DARZALEX

Antineoplastic Monoclonal Antibodies Targeting CD38

Emetic Risk
Minimal

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
The daratumumab solution in single-dose vials is colorless to pale yellow. It is a protein and the diluted solution may develop very small, translucent to white particles; do not use diluted solutions containing visibly opaque particles, discoloration, or foreign particles.[60311]

Daratumumab is available as a 20 mg/mL solution in 100 mg/5 mL and 400 mg/20 mL vials; each of these vial strengths has 2 National Drug Codes (NDCs).
Dilute prior to administration; vials of the same strength with different NDCs may be admixed in the same infusion bag.
Premedication with acetaminophen PO, diphenhydramine IV or PO, and a corticosteroid is required prior to each infusion; hold therapy for infusion-related reactions.
If a dose is missed, administer daratumumab as soon as possible and adjust the dosing schedule to maintain the treatment interval.
Initial dilution volume and/or infusion rate differ for first, second, and subsequent infusions; the maximum infusion rate is 200 mL/hour.
Dilution:
Withdraw the appropriate amount (mL) from the daratumumab 20 mg/mL vials for the calculated dose (use actual body weight); discard any unused portion left in the vial.
For the first infusion (week 1), dilute the calculated amount in 0.9% sodium chloride injection to a total infusion bag volume of 1,000 mL for a single-dose infusion (16 mg/kg) or 500 mL for split-dose infusions (8 mg/kg). For subsequent infusions, dilute the calculated amount in 0.9% sodium chloride injection to a total infusion bag volume of 500 mL. Following a single-dose infusion (16 mg/kg), reduce the total infusion bag volume to 500 mL only if there were no grade 1 or higher infusion reactions during the previous week.
Gently invert the bag to mix the solution but do not shake.
Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend.
Storage of admixture: store at room temperature (15 to 25 degrees C or 59 to 77 degrees F) for up to 15 hours (includes infusion time) or for up to 24 hours refrigerated (2 to 8 degrees C or 36 to 46 degrees F) and protected from light; allow refrigerated admixtures to warm to room temperature prior to use.
Intravenous Infusion:
Administer daratumumab using an infusion-set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone filter (pore size of 0.2 or 0.22 micrometer); polyurethane, polybutadiene (PBD), PVC, PP, or PE administration sets must be used.
Do not infuse other drugs concomitantly in the same IV line.
Administer the diluted infusion intravenously at the appropriate infusion rate as follows: Week 1 infusion(s): start at 50 mL/hour, increase by 50 mL/hour every hour to a maximum rate of 200 mL/hour.Week 2 infusion (following a single 16 mg/kg dose infusion only): start at 50 mL/hour, increase by 50 mL/hour every hour to a maximum rate of 200 mL/hour.Subsequent infusions: start at 100 mL/hour, increase by 50 mL/hour every hour to a maximum rate of 200 mL/hour if there were no grade 1 or higher infusion reactions during the previous week.
Do not save or store unused daratumumab for reuse.[60311]

neutropenia / Delayed / 15.0-82.0
lymphopenia / Delayed / 25.0-71.0
thrombocytopenia / Delayed / 9.0-47.0
infection / Delayed / 0-37.0
leukopenia / Delayed / 0-35.0
anemia / Delayed / 4.0-30.0
hypertension / Early / 4.0-20.0
fatigue / Early / 2.0-18.0
pulmonary edema / Early / 0-15.0
atrial fibrillation / Early / 0-15.0
pancreatitis / Delayed / 0-15.0
leukoencephalopathy / Delayed / 0-15.0
infusion-related reactions / Rapid / 2.0-12.0
diarrhea / Early / 1.0-7.0
dyspnea / Early / 0-7.0
hyperglycemia / Delayed / 0-7.0
back pain / Delayed / 0-6.0
peripheral neuropathy / Delayed / 0-5.0
insomnia / Early / 0-4.7
skin cancer / Delayed / 0-4.7
nausea / Early / 0-4.0
bone pain / Delayed / 0-4.0
edema / Delayed / 1.0-4.0
peripheral edema / Delayed / 1.0-4.0
influenza / Delayed / 0-3.5
hypercalcemia / Delayed / 0-3.5
fever / Early / 1.0-3.0
tremor / Early / 0-3.0
hypokalemia / Delayed / 0-3.0
vomiting / Early / 0-2.0
musculoskeletal pain / Early / 0-2.0
arthralgia / Delayed / 0-2.0
dizziness / Early / 0-2.0
headache / Early / 0-1.2
constipation / Delayed / 0-1.0
anorexia / Delayed / 0-1.0
muscle cramps / Delayed / 0-1.0
cough / Delayed / 0-1.0
hypocalcemia / Delayed / 0-1.0
hepatitis B exacerbation / Delayed / 0-1.0
laryngeal edema / Rapid / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
new primary malignancy / Delayed / Incidence not known

