Combination Therapy Holds Promise for Newly Diagnosed Systemic AL Amyloidosis Patients

Updated research regarding the ANDROMEDA study presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, indicated 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.

Daratumumab is a previously approved CD38-directed cytolytic antibody agent for the treatment of multiple myeloma via infusion. CyBorD is a 3-drug combination. Cyclophosphamide is an immunosuppressive and chemotherapy, bortezomib is a potent first-in-class proteasome inhibitor, and dexamethasone is a corticosteroid. All drugs have been previously approved independently or with other combinations.

Systemic AL amyloidosis is caused by the disposition of insoluble amyloid fibrils into tissues and organs via clonal expansion of CD38⁺ plasma cells.

“In this study, the ANDROMEDA trial, [daratumumab is] being used in a novel way because the preparation of daratumumab is being given subcutaneously and not intravenously,” said 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, in an exclusive interview to Rare Disease Report ^®. “This is a big deal for patients with systemic 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.”

Eligibility for participation in the study included having ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, an absolute neutrophil count of ≥1.0 × 10⁹/L; hemoglobin ≥8.0 g/dL; a platelet count of ≥50 × 10⁹/L; an estimated glomerular filtration rate of ≥20 mL/min/1.73m², and NT-ProBNP of ≤8,500 ng/L.

Patients were administered a concentrated co-formulation of DARA (1,800 mg in 15 mL) and recombinant human hyaluronidase enzyme (rHuPH20; 30,000 U) in a single, pre-mixed vial, given by manual SC injection once weekly (qw) in cycles 1 to 2, once every 2 weeks (q2w) in cycles 3 to 6, and one every 4 weeks (q4w) thereafter ≤2 y in the safety run-in. On days 1, 8, 15, 22 of each 28-day cycle for ≤6 cycles, Cy 300 mg/m² PO or IV and Bor 1.3 mg/m² SC were administered while D 40 mg was administered qw. Between patients, dosing was staggered ≥48 hours to assess infusion related reactions (IRRs). Safety was evaluated after ≥10 patients received ≥1 treatment cycle.

The results were based off of a patient population (n = 15) that had a median age of 63 years and a median of 58 days from diagnosis. In addition, patients had a median of 1 involved organ with kidney involvement affecting 67% and 40% of patients with ≥2 organs involved.

Patients were grouped into New York Heart Association class 1 and 2, respectively, and 93% of patients had an ECOG score of ≤1 at baseline. Patients also received a median of 2 treatment cycles and a median of 5 DARA injections. Nausea (47%), diarrhea (33%), fatigue (33%), injection site erythema (20%), anemia (20%), and rash (20%) were the most common ( > 2 patients) treatment emergent adverse events (TEAEs) occurring in 1 (7%) patient each. No serious TEAEs; one grade 3/4 TEAE of hypertension was reported though it unrelated to treatment. The researchers reported that 2 (13.3%) patients experienced IRRs, all of them grade 1.

“The news from the ANDROMEDA trial being presented here at ASCO in June 2018 is good news,” Dr Comenazo told RDR^®. “There were no safety problems with the subcutaneous daratumumab, the response rates were really stunning even though these patients in the rampant trial did not go through the entire course of therapy before the responses were scored. They are still being treated, but 3 quarters experienced very deep responses. This is extremely encouraging.”

Based off of the results, the study concluded that DARA-CyBorD is tolerable in patients with AL amyloidosis with a low IRR rate and no new safety signals. The limited incidence of dyspnea and peripheral edema display a low risk for volume overload. Randomization into ANDROMEDA trial has begun.

“If daratumumab and CyBorD work better together than alone, we have a new standard of therapy for patients with light chain amyloidosis,” Dr Comenzo stressed. “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 is what we expect; we expect many patients to be treated and to recover.”

Additional data will be presented in the future as it becomes available, he added.