Darzalex (daratumumab); Darzalex Faspro (daratumumab and hyaluronidase-fihj) - 3 indications

Scroll down for information on each indication:

• Darzalex, multiple myeloma; approved November of 2015
• Darzalex Faspro, adults with newly diagnosed or relapsed/refractory multiple myeloma; approved May of 2020
• Darzalex Faspro, adults with newly diagnosed light chain (AL) amyloidosis; approved January of 2021

General Information

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

Darzalex Faspro is a combination of daratumumab and hyaluronidase, an endoglycosidase.

Darzalex is specifically indicated for the following:

• as a single agent 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
• 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 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 combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT)
• in combination with lenalidomide and dexamethasone (Rd) for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT
• in combination with bortezomib, thalidomide and dexamethasone (VTd) for newly diagnosed patients with multiple myeloma who are eligible for ASCT
• 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 Faspro is specifically indicated for the following multiple myeloma patients:

• in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant,
• in combination with lenalidomide and dexamethasone  in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy,
• in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy,
• as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.
• in combination with pomalidomide and dexamethasone (Pd) for the treatment in patients who have received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor
• in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy

Darzalex Faspro is also specifically indicated for use in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd) for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis.

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. 

See full prescribing information for drugs used in combination and schedule.

Darzalex Faspro is supplied as an injection for subcutaneous administration. Patients should be pre-medicated with a corticosteroid, acetaminophen and a histamine-1 receptor antagonist.

The recommended dosage of Darzalex Faspro for multiple myeloma is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately 3 to 5 minutes according to recommended schedule. Please see the drug label for specific dosing schedule when Darzalex Faspro is administered as monotherapy or as part of a combination therapy.

The recommended dosage of Darzalex Faspro for Light Chain Amyloidosis is as follows:

• Weeks 1 to 8: weekly (total of 8 doses)
• Weeks 9 to 24:- every two weeks (total of 8 doses) - First dose of the every-2-week dosing schedule is given at Week 9
• Week 25 onwards until disease progression or a maximum of 2 years: every four weeks - First dose of the every-4-week dosing schedule is given at Week 25

When Darzalex Faspro is administered as part of a combination therapy, see prescribing information for dosage recommendations for the other drugs.

Mechanism of Action

Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody that binds to the CD38 antigen. Hyaluronidase (recombinant human) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously.

CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including clonal plasma cells in multiple myeloma and light chain (AL) amyloidosis, as well as other cell types. Surface CD38 has multiple functions, including 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). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab.

Side Effects

Adverse effects associated with the use of Darzalex may include, but are not limited to, the following:

• infusion reactions
• fatigue
• nausea
• back pain
• pyrexia
• cough
• upper respiratory tract infection

Adverse reactions associated with the use of Darzalex Faspro may include, but are not limited to, the following:

Patients with multiple myeloma who received Darzalex Faspro monotherapy:

• upper respiratory tract infection

Patients with multiple myeloma who received D-VMP:

• upper respiratory tract infection
• constipation
• nausea
• fatigue
• pyrexia
• peripheral sensory neuropathy
• diarrhea
• cough
• insomnia
• vomiting
• back pain

Patients with multiple myeloma who received D-Rd:

• fatigue
• diarrhea
• upper respiratory tract infection
• muscle spasms
• constipation
• pyrexia
• pneumonia
• dyspnea

Patients with light chain (AL) amyloidosis who received Darzalex Faspro as monotherapy:

• upper respiratory tract infection
• diarrhea
• peripheral edema
• constipation
• fatigue
• peripheral sensory neuropathy
• nausea
• insomnia
• dyspnea
• cough

The most common (≥40%) hematology laboratory abnormalities with Darzalex Faspro are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

Indication 1 - Darzalex, multiple myeloma

approved November 2015

Clinical Trial Results

The FDA approval of Darzalex was based on two trials:

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).

Indication 2 - Darzalex Faspro, adults with newly diagnosed or relapsed/refractory multiple myeloma

approved May of 2020

Clinical Trial Results

The FDA approval of Darzalex Faspro in patients with multiple myeloma was based on the following:

Efficacy of daratumumab and hyaluronidase-fihji (monotherapy) was evaluated in COLUMBA, an open-label non-inferiority trial randomizing 263 patients to daratumumab and hyaluronidase-fihj and 259 to intravenous daratumumab (daratumumab IV). The trial’s co-primary endpoints were overall response rate (ORR) and pharmacokinetic (PK) endpoint of the maximum Ctrough on cycle 3, day 1 pre-dose. Daratumumab and hyaluronidase-fihj was non-inferior to daratumumab IV in evaluating these two endpoints. The ORR was 41.1% for daratumumab and hyaluronidase-fihj and 37.1% for daratumumab IV. The geometric mean ratio comparing daratumumab and hyaluronidase-fihj to daratumumab IV for maximum Ctrough was 108%.

Efficacy of daratumumab and hyaluronidase-fihj in combination with bortezomib, melphalan and prednisone (D-VMP) was evaluated in a single-arm cohort of PLEIADES, a multi-cohort, open‑label trial. Eligible patients were required to have newly diagnosed multiple myeloma and were ineligible for transplant. The major efficacy outcome measure, ORR,  was 88.1%. The efficacy of daratumumab and hyaluronidase-fihj in combination with lenalidomide and dexamethasone (D-Rd) was evaluated in a single-arm cohort of this trial. Eligible patients had received at least one prior line of therapy. ORR was 90.8%

Indication 3 - Darzalex Faspro, adults with newly diagnosed light chain (AL) amyloidosis

approved January of 2021

Clinical Trial Results

The FDA approval of Darzalex Faspro for newly diagnosed AL amyloidosis was based on ANDROMEDA, an ongoing Phase 3, randomized, open-label study investigating the safety and efficacy of Darzalex Faspro (daratumumab and hyaluronidase-fihj) in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd), compared to VCd alone. The study includes 388 patients with newly diagnosed AL amyloidosis with measurable hematologic disease and one or more organs affected. The primary endpoint is overall complete hematologic response rate by intent-to-treat (ITT). Patients received Darzalex Faspro 1,800 mg/ 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity or a maximum of 2 years. Among patients who received D-VCd, 74% were exposed for 6 months or longer and 32% were exposed for greater than one year. Patients receiving treatment with Darzalex Faspro experienced a hemCR more than triple that of patients receiving VCd alone (42% for D-VCd versus 13% for VCd).