Subcutaneous Daratumumab Approved in Europe for Newly Diagnosed Light-Chain Amyloidosis, Pretreated Myeloma

The European Commission has granted marketing authorization for the expanded use of subcutaneous daratumumab for use in 2 new indications.

The European Commission has granted marketing authorization for the expanded use of subcutaneous daratumumab (Darzalex) for use in 2 new indications, according to an announcement from The Janssen Pharmaceutical Companies of Johnson & Johnson.1

The first authorization is for the use of subcutaneous daratumumab plus bortezomib (Velcade), cyclophosphamide, and dexamethasone (D-VCd) for use in adult patients with newly diagnosed systemic light chain (AL) amyloidosis.

Subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) was also given the green light for use in adult patients with multiple myeloma who previously received 1 therapy containing a proteasome inhibitor and lenalidomide (Revlimid) and were lenalidomide refractory; or who have received at least 2 previous therapies that included lenalidomide and a proteasome inhibitor and have experienced progression on, or after, their last therapy.

“Today’s approvals mark significant progress for patients living with these blood disorders, especially for AL amyloidosis where patients have long faced an urgent need for approved treatment options,” Edmond Chan, senior director, EMEA Therapeutic Area Lead Hematology, at Janssen-Chiang Limited, stated in a press release. “The outlook for untreated patients has been poor with an average survival of 12 to 18 months, and only 6 months for those with severely impaired heart function. Our goal is to change these statistics and offer new hope to patients facing an AL amyloidosis diagnosis.”

Data from the phase 3 ANDROMEDA trial (NCT03201965) were used to support the indication for the subcutaneous daratumumab regimen in patients with AL amyloidosis. In the open-label, active-controlled trial, investigators compared the safety and efficacy of D-VCd with VCd alone in patients with newly diagnosed AL amyloidosis.

To enroll to the trial, patients needed to have AL amyloidosis with at least 1 organ impacted, have cardiac stage I to IIIA disease per 2004 Mayo criteria, and an estimated glomerular filtration rate of 20 mL/min or higher. Patients could not have received prior therapy for their disease.

A total of 388 participants were randomized in a 1:1 fashion. Patients in the investigative arm received subcutaneous daratumumab at 1800 mg once weekly in cycles 1 and 2 and every 2 weeks in cycles 3 through 6 plus weekly VCd for 6 cycles (n = 195). This was followed by subcutaneous daratumumab at 1800 mg every 4 weeks until major organ deterioration–progression-free survival (PFS) or for a maximum of 24 total cycles. In the control arm, patients were given VCd weekly for 6 cycles (n = 193).

The median age of participants was 63 years, with 47.5% of patients aged 65 years or older. Moreover, 58% of patients were male, 75.5% were White, 41.5% had an ECOG performance status of 0, and 79% had a Lambda AL isotype. The median time from diagnosis was 45.5 days and patients had a median baseline dFLC of 193 mg/L. Additionally, the median number of involved organs was 2 (range, 1-6), with the heart being involved for most patients.

At a median follow-up of 20.3 months, rates of hematologic complete response (CR) were significantly higher with D-VCd compared with VCd alone, at 59% vs 19%, respectively (odds ratio, 5.9; 95% CI, 3.7-9.4; P <.0001).2 Hematologic CR rates continued to be high across all prespecified subgroups.

Additionally, a significantly higher rate of hematologic overall response and very good partial response (PR) or better (≥VGPR) was observed with D-VCd vs VCd. Rates of hematologic overall response in the investigative and control arms were 92% and 77%, respectively, and rates of VGPR were 79% and 50%, respectively.

Cardiac response rates were found to improve with longer follow-up, with a doubling of response observed with the addition of subcutaneous daratumumab to VCd vs VCd alone at 12 months, at 57% (n = 118) vs 28% (n = 117), respectively (odds ratio, 3.5; 95% CI, 2.0-6.2; P <.0001). Renal response rates were also found to improve with D-VCd over VCd alone at the same time point, at 57% vs 27%, respectively (odds ratio, 4.1; 95% CI, 2.3-7.3; P <.0001).

The median duration of treatment with D-VCd was 18.5 months, and it was 5.3 months with VCd alone. From cycle 7 onward in the investigative arm, any grade 3 or 4 treatment-emergent adverse effects (TEAEs) were reported in less than 5% of patients. Rates of infections in the investigative and control arms were 13% and 9%, respectively.

Serious TEAEs were experienced by 38% of patients who received D-VCd in cycles 1 through 6 and 21% in cycle 6 and beyond; 36% of patients who were given VCd experienced serious TEAEs. The most common serious TEAE reported in both arms was pneumonia.

