Subcutaneous daratumumab approved in Europe for newly diagnosed light chain amyloidosis and pretreated myeloma

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 (LA) amyloidosis.

Subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) was also approved for use in adult patients with multiple myeloma who previously received 1 treatment containing proteasome inhibitor and lenalidomide (Revlimid) and were refractory to lenalidomide; or who have received at least 2 previous treatments including lenalidomide and a proteasome inhibitor and who have experienced progression during or after their last treatment.

“Today’s approvals mark significant progress for patients living with these blood disorders, particularly for AL amyloidosis where patients have a long history of urgent need for approved treatment options,” Edmond Chan, Senior Director , EMEA Therapeutic Area Lead Hematology, at Janssen-Chiang Limited, reported 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 a diagnosis of AL amyloidosis.

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

To participate in the trial, patients had to have AL amyloidosis with at least one affected organ, have Mayo 2004 criteria stage I to IIIA heart disease, and an estimated glomerular filtration rate of 20 mL / min or greater . The patients could not have received previous treatment for their disease.

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

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

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

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

Cardiac response rates improved with longer follow-up, with a doubling of response seen with the addition of subcutaneous daratumumab to VCd vs VCd alone at 12 months, to 57% (n = 118) vs 28% (n = 117), respectively (odds ratio, 3.5; 95% CI, 2.0-6.2; P <.0001 renal response rates also improved with d-vcd compared vcd alone at the same time to vs. respectively ratio ci:>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 in the investigation arm, Grade 3 or 4 treatment-related adverse reactions (TREs) were reported in less than 5% of patients. The infection rates in the investigation and control arms were 13% and 9%, respectively.

Serious ADEs were observed by 38% of patients who received D-VCd in cycles 1 to 6 and 21% in cycle 6 and beyond; 36% of patients who received VCd experienced serious side effects. The most frequently reported serious TSE in both arms was pneumonia.

Additionally, the rates of treatment discontinuation due to TIA were 5% versus 4% with D-VCd and VCd, respectively. As of November 2020, 31 deaths had been reported in the investigative arm compared to 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 to Pd alone in this population.

To be eligible for recruitment, patients must be at least 18 years old, have relapsed or refractory multiple myeloma, measurable disease, an ECOG performance index of 0 to 2, and have received at least 1 prior line of treatment, including including lenalidomide (Revlimid) and a proteasome inhibitor. They also had to have achieved RA or better for one or more previous lines of cancer treatment. If only one line of pre-treatment was received, they must be refractory to lenalidomide.

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

Those in the investigational arm also received daratumumab 1800 mg subcutaneously or daratumumab intravenously 16 mg / kg per week during cycles 1 and 2, every 2 weeks during cycles 3 to 6, then every 4 weeks thereafter. Treatment was administered until disease progression or intolerable toxicity.

The primary endpoint 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 compared to Pd alone, with a median of 12.4 months (95% CI, 8.3-19, 3) and 6.9 months (95% CI, 5.5-9.3), respectively (RR: 0.63; 95% CI: 0.47-0.85; P = 0.0018).

In addition, the overall response obtained with D-Pd was also found to be significantly higher than that reported with Pd alone, at 69% (95% CI, 61% to 76%) versus 71% (95% CI %, 38% – 55%), respectively (odds ratio, 2.7; 95% CI, 1.7-4.4; P <.0001 the complete or better response rates in investigation and control arms were respectively of vgpr versus respectively.>

Notably, the minimal residual disease negativity rates were 9% versus 2% in the investigation and control arms, respectively.

Additional data presented at the 2021 ASCO annual meeting showed that the overall patient-reported results revealed no changes in health-related quality of life when daratumumab was added to Pd. A noticeable reduction in pain was observed, however, which favored D-Pd.4 In addition, at several times, patients who received Pd have been reported to have decreased 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 COLUMBA Phase 3 trial (MMY3012) (NCT03277105).5 More recently, in January 2021, the the agency gave the green light to D-VCd for use in patients with newly diagnosed AL amyloidosis based on previous ANDROMEDA data.6

The references

  1. DARZALEX (daratumumab) subcutaneous (SC) formulation becomes first approved treatment for newly diagnosed systemic light chain amyloidosis in Europe and receives additional approval in pretreated multiple myeloma. Press 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 amyloidosis (LA): updated results from the ANDROMEDA phase 3 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, randomized 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 relapsed / refractory multiple myeloma (RRMM) patients treated with pomalidomide and dexamethasone ± daratumumab subcutaneous: patient reported results (PRO). J Clin Oncol. 2021; 39 (suppl 15): 8046. doi: 10.1200 / JCO.2021.39.15_suppl.8046
  5. The FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. News published. FDA May 1, 2020. Accessed June 22, 2021.
  6. Genmab announces that Janssen has obtained US FDA approval for DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) for patients with newly diagnosed light chain (LA) amyloidosis. Press release. Genmab A / S. January 15, 2021. Accessed June 22, 2021.

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