Daratumumab, a recombinant humanized anti-CD38 monoclonal antibody, is an antineoplastic agent.1, 2, 5, 12
Daratumumab and hyaluronidase-fihj is a fixed combination of daratumumab (a recombinant humanized anti-CD38 monoclonal antibody) and hyaluronidase (an endoglycosidase).14
Daratumumab (Darzalex®) is commercially available in the US as an injection for IV use.1 It is also commercially available in a fixed combination with hyaluronidase (Darzalex Faspro®), an endoglycosidase, for subcutaneous injection.14
Daratumumab and daratumumab/hyaluronidase-fihj are used for the treatment of multiple myeloma in combination with lenalidomide and dexamethasone in newly diagnosed adults who are ineligible for autologous stem cell transplant and in adults with relapsed or refractory multiple myeloma who have received at least 1 prior therapy.1, 14 Daratumumab is designated an orphan drug by FDA for this use.3
Daratumumab and daratumumab/hyaluronidase-fihj are also used for the treatment of multiple myeloma in combination with bortezomib, melphalan, and prednisone in newly diagnosed adults who are ineligible for autologous stem cell transplant.1, 14 Daratumumab is designated an orphan drug by FDA for this use.3
Daratumumab and daratumumab/hyaluronidase-fihj are also used for the treatment of multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed adults who are eligible for autologous stem cell transplant.1, 14 Daratumumab is designated an orphan drug by FDA for this use.3
Daratumumab and daratumumab/hyaluronidase-fihj are also used for the treatment of multiple myeloma in adults in combination with bortezomib and dexamethasone in patients who received at least 1 prior therapy.1, 14 Daratumumab is designated an orphan drug by FDA for this use.12
Daratumumab and daratumumab/hyaluronidase-fihj are also used for the treatment of multiple myeloma in adults in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy.1, 14 Daratumumab is designated an orphan drug by FDA for this use.3
Daratumumab and daratumumab/hyaluronidase-fihj are also used for the treatment of multiple myeloma in adults in combination with pomalidomide and dexamethasone in patients who have received at least 1 prior line of therapy (daratumumab/hyaluronidase-fihj) or 2 prior therapies (daratumumab) including lenalidomide and a proteasome inhibitor.1, 14 Daratumumab is designated an orphan drug by FDA for this use.3
Daratumumab and daratumumab/hyaluronidase-fihj are also used as monotherapy for the treatment of multiple myeloma in adults who have received at least 3 prior therapies including a proteasome inhibitor and an immunomodulatory agent or in those double refractory to a proteasome inhibitor and an immunomodulatory agent.1, 14 Daratumumab is designated an orphan drug by the FDA for this use.3
Daratumumab/hyaluronidase-fihj is also used for the treatment of multiple myeloma in adults in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant.14
Combination Therapy with Lenalidomide and Dexamethasone
The current indication for IV daratumumab in combination with lenalidomide and dexamethasone in adults with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant is based principally on the results of an open-label, multicenter phase 3 study (MAIA) in 737 adults.1, 15, 16 Patients were randomized to receive daratumumab plus oral lenalidomide (25 mg once daily on days 1-21) and oral dexamethasone (40 mg on days 1, 8, 15, and 22) or lenalidomide and dexamethasone alone (at the same dosages) in 28-day cycles.1, 15 Patients in the daratumumab group received IV daratumumab 16 mg/kg once a week for the first 2 cycles, then every 2 weeks during cycles 3-6, then every 4 weeks thereafter until disease progression or unacceptable toxicity occurred.1, 15 The median age of patients enrolled in the study was 73 years, and patients had a median time since diagnosis of multiple myeloma of 0.9 months.1, 15 There were 52% of patients who were male; 92% were white and 4% were Black.1 The main efficacy endpoint of this study was progression-free survival, defined as the time from randomization to either disease progression or death.1, 15 At a median follow-up of 28 months, disease progression or death had occurred in 26.4% of patients in the daratumumab group versus 38.8% of patients in the control group.15 For the daratumumab group, there was a substantial prolongation of median progression-free survival (not reached) when compared with the control group (31.9 months).15 At a median follow-up of 56.2 months, the median progression-free survival was not reached for the daratumumab group versus 34.4 months in the control group.16 The median overall survival was not reached for either the daratumumab or control group.1, 16
The current indication for IV daratumumab in combination with lenalidomide and dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least 1 prior therapy is based principally on the results of an open-label, randomized, active-controlled phase 3 trial (POLLUX) in 569 adults.1, 17, 18 Patients with relapsed or refractory multiple myeloma were randomized to receive either daratumumab plus oral lenalidomide (25 mg once daily on days 1-21) and dexamethasone (40 mg once weekly split into 20 mg before daratumumab infusion and 20 mg day after daratumumab infusion), or lenalidomide (same dosage) and dexamethasone (40 mg once weekly) in 28-day cycles.1, 17 Patients in the daratumumab group received IV daratumumab 16 mg/kg once a week for the first 2 cycles, then every 2 weeks during cycles 3-6, and then every 4 weeks thereafter until disease progression or unacceptable toxicity occurred.17 The median age of patients enrolled was 65 years, and patients had a median time since diagnosis of multiple myeloma of 3.6 years.17 There were 59% of patients who were male; 69% were white, 18% were Asian, and 3% were Black.1 Patients had received a median of 1 prior line of therapy including autologous stem cell transplant (63%), a proteasome inhibitor (86%), an immunomodulatory agent (55%), or a proteasome inhibitor and immunomodulatory agent (44%).1, 17 The main efficacy endpoint was progression-free survival, defined by International Myeloma Working Group (IMWG) criteria.1 At a median follow-up of 13.5 months, disease progression or death had occurred in 18.5% of patients in the daratumumab group versus 41% of patients in the control group.17 For the daratumumab group, the median progression-free survival was not reached; for the control group, the median progression-free survival was 18.4 months.17 After a median follow-up of 55 months, patients in the daratumumab group had a median progression-free survival of 45 months compared to a median of 17.5 months for patients in the control group.1 An overall survival analysis at a median follow-up of 79.7 months found a median overall survival of 67.6 months for patients in the daratumumab group versus 51.8 months for patients in the control group.1, 18
The current indication for subcutaneous daratumumab/hyaluronidase-fihj in combination with lenalidomide and dexamethasone in adults with relapsed or refractory multiple myeloma is based principally on the results of a single-arm cohort of a multi-cohort open-label trial (PLEIADES).14, 19 In this cohort, 65 adults with relapsed or refractory multiple myeloma who received at least 1 prior therapy received subcutaneous daratumumab at a flat dose of 1800 mg (with 30,000 units of hyaluronidase) once weekly for 8 weeks, then once every 2 weeks from weeks 9-24, and then once every 4 weeks thereafter until disease progression or unacceptable toxicity.14, 19 Patients in this cohort also received oral lenalidomide 25 mg once daily for days 1-21 of each 28-day cycle and dexamethasone (orally or IV) 40 mg once weekly.14, 19 The median age was 69 years; 69% were male, 69% were white, and 3% were Black.14, 19 The median time since diagnosis was 35 months.[r19] Patients received a median of 1 prior line of therapy that may have included autologous stem cell transplant (52%), a proteasome inhibitor (95%), a prior immunomodulatory agent (59%), or a proteasome inhibitor and an immunomodulatory agent (54%).14 The main efficacy endpoint was overall response rate.14, 19 At a median follow-up of 7.1 months, the overall response rate for this cohort was 90.8%.14, 19
Combination Therapy with Bortezomib, Melphalan, and Prednisone