chest pain (unspecified) / Early / 0-15.0
dehydration / Delayed / 0-15.0
antibody formation / Delayed / 0.3-0.3
hypoxia / Early / Incidence not known
blurred vision / Early / Incidence not known
hypotension / Rapid / Incidence not known
sinus tachycardia / Rapid / Incidence not known
wheezing / Rapid / Incidence not known
myopia / Delayed / Incidence not known

asthenia / Delayed / 0-28.0
chills / Rapid / 0-20.0
nasal congestion / Early / 0-17.0
paresthesias / Delayed / 0-16.0
pruritus / Rapid / 0-15.0
rash / Early / 0-15.0
anxiety / Delayed / 0-13.0
ocular pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
myalgia / Early / Incidence not known
throat irritation / Early / Incidence not known
syncope / Early / Incidence not known

DARZALEX

Rx

Anti-CD38 monoclonal antibody
Used as monotherapy or in combination with other agents for multiple myeloma
Type and cross-match patient blood prior to starting treatment

16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (8 doses), 16 mg/kg IV every other week on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO and diphenhydramine 25 to 50 mg (or equivalent) PO or IV prior to every infusion, and methylprednisolone 100 mg (or equivalent) IV prior to the first and second infusions and methylprednisolone 60 mg IV (or equivalent IV or PO) prior to subsequent infusions. All patients should receive an oral corticosteroid (equivalent to methylprednisolone 20 mg) for 2 days beginning the day after every infusion. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy.[60311] The overall response rate (ORR) was 29.2% in patients with relapsed or refractory multiple myeloma who received daratumumab (median of 4 cycles; range, 1 to 16 cycles) in a multinational, nonrandomized, phase 2 trial (n = 106; SIRIUS trial); the CR rate was 2.8%. The median time to response and median response duration were 1 month (range, 0.9 to 5.6 months) and 7.4 months, respectively. At a median follow-up time of 9.3 months (range, 0.5 to 14.4 months), the median progression-free survival (PFS) time was 3.7 months and the median overall survival (OS) time had not been reached. The 12-month OS rate was 64.8%. Patients (median age, 63.5 years; range, 31 to 84 years) in this study had received a median of 5 prior therapies (range, 2 to 14 therapies); 97% of patients were refractory to the last line of therapy and 80% of patients had previously received an autologous stem cell transplantation (ASCT).[61025] The ORR was 36% and the median PFS time was 5.6 months in 42 patients with previously treated multiple myeloma who received daratumumab (16 mg/kg IV cohort) in a multicenter, open-label, phase 1/2 trial. Patients in this dose cohort had received a median of 4 prior therapies (range, 2 to 12 therapies); 76% of patients had refractory disease to the last therapy and 74% of patients had received a prior ASCT.[60312]

16 mg/kg (actual body weight) IV weekly on weeks 1 to 9 (9 doses), 16 mg/kg IV every 3 weeks on weeks 10 to 24 (5 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (given IV prior to the first infusion; oral administration may be considered thereafter). Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion unless the regimen already has a scheduled dexamethasone dose on this day. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy.[60311] Daratumumab was given in combination with bortezomib (1.3 mg/m2 as a subcutaneous injection or IV infusion on days 1, 4, 8, and 11) and dexamethasone (20 mg PO/IV on days 1, 2, 4, 5, 8, 9, 11, and 12) repeated every 3 weeks for 8 cycles of therapy in a multinational, randomized, open-label, phase 3 trial (n = 498; CASTOR trial). Dexamethasone was administered prior to daratumumab when these drugs were scheduled on the same day and was continued as a pre-infusion medication as long as daratumumab was continued. Dexamethasone was given at a reduced dose of 20 mg PO/IV once weekly in patients older than 75 years, with a body-mass index less than 18.5, or who had poorly controlled diabetes mellitus or a prior intolerance to glucocorticoid therapy.[61207] 

16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (8 doses), 16 mg/kg IV every 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (give IV prior to the first infusion; oral administration may be considered thereafter). Give the treatment dexamethasone dose as the daratumumab premedication steroid when these drugs are scheduled on the same day. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. Daratumumab was given in combination with lenalidomide (25 mg PO daily on days 1 to 21 repeated every 28 days) and dexamethasone (40 mg IV/PO once weekly) in a multinational, randomized, open-label, phase 3 trial (n = 569; POLLUX trial). In patients with a reduced creatinine clearance of 30 to 60 mL/min, the lenalidomide dosage was reduced (10 mg PO daily on days 1 to 21 repeated every 28 days). Dexamethasone was given at a reduced dose of 20 mg PO/IV once weekly in patients older than 75 years or who had a body-mass index less than 18.5. In patients receiving full dose dexamethasone, it was administered as 20 mg IV prior to the daratumumab infusion and then 20 mg orally the next day when these drugs were scheduled on the same week; patients receiving a 20 mg/week dexamethasone dose had the entire dose administered prior to the daratumumab infusion.

