The FDA has approved a new subcutaneous formulation of daratumumab and hyaluronidase-fihj for adult patients with newly-diagnosed or relapsed/refractory multiple myeloma (MM). Daratumumab was previously approved as an intravenous treatment for patients with MM. The combination of daratumumab and hyaluronidase-fihj is co-formulated with recombinant human hyaluronidase PH20 to allow subcutaneous injection.
The treatment is approved in 4 regimens:
- in combination with bortezomib, melphalan and prednisone in newly diagnosed patients ineligible for autologous stem cell transplant
- with lenalidomide and dexamethasone in newly diagnosed patients ineligible for transplant, and in patients with relapsed or refractory MM who received at least 1 prior therapy
- with bortezomib and dexamethasone in patients who received at least 1 prior therapy, as monotherapy
- in patients who received at least 3 prior therapies including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or who are double-refractory to these treatments
Approval is based on the phase III COLUMBA and phase II PLEIADES studies.
The phase III COLUMBA trial included 522 adult patients with MM who received at least 3 prior treatments including a PI and an IMiD, or who were refractory to both a PI and an IMiD. Patients were randomized to receive either subcutaneous or intravenous (IV) daratumumab. The subcutaneous treatment was noninferior to the IV treatment, with an overall response rate (ORR) of 41.1% and 37.1%, respectively.
In the non-randomized parallel assignment phase II PLEIADES trial, 67 patients with newly-diagnosed MM ineligible for transplant received subcutaneous daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP), and 65 patients with relapsed or refractory MM were given the subcutaneous formula plus lenalidomide and dexamethasone (D-Rd). The ORR for the D-VMP cohort was 88.1%, and it was 90.8% for the D-Rd cohort.
A subcutaneous daratumumab option could also dramatically cut treatment times from several hours to only a few minutes. In the COLUMBA study, the median subcutaneous injection time was 5 minutes, while median durations of the first, second, and subsequent IV infusions were 7.0, 4.3, and 3.4 hours, respectively.
The most common adverse event (AE), occurring in ≥20% of patients who received subcutaneous daratumumab and hyaluronidase-fihj monotherapy, was upper respiratory tract infection. For D-VMP, ≥20% of patients experienced upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. More than 20% of patients receiving the D-Rd treatment reported fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.
Recommended dosing for this formulation is 1,800 mg daratumumab and 30,000 units hyaluronidase administered subcutaneously into the abdomen over approximately 3-5 minutes.