The current indication for IV daratumumab in combination with bortezomib, melphalan, and prednisone in adults with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant is based principally on the results of an open-label, randomized, active-controlled phase 3 trial (ALCYONE) in 706 adults.1, 20, 21 Patients with newly diagnosed multiple myeloma ineligible for stem cell transplant were randomized to receive IV daratumumab in combination with subcutaneous bortezomib (1.3 mg/m2of body-surface area [BSA] twice weekly on weeks 1, 2, 4, and 5 for cycle 1 followed by once weekly on weeks 1, 2, 4, and 5 for cycles 2-9), oral melphalan (9 mg/m2once daily on days 1-4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1-4 of each cycle) or the combination of subcutaneous bortezomib, oral melphalan, and oral prednisone at the same dosages without daratumumab in 6-week cycles.1, 20, 21 Patients in the daratumumab group received IV daratumumab 16 mg/kg once weekly for 1 cycle, once every 3 weeks in cycles 2-9, and once every 4 weeks thereafter until disease progression or unacceptable toxicity.21 Patients in the daratumumab group also received oral or IV dexamethasone 20 mg to manage infusion reactions, which was substituted for prednisone on day 1 of each cycle.20 The median age of patients enrolled was 71 years; 85% were white and 54% were female.1 The median time since diagnosis was 0.8 months.20 The main efficacy endpoint was progression-free survival.1, 20, 21 After a median follow-up of 16.5 months, disease progression or death had occurred in 25.1% of patients in the daratumumab group compared with 40.2% of patients in the control group.20 For the daratumumab group, the median progression-free survival was substantially prolonged (median not reached) compared with the control group (18.1 months).20 After a median follow-up of 40 months, the median progression-free survival was 36.4 months for patients who received daratumumab compared to 19.3 months for patients who received control.1 Median overall survival had not been reached for either group at 40 months.1, 21 After a median follow-up of 87 months, the median overall survival for the daratumumab group was 83 months versus 53.6 months for the control group.1
The current indication for subcutaneous daratumumab/hyaluronidase-fihj in combination with bortezomib, melphalan, and prednisone in adults with newly diagnosed multiple myeloma who are ineligible for transplant is based principally on the results of a single-arm cohort of the multi-cohort open-label PLEIADES trial.14, 19 In this cohort, 67 adults received subcutaneous daratumumab at a flat dose of 1800 mg (with 30,000 units of hyaluronidase) once weekly for 6 weeks, then once every 3 weeks from weeks 7-54, and then once every 4 weeks thereafter until disease progression or unacceptable toxicity.14, 19 Patients in this cohort also received the following in 6-week cycles: subcutaneous bortezomib 1.3 mg/m2 twice weekly on weeks 1, 2, 4, and 5 for cycle 1, followed by once weekly on weeks 1, 2, 4, and 5 for cycles 2-9; and oral melphalan 9 mg/m2 and prednisone 60 mg/m2 on days 1-4 of the first 9 cycles.14, 19 The median age was 75 years; 46.3% were male, 69% were white, 8% were Asian, and 2% were Black.14, 19 The median time since diagnosis was 1.2 months.19 The main efficacy outcome was overall response rate.14, 19 At a median follow-up of 6.9 months, the overall response rate for this cohort was 88.1%.14, 19
Combination Therapy with Bortezomib, Thalidomide, and Dexamethasone
The current indication for IV daratumumab in combination with bortezomib, thalidomide, and dexamethasone in adults who are eligible for autologous stem cell transplant is based principally on the results of an open-label, two-part, multicenter, randomized, active-controlled, phase 3 trial (CASSIOPEIA) in 1085 adults.1, 22, 23 Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplant were randomized to receive induction and consolidation treatment with either daratumumab in combination with bortezomib, thalidomide, and dexamethasone or bortezomib, thalidomide, and dexamethasone alone.1, 22 All patients received up to 4 pre-stem cell transplant induction cycles and 2 post-transplant consolidation cycles of therapy; cycles were each 28 days in length.22 Subcutaneous bortezomib (1.3 mg/m2) was given twice weekly for 2 weeks on days 1, 4, 8, and 11 for the induction and consolidation cycles.1, 22 Oral thalidomide (100 mg daily) was administered during all cycles.1, 22 Oral or IV dexamethasone was administered at 40 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 for cycles 1 and 2 and days 1 and 2 for cycles 3 and 4 and at 20 mg on days 8, 9, 15, and 16 for cycles 3 and 4 and days 1, 2, 8, 9, 15, and 16 of cycles 5 and 6.1, 22 Patients in the daratumumab group received IV daratumumab 16 mg/kg once weekly for cycles 1 and 2, followed by once every 2 weeks for cycles 3-6.22 The median age of patients enrolled in this study was 58 years; 59% were male.1 The median time since diagnosis was 0.9 months.22 For part 1 of the CASSIOPEIA study, the main efficacy endpoint was stringent complete response assessed 100 days after transplant.22 The median duration of follow-up for part 1 of CASSIOPEIA was 18.8 months.22 At day 100 post-transplant, 29% of patients in the daratumumab group had achieved a stringent complete response versus 20% of patients in the control group.1, 22 For part 2 of the CASSIOPEIA study, 886 adults (who were included in part 1 and had a partial response or better) were randomized to receive maintenance IV daratumumab 16 mg/kg every 8 weeks or observation only for up to 2 years.23 The main efficacy endpoint for part 2 was progression-free survival from second randomization.23 After a median follow-up of 35.4 months, the median progression-free survival had not been reached for patients re-randomized to the daratumumab group versus 46.7 months for patients re-randomized to the observation only group.23 A long-term follow-up of the CASSIOPEIA study reported results after a median follow-up of 80.1 months from the first randomization (part 1) and 70.6 months from second randomization (part 2).24 From first randomization (regardless of second randomization), median progression-free survival was substantially prolonged for patients who were originally randomized to the daratumumab group (83.7 months) versus patients originally randomized to the active-control group (52.8 months); median overall survival had not been reached for either group.24 From second randomization, the median progression-free survival was also substantially prolonged for patients in the daratumumab maintenance group (median not reached) compared with patients in the observation group (45.8 months).24 Median progression-free survival was also substantially prolonged for patients originally randomized and re-randomized to the daratumumab group (median not reached) versus patients originally randomized to daratumumab and re-randomized to observation only (72.1 months), as well as for patients originally randomized to active-control and re-randomized to daratumumab (median not reached) versus patients originally randomized to active-control and re-randomized to observation only (32.7 months).24
Combination Therapy with Bortezomib and Dexamethasone
The current indication for IV daratumumab in combination with bortezomib and dexamethasone in adults who have received at least 1 prior therapy for multiple myeloma is based principally on the results of an open-label, multicenter, randomized, active-controlled, phase 3 trial (CASTOR) in 498 adults.1, 25, 26 Patients with relapsed or refractory multiple myeloma were randomized to receive IV daratumumab in combination with bortezomib and dexamethasone or bortezomib and dexamethasone alone for up to 8 cycles, with 21 days per cycle.1, 25, 26 All patients received subcutaneous bortezomib (1.3 mg/m2) twice weekly for 2 weeks on days 1, 4, 8, and 11 of each cycle.1, 25, 26 Oral or IV dexamethasone was administered at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle for a total of 160 mg per cycle.1, 25, 26 Patients who were randomized to receive daratumumab received IV daratumumab 16 mg/kg once weekly on days 1, 8, and 15 during cycles 1-3, followed by once every 3 weeks during cycles 4-8, and then once every 4 weeks thereafter until disease progression or unacceptable toxicity.1, 25, 26 The median age was 64 years; 57% were male, 87% were white, 5% were Asian, and 4% were Black.1 Patients had received a median of 2 prior lines of therapy which may have included autologous stem cell transplant (61%), a proteasome inhibitor (69%), and/or an immunomodulatory agent (76%).1, 25 The median time since initial diagnosis for this study was 3.8 years.25 The main efficacy endpoint was progression-free survival.1, 25 After a median follow-up of 7.4 months, disease progression or death had occurred in 67 patients in the daratumumab group and in 122 patients in the control group.25 The median progression-free was significantly prolonged for patients in the daratumumab group (median not reached) compared with patients in the control group (7.2 months).25 After a 50-month median follow-up, the median progression-free survival was 16.7 and 7.1 months for patients in the daratumumab and control groups, respectively.1 An overall survival analysis at a median follow-up of 72.6 months found a median overall survival of 49.6 months for patients in the daratumumab group versus 38.5 months for patients in the control group.1, 26
Combination Therapy with Carfilzomib and Dexamethasone
