General Information

Darzalex (daratumumab) is a human CD38-directed monoclonal antibody.

Darzalex is specifically indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. The FDA expanded the approved indication in November of 2016 for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in June of 2017 for use in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a PI; in May of 2018 for use in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT and in June of 2019 to include the use of Darzalex in combination with lenalidomide and dexamethasone (Rd) for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT). The FDA approval was expanded again in September of 2019 to include the use of Darzalex in combination with bortezomib, thalidomide and dexamethasone (VTd) for newly diagnosed patients with multiple myeloma who are eligible for autologous stem cell transplant (ASCT). The FDA approval was expanded in August of 2020 to include the use of Darzalex in combination with Kyprolis (carfilzomib) and dexamethasone (DKd) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received one to three previous lines of therapy.

Darzalex is supplied as a solution for intravenous infusion. The recommended dose of Darzalex is 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule:

Schedule: Weekly - Weeks 1 to 8

Schedule: Every two weeks - Weeks 9 to 24

Schedule: Every four weeks - Week 25 onwards until disease progression

The Darzalex drug label allows for an option to split the first infusion over two consecutive days.

If a planned dose of Darzalex is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval.

Clinical Results

FDA Approval

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.The accelerated FDA approval of Darzalex was based on two studies.

Study 1:

This open-label trial evaluated Darzalex monotherapy in 106 patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. Darzalex 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression. The overall response rate was 29.2%, including a PI and an IMiD. Stringent complete response was reported in 2.8%f patients, very good partial response was reported in 9.4% of patients, and partial response was reported in 17% of patients. The median time to response was 1 month and the median duration of response was 7.4 months.

Study 2:

This open-label dose escalation trial evaluated Darzalex monotherapy in 42 patients with relapsed or refractory multiple myeloma who had received at least 2 different cytoreductive therapies. Darzalex 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression. Overall response rate was 36%, with 1 CR and 3 VGPR. The median time to response was 1 month. The median duration of response was not estimable (range: 2.2 to 13.1+ months).

Mechanism of Action

CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Myeloid derived suppressor cells (MDSCs) and a subset of regulatory T cells (CD38+Tregs) express CD38 and are susceptible to daratumumab mediated cell lysis.