16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (8 doses), 16 mg/kg IV every other week on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression; give daratumumab in combination with pomalidomide (4 mg PO daily on days 1 to 21 repeated every 28 days) and dexamethasone (40 mg IV/PO once weekly or 20 mg PO/IV once weekly in patients older than 75 years or who had a body-mass index less than 18.5) until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (give IV prior to the first infusion; oral administration may be considered thereafter). Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. The overall response rate (ORR) was 60% in patients with relapsed or refractory multiple myeloma who received daratumumab, pomalidomide, and low-dose dexamethasone in a nonrandomized, phase 1b trial (n = 103; EQUULEUS trial); the stringent complete response (CR) rate was 8% and the CR rate was 9%. At a median follow-up time of 13.1 months (range, 0.2 to 25.8 months), the median progression-free survival (PFS) and overall survival (OS) times were 8.8 months and 17.5 months, respectively; the estimated 12-month PFS and OS rates were 42% and 66%, respectively. Patients (median age, 64 years; range, 35 to 86 years) in this study had received a median of 4 prior therapies (range, 1 to 13 therapies); 74% of patients had previously received an autologous stem cell transplantation.

16 mg/kg (actual body weight) IV weekly on weeks 1 to 6 (6 doses), 16 mg/kg IV every 3 weeks on weeks 7 to 54 (16 doses), and then 16 mg/kg IV every 4 weeks starting on week 55 until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (given IV prior to the first infusion; oral administration may be considered thereafter). Omit the prednisone dose on days when dexamethasone is administered as a premedication. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion unless there is a scheduled prednisone dose on this day. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Daratumumab was administered in combination with VMP consisting of bortezomib 1.3 mg/m2 subcutaneously twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and 1.3 mg/m2 subcutaneously once weekly on weeks 1, 2, 4, and 5 of cycles 2 to 9; melphalan 9 mg/m2 orally daily on days 1, 2, 3, and 4 on cycles 1 to 9; and prednisone 60 mg/m2 orally daily on days 1, 2, 3, and 4 on cycles 1 to 9 was evaluated in a randomized, phase 3 trial (the ALCYONE trial; n = 706). VMP treatment cycles were repeated every 6 weeks. Dexamethasone 20 mg IV or PO was substituted for prednisone on day 1 of each cycle. In the ALCYONE trial (median follow-up of 40.1 months), the primary endpoint of PFS time was significantly higher with daratumumab plus VMP compared VMP alone (36.4 months vs. 19.3 months; hazard ratio (HR) = 0.42; 95% CI, 0.34 to 0.51; p less than 0.0001) in adult patients (median age, 71 years; range, 40 to 93 years) with multiple myeloma who were ineligible for high-dose chemotherapy with stem-cell transplant (SCT) due to coexisting conditions or age of 65 years or older and who had not received prior systemic therapy or SCT. At the time of this analysis, the median overall survival time was significantly improved in patients in the daratumumab plus VMP arm compared with the VMP alone arm (median time not reached in either arm; HR = 0.6; 95% CI, 0.46 to 0.8; p = 0.0003).