The current indication for IV daratumumab in combination with carfilzomib and dexamethasone in adults with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy was based principally on the results of an open-label, multicenter, randomized, active-controlled, phase 3 trial (CANDOR) and an open-label, multi-cohort phase 1b study (EQUULEUS).27, 28, 29, 30 In CANDOR, 466 adults with relapsed or refractory multiple myeloma were randomized to receive IV daratumumab in combination with carfilzomib and dexamethasone or carfilzomib and dexamethasone alone in 28-day cycles.1, 27 All patients received carfilzomib as a 30-minute IV infusion at a dose of 20 mg/m2 on days 1 and 2 of cycle 1; at a dose of 56 mg/m2 on days 8, 9, 15, and 16 of cycle 1; and at a dose of 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 for each cycle thereafter.1, 27 Oral or IV dexamethasone was administered at 20 mg on days 1, 2, 8, 9, 15, and 16 and at 40 mg on day 22 of each cycle.1 Patients who were randomized to receive daratumumab received IV daratumumab 8 mg/kg for days 1 and 2 of cycle 1, followed by 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3 to 6), and every 4 weeks thereafter.1, 27 For both groups, treatment was continued until disease progression or unacceptable toxicity.1 The median age of patients in this study was 64 years; 58% were male, 79% were white, 14% were Asian, and 2% were Black.1 Patients had received a median of 2 prior lines of therapy which may have included autologous stem cell transplantation (58%) and/or a proteasome inhibitor (92%).1 The main efficacy outcome was progression-free survival.1, 27 At a median follow-up of about 17 months, the median progression-free survival was not reached for patients in the daratumumab group compared with 15.8 months for patients in the control group.27 In an updated analysis, after a median follow-up of 27.8 months for patients in the daratumumab group and 27 months for patients in the control group, the median progression-free survival was 28.6 months and 15.2 months for each group, respectively.28 Another analysis of the CANDOR study reported results after a median follow-up of 50 months.29 The median progression-free survival and overall survival at this time point was 28.4 months and 50.8 months ,respectively for patients in the daratumumab group and 15.2 months and 43.6 months respectively for patients in the control group.29
In EQUULEUS, 85 adults (carfilzomib- and daratumumab-naïve) with relapsed or refractory multiple myeloma who received at least 1 prior therapy, were administered IV daratumumab plus carfilzomib and dexamethasone in 28-day cycles until disease progression.1, 30 Of these patients, 10 received daratumumab 16 mg/kg IV on day 1 of cycle 1.1, 30 The other 75 patients received daratumumab 8 mg/kg IV on days 1 and 2 of cycle 1.1, 30 Thereafter, all groups were given IV daratumumab 16 mg/kg on days 8, 15, and 22 of cycle 1; days 1, 8, 15, and 22 of cycle 2; days 1 and 15 of cycles 3-6; and day 1 of each cycle thereafter.1, 30 All patients also received IV carfilzomib once weekly at a dose of 20 mg/m2 on day 1 of cycle 1, followed by a dose of 70 mg/m2 on days 8 and 15 of cycle 1 and days 1, 8, and 15 of each cycle thereafter.1, 30 Oral or IV dexamethasone was also administered at a dosage of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1 and 2; days 1, 2, 15, and 16 of cycles 3-6 followed by a dosage of 40 mg on days 8 and 22 of cycles 3-6.1 For cycle 7 and beyond, dexamethasone 20 mg was administered on days 1 and 2, and dexamethasone 40 mg was administered on days 8, 15, and 40.1 The median patient age was 66 years; 54% were male, 80% were white, 3.5% were Asian, and 3.5% were Black.1 Patients had received a median of 2 prior lines of therapy which may have included autologous stem cell transplant (73%).1, 30 All patients had received prior therapy with bortezomib, and 95% had received prior lenalidomide.1, 30 The main efficacy endpoint was overall response rate using IMWG criteria.1 At a median follow-up of 16.6 months, the overall response rate for all treated patients was 84%.30 Median progression-free survival and overall survival had not been reached.30
The current indication for subcutaneous daratumumab/hyaluronidase-fihj in combination with carfilzomib and dexamethasone in adults with relapsed or refractory multiple myeloma who have received 1-3 prior therapies is based principally on the results of a single-arm of an open-label multi-cohort study (PLEIADES).14, 31 This cohort of PLEIADES enrolled 66 adults who all received subcutaneous daratumumab 1800 mg (with 30,000 units of hyaluronidase) once weekly for 8 weeks, followed by once every 2 weeks for weeks 9-24, and finally once every 4 weeks thereafter until disease progression or unacceptable toxicity.14, 31 All patients also received IV carfilzomib at a dose of 20 mg/m2 on day 1 of cycle 1, followed by 70 mg/m2 on days 8 and 15 of cycle 1 and then days 1, 8, and 15 of each subsequent cycle.14 Dexamethasone was administered at a dosage of 40 mg per week.14 The median age of this cohort of the PLEIADES study was 61 years; 52% were male, 73% were white, and 3% were Black.14 Patients had received a median of 1 prior therapy, which may have included autologous stem cell transplant (79%) and/or a proteasome inhibitor (91%).14, 31 The median treatment duration was 12 months.31 The main efficacy outcome was overall response rate.14, 31 After a median follow-up of 12.4 months, the overall response rate for all patients in this PLEIADES cohort was 84.8%.14, 31 Progression-free survival and overall survival were not assessed for this study.31
Combination Therapy with Pomalidomide and Dexamethasone
The current indication for IV daratumumab in combination with pomalidomide and dexamethasone in adults with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor, is based principally on the results of an open-label, multi-cohort phase 1b study (EQUULEUS).1, 32 In one cohort of EQUULEUS, 103 patients received IV daratumumab 16 mg/kg in combination with oral pomalidomide (4 mg once daily on days 1-21 of each cycle) and dexamethasone (40 mg per week) in 28-day cycles.1, 32 Daratumumab was administered once weekly for cycles 1 and 2, followed by once every 2 weeks for cycles 3-6, and then once every 4 weeks thereafter until disease progression.32 The median age of this cohort of the EQUULEUS study was 64 years; 55% were male, and 77% were white.32 Patients had received a median of 4 prior lines of therapy in this study, which may have included autologous stem cell transplant (74%), bortezomib (98%), and/or carfilzomib (33%).1, 32 All patients had previously received lenalidomide treatment.1, 32 The median time since diagnosis of multiple myeloma was 5.1 years.32 The main efficacy outcome was overall response rate, determined by IMWG criteria.1, 32 For all patients in this cohort, the overall response rate was 60%.1, 32 After a median follow-up of 13.1 months, the median progression-free survival and overall survival were 8.8 months and 17.5 months, respectively.32
The current indication for subcutaneous daratumumab/hyaluronidase-fihj in combination with pomalidomide and dexamethasone in adults with multiple myeloma who have received at least 1 prior line of therapy including lenalidomide and a proteasome inhibitor is based principally on the results of an open-label, randomized, active-controlled phase 3 trial (APOLLO) in 304 adults.14, 33, 34 Patients with relapsed or refractory multiple myeloma were randomized to receive daratumumab in combination with oral pomalidomide (4 mg once daily on days 1-21 of each cycle) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22 of each cycle) or pomalidomide and dexamethasone alone (at same dosages) in 28-day cycles.14, 33 Patients in the daratumumab group received IV daratumumab 16 mg/kg or subcutaneous daratumumab 1800 mg (with 30,000 units of hyaluronidase) once weekly from weeks 1-8, then once every 2 weeks from weeks 9-24, then once every 4 weeks thereafter until disease progression or unacceptable toxicity.14, 33 The median age of patients was 67 years; 53% were male and 89% were white.14 Patients had received a median of 2 prior lines of therapy, which may have included autologous stem cell transplantation (56%).14 All patients had received prior treatment with a proteasome inhibitor and lenalidomide.14 The median time since diagnosis was 4.4 years.33 Of the patients in the daratumumab group, 142 patients (95%) received only the subcutaneous dosage form.33 Only 7 patients initiated treatment with IV daratumumab; among these patients, 4 patients switched to the subcutaneous formulation, and 3 progressed on IV treatment before switching was permitted.33 The main efficacy endpoint was progression-free survival.33 After a median follow-up of 16.9 months, 56% of patients in the daratumumab group had disease progression or death occur compared with 69% of patients in the control group.33 Median progression-free survival was substantially prolonged in the daratumumab group (12.4 months) versus the control group (6.9 months).14, 33 An overall survival analysis of the APOLLO trial was also conducted at a median follow-up of 39.6 months.34 The median overall survival for the daratumumab group was 34.4 months versus 23.7 months in the control group.34
Monotherapy in Relapsed/Refractory Disease
