Doctors warn Korea is falling behind global standards in AL amyloidosis treatment

Amyloid light-chain amyloidosis (AL amyloidosis) is an extremely rare disease. Early diagnosis is difficult, and most patients present at the hospital with already significantly impaired heart or kidney function. Consequently, the later the point of therapeutic intervention, the worse the prognosis becomes.

Although treatment options have rapidly evolved over the past two decades, in the clinical setting, the key factor determining patient survival remains how quickly patients can access standard treatment.

In this regard, the DVCd (daratumumab, velcade, cyclophosphamide, and dexamethasone) combination therapy based on Darzalex (daratumumab) is regarded as a “game changer” that has created a watershed moment in the treatment of this disease. Specifically, the ANDROMEDA clinical trial presented data showing that adding Darzalex significantly improved overall survival (OS) and long-term response rates.

Consequently, it has already established itself as the standard first-line therapy for AL amyloidosis in Europe and the United States.

However, the situation in Korea is entirely different.

Due to the pharmaceutical company's delayed approval application following its launch strategy for the subcutaneous injection formulation, and the subsequent delay in reimbursement, Korean patients still must bear the cost of treatment under non-reimbursed status.

Against this backdrop, Korea Biomedical Review met with Professor Stefan Schönland of Heidelberg University Hospital in Germany, an authority in the field of AL amyloidosis, and Professor Kim Ki-hyun of the Department of Hematology-Oncology at Samsung Medical Center. The two experts examined the shift in the treatment paradigm, the clinical value of the combination therapy with Darzalex, and future improvement tasks based on the differences in the Korean and international treatment environments.

Amid typically over a year of diagnostic wandering, early diagnosis is difficult

“AL amyloidosis isn't rare only in Korea. Globally, it's a disease that only began receiving serious attention about 20 years ago, when research truly started.”

Professor Schönland highlighted the rarity of light-chain amyloidosis. This disease occurs when abnormally produced immunoglobulin light chains in the bone marrow deposit in vital organs, such as the heart and kidneys, causing damage.

“Deposition in the heart leads to symptoms, including edema, dyspnea, and weight loss. Some patients also exhibit specific symptoms, such as bleeding around the eyes or glossitis, where the tongue thickens,” Professor Schönland explained.

Professor Kim Ki-hyun added, “Neurological abnormalities like numbness in the hands and feet, and gastrointestinal involvement symptoms, such as digestive disorders or vomiting, are also common. The problem is that most symptoms are non-specific, meaning patients typically see an average of two or three doctors before receiving a diagnosis. It usually takes over a year from symptom onset to confirmation.”

Delayed diagnosis directly worsens patient prognosis. Professor Schönland noted, “Patients often present to hospitals with already severely damaged hearts or kidneys, meaning they frequently miss the window for recovery even after treatment begins.”

AL amyloidosis faces a turning point with the emergence of Darzalex

Historically, treatment for AL amyloidosis largely relied on drugs borrowed from multiple myeloma therapy, such as melphalan, cyclophosphamide, and steroids. While the addition of immunomodulators and proteasome inhibitors later improved outcomes, the prognosis remained limited.

Professor Kim stated, “The emergence of daratumumab has significantly shifted the treatment paradigm. By targeting the CD38 antigen to eliminate plasma cells, it has meaningfully extended patient survival. Crucially, daratumumab is characterized by relatively fewer side effects on other organs compared to conventional chemotherapy.”

Professor Schönland also assessed it positively, saying, “Daratumumab has been confirmed to significantly improve overall survival and cardiac/renal response rates when combined with existing therapies. Despite the inherent difficulty in establishing control groups for rare diseases, recent clinical studies have been quite successful.”

ANDROMEDA study’s clinical success was a ‘game changer’

The status of the DVCd combination therapy was solidified through the ANDROMEDA clinical study. The final data presented at the American Society of Hematology (ASH 2024) conference late last year delivered a powerful message to hematology-oncology specialists worldwide.

"The 60-month overall survival (OS) rate was 76.1 percent in the daratumumab combination group. The existing VCd group was 64.7 percent, with a hazard ratio of 0.62,” Professor Schönland said. “Initially, we anticipated an OS of around 50 percent, but the daratumumab combination group actually showed remarkable results with over 80 percent survival."

Professor Kim added, “The hematologic complete remission rate was 59.5 percent in the daratumumab combination group and 19.2 percent in the control group, and cardiac and renal response rates also improved more than twofold. These results prove that Darzalex is not just an effective new drug, but a game-changer that completely alters the survival curve of the disease.”

One notable point is that despite approximately 70 percent of patients who received the standard VCd therapy subsequently adding Darzalex treatment, the overall survival gap remained substantial. This clearly demonstrates the importance of using Darzalex as a first-line treatment, rather than as a second-line therapy.

Professor Kim Ki-hyun emphasized this point, saying, “The hazard ratio derived from the study was approximately 0.6, meaning that mortality was halved when daratumumab was used in combination. Therefore, not using this therapy as first-line treatment could clearly have a negative impact on patient care.”

DVCd combo has long been the golden standard overseas. What about Korea?

This data was promptly reflected in overseas clinical guidelines and insurance coverage. Professor Schönland noted, “In Germany, daratumumab combination therapy has been fully covered by insurance for four years now,” adding, “Any patient who needs it can receive treatment without financial burden.”

Professor Kim Ki-hyun also provided a detailed comparison of the international situation. He explained, “The U.K. has already approved and reimbursed daratumumab quadruple therapy as first-line treatment, and Spain permits its use under certain patient conditions, albeit with some restrictions. Australia, traditionally known for stringent insurance listing criteria, surprisingly included daratumumab quadruple therapy in its insurance coverage relatively early among OECD countries.”

Professor Kim further pointed out, “While major countries are competing to ensure patient access, the fact that it remains non-covered in Korea is problematic. Globally, the debate over this treatment has already concluded. The reality that only Korean patients cannot receive timely treatment is embarrassing and regrettable to the outside world.”

According to Professor Kim, at Samsung Medical Center, only 5-10 percent of AL amyloidosis patients are using Darzalex at their own expense. He explained that while the subcutaneous injection formulation offers the advantage of simple outpatient administration, it does not qualify as a reason for hospitalization, making it difficult to apply for reimbursement under indemnity insurance.

Professor Kim emphasized, “Daratumumab quadruple therapy is a treatment that more than doubles overall survival. The reality that patients cannot access this drug in a timely manner is extremely critical. Since OS data has already been published in the ANDROMEDA study, there is no reason to delay any further. Delaying reimbursement coverage is clearly unreasonable.”

For patients with AL amyloidosis, the combination therapy with Darzalex is no longer a novel option. The ANDROMEDA clinical trial has already altered survival curves, and Europe and the U.S. swiftly adopted it to ensure patient access. Germany implemented full coverage four years ago, while the U.K. and Australia also incorporated it into their insurance systems. The global medical community no longer debates the necessity of this treatment.

Yet Korea remains stuck in place. Caught between the pharmaceutical company's delayed application for approval and the government's delayed reimbursement decision, patients are suffering alone.

“As the disease progresses, treatment options become increasingly limited. It is shameful that patients' lives are sacrificed before the barrier of administrative procedures,” Professor Kim said.

Korean health authorities should keep those words in mind.