16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (8 doses), 16 mg/kg IV every 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (give IV prior to the first infusion; oral administration may be considered thereafter). Give the treatment dexamethasone dose as the daratumumab premedication steroid when these drugs are scheduled on the same day. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy.[60311] Daratumumab was given in combination with lenalidomide (25 mg PO daily on days 1 to 21 repeated every 28 days) and dexamethasone (40 mg IV/PO once weekly) in a multinational, randomized, open-label, phase 3 trial (n = 737; MAIA trial). In patients with a reduced creatinine clearance of 30 to 50 mL/min, the lenalidomide dosage was reduced (10 mg PO daily on days 1 to 21 repeated every 28 days). Dexamethasone was given at a reduced dose of 20 mg PO/IV once weekly in patients older than 75 years or who had a body-mass index less than 18.5. In the MAIA trial (median follow-up, 56.2 months), the median progression-free survival (time not reached vs. 34.4 months; hazard ratio (HR) = 0.53; 95% CI, 0.43 to 0.66, p less than 0.0001) and overall survival (time not reached in either arm; HR = 0.68; 95% CI, 0.53 to 0.86) times were significantly improved in the daratumumab plus lenalidomide and dexamethasone arm compared with the lenalidomide and dexamethasone arm in patients (median age, 73 years; range, 45 to 90 years) with newly diagnosed multiple myeloma who were ineligible for a stem-cell transplant. Of note, 46% of patients in the lenalidomide and dexamethasone arm received a daratumumab-containing regimen as a subsequent line of therapy. In addition, 37% of patients in the daratumumab-containing arm switched from IV to subcutaneous daratumumab following a protocol amendment. At a median follow-up of 64 months, the median PFS times were 61.9 months vs. 34.4 months in the daratumumab plus lenalidomide and dexamethasone and lenalidomide and dexamethasone arms, respectively.

16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (cycles 1 and 2; total of 8 doses), then 16 mg/kg IV every other week starting week 9 through week 16 (cycles 3 and 4; total of 4 doses). Therapy is then interrupted for high dose chemotherapy and autologous stem cell transplant (ASCT), followed by daratumumab 16 mg/kg IV consolidation every 2 weeks on weeks 1 to 8 (cycles 5 and 6; total of 4 doses). In the clinical trial, the consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. Daratumumab is administered in combination with bortezomib (1.3 mg/m2 IV or SC on days 1, 4, 8, and 11 every 4 weeks during induction [cycles 1 to 4] and consolidation [cycles 5 and 6]), thalidomide (100 mg PO once daily during bortezomib cycles), and dexamethasone (40 mg IV or PO on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1 and 2; 40 mg on days 1 and 2, then 20 mg on days 8, 9, 15, and 16 of cycles 3 and 4; and 20 mg on days 1, 2, 8, 9, 15, and 16 in cycles 5 and 6). The first dose of daratumumab on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). Hold daratumumab if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (give IV prior to the first infusion; oral administration may be considered thereafter). Give the treatment dexamethasone dose as the daratumumab premedication steroid when these drugs are scheduled on the same day. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion; however, if dexamethasone is administered the day after the daratumumab infusion, additional post-infusion medications may not be needed. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. Treatment with DVT-d significantly improved the overall response rate at Day 100 post-transplant compared with those who received bortezomib, thalidomide, and dexamethasone (VTd) in a multicenter, randomized, phase 3 trial (CASSIOPEIA) (92.6% vs. 89.9%); the stringent complete response rate was also significantly improved in the DVTd arm (28.9% vs. 20.3%). After a median follow-up of 18.8 months, the median progression-free survival had not been reached in either arm; however, the reduction in the risk of progression or death was significantly reduced by 53% in the DVTd arm compared with VTd.[64528] [60311]

8 mg/kg (actual body weight) IV on days 1 and 2, 16 mg/kg IV weekly on weeks 2 to 8 (7 doses), 16 mg/kg IV every 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25. Administer in combination with IV carfilzomib (20 mg/m2 and 56 mg/m2 twice weekly regimen or 20 mg/m2 and 70 mg/m2 once weekly regimen) and PO/IV dexamethasone until disease progression or unacceptable toxicity. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (give IV prior to the first infusion; oral administration may be considered thereafter). Give the treatment dexamethasone dose as the daratumumab premedication steroid when these drugs are scheduled on the same day. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. At a median follow-up time of about 17 months, the median progression-free survival was significantly improved in patients with relapsed or refractory multiple myeloma who received carfilzomib 20 mg/m2 and 56 mg/m2 twice weekly regimen, daratumumab, and dexamethasone compared with carfilzomib and dexamethasone alone (median time not reached vs. 15.8 months; hazard ratio = 0.63; 95% CI, 0.46 to 0.85; p = 0.0027) in a multicenter, randomized (2:1), open-label, phase 3 trial (n = 466; the CANDOR trial). At a median follow-up time of 16.6 months (range, 0.5 to 27.4 months), the overall response rate was 84% (complete response rate, 33%) in patients with relapsed or refractory multiple myeloma who received carfilzomib 20 mg/m2 and 70 mg/m2 once weekly regimen, daratuzumab, and dexamethasone in a multicenter, multi-arm, phase 1b trial (n = 85; EQUULEUS trial).