The current indication for IV daratumumab as monotherapy is based principally on the results of an open-label, multicenter phase 2 study (SIRIUS) in 106 adults with relapsed or refractory multiple myeloma, with supporting data from an open-label, multicenter phase 1/2 study.1, 2, 5 In the SIRIUS study, 106 patients with relapsed or refractory multiple myeloma received IV daratumumab 16 mg/kg once a week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), then every 4 weeks thereafter until disease progression or unacceptable toxicity occurred.1, 2 The median age of patients enrolled in the study was 63.5 years, and patients had received a median of 5 prior therapies for their disease, including bortezomib (99%), lenalidomide (99%), pomalidomide (63%), carfilzomib (50%), and thalidomide (44%).1, 2 The majority of patients were refractory to their last line of therapy (97%), a proteasome inhibitor and an immunomodulatory agent (95%), or an alkylating agent (77%).1 Most patients (80%) had received an autologous stem-cell transplant.1 The primary endpoint of this study was overall response rate as assessed by an independent review committee according to the IMWG criteria; secondary endpoints included progression-free survival, overall survival, clinical benefit rate, and duration of response.1, 2 The overall response rate with daratumumab was 29.2% with a median duration of response of 7.4 months; 3 patients (2.8%) achieved a stringent complete response.1, 2 The clinical benefit rate (defined as overall response rate and minimal response) was 34%.2 The median time to initial response was 1 month.1 Median progression-free survival was 3.7 months; however, median overall survival had not been reached in patients who achieved a response, but was 13.7 months in nonresponders.2
In the phase 1/2 study, 42 patients with relapsed or refractory multiple myeloma received IV daratumumab 16 mg/kg once a week for 7 weeks, then every 2 weeks for 14 weeks, then every 4 weeks thereafter until disease progression or unacceptable toxicity occurred.1, 5 The median age of patients enrolled in the study was 64 years, and patients had received a median of 4 prior therapies for their disease, including bortezomib (100%), lenalidomide (95%), pomalidomide (36%), and carfilzomib (19%).1 Most patients were refractory to their last line of therapy (76%), a proteasome inhibitor and an immunomodulatory agent (64%), or an alkylating agent (60%).1 Most patients (74%) had received an autologous stem-cell transplant.1 The overall response rate with daratumumab was 36% with a median time to response of 1 month;1, 5 1 patient achieved a complete response.1 The median duration of response had not been reached at the time of the analysis.1
The current indication for subcutaneous daratumumab/hyaluronidase-fihj as monotherapy is based principally on the results of an open-label, randomized, non-inferiority phase 3 trial (COLUMBA) in 522 adults with relapsed or refractory multiple myeloma who had received at least 3 prior therapies including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent.14, 35, 36 Patients were randomized to receive IV daratumumab (16 mg/kg) or subcutaneous daratumumab (1800 mg with 30,000 units of hyaluronidase).14, 35 Both groups received daratumumab once weekly from weeks 1-8, once every 2 weeks from weeks 9-24, and then once every 4 weeks thereafter until disease progression or unacceptable toxicity.14, 35 The median age of this study was 67 years; 55% were male, 78% were white, 14% were Asian, and 3% were Black.14 Patients received a median of 4 prior lines of therapy which may have included autologous stem cell transplant (51%).14 All patients had previously received a proteasome inhibitor and an immunomodulatory agent.14 The main efficacy outcomes were overall response rate and maximum trough concentration (Ctrough) at pre-dose on day 1 of cycle 3.14, 35 At a median follow-up of 7.5 months, subcutaneous daratumumab/hyaluronidase-fihj was found non-inferior to IV daratumumab, with overall response rates of 41% and 37%, respectively.14, 35 Median progression-free survival was 5.6 months for the subcutaneous daratumumab/hyaluronidase-fihj group and 6.1 months for the IV daratumumab group.14, 35 A follow-up analysis of the COLUMBA was conducted at a median follow-up of 29.3 months.36 The overall response rate at this time point was 44% for subcutaneous daratumumab/hyaluronidase-fihj and 40% for IV daratumumab.36 The median progression-free survival remained consistent at 5.6 months and 6.1 months for subcutaneous daratumumab/hyaluronidase-fihj and IV daratumumab, respectively.36 The median overall survival was 28.2 months for subcutaneous daratumumab/hyaluronidase-fihj versus 25.6 months for IV daratumumab.36
Combination Therapy with Bortezomib, Lenalidomide, and Dexamethasone
The current indication for subcutaneous daratumumab/hyaluronidase-fihj in combination with bortezomib, lenalidomide, and dexamethasone in adults who are eligible for autologous stem cell transplant is based principally on the results of an open-label, randomized, active-controlled phase 3 trial (PERSEUS) in 709 adults.14, 37 Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplant were randomized to receive induction and consolidation treatment with either subcutaneous daratumumab/hyaluronidase-fihj in combination with bortezomib, lenalidomide, and dexamethasone or bortezomib, lenalidomide, and dexamethasone alone.13, 37 All patients were to receive 4 pre-stem cell transplant induction cycles and 2 post-transplant cycles.37 All cycles were 28 days in length each.37 For all patients in each cycle, subcutaneous bortezomib (1.3 mg/m2) was given on days 1, 4, 8, and 11.14, 37 Also, for all patients for each cycle, oral lenalidomide (25 mg) was given on days 1-21, and oral or IV dexamethasone (40 mg) was given on days 1-4 and days 9-12.37 Patients in the daratumumab group received subcutaneous daratumumab 1800 mg (with 30,000 units of hyaluronidase) every week for cycles 1 and 2, followed by once every 2 weeks during cycles 3-6.14, 37 The median age of patients in this study was 60 years; 59% were male, 92% were white, 1% were Black, and 1% were Asian.14 The main efficacy outcome was progression-free survival.14, 37 Disease progression or death had occurred in 14.1% of patients in the daratumumab group versus 29.1% of patients in the control group after a median follow-up of 47.5 months.37 Median progression-free survival had not been reached in either the daratumumab group or the control group.14
In 2019, the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) published evidence-based recommendations for the treatment of multiple myeloma, including recommendations for patients who are autologous stem cell transplant eligible, patients who are transplant ineligible, and patients with relapsed or refractory disease.38 For transplant eligible patients, the guideline states that at least 3-4 cycles of induction therapy, including an immunomodulatory drug (e.g., thalidomide, lenalidomide), a proteasome inhibitor (e.g., bortezomib, carfilzomib), and steroids (e.g., dexamethasone), is advised prior to stem cell collection.38 ASCO and CCO state that consolidation therapy post-transplant is not routinely recommended but may be considered in the context of a clinical trial; at least 2 cycles may also be considered for patients ineligible or unwilling to consider maintenance therapy.38 For patients who are transplant ineligible, initial treatment should include, at minimum, an immunomodulatory drug or proteasome inhibitor and steroid if possible.38 Triplet therapies (e.g., bortezomib, lenalidomide, and dexamethasone) should be considered; daratumumab plus bortezomib, melphalan, and prednisone may also be considered.38 For the treatment of relapsed or refractory disease, the guideline recommends triplet therapy with 2 novel agents (i.e., an immunomodulatory drug, a proteasome inhibitor, or a monoclonal antibody) plus a corticosteroid.38 ASCO and CCO state that prior therapies should be taken into consideration when selecting the treatment at first relapse.38 Choice of therapy should be based on patient, disease, and treatment factors, including prior therapies.38 Additional indications in multiple myeloma have been added to the daratumumab labeling after publication of this guideline.1, 38 Daratumumab/hyaluronidase-fihj was also approved after the guideline was published.14, 38
Updated information on treatment of multiple myeloma is also available from the National Cancer Institute (NCI).39 These experts note that while there have been many new therapeutic agents over the past 20 years, there is currently no confirmed curative approach for the treatment of multiple myeloma.39 Patients who are newly diagnosed and require therapy are categorized as either in good or well-controlled health (i.e., transplant eligible) or as less fit with significant comorbidities or advanced age (i.e., transplant ineligible).39 For patients in good or well-controlled health, triplet or quadruplet induction chemotherapy that includes bortezomib may be used in the absence of a clinical trial.39 NCI lists the following as commonly used regimens: daratumumab in combination with bortezomib, lenalidomide, and dexamethasone; bortezomib, lenalidomide, and dexamethasone; and cyclophosphamide, bortezomib, and dexamethasone.39 Patients responding to therapy after 4-8 months may then receive autologous stem cell transplant consolidation.39 Maintenance therapy is then given until disease relapse.39 For patients who are less fit who have significant comorbidities or advanced age, induction chemotherapy with a triplet or quadruplet regimen may be received; for better tolerability, a doublet regimen that includes either daratumumab or isatuximab may also be received.39 Therapy is continued until maximal response, and maintenance therapy is then given until disease relapse.39 Options for maintenance therapy include lenalidomide, ixazomib, and daratumumab alone or in combination, as well as bortezomib.39 For patients who relapse after therapy, new combinations of drugs or single agents may be given sequentially as required.39 Monoclonal antibodies (e.g., daratumumab, elotuzumab, isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), chimeric antigen receptor (CAR) T-cell therapy (e.g., ciltacabtagene autoleucel and idecabtagene vicleucel), bispecific antibody therapy (e.g., teclistamab, talquetamab, elranatamab), immunomodulatory agents (e.g., pomalidomide, lenalidomide, thalidomide), and B-cell maturation antigen-targeting antibody-drug conjugates (e.g., belantamab mafodotin) are all treatment options for relapsed or refractory multiple myeloma.39 Additional treatment options for relapsed or refractory multiple myeloma include cytotoxic chemotherapy agents, selinexor, venetoclax, BRAF/MEK inhibitors, and corticosteroids.39
