Rare Disease Report

Ray Comenzo, MD, Discusses ANDROMEDA Trial in AL Amyloidosis Patients

JUNE 19, 2018
Krista Rossi
At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Rare Disease Report® sat down with Ray Comenzo, MD, investigator of the ANDROMEDA trial and director of the John C. Davis Myeloma and Amyloid Program at Tufts Medical Center, and professor at Tufts University School of Medicine, for an exclusive interview regarding the ANDROMEDA study, which evaluated the efficacy of subcutaneous daratumumab (DARA SC) and cyclophosphamide, bortezomib, and dexamethasone (CyBorD) as a combination therapy in newly diagnosed light chain (AL) amyloidosis patients.

Rare Disease Report® (RDR®): Could you explain the ANDROMEDA trial in light-chain (AL) amyloidosis patients and the significance of its findings?      

Comenzo: The ANDROMEDA trial is a trial that is extremely important for patients who have systemic light chain or AL-amyloidosis. I’d like to begin by thanking Janssen Oncology, the investigators on the study, and, particularly, the brave patients who enrolled on the first part of the study, which is called a ramp-in.

The study itself is a phase 3 trial asking whether or not the addition of the monoclonal antibody daratumumab to a standard treatment combination called CyBorD will benefit patients who are newly diagnosed with systemic amyloidosis. Daratumumab is an approved agent for multiple myeloma. In this study, the ANDROMEDA trial, it’s being used in a novel way because the preparation of daratumumab is being given subcutaneously not intravenously.

This is a big deal for patients with systematic AL amyloidosis because these patients often have some degree of cardiac compromise; therefore, getting IV infusions can be challenging for them. The subcutaneous administration of daratumumab is an exciting option if it is safe and if it works. The news from the ANDROMEDA trial being presented here at ASCO in June 2018 is good news, 2 dozen patients were treated in the ramp-in, there was no safety problems with the subcutaneous daratumumab, and all of the 2 dozen patients received daratumumab with CyBorD.

The response rates were really stunning even though these patients in the ramp-in didn’t go through the entire course of therapy before the responses were scored. They are still getting treated, obviously, but three-quarters of patients recorded very deep responses.

This is extremely encouraging. The trial was approved by the US Food and Drug Administration (FDA) to begin randomization, which means that in 30 countries patients will be offered the study and will be randomized to receive either daratumumab with CyBorD or standard therapy of CyBorD alone.

If daratumumab and CyBorD works better than CyBorD alone, we have a new standard of therapy for patients with light chain amyloidosis. In addition, the study is designed to allow patients to have their blood stem cells collected after 6 months of treatment. This means that they will have the additional option of undergoing a stem cell transplant in the future should they need to.

It’s a very exciting prospect for the newly diagnosed amyloid patients of the future to potentially have a combination of 4 drugs that are safe and that are almost 100% effective. That’s what we expect; we expect many, many patients to be effectively treated and to recover.

RDR®: What does the timeline look for this randomization trial?

Comenzo: As far as I can tell, the trial is accruing very quickly. It’s open in 30 countries, and we do expect, perhaps as short a period as a year and a half, that the trial will complete accrual, and we will have some information on the activity of the 4-drug combination.

RDR®: Darzalex daratumumab has been approved for multiple myeloma in combination with other drugs. Do you think those findings transfer to this type of study?

Comenzo: Darzalex daratumumab is approved for relapsed myeloma in combination with several other drugs and just recently has been approved for newly diagnosed patients with multiple myeloma in combination with bortezomib, melphalan, and steroids.
  
That means that for newly diagnosed myeloma patients that are not candidates for stem-cell transplant they can get combination therapy with daratumumab. It also means that patients who are relapsed can get combination therapy with daratumumab and other different drugs. Extremely importantly, these results and these approvals do impact patients with light-chain amyloidosis, some of whom have myeloma as well.

In addition, there are clinical trials, which are ongoing comparing the intravenous form of daratumumab, which is FDA approved, with the subcutaneous form, which is under investigation. The results of these trials in multiple myeloma can be expected within a matter of a year or 2 and will be very relevant to the outcome of ANDROMEDA as well.

RDR®: If the ANDROMEDA randomization trial experiences success, how soon would this treatment be available for AL amyloidosis patients and how would it be significant for this patient population?

Comenzo: Systemic light-chain amyloidosis is a very challenging diagnosis because patients have not only a malignant plasma cell disease in their bone marrow, but they also have organ damage, and classically, the organs that are damaged are the heart and the kidneys.

The later the diagnosis is made, the more damage the patient may have. The processes of organ damage are, to a certain degree, reversible. Reversibility depends on rapid reduction of the plasma cell disease, rapid reduction of the light chains made by the plasma cells that cause AL amyloidosis. The faster the reduction, the more likely it is that organ improvement can occur.

In the future, if there is a combination therapy that includes daratumumab, cyclophosphamide, bortezomib, and dexamethasone that can achieve very deep responses very quickly, patients will get better faster, and more patients overall will get better.

On top of that, currently 25% of newly diagnosed patients with AL die within 6 months. In many cases, the deaths occur because the plasma cell disease is resistant to treatment. The faster the disease is treated, the light chains are reduced to as low a level as possible, and it is more likely some of those folks will live.

RDR®: How exciting would this drug combination approval be for this AL amyloidosis patients and even other rare cancers?

Comenzo: I must tell you 2 American companies have really established beachheads in the treatment of light-chain amyloidosis and those companies are Millennium Takeda and Jansen.

One of the first medicines that was brought forward to treat light chain-amyloidosis was brought forward by both companies; it’s called bortezomib. Those studies were done 13, 14, years ago and resulted in the widespread use in bortezomib to treat light-chain amyloid patients.

Today, Janssen has decided to expand the application of daratumumab to light-chain amyloidosis in a way that’s quite novel by using a subcutaneous preparation that’s actually better for this population of patients; it’s very innovating and very exciting.

Other companies in American pharma are actively pursuing treatments for both AL amyloidosis and other forms of amyloidosis. Within the next 2 years, we will see approvals for some of those agents that treat other types of amyloidosis.

I must say American pharma has really done its due diligence in attempting to come up with innovative and hopefully effective therapies for amyloid patients in general.

RDR®: Do you see this drug combination potentially being submitted to the FDA for approval? 

Comenzo: It’s a good question. I would hope that 2 years from now, the FDA will be in the process of considering a new drug application (NDA) for subcutaneous daratumumab for light-chain amyloidosis; that would be my hope.

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