) amyloidosis.
This updated analysis demonstrates the impact of achieving deep hematologic responses on major organ deterioration progression-free survival, a key secondary endpoint of the study.
These results were presented at the virtual 62nd Annual Meeting and Exposition.
Transcript
My name is Ray Comenzo. I'm a hematologist at Tufts Medical Center in Boston.
For the past 30 years or so, I've had a particular interest in a disease called light-chain amyloidosis, it goes by the abbreviation of AL amyloidosis, and also a particular interest in its cousin disease, multiple myeloma. Recently, I've been involved in a trial—which we'll talk about today—called the ANDROMEDA study.
Very often, agents that are active against multiple myeloma are also active in patients with light chain amyloidosis. The difference between the 2 diseases is that the plasma cells that are malignant in multiple myeloma tend to grow fast and cause disease because of proliferation.
The organs that are damaged in multiple myeloma include the bones, the blood-forming organ, and in certain cases, the kidneys, as well as the immune system. In light-chain amyloidosis, it's not the proliferation of the malignant cells, but rather the protein that they make, part of an immunoglobulin we call the light chain because it's the smaller part.
These light chains in AL amyloidosis tend to self-assemble and tend to be toxic to the body's organs and to deposit. Once the deposits become massive, the organs fail, the patients often die.
The organs that are damaged in AL amyloidosis are the heart, the kidneys, the nervous system, the liver, and GI tract, as well as the skin. What characterizes the damage is both toxicity of the clumped light chains, and also the massive deposits that develop over time in these organs, causing the organs to fail and the patients to die.
The survival nowadays with modern medicines for multiple myeloma approaches 10 years. In AL amyloidosis, ironically, there have been no medicines approved for its treatment, and that has created obstacles to patients getting therapy.
The availability of monoclonal antibody therapy for plasma cell diseases in the form of anti-CD38 monoclonal antibodies such as daratumumab, propelled investigators across the country under the aegis of sponsorship by Janssen to conduct a randomized prospective trial called ANDROMEDA, in which patients with AL amyloidosis who were newly diagnosed received either standard chemotherapy with bortezomib, cyclophosphamide, and dexamethasone, or standard chemotherapy with daratumumab.
The important aspect of this study, in addition to its size, is that daratumumab was given subcutaneously. The preparation of subcutaneous daratumumab is called Faspro. It's a 15ml injection under the skin.
It takes 3 to 5 minutes to administer, and it's of benefit to patients with heart damage due to light chain amyloid because intravenous infusions can cause heart failure in these patients.
In the ANDROMEDA study, newly diagnosed patients were randomized 1:1 to receive standard therapy, bortezomib, cyclophosphamide, and dexamethasone for 6 months, or standard therapy for 6 months plus daratumumab.
After that 6-month period ended in those patients who were receiving daratumumab and standard chemotherapy, they continued to receive daratumumab for another 18 months, so it was a 2-year course of daratumumab administered subcutaneously.
The primary endpoint of the study was response rate at 6 months. What was most interesting is that the best response overall was very similar to the response rate at 6 months. That is to say, patients who received daratumumab and standard chemotherapy had a complete response rate of 53%. Those who received standard chemotherapy alone had a complete response rate of 18%.
The scale of the response rate in those receiving daratumumab was a bit surprising. It is no exaggeration to say that a 54% complete response rate in that arm was indeed stunning.
The other aspects of the study that are important have to do with an endpoint that was constructed in coordination with the FDA. It's called a major organ deterioration progression-free survival endpoint, and it involves not only progression of the hematologic disease, the plasma cell disease, but also the deterioration of major organs, heart and kidneys.
A patient, for example, who went on dialysis, or a patient, for example, who needed mechanical help with the heart or a heart transplant, those patients would have a shorter major organ deterioration progression-free survival than patients who did not experience those occurrences.
In the ANDROMEDA trial, the occurrence of major organ deterioration progression-free survival was much, much lower than those patients who received daratumumab and combination chemotherapy than in those patients who received combination chemotherapy alone.
For example, in those who received standard therapy, I believe seven patients went on to dialysis or kidney transplant, whereas that only happened in one case in the daratumumab standard therapy arm.
Both of these arms had large numbers of patients, almost 200 patients in each group, so the data are robust.
Number one, having effective therapy should this combination of daratumumab and standard chemotherapy be approved by the FDA, which we anticipate, given the results of ANDROMEDA, the incentive just to make the diagnosis a little faster because effective therapy will be available and will be supported by insurers.
Number two, it's very important to stress just how safe the therapy is. The signal regarding safety from ANDROMEDA was quite good, and there were no unanticipated adverse effects of combining daratumumab with bortezomib, cyclophosphamide, and dexamethasone, or with giving daratumumab continuously for a 2-year period.
Number three, if patients are diagnosed promptly and treated effectively, more patients will have preservation and improvement of organ function and will also have, we believe, better overall survival long-term.
There are a lot of aspects of the clinical trial that are currently being evaluated, including aspects such as quality of life changes in the two groups, in the two arms, and the impact of early response on patients with heart involvement, for example.
There are numerous aspects of the clinical trial that are currently being evaluated. Indeed, patients will be followed for overall survival as well, and we'll see where that takes us. We expect to see remarkable findings in that regard as well, but we'll see.
Light chain amyloid remains a very challenging disease for patients and for their families.
It's a disease that's very difficult for patients to get their arms around because the bad cells in the bone marrow can be present at 5 or 10%, but the impact of the disease on organ function can cause a tremendous decrement in function as well as impose a huge financial burden on patients and their families.
I hope that more attention will be paid to things like quality of life, patient and caregiver support, and also distribution of effective therapies in the United States and around the world.