Daratumumab/hyaluronidase-fihj is used for the treatment of light chain amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone in newly diagnosed adults.14 The accelerated approval of daratumumab/hyaluronidase-fihj for this indication is based on response rate.14 Continued approval for this indication may be contingent on verification and description of clinical benefit of daratumumab/hyaluronidase-fihj in confirmatory studies.14 Daratumumab/hyaluronidase-fihj is designated an orphan drug by FDA for this use.3
Daratumumab/hyaluronidase-fihj is not indicated and not recommended for the treatment of light chain amyloidosis in patients who have New York Heart Association (NYHA) Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.14
The current indication for subcutaneous daratumumab/hyaluronidase-fihj in combination with bortezomib, cyclophosphamide, and dexamethasone for light chain amyloidosis is based principally on the results of an open-label, randomized, active-controlled, phase 3 trial (ANDROMEDA) in 388 adults.14, 40 Patients with newly diagnosed light chain amyloidosis were randomized to receive either subcutaneous daratumumab plus bortezomib, cyclophosphamide, and dexamethasone or bortezomib, cyclophosphamide, and dexamethasone alone in 28-day cycles.14, 40 All patients received subcutaneous bortezomib (1.3 mg/m2), oral or IV cyclophosphamide (300 mg/m2; maximum dose, 500 mg), and oral or IV dexamethasone (40 mg) once weekly for 6 cycles.14, 40 Patients in the daratumumab group received subcutaneous daratumumab 1800 mg (with 30,000 units of hyaluronidase) once weekly for weeks 1-8, then once every 2 weeks for weeks 9-24, and then once every 4 weeks thereafter until disease progression or to a maximum of 2 years of therapy.14, 40 The median patient age in this study was 64 years; 58% were male, 76% were white, 17% were Asian, and 3% were Black.14 The median number of organs involved was 2, which included those with cardiac involvement (71%), renal involvement (59%), and hepatic involvement (8%).14 The median time since diagnosis was 43 days.40 The main efficacy endpoint was hematologic complete response rate, defined as an involved free light-chain level less than the upper limit of normal with negative serum and urine immunofixation.40 At a median follow-up of 11.4 months, the daratumumab group had a substantially higher rate of hematologic complete response (53.3%) compared with the control group (18.1%).40
Amyloidosis occurs when there is a misfolding of protein that leads to an accumulation of insoluble fibrils deposited in various tissues.41 This protein build-up can cause organ dysfunction and eventually death.41 Primary or light chain amyloidosis is the most common type of systemic amyloidosis and occurs from the overproduction of light chains from clonal plasma cells.41, 42 Treatment options for light chain amyloidosis have been adopted from regimens studied in the treatment of multiple myeloma.41, 42 International experts suggest that treatment follow clinical presentation and that all patients should be considered for clinical trials where available.42 Choice of therapy should be based on the degree of organ involvement, performance status, age, and bone marrow findings.42 For untreated patients who are ineligible for high-dose therapy, daratumumab, in combination with bortezomib, cyclophosphamide, and dexamethasone, is recommended.42 If daratumumab is unavailable, bortezomib with oral melphalan and dexamethasone or bortezomib with cyclophosphamide and dexamethasone is recommended.42 Routine maintenance and consolidation are not currently recommended.42 For relapsed disease, the general treatment approach includes the use of a class of agents not previously used with consideration of limitations due to the fitness and frailty of the patient and any end organ damage.42
Dispensing and Administration Precautions
Daratumumab is available as a single agent (Darzalex®) and coformulated with hyaluronidase (daratumumab/hyaluronidase-fihj; Darzalex Faspro®).1, 14 The single agent product is administered via IV infusion, while daratumumab/hyaluronidase-fihj is administered via subcutaneous injection.1, 14
Daratumumab is administered by IV infusion.1 Daratumumab infusion solution should be administered using polyurethane, polybutadiene, polyvinyl chloride (PVC), polypropylene, or polyethylene administration sets fitted with a flow regulator and a low-protein-binding 0.2- or 0.22-µm inline polyethersulfone filter.1
Other drugs should not be administered simultaneously through the same IV line with daratumumab infusion.1
If a dose is missed or delayed, the dose of daratumumab should be administered as soon as possible.1 The schedule of administration should be adjusted to maintain the appropriate treatment interval between doses.1
Daratumumab vials of the same strength but with different NDCs can be combined in the same infusion bag.1 Unopened vials of daratumumab injection concentrate should be protected from light and stored at 2-8°C, and should not be frozen or shaken.1
Prior to administration, commercially available daratumumab injection concentrate must be diluted using proper aseptic technique.1
Daratumumab injection concentrate should be inspected visually for particulate matter and discoloration; the injection concentrate should be colorless to pale yellow and should not be used if it is discolored or if particulate matter is present.1
The manufacturer states that daratumumab should be diluted in PVC, polypropylene, polyethylene, or polyolefin blend bags.1
For the first dose, 16 mg/kg of daratumumab injection concentrate should be diluted in 0.9% sodium chloride injection to provide a total volume of 1 L; alternatively, the first dose may be split into 2 infusions of 8 mg/kg each and diluted in 0.9% sodium chloride injection to provide a total volume of 500 mL per infusion.1 For subsequent doses of 16 mg/kg, daratumumab injection concentrate may be diluted in 0.9% sodium chloride injection to provide a total volume of 500 mL, provided that no infusion-related reactions were observed with the first dose.1 A volume of diluent equal to the total required volume of daratumumab injection concentrate should be removed from the infusion bag prior to addition of the injection concentrate.1 The total required volume of daratumumab injection concentrate should then be added slowly to the diluent in the infusion bag.1
Diluted solutions of daratumumab should be mixed by gentle inversion and should not be shaken.1 Diluted solutions of daratumumab should be inspected visually for particulate matter and discoloration prior to administration; the solution may contain small translucent-to-white proteinaceous particulates and should not be administered if visibly opaque particles, foreign particles, or discoloration is observed.1 If not used right away, keep the diluted solution refrigerated at 2-8°C for up to 24 hours or at room temperature (15-25°C) for a maximum of 15 hours (including infusion time).1 Store the diluted solution away from light and do not freeze.1 If refrigerated, let the solution reach room temperature before use.1
Any unused portion of injection concentrate left in the vial or diluted solution should be discarded since the injection contains no preservative.1
Administer daratumumab IV at the infusion rates specified in Table 1.1 Consider increasing the infusion rate gradually after the first hour if no infusion-related reactions occur.1
Infusion Week and Dose per Infusion | Dilution Volume (mL) | Initial Rate (First Hour) | Rate Increment | Maximum Rate |
|---|---|---|---|---|
Week 1 (single dose infusion) 16 mg/kg | 1000 | 50 mL/hour | 50 mL/hour every hour | 200 mL/hour |
Week 1 (split dose infusions) 8 mg/kg | 500 | 50 mL/hour | 50 mL/hour every hour | 200 mL/hour |
Week 2 16 mg/kg | 500 (if no infusion-related reaction in week 1; otherwise, continue 1000) | 50 mL/hour | 50 mL/hour every hour | 200 mL/hour |
Week 3 onwards 16 mg/kg | 500 (if no infusion-related reactions in week 1; otherwise, continue 1000) | 100 mL/hour (if no infusion-related reactions in week 2; otherwise, continue 50 mL/hour) | 50 mL/hour every hour | 200 mL/hour |
Daratumumab/hyaluronidase-fihj is administered subcutaneously.14 Do not administer IV.14
