OPTIMAL COMBINATION FOR AL AMYLOIDOSIS

Patients with newly diagnosed light chain (AL) amyloidosis could soon have a new treatment option: daratumumab (Darzalex, Janssen) along with the standard treatment used in these patients ― the chemotherapy combination of bortezomib, cyclophosphamide, and dexamethasone (CyBorD).

The addition of daratumumab substantially improved hematologic response to treatment and delayed the time to organ failure, according to results from the phase 3 ANDROMEDA study. Those results were presented as part of the virtual European Hematology Association 25th Annual Congress (EHA) 2020.

"This represents a major step forward in the treatment of light chain amyloidosis," Morie A. Gertz, MD, from the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News. He was not involved in the study and was approached for comment. "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.

The new data will be used to support an approval application for this new indication for daratumumab, which is currently marketed for use in the treatment of multiple myeloma.

"I think this will likely become the first approved therapy for AL amyloidosis," commented first author Efstathios Kastritis, MD, an associate professor of clinical therapeutics/medical oncology in the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Greece.

He also predicted that daratumumab plus CyBorD will become "the global standard of care for these patients.

"The combination of subcutaneous daratumumab with the most commonly used combination therapy, CyBorD, improved substantially the complete hematologic responses in patients with newly diagnosed AL amyloidosis compared to the CyBorD combination alone," he told Medscape Medical News.

More Effective Therapies Needed

Systemic AL amyloidosis is a rare and potentially fatal multiorgan disorder. Diagnoses are often delayed, and approximately 30% of patients die within the first year of diagnosis.

Novel combinations based on bortezomib, such as CyBorD, have improved outcomes; however, more effective therapies are urgently needed, Kastritis explained.

"In AL amyloidosis, it is of the utmost importance to achieve rapid, deep, and sustained pathological responses in order to reverse amyloid-mediated organ dysfunction and improve overall survival," he said.

The amyloid depositions that result in organ dysfunction in AL amyloidosis are produced by clonal CD38 plasma cells. Daratumumab, a standard treatment in multiple myeloma, is the only subcutaneous antibody targeting CD38. It is a promising agent in relapsed and refractory AL amyloidosis and has an acceptable safety profile, Kastritis said.

Hematologic Response "Substantial"

The phase 3 ANDROMEDA study involved 388 patients with newly diagnosed AL amyloidosis who had measurable hematologic disease with one or more involved organs.

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 randomly assigned to the chemotherapy-only group (n = 193) received the CyBorD regimen, which included cyclophosphamide 300 mg/m² PO or IV once weekly (QW); bortezomib 1.3 mg/m² SC QW; and dexamethasone 20 – 40 mg PO or IV QW alone for six 28-day cycles.

Patients who were assigned to the experimental group (n = 195) received the CyBorD regimen along with subcutaneous daratumumab (1800 mg, coformulated with recombinant human hyaluronidase PH20 15 mL; n = 195).

Daratumumab was administered by injection QW in cycles 1–2, Q2W in cycles 3–6, and Q4W thereafter for up to 24 cycles (28-day cycles).

Among patients in the daratumumab group, the median duration of treatment was 9.6 months; among those in the CyBorD group, the median duration was 5.3 monthsFor the primary endpoint of overall hematologic complete response, results at a median follow-up of 11.4 months were 53% in the daratumumab group, compared to just 18% in the CyBorD-only group (odds ratio, 5.1; P < .0001).

"There was a substantial increase in complete hematologic response rates," Kastritis said.

"Complete hematologic responses correspond to the elimination of the toxic free light chains that form the amyloid fibrils and is the strongest predictor for a favorable outcome in patients with AL amyloidosis," he explained.

The median time to the response was 60 days for the daratumumab group and 85 days for CyBorD-alone group.

Organ Response Rates Nearly Doubled

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% and 27%, respectively; P < .0001).

The numbers of deaths in each group were similar (daratumumab, 27; CyBorD, 29).

"Patients who were treated with the daratumumab combination had almost doubled organ response rates and also an increase in the time to major organ failure (heart or kidney) or time to hematologic relapse or progression, need for subsequent therapy, or death," Kastritis said.

"It is reassuring that daratumumab with CyBorD showed similar high complete hematologic response rates in patients of different cardiac stages, which is especially important for patients with advanced cardiac disease," he added.

Also important was that the effects were seen in patients with different degrees of renal involvement and in patients with high-risk cytogenetics, which in AL amyloidosis is the presence of t(11;14), he noted.

"Importantly, despite the use of a fixed subcutaneous dose for daratumumab, the complete hematologic response rates were similar for patients with different weights and in both genders," Kastritis said.

The safety profiles in the two groups were consistent with those previously observed with daratumumab or CyBorD alone, he reported. Common grade 3/4 treatment-emergent adverse events that occurred in more than 5% of patients included lymphopenia (daratumumab, 13%; CyBorD, 10%), pneumonia (8%, 4%), diarrhea (6%, 4%), cardiac failure (congestive; 6%, 5%), neutropenia (5%, 3%), syncope (5%, 6%), and peripheral edema (3%, 6%).

Systemic reactions with daratumumab that were associated with the subcutaneous administration in the daratumumab group occurred in 14 (7%) patients; all were rated as grade 1–2, and most occurred during the first infusion.

The study did not include patients with stage 3B disease, who have worse prognoses owing to the advanced disease stage. Kastritis noted that another phase 2 study in Europe is evaluating the treatment in these ultra–high-risk patients.

Diagnosis Often Missed

Kastritis commented that AL amyloidosis often goes unrecognized because the presenting symptoms are often subtle and nonspecific and there is no specific blood test for diagnosis.

These missed diagnoses place the patients in peril, inasmuch as the disease can proceed unchecked and cause organ damage, commented Gertz. "The major unmet need is an earlier diagnosis before significant organ impairment develops," he said. "With end-stage renal or cardiac failure, even the most effective therapies are unlikely to produce significant benefit."

Kastritis called on clinicians to keep a watchful eye for telltale signs of AL amyloidosis.

"Clinicians should suspect the disease in patients with symptoms from several different organ systems, and especially in patients with a known history of a monoclonal gammopathy," he said.

The study was sponsored by Janssen Pharmaceuticals. Kastritis has relationships with Amgen, Genesis Pharma, Janssen, Takeda, and Prothena. Gertz has relationships with Ionis/Akcea, Alnylam, Prothena, Janssen, Spectrum, Annexon, Appellis, Amgen, Medscape, Physicians Education Resource, Abbvie and Celgene, Research to Practice, Sanofi, Teva, Johnson & Johnson, DAVA Oncology; Pharmacyclics, Proclara, and i3Health.

European Hematology Association 25th Annual Congress (EHA) 2020: Abstract LB2604, presented June 12, 2020.

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