Moreover, the rates of treatment discontinuation because of TEAEs were 5% vs 4% with D-VCd and VCd, respectively. As of November 2020, 31 deaths were reported in the investigative arm vs 40 deaths in the control arm.

The decision to approve D-Pd in patients with pretreated multiple myeloma was supported by data from the phase 3 APOLLO trial (NCT03180736).3 In this open-label phase 3 trial, investigators examined whether D-Pd would improve PFS compared with Pd alone in this population.

To be eligible for enrollment, patients needed to be at least 18 years of age, have relapsed or refractory multiple myeloma, measurable disease, an ECOG performance status of 0 to 2, and have received at least 1 previous line of therapy, including lenalidomide (Revlimid) and a proteasome inhibitor. They also needed to have achieved a PR or better to one or more prior lines of anticancer treatment. If only 1 prior line of therapy was received, they had to be refractory to lenalidomide.

Participants were randomized 1:1 to D-Pd (n = 151) or Pd alone (n = 153). All participants were given oral pomalidomide at a once-daily dose of 4 mg on days 1 to 21 and oral dexamethasone at a once-daily dose of 40 mg on days 1, 8, 15, and 22. Patients who were aged 75 years or older received dexamethasone at a dose of 20 mg. Treatment was given in 28-day treatment cycles.

Those in the investigative arm also received subcutaneous daratumumab at 1800 mg or intravenous daratumumab at 16 mg/kg weekly during cycles 1 and 2, every 2 weeks during cycles 3 to 6, and every 4 weeks thereafter. Treatment was given until progressive disease or intolerable toxicity.

The primary end point of the trial was PFS in the intention-to-treat population.

Results indicated that D-Pd resulted in a significant 37% reduction in the risk of progression or death vs Pd alone, at a median of 12.4 months (95% CI, 8.3-19.3) and 6.9 months (95% CI, 5.5-9.3), respectively (HR, 0.63; 95% CI, 0.47-0.85; 2-sided P = .0018).

Moreover, the overall response achieved with D-Pd was also found to be significantly higher than what was reported with Pd alone, at 69% (95% CI, 61%-76%) vs 71% (95% CI, 38%-55%), respectively (odds ratio, 2.7; 95% CI, 1.7-4.4; P <.0001). Rates of complete response or better in the investigative and control arms were 25% and 4%, respectively, and rates of VGPR or better were 51% vs 20%, respectively.

Notably, rates of minimal residual disease negativity were 9% vs 2% in the investigative and control arms, respectively.

Additional data presented during the 2021 ASCO Annual Meeting showed that overall patient-reported outcomes results did not reveal any changes in health-related quality of life when daratumumab was added to Pd. A notable reduction in pain was observed, however, and this favored D-Pd.4 Moreover, at several time points, patients who received Pd were reported to experience declines in functional status and symptoms, thereby favoring the daratumumab regimen.

Previously, in May 2020, the FDA approved subcutaneous daratumumab (Darzalex Faspro) for the treatment of adult patients with newly diagnosed or relapsed/refractory multiple myeloma based on data from the phase 3 COLUMBA (MMY3012) trial (NCT03277105).5 More recently, in January 2021, the agency gave the green light to D-VCd for use in patients with newly diagnosed AL amyloidosis based on earlier data from ANDROMEDA.6


  1. DARZALEX (daratumumab) subcutaneous (SC) formulation becomes the first approved treatment for newly diagnosed systemic light chain amyloidosis in Europe and gains an additional approval in pre-treated multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. June 22, 2021. Accessed June 22, 2021.
  2. Kastritis E, Sanchorawala V, Merlini G, et al. Subcutaneous daratumumab + bortezomib, cyclophosphamide, and dexamethasone (VCd) in patients with newly diagnosed light chain (AL) amyloidosis: updated results from the phase 3 ANDROMEDA study. J Clin Oncol. 2021;39(suppl 15):8003. doi:10.1200/JCO.2021.39.15_suppl.8003
  3. Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812. doi:10.1016/S1470-2045(21)00128-5
  4. Terpos E, Dimopoulos MA, Boccadoro M, et al. Health-related quality of life (HRQoL) in patients with relapsed/refractory multiple myeloma (RRMM) treated with pomalidomide and dexamethasone ± subcutaneous daratumumab: patient-reported outcomes (PROs). J Clin Oncol. 2021;39(suppl 15):8046. doi:10.1200/JCO.2021.39.15_suppl.8046
  5. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. News released. FDA May 1, 2020. Accessed June 22, 2021.
  6. 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 June 22, 2021.