Store unopened vials in the refrigerator at 2-8°C; store in the original carton to protect from light, and do not freeze or shake.14 To prepare the solution for subcutaneous administration, remove the vial from refrigerated storage and allow it to come to room temperature (15-30°C) before use.14 Unopened vials may be stored at room temperature and normal lighting for up to 24 hours.14 Avoid direct sunlight and do not shake.14
Withdraw 15 mL of daratumumab/hyaluronidase-fihj from the vial into a polypropylene or polyethylene syringe using a stainless steel transfer needle.14 After the drug is withdrawn into the syringe, replace the transfer needle with a syringe closing cap and label the syringe appropriately to include the administration route per institutional standards.14 To avoid needle clogging, attach the hypodermic stainless steel injection needle or subcutaneous infusion set to the syringe immediately prior to injection.14 Ensure the solution is free from particulate matter and discoloration before administration.14 The solution should not be administered if opaque particles, foreign particles, or discoloration is observed.14 Daratumumab/hyaluronidase-fihj can be used with polypropylene, polyethylene, or PVC subcutaneous infusion sets.14 Administer the drug immediately after preparation of the syringe.14 If not used immediately, store the prepared syringe refrigerated at 2-8°C for up to 24 hours or at room temperature (15-25°C) for up to 12 hours under ambient light.14
Inject daratumumab and hyaluronidase-fihj subcutaneously into the abdominal tissue approximately 3 inches (7.5 cm) to the left or right of the navel, rotating injection sites with each dose.14 Avoid areas that are red, bruised, tender, or hardened, and areas with scars.14 Administer the injection over 3-5 minutes.14 If the patient experiences pain, pause or slow the injection rate; if pain is not alleviated by pausing or slowing down the delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.14 Do not administer other subcutaneous medications at the same injection site.14
If a dose is missed or delayed, the dose of daratumumab/hyaluronidase-fihj should be administered as soon as possible.14 The schedule of administration should be adjusted to maintain the appropriate treatment interval between doses.14
Multiple Myeloma (Daratumumab)
When daratumumab is administered as part of a combination therapy regimen, consult the prescribing information of the other drugs included in the regimen for dosage recommendations pertaining to those drugs.1
For the treatment of multiple myeloma in combination with lenalidomide and dexamethasone in newly diagnosed adults who are ineligible for autologous stem cell transplant and in adults with relapsed or refractory multiple myeloma who have received at least 1 prior therapy, the recommended dosage of daratumumab is 16 mg/kg (actual body weight) once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 16 weeks (weeks 9-24), then every 4 weeks thereafter (from week 25 onward).1 Therapy should be continued until disease progression.1
For the treatment of multiple myeloma in combination with bortezomib, melphalan and prednisone in newly diagnosed adults who are ineligible for autologous stem cell transplant, the recommended dosage of daratumumab is 16 mg/kg (actual body weight) once a week for 6 weeks (weeks 1-6), followed by every 3 weeks for 48 weeks (weeks 7-54), then every 4 weeks thereafter (from week 55 onward).1 Therapy should be continued until disease progression.1
For the treatment of multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed adults who are eligible for autologous stem cell transplant, the recommended dosage of daratumumab is 16 mg/kg (actual body weight).1 For the induction phase, the dose is given once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 8 weeks (weeks 9-16).1 The dosing schedule is then paused for high dose chemotherapy and autologous stem cell transplant.1 For the consolidation phase, the dose is given every 2 weeks for 4 total doses (weeks 1-8).1
For the treatment of multiple myeloma in combination with bortezomib and dexamethasone in adults with relapsed/refractory multiple myeloma who have received at least one prior therapy, the recommended dosage of daratumumab is 16 mg/kg (actual body weight) once a week for 9 weeks (weeks 1-9), then every 3 weeks for 15 weeks (weeks 10-24), then every 4 weeks thereafter (from week 25 onward).1 Therapy should be continued until disease progression.1
For the treatment of multiple myeloma in combination with carfilzomib and dexamethasone in adults with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy, the recommended dosage of daratumumab is 8 mg/kg (actual body weight) for 2 doses in week 1 (days 1 and 2), followed by 16 mg/kg once a week for 7 weeks (weeks 2-8), then 16 mg/kg every 2 weeks for 8 doses (weeks 9-24), then 16 mg/kg every 4 weeks thereafter (from week 25 onward).1 Therapy should be continued until disease progression.1
For the treatment of multiple myeloma in combination with pomalidomide and dexamethasone in adults who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor, the recommended dosage of daratumumab is 16 mg/kg (actual body weight) once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 16 weeks (weeks 9-24), then every 4 weeks thereafter (from week 25 onward).1 Therapy should be continued until disease progression.1
For the treatment of multiple myeloma as monotherapy in patients who have received at least 3 prior therapies including a proteasome inhibitor and an immunomodulatory agent or in those with disease refractory to a proteasome inhibitor and an immunomodulatory agent, the recommended adult dosage of daratumumab is 16 mg/kg (actual body weight) once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 16 weeks (weeks 9-24), then every 4 weeks thereafter (from week 25 onward).1 Therapy should be continued until disease progression.1
For all indications with a recommended 16 mg/kg dose on day 1, this dose can be divided and administered over 2 consecutive days, with 8 mg/kg administered on both day 1 and day 2.1
Multiple Myeloma (Daratumumab/hyaluronidase-fihj)
When daratumumab/hyaluronidase-fihj is administered as part of a combination therapy regimen, consult the prescribing information of the other drugs included in the regimen for dosage recommendations pertaining to those drugs.14
For the treatment of multiple myeloma in combination with lenalidomide and dexamethasone in newly diagnosed adults who are ineligible for autologous stem cell transplant and in adults with relapsed or refractory multiple myeloma who have received at least 1 prior therapy, the recommended dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units administered subcutaneously once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 16 weeks (weeks 9-24), then every 4 weeks thereafter (from week 25 onward).14 Therapy should be continued until disease progression.14
For the treatment of multiple myeloma in combination with bortezomib, melphalan and prednisone in newly diagnosed adults who are ineligible for autologous stem cell transplant, the recommended dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units administered subcutaneously once a week for 6 weeks (weeks 1-6), followed by every 3 weeks for 48 weeks (weeks 7-54), then every 4 weeks thereafter (from week 55 onward).14 Therapy should be continued until disease progression.14
For the treatment of multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed adults who are eligible for autologous stem cell transplant, the recommended dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units administered subcutaneously.14 For the induction phase, the dose is given once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 8 weeks (weeks 9-16).14 The dosing schedule is then paused for high dose chemotherapy and autologous stem cell transplant.14 For the consolidation phase, the dose is given every 2 weeks for 4 total doses (weeks 1-8).14
For the treatment of multiple myeloma in combination with bortezomib and dexamethasone in adults who have received at least 1 prior therapy, the recommended dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units administered subcutaneously once a week for 9 weeks (weeks 1-9), followed by every 3 weeks for 15 weeks (weeks 10-24), then every 4 weeks thereafter (from week 25 onward).14 Therapy should be continued until disease progression.14
For the treatment of multiple myeloma in combination with carfilzomib and dexamethasone in adults with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy, the recommended adult dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units administered subcutaneously once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 16 weeks (weeks 9-24), then every 4 weeks thereafter (from week 25 onward).14 Therapy should be continued until disease progression.14
For the treatment of multiple myeloma in combination with pomalidomide and dexamethasone in adults who have received at least 1 prior line of therapy including lenalidomide and a proteasome inhibitor, the recommended adult dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units administered subcutaneously once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 16 weeks (weeks 9-24), then every 4 weeks thereafter (from week 25 onward).14 Therapy should be continued until disease progression occurs.14
