FDA approves split-dosing of daratumumab for patients with multiple myeloma

On 12 February 2019, the U.S. Food and Drug Administration (FDA) approved a split dosing schedule of daratumumab (Darzalex®) for the treatment of patients with multiple myeloma (MM) allowing physicians to split the first infusion over two consecutive days, or complete in a single session.¹ Daratumumab is the only CD38-directed monoclonal antibody currently approved for the treatment of MM.

The approval by the FDA was based on the results of the phase 1b study EQUULEUS (MMY1001) (NCT01998971) which was an international, non-randomized, open-label, multi-arm trial. The study compared the safety, tolerability and dose of daratumumab when administered in triplet and quadruplet combinations in various MM settings.²

A subgroup analysis of patients treated with a daratumumab-carfilzomib-dexamethasone triplet was presented at ASCO 2018 by Ajai Chari who provided the MM Hub with his expert opinion. In the analysis, daratumumab was administered to 85 patients intravenously as a single dose (N = 10) or as a split dose (N = 75). At the end of weekly dosing, the concentrations of daratumumab at 16mg/kg were comparable irrespective of whether it had been administered as a single infusion or a split-dose. The safety profile was also comparable between dosing schedules.³

• Infusion-related reactions:
  • Single infusion: 50% (N = 5)
  • First split dose: 36% (N = 27)
  • Second split dose: 4% (N = 3)
• Median infusion time:
  • Single infusion: 7.1 hours (6.5–8.9)
  • First split dose: 4.3 hours (3.9–10.6)
  • Second split dose: 4.2 hours (3.9–8.6)

Daratumumab was first granted accelerated approval by the FDA in 2015 for patients who have received at least three prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMID]) who are double-refractory to a PI and an IMID. In November 2016 the FDA approved daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone for the treatment of patients with MM who have received at least one prior therapy.⁴ It subsequently received further approvals and is currently indicated in:¹

• Patients who have received ≥3 prior lines of therapy
  • With lenalidomide (Revlimid®) and dexamethasone
• Patients who have received ≥2 prior lines of therapy including lenalidomide and a PI
  • With pomalidomide (Pomalyst®) and dexamethasone
• Patients who have received ≥1 prior lines of therapy
  • With bortezomib (Velcade®) and dexamethasone
• Patients with newly diagnosed MM who are ineligible for transplant
  • With bortezomib, melphalan and prednisone