16 mg/kg IV on days 1, 8, and 15 repeated every 21 days on cycles 1, 2, 3, and 4 followed by high-dose chemotherapy and an autologous stem-cell transplant and then 2 additional cycles of daratumumab 16 mg/kg IV day 1 repeated every 21 days (cycles 5 and 6) plus lenalidomide, bortezomib, and dexamethasone (VRd regimen) was evaluated in a randomized, phase 2 trial (the GRIFFIN trial; n = 207). VRd treatment consisted of lenalidomide 25 mg orally daily on days 1 to 14; bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16 repeated every 21 days for 6 cycles. Maintenance therapy was given for up to 2 years and consisted of daratumumab 16 mg/kg IV on day 1 repeated every 4 or 8 weeks and lenalidomide 10 mg PO daily on days 1 to 21 (increased to 15 mg after 3 cycles if tolerated) repeated every 28 days. Patients received premedication with acetaminophen (650 mg to 1,000 mg PO), an antihistamine (H1-receptor agonist), and montelukast 10 mg orally prior to the first daratumumab infusion and then as necessary prior to subsequent infusions. Patients with mild asthma, mild chronic obstructive pulmonary disease, or a higher risk of respiratory complications (e.g., patients with a FEV1 of less than 80%) could receive post-infusion medications (e.g., antihistamines, short-acting beta-2 adrenergic receptor agonist, inhaled corticosteroids, long-acting bronchodilators, and/or long-acting beta-2 adrenergic receptor agonists). Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy.

No dosage adjustments are necessary for patients with pre-existing mild (total bilirubin level of 1 to 1.5-times the upper limit of normal (ULN) and any ALT level) or moderate (total bilirubin level 1.5 to 3-times the ULN and any ALT level) hepatic impairment based on a population pharmacokinetic analysis. Daratumumab has not been evaluated in patients with severe hepatic impairment (total bilirubin level greater than 3-times the ULN and any ALT level).

No daratumumab dosage adjustment is necessary for patients with pre-existing renal impairment based on a population pharmacokinetic analysis.

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

Daratumumab/DARZALEX Intravenous Inj Sol: 1mL, 20mg

16 mg/kg/dose (actual body weight) IV.

16 mg/kg/dose (actual body weight) IV.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

Daratumumab is a human monoclonal antibody that binds to CD38 IgG1 (kappa subclass), a type II transmembrane glycoprotein, resulting in apotosis via Fc-mediated cross linking, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis. CD38 is expressed on myeloid-derived suppressor cells and some regulatory T-cells (CD38+Tregs ); these cells are sensitive to daratumumab.

Daratumumab is administered as an IV infusion. In a population pharmacokinetic analysis of daratumumab as monotherapy and as part of combination therapy, the mean central volume of distribution (Vd) values were 4.7 +/- 1.3 L and 4.4 +/- 1.5 L, respectively. The mean estimated terminal half-life value associated with linear clearance was 18 +/- 9 days following daratumumab monotherapy; the mean terminal half-life was similar following daratumumab as combination therapy. Daratumumab clearance decreased with increasing dose and repeated dosing. The mean linear clearance was 171.4 +/- 95.3 mL/day for monotherapy.[60311]

At the end of weekly dosing, the mean daratumumab Cmax level was about 2.7- to 3-times higher than the mean Cmax level following the first dose. Additionally, the mean Cmin level (trough) was 573 +/- 332 mcg/mL when daratumumab was administered as monotherapy and 502 +/- 196 mcg/mL to 607 +/- 231 mcg/mL when daratumumab was administered as part of combination therapy. In a population pharmacokinetic analysis in patients with multiple myeloma, steady-state levels were achieved at about 5 months after the daratumumab 16 mg/kg IV every 4-week dosing period (by the 21st infusion); the mean steady-state to first dose Cmax ratio was 1.6 (SD +/- 0.5). The AUC values increased more than dose-proportionally over the range of 1 to 24 mg/kg for monotherapy and 1 to 16 mg/kg for combination therapy. A week 1 day 1 split-dose infusion of 8 mg/kg IV resulted in a different pharmacokinetic profile in the first day compared with a single-dose infusion of 16 mg/kg; however, similar Cmax and Cmin concentrations occurred following the administration of the second 8 mg/kg split dose on week 1 day 2.[60311]

It is not known whether daratumumab is secreted in human milk or if it affects the breastfed child or milk production. It is known that human IgG is present in human milk; however, published data suggest that only small amounts of antibodies enter the neonatal and infant circulation. Advise women who are receiving daratumumab in combination with thalidomide or a thalidomide analog (e.g., lenalidomide and pomalidomide) to avoid breast-feeding due to the potential for serious adverse reactions in the breastfed child with this combination therapy.