For the treatment of multiple myeloma as monotherapy in adults who have received at least 3 prior therapies including a proteasome inhibitor and an immunomodulatory agent or in those double refractory to a proteasome inhibitor and an immunomodulatory agent, the recommended dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units administered subcutaneously once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 16 weeks (weeks 9-24), then every 4 weeks thereafter (from week 25 onward).14 Therapy should be continued until disease progression.14
For the treatment of multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed adults who are eligible for autologous stem cell transplant, the recommended dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units administered subcutaneously.[r14] For the induction phase, the dose is given once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 8 weeks (weeks 9-16).14 The dosing schedule is then paused for high dose chemotherapy and autologous stem cell transplant.14 For the consolidation phase, the dose is given every 2 weeks for 4 total doses (weeks 1-8).14
For the treatment of light chain amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone in newly diagnosed adults, the recommended dosage of daratumumab/hyaluronidase-fihj is 1800 mg/30,000 units once a week for 8 weeks (weeks 1-8), followed by every 2 weeks for 16 weeks (weeks 9-24), then every 4 weeks thereafter (from week 25 onward).14 Therapy should be continued until disease progression or for a maximum of 2 years.14
Consult the prescribing information of the other drugs included in the regimen for dosage recommendations pertaining to those drugs.14
Therapy Interruption for Toxicity
Infusion- or Systemic Administration-Related Reactions: If infusion-related reactions occur with IV daratumumab, the infusion should be interrupted and the infusion rate should be reduced or therapy with the drug permanently discontinued depending on the severity of the reaction.1 If the infusion-related reaction is grade 4 in severity, therapy with IV daratumumab should be permanently discontinued.1 For the first or second occurrence of grade 3 infusion-related reactions, the daratumumab infusion should be interrupted; once the reaction has improved to grade 2 or less, the infusion may be resumed but the rate of infusion should be reduced by at least 50%.1 If no further infusion-related reactions occur, the infusion rate may be increased in increments and intervals appropriate for the treatment dose.1 For the third occurrence of grade 3 infusion-related reactions, treatment with IV daratumumab should be permanently discontinued.1 For grade 1 and 2 infusion-related reactions, the daratumumab infusion should be interrupted; once the reaction has resolved, the infusion may be resumed but the rate of infusion should be reduced by at least 50%.1 If no further infusion-related reactions occur, the infusion rate may be increased in increments and intervals appropriate for the treatment dose up to a maximum rate of 200 mL/hour.1
For systemic administration-reactions that occur with daratumumab/hyaluronidase-fihj, discontinue treatment immediately for anaphylactic or life-threatening (grade 4) reactions.14 Post-administration corticosteroids may help reduce the risk of delayed reactions.14
Myelosuppression : No dosage reductions of IV daratumumab or subcutaneous daratumumab/hyaluronidase-fihj are recommended; consider withholding treatment to allow recovery of blood cell counts in the event of myelosuppression (e.g.., neutropenia, thrombocytopenia).1, 14
Ocular Symptoms : If ocular symptoms (e.g., acute myopia, ciliochoroidal effusions) occur during IV daratumumab infusion, interrupt the infusion immediately and seek an ophthalmologic evaluation before resuming treatment.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1, 14
The manufacturer makes no specific dosage adjustment recommendations in patients with renal impairment.1, 14
The manufacturer makes no specific dosage recommendations for geriatric patients.1, 14
Infusion-related reactions (sometimes serious) have been reported frequently in patients receiving daratumumab.1 In clinical studies of daratumumab (monotherapy and combination), infusion-related reactions occurred in 37% of patients during the week 1 infusion; however, the incidence declined to 2-6% with subsequent infusions.1 Infusion-related reactions generally occurred with a median onset time of 1.5 hours (range: 0-73 hours).1 Infusion modifications due to reactions occurred in 36% of cases.1 The median infusion durations for 16 mg/kg doses were approximately 7 hours in week 1, 4 hours in week 2, and 3 hours for subsequent infusions.1 Prior to routine use of post-infusion medication in clinical studies, delayed infusion-related reactions occurred up to 48 hours following completion of the daratumumab infusion.1 Serious infusion-related reactions including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions have been reported.1 Signs or symptoms of such reactions may include respiratory effects (e.g., cough, throat irritation, nasal congestion) as well as chills, nausea, and vomiting.1 Hypotension, pruritus, wheezing, allergic rhinitis, pyrexia, chest discomfort, and blurred vision have occurred less frequently.1
When daratumumab dosing was interrupted for a median of 3.75 months during autologous stem cell transplant in the CASSIOPEIA study, the incidence of infusion-related reactions upon re-initiation was 11% for the first infusion post-autologous stem cell transplant.1 The infusion rate and dilution volume used upon re-initiation matched those from the last dose before interruption.1 The symptoms and severity of these reactions, with grade 3 or 4 reactions occurring in less than 1% of cases, were consistent with those observed in previous studies at week 2 or later infusions.1
In the EQUULEUS study, patients receiving combination treatment were given the first 16 mg/kg dose split over 2 days in week 1.1 Infusion-related reactions of any grade occurred in 42% of patients, with 36% on day 1, 4% on day 2, and 8% during subsequent infusions.1 The median onset time was 1.8 hours (range: 0.1-5.4 hours), and 30% of patients required infusion interruptions due to reactions.1 Median infusion durations were 4.2 hours for both days in week 1 and 3.4 hours for later infusions.1
Patients should be monitored frequently for signs or symptoms of infusion reactions during each daratumumab infusion in a setting where resuscitation equipment and agents necessary to treat infusion reactions are readily available.1 To minimize the risk of infusion-related reactions, patients receiving daratumumab should receive premedication with an antihistamine, antipyretic, and corticosteroid prior to each infusion of the drug.1 Because delayed infusion-related reactions may occur, patients also should receive therapy with an oral corticosteroid following each infusion to reduce the risk of such reactions.1 Patients with a history of chronic obstructive pulmonary disorders may require short- and long-acting inhaled bronchodilators and/or inhaled corticosteroids following the infusion.1 If infusion-related reactions occur, reduction in infusion rate or temporary interruption or permanent discontinuance of daratumumab may be required; medical management also should be instituted as necessary.1 For patients experiencing a life-threatening infusion-related reaction, the manufacturer recommends permanent discontinuance of therapy.1
Ocular adverse effects, such as acute myopia and ciliochoroidal effusions that may increase intraocular pressure or lead to glaucoma, have been reported with IV daratumumab.1 If ocular symptoms arise, interrupt the infusion immediately and seek an ophthalmologic evaluation before resuming treatment.1
Hypersensitivity and Other Administration Reactions
Daratumumab/hyaluronidase-fihj can cause both systemic and local administration-related reactions, including severe or life-threatening events, with fatal cases reported.14 In a pooled safety analysis of 1249 patients, 7% experienced systemic administration-related reactions, primarily occurring during the first injection (7%) and rarely with subsequent doses (≤1%).14 These reactions were considered to be grade 2 in 3.2% of patients, grade 3 in 0.7%, and grade 4 in 0.1%.14 The median onset time was 2.9 hours (range: 5 minutes to 3.5 days), with most reactions (84%) occurring on the day of administration.14 Delayed systemic administration-related reactions have occurred in 1% of patients.14
Severe reactions included hypoxia, dyspnea, hypertension, tachycardia, and ocular issues such as choroidal effusion, acute myopia, and acute angle closure glaucoma.14 Other symptoms included respiratory symptoms (e.g., bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wh14 eezing), anaphylaxis, fever, chest pain, chills, pruritus, nausea, vomiting, hypotension, and blurred vision.1
Monitor for systemic administration-related reactions in patients receiving daratumumab/hyaluronidase-fihj, particularly following the first and second injections.14 Prior to administration of daratumumab/hyaluronidase-fihj, premedicate patients with a histamine-1 receptor antagonist, acetaminophen, and corticosteroids.14 Consider administering corticosteroids and other medications after administration of daratumumab/hyaluronidase-fihj depending on the dosing regimen and medical history to minimize the risk of delayed systemic administration-related reactions.14 Immediately and permanently discontinue daratumumab/hyaluronidase-fihj in patients who experience anaphylactic or life-threatening (grade 4) administration-related reactions.14
