The first and only treatment for a rare and often fatal blood cell disorder has been approved in the United States.
The new indication is newly diagnosed light-chain (AL) amyloidosis, which affects about 4500 people in the United States each year. It occurs when blood plasma cells in the bone marrow produce amyloid deposits, which may then build up in vital organs (notably, the heart, kidneys, and liver) and eventually cause organ deterioration. Diagnoses are often delayed, and approximately 30% of patients die within the first year of diagnosis.
The new approval is for subcutaneous daratumumab (Darzalex Faspro), to be used in combination with bortezomib, cyclophosphamide, and dexamethasone. This combination of drugs is often used in the treatment of multiple myeloma.
The US Food and Drug Administration granted an accelerated approval for daratumumab for use in AL amyloidosis on the basis of the hematologic complete response rate from the phase 3 ANDROMEDA study.
This "milestone is an important step for patients diagnosed with this rare disease," said Isabelle Lousada, founder and CEO, Amyloidosis Research Consortium, in a statement. "Sadly, most patients with AL amyloidosis are diagnosed more than one year after their initial symptoms present, at a time when they may already be experiencing organ deterioration or failure.
"I believe this approval will increase awareness of and education around this life-threatening disease and offer new hope for people with AL amyloidosis and their caregivers," she said.
Positive results from the phase 3 ANDROMEDA study were presented at the European Hematology Association 25th Annual Congress (EHA) in June 2020 and were reported by Medscape Medical News at that time.
They show that the addition of daratumumab to the combination of bortezomib (Velcade), cyclophosphamide, and dexamethasone (VCd) substantially improved hematologic response to treatment and delayed the time to organ failure in comparison with VCd alone.
"This represents a major step forward in the treatment of light chain amyloidosis," Morie A. Gertz, MD, from the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. He was not involved in the trial and was approached for comment at the time of the EHA presentation. "The high-level activity of adding daratumumab in terms of deeper hematologic responses as well as demonstrated organ responses will likely be practice changing for newly diagnosed AL amyloidosis," he added.
ANDROMEDA is an ongoing randomized, open-label study that involves 388 treatment-naive patients with measurable hematologic disease and in whom one or more organs are affected.
About a third (37%) of the patients had severe cardiac dysfunction (cardiac stage III) due to amyloidosis; 40% had cardiac stage II; and 23% had stage I.
Patients were randomly assigned to receive subcutaneous daratumumab plus the VCd combination or VCd alone.
The primary endpoint was overall hematologic complete response. At a median follow-up of 11.4 months, 53% in the daratumumab group had experienced a complete response, vs 18% in the VCd group (odds ratio, 5.1; P < .0001).
For the secondary endpoint of major organ deterioration progression-free survival, the rate favored the daratumumab group (hazard ratio, 0.58; P = .02).
Other secondary endpoints also were superior in the daratumumab group, including the 6-month cardiac response rate (42% vs 22%; P = .002) and the 6-month renal response rate (54% vs 27%; P < .0001).
The numbers of deaths in each group were similar (daratumumab, 27; VCd, 29).
The safety profiles were consistent with those previously observed with daratumumab or VCd alone. Common grade 3/4 treatment-emergent adverse events that occurred in more than 5% of patients included lymphopenia (daratumumab, 13%; VCd, 10%), pneumonia (8%, 4%), diarrhea (6%, 4%), congestive cardiac failure (6%, 5%), neutropenia (5%, 3%), syncope (5%, 6%), and peripheral edema (3%, 6%).
Daratumumab is not indicated and is not recommended for the treatment of patients with AL amyloidosis who have NYHA class IIIB or class IV cardiac disease or Mayo stage IIIB disease outside of controlled clinical trials.
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Cite this: FDA Approves First and Only Treatment for AL Amyloidosis - Medscape - Jan 20, 2021.