FDA Approves Subcutaneous Daratumumab Plus VCd for Newly Diagnosed Light-Chain Amyloidosis


January 15, 2021 - The FDA has approved daratumumab and hyaluronidase-fihj, a subcutaneous formulation of daratumumab, for use in combination with bortezomib, cyclophosphamide, and dexamethasone in the treatment of patients with newly diagnosed light-chain amyloidosis.


The FDA has approved daratumumab and hyaluronidase-fihj (Darzalex Faspro), a subcutaneous formulation of daratumumab, for use in combination with bortezomib, cyclophosphamide, and dexamethasone (D-VCd; VCd) in the treatment of patients with newly diagnosed light-chain amyloidosis.1

Continued approval for this indication could be dependent upon verification and description of clinical benefit in a confirmatory trial, according to Genmab.

Notably, the subcutaneous formulation is not indicated and is not recommended for the treatment of patients with light-chain myloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.

The regulatory decision was based on data from the phase 3 ANDROMEDA (AMY3001), which showed that the regimen resulted in an improved hematologic complete response (CR) rate versus VCd alone in this patient population.

“AL amyloidosis is a devastating and potentially fatal blood disorder that, until now, did not have any US FDA-approved therapies. This makes today’s approval of Darzalex Faspro a critical step forward for patients in the United States in dire need of treatment options,” said Jan van de Winkel, PhD, chief executive officer of Genmab, stated in a press release.

Results from the trial were presented during the 2020 ASH Annual Meeting & Exposition and showed a 53% hematologic CR rate, which was defined as normalization of free light chain (FLC) levels and FLC ratio, along with negative serum and urine immunofixation, in the investigational arm (n = 195) versus 18% in the control arm (n = 193; odds ratio, [OR], 5.1; 95% CI, 3.2-8.2; P < .0001).2

Additionally, higher rates of best hematologic response at any time were reported with D-VCd compared with VCd in patients who were evaluated for the primary end point, at 56.9% and 18.7%, respectively (OR, 5.68; 95% CI, 3.58-9.00; P < .0001). This also proved to be true for those with involved FLC of 20 mg/L or lower, at 71.3% versus 20.2%, respectively (OR, 9.8; 95% CI, 6.1-15.7; P < .0001); those with a difference between involved and uninvolved FLC of less than 10 mg/L, at 65.6% versus 30.6%, respectively (OR, 4.3; 95% CI, 2.8-6.6; P < .0001); and those with International Society of Amyloidosis criteria, at 49.2% versus 23.3%, respectively (OR, 3.25; 95% CI, 2.09-5.06; P < .0001).

The open-label, active-controlled ANDROMEDA protocol randomized a total of 388 eligible participants in a 1:1 fashion to receive weekly VCd for 6 cycles in combination with 1800 mg of subcutaneous daratumumab for 2 weekly cycles, followed by an additional 3 to 6 cycles every 2 weeks, followed by 1800 mg of subcutaneous daratumumab every 4 weeks until major organ deterioration–progression-free survival (MOD-PFS) or a maximum of 24 treatment cycles, or weekly VCd for 6 cycles. Participants were assessed until MOD-PFS.

To be eligible for enrollment, patients had to have AL amyloidosis with at least 1 organ impacted, have not received any prior therapy for AL amyloidosis or multiple myeloma, have cardiac stage I to IIIA disease, and an estimated glomerular filtration rate of at least 20 mL/min. Patients were stratified by cardiac stage, whether transplant was typically offered in the patient’s local country, and creatinine clearance.

The primary end point of the trial was overall hematologic CR rate, while key secondary end points comprised MOD-PFS, organ response rate, time to hematologic response, overall survival, and safety.

Baseline patient characteristics and demographics were well balanced across cohorts; these included age, sex, race, ECOG performance status, baseline difference between involved and uninvolved FLC, cardiac stage, and renal stage.

The median follow-up time was 15.7 months and the median duration of treatment was 15.8 months in patients who were given D-VCd versus 5.3 months in those who received VCd.

Moreover, D-VCd was found to significantly prolong MOD-PFS versus VCd alone. Specifically, MOD-PFS events were reported in 17.4% (n = 34) of those in the investigative arm compared with 27.5% (n = 53) of those in the control arm (HR, 0.58; 95% CI, 0.36-0.93; P = .0211).

Additional data revealed that 23.5% (n = 8) of patients in the D-VCd group had hematologic progressive disease; 1 patient died after hematologic progressive disease. Just under half (47.2% n = 25) of patients in the VCd group experienced hematologic progressive disease; 6 deaths were reported. End-stage cardiac or renal failure was observed in 2.9% (n = 1) and 13.2% (n = 7) of patients, respectively, with 1 patient each dying after end-stage organ failure. Moreover, 73.5% (n = 25) of patients on D-VCd and 39.6% (n = 21) of patients on VCd died during the study.

Additional data indicated that the depth of response, measured by all hematologic response criteria, was prolonged in the D-VCd arm compared with the VCd arm.

Safety signals were determined to have been consistent with the known toxicities associated with subcutaneous daratumumab and VCd. However, higher rates of cardiac and renal responses at 6 months were observed in the investigational arm versus the control arm (cardiac, 42% vs 22%, respectively; renal, 54% vs 27%, respectively).


  1. Genmab announces that Janssen has been granted US FDA approval for DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) for patients with newly diagnosed light-chain (AL) amyloidosis. News release. Genmab A/S. January 15, 2021. Accessed January 15, 2021. http://bit.ly/38P8hlc.
  2. Comenzo RL, Kastritis E, Minnema MC, et al. Reduction in absolute involved free light chain and difference between involved and uninvolved free light chain is associated with prolonged major organ deterioration progression-free survival in patients with newly diagnosed AL amyloidosis receiving bortezomib, cyclophosphamide, and dexamethasone with or without daratumumab: results from ANDROMEDA. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 552.
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