The ANDROMEDA Study: Is Daratumumab Plus CyBorDex the New Standard of Care for Newly Diagnosed AL Amyloidosis?

Immunoglobulin light chain (AL) amyloidosis is a monoclonal plasma cell disorder characterized by extracellular deposition of insoluble aggregates of β-pleated amyloid fibrils that leads to major organ dysfunction affecting heart (75%), kidneys (65%), liver (17%), soft tissues (17%), and the peripheral and autonomic nervous system (15%).¹  Treatment strategies are directed at the control of plasma cell proliferation in the bone marrow to decrease the production of amyloidogenic proteins, eventually leading to the recovery of organ function over months and years.² 

On January 15, 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to subcutaneous (SC) daratumumab (DARA) in combination with bortezomib, cyclophosphamide and dexamethasone (VCd) for newly diagnosed AL amyloidosis. Safety and efficacy of DARA in combination with VCd was evaluated in the ANDROMEDA study, an open-label, randomized controlled trial in patients with newly diagnosed AL amyloidosis with measurable disease and at least one affected organ.

Patients were randomly assigned to receive bortezomib, cyclophosphamide, and dexamethasone with (D-VCd arm) or without (VCd arm) DARA. The primary endpoint of the trial was overall hematologic complete response rate (CR), and key secondary endpoints included major organ deterioration progression-free survival (MOD-PFS), organ response rate, survival, and safety. MOD-PFS was defined as any one of the following events (whichever came first): death; cardiac deterioration (requiring cardiac transplant, left ventricular assist device, or intra-aortic balloon pump); end-stage renal disease requiring hemodialysis or renal transplantation; hematologic progression per consensus guidelines.³ 

All participants were given cyclophosphamide at a weekly dose of 300 mg/m² either orally or intravenously (IV), SC bortezomib at a weekly dose of 1.3 mg/m², and dexamethasone at 20 mg to 40 mg either orally or IV for the duration of six 28-day cycles. SC DARA was given once weekly in cycles 1 and 2, once every two weeks in cycles 3 to 6, and once every four weeks thereafter for up to 24 treatment cycles. A total of 388 patients were randomized to receive D-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The proportions of patients with cardiac and kidney involvement were 71 percent and 59 percent, respectively, and the proportions of patients with cardiac stage I, II, and IIIA were 23 percent, 40 percent, and 37 percent, respectively. The median duration of treatment was 9.6 months for D-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+).

Results presented at the 2020 ASH Annual Meeting⁴  showed a significantly better hematologic CR of 53 percent with D-VCd versus 18 percent with VCd alone (odds ratio [OR], 5.1; 95% CI, 3.2-8.2; p<.0001). The six-month organ response rate achieved with D-VCd was approximately double to that achieved with VCd for both cardiac (42% vs. 22%) and renal (54% vs. 27%) responses, respectively. Moreover, the MOD-PFS also favored the D-VCd arm (HR, 0.58; 95% CI, 0.37-0.93; p=.0230). Hematologic CR/very good partial response (VGPR) at one and three months were superior in the D-VCd arm and were associated with reduced risk of death or MOD in the multivariate analysis.⁵  At one and three months, cardiac and renal responses were higher in patients who achieved hematologic CR/VGPR. The benefit of D-VCd was retained over VCd alone across all cardiac stages for hematologic CR, MOD-PFS, and organ responses.⁶  Corresponding hazard ratios for MOD-PFS were 0.33, 0.55, and 0.66 for cardiac stages 1, 2, and 3, respectively, favoring D-VCd.

D-VCd was well tolerated, with the most common adverse reactions (≥ 20%) consisting of upper respiratory tract infection, diarrhea, peripheral edema, constipation, and peripheral sensory neuropathy. The rate of discontinuation due to treatment-emergent adverse effects was 4 percent in both cohorts.

Based on the abstract by Dr. Vaishali Sanchorawala and colleagues,⁷  patients in the D-VCd arm experienced clinical improvements without any decline in health-related quality of life over the first six cycles. Following cycle 6, superior improvement in global health scale and fatigue was reported in patients receiving D-VCd. The abstract by Dr. Raymond Comenzo and colleagues⁴  also evaluated “deep hematological response,” defined as involved free light chain (FLC) less than 20 mg/L regardless of FLC ratio, and difference in involved and uninvolved FLCs (dFLC) less than 10 mg/L regardless of FLC ratio. Regardless of the criteria used, the addition of DARA to VCd increases the rate of deep hematologic responses that correlated with longer MOD-PFS.