Investigators find study drug was well-tolerated with no new safety concerns.
Currently, there are no therapies approved for light chain (AL) amyloidosis, with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) considered the standard of care.
However, there is a growing belief that daratumumab could be added to the regimen to improve treatment.
A team, led by Giovanni Palladini, MD, PhD, Department of Molecular Medicine, University of Pavia, evaluated daratumumab-CyBorD compared to just CyBorD in newly diagnosed AL amyloidosis patients.
The randomized, open-label, active-controlled, multicenter, phase 3 ANDROMEDA study with a safety run-in phase included 28 patients who received either subcutaneous daratumumab (DARA SC) weekly in cycles 1-2, every 2 weeks in cycles 3-6, and every 4 weeks thereafter for up to 2 years. CyBorD was also given weekly for 6 cycles.
Eligible patients were at least 18 years old with a histopathologic diagnosis of systemic AL amyloidosis and measurable hematologic disease without prior therapy. The median age was 67.5 years old and the median time from diagnosis was 59.5 days.
Patients had a median of 2 involved organs—with kidneys (68%) and the heart (61%) the most common involved organs. Patients also received a median of 16 (1-23) treatment cycles.
Histopathologic diagnosis was based on the detection by immunohistochemistry and polarizing light microscopy of green birefringent material in tissue specimens stained with Congo red in an organ other than bone marrow or characteristic electron microscopy appearance (unbranched 10-nm-thick fibrils).
In the safety run-in phase, the investigators sought endpoints of the absence of a safety signal—particularly with regard to volume overload. This was required before the randomization period of the study could begin.
The team sought primary endpoints in the randomization portion of overall complete hematologic response rate (CR) based on International Amyloidosis Consensus Criteria guidelines, which require normalization of FLC levels and ratio, and negative serum and urine immunofixation (IFE).
The investigators also sought a secondary endpoint of major organ deterioration progression-free survival, a composite of endpoints occurring from randomization to whichever of death, clinical manifestation of cardiac or renal failure or hematologic progressive disease per consensus guidelines occurs first.
Other secondary endpoints include organ response rate assessed by biomarkers, progression-free survival, OS, improvement in patient-reported fatigue according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, time to next treatment, rate of hematologic VGPR or better, time to hematologic and organ response, and duration of organ response.
The investigators found treatment-emergent adverse events were consistent with DARA SC in patients with multiple myeloma and CyBorD. Overall infusion-related reactions occluded in 1 patient that was grade 1, but no grade 5 treatment-emergent adverse events occurred.
In addition, 5 patients died, including 3 after transplant.
Overall, the hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients.
At least a partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients at 3, 6, and 12 months, respectively.
A cardiac response also occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 month, respectively. A hepatic response occurred in 2 of 3 patients at 12 months.
Overall, the study drug was well-tolerated, with no new safety concerns when compared to the intravenous formulation. Daratumumab-CyBorD also demonstrated robust hematologic and organ responses.
Systemic amyloid light chain amyloidosis is a rare plasma cell disorder that primarily affects older adults, with an unadjusted incidence of 10-14 cases per million person-years in the US. Researchers generally believe this count is underestimated due to delayed or missed diagnosis.
The disease is characterized by the deposition of insoluble amyloid fibrils into tissues and organs, resulting in progressive organ damage.
“The depth and rapidity of hematologic response to DARA SC plus CyBorD were notable,” the authors wrote. “In addition, the majority of patients achieved an absolute dFLC level lower than 10 mg/L or an iFLC level lower than 20 mg/L. These results indicate that DARA SC plus CyBorD is a promising treatment of AL amyloidosis, and support the ongoing randomized portion of ANDROMEDA.”
The study, “Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA,” was published online in Blood.