Ocular adverse effects, such as acute myopia and ciliochoroidal effusions that may increase intraocular pressure or lead to glaucoma, have been reported with daratumumab-containing products.14 If ocular symptoms arise, interrupt treatment immediately and seek an ophthalmologic evaluation before resuming treatment.14
Local injection-site reactions occurred in 7% of patients in the pooled safety analysis, with 0.8% classified as grade 2.14 The most common reaction (≥1%) was injection site erythema, typically appearing within 5 minutes (range: 0 minutes to 6.5 days).13 Patients should be monitored for local reactions, and symptomatic management should be considered as needed.14
Interference with Serologic Testing
Because daratumumab binds to CD38, a protein expressed on the surface of erythrocytes, positive indirect antiglobulin (Indirect Coombs') test results have occurred in patients receiving the drug.1, 14 Daratumumab-mediated positive indirect antiglobulin test results may persist for up to 6 months after the last administration of daratumumab-containing products.1, 14 Daratumumab masks the detection of antibodies to minor antigens in serum; however, determination of ABO and Rh blood type is not affected.1, 14
Blood typing and screening should be performed prior to initiation of daratumumab or daratumumab/hyaluronidase-fihj.1, 14 If blood transfusion is required, clinicians must notify the blood center of the serologic test interference and inform them that the patient has received a daratumumab-containing product.1, 14 If blood typing and screening occur after initiation of daratumumab or daratumumab/hyaluronidase-fihj, genotyping or treatment of reagent erythrocytes with the reducing agent dithiothreitol (DTT) should be used to disrupt daratumumab binding.1, 14 Because Kell antigens are also sensitive to DTT treatment, patients receiving daratumumab-containing products who require a blood transfusion should receive K-negative units after ruling out or identifying alloantibodies using erythrocytes treated with DTT.1, 14 If an immediate transfusion is required because of emergency, non-cross-matched ABO/RhD blood type-compatible red blood cell (RBC) units can be administered according to local blood center practices.1
Daratumumab-containing products may exacerbate neutropenia caused by background therapy.1, 14 Monitor CBC periodically during treatment, according to the prescribing information guidelines for background therapies.1, 14 Patients with neutropenia should be monitored for signs of infection, and treatment with daratumumab-containing products may be temporarily withheld until neutrophil levels recover.1, 14
Daratumumab-containing products may worsen thrombocytopenia caused by background therapies.1, 14 Monitor CBC periodically during treatment, according to the prescribing information guidelines for background therapies.1, 14 Treatment with daratumumab-containing products may be temporarily withheld until platelet levels recover.1, 14
Interference with Serum Protein Electrophoresis and Immunofixation Electrophoresis Assays
Daratumumab is a human IgG kappa immunoglobulin; therefore, the drug may be detected on serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) assays used for clinical monitoring of myeloma (M) protein.1, 14 False-positive SPE and IFE assay results may occur; this may impact the determination of complete response or disease progression in some patients with IgG kappa M protein.1, 14
The manufacturer recommends using an FDA-approved daratumumab-specific IFE assay to differentiate daratumumab from any residual endogenous M protein in the patient's serum and aid in the determination of a complete response.1, 14
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, daratumumab may cause fetal harm if administered during pregnancy, potentially leading to fetal immune cell depletion and reduced bone density.1, 14 Advise pregnant women of the potential risk to a fetus; females of reproductive potential should use effective contraception during treatment and for 3 months after the final dose of the daratumumab-containing product.1, 14
Combination therapy with daratumumab-containing products and lenalidomide, pomalidomide, or thalidomide is contraindicated during pregnancy, as these medications can result in birth defects and fetal death.1, 14 Refer to the prescribing information for lenalidomide, pomalidomide, or thalidomide for guidance on use during pregnancy.1, 14
Cardiac Toxicity in Patients with Light Chain Amyloidosis
Serious or fatal cardiac adverse reactions have been reported in patients with light chain amyloidosis receiving daratumumab/hyaluronidase-fihj in combination with bortezomib, cyclophosphamide, and dexamethasone.14 Serious cardiac disorders occurred in 16% of patients, while 10% experienced fatal cardiac events.14 Patients with New York Heart Association (NYHA) class IIIA or Mayo Stage IIIA disease may be at higher risk; patients with NYHA Class IIIB or IV disease were not studied.14 Patients with cardiac involvement of light chain amyloidosis should be monitored more frequently for cardiac adverse reactions, with supportive care provided as needed.14
Anti-daratumumab antibodies, including neutralizing antibodies, have been observed in patients treated with daratumumab or daratumumab/hyaluronidase-fihj.1, 14
Across 10 clinical trials of patients with multiple myeloma treated with IV daratumumab (alone or in combination with other agents), anti-daratumumab antibodies developed in 0.6% (14/2179) of patients.1 Of these patients, 12 tested positive for neutralizing antibodies.1 Across 7 clinical trials of patients with multiple myeloma or light chain amyloidosis treated with daratumumab/hyaluronidase-fihj (alone or in combination with other agents), anti-daratumumab antibodies developed in 0.6% (7/1200) of patients; among these patients, 6 tested positive for neutralizing antibodies.14 Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of daratumumab-containing products is unknown.1, 14
Across 7 clinical trials of patients with multiple myeloma and light chain amyloidosis treated with daratumumab/hyaluronidase-fihj (alone or in combination with other agents), antibodies against recombinant human hyaluronidase developed in 8.9% (106/1193) of patients; 1 patient tested positive for neutralizing antibodies.14 There was no identified clinically important effect of these antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of daratumumab/hyaluronidase-fihj.14
There are no adequate and well-controlled studies of daratumumab-containing products in pregnant women; however, based on its mechanism of action and data from target antigen CD38 knockout animal models, daratumumab can cause fetal harm.1, 14 Because human immunoglobulin G (IgG) crosses the placenta in humans, and because of the potential for serious adverse reactions to daratumumab (e.g., fetal CD38 positive immune cell depletion, decreased bone density) in infants born to pregnant women treated with daratumumab-containing products, pregnancy should be avoided during daratumumab product therapy.1, 14 Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.1, 14
Combination therapy with daratumumab-containing products and lenalidomide, pomalidomide, or thalidomide is contraindicated during pregnancy, as these drugs can cause birth defects and fetal death.1, 14 These medications are only available through a REMS program.1, 14 Consult the prescribing information for lenalidomide, pomalidomide, or thalidomide for guidance on use during pregnancy.1, 14
Administration of live vaccines should be avoided in infants exposed to daratumumab-containing products in utero until a hematologic evaluation has been completed.1, 14
It is not known whether daratumumab or hyaluronidase is distributed into human milk; however, maternal IgG is distributed into milk.1, 14 Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts.1 The effects of daratumumab and hyaluronidase on breast-fed infants or on the production of human milk are unknown.1
Due to the risk of serious adverse reactions in breast-fed infants when daratumumab-containing products are used with lenalidomide, pomalidomide, or thalidomide, advise women not to breast-feed during treatment with daratumumab-containing products.1, 14 For further information, refer to the prescribing information for lenalidomide, pomalidomide, or thalidomide.1, 14
Females and Males of Reproductive Potential
Daratumumab-containing products can cause fetal harm if administered during pregnancy.1, 14 Advise females of reproductive potential to use effective contraception during treatment with daratumumab-containing products and for 3 months after the final dose.1, 14
For patients receiving daratumumab-containing products in combination with lenalidomide, pomalidomide, or thalidomide, refer to the drug labeling of lenalidomide, pomalidomide, or thalidomide for pregnancy testing requirements before initiating treatment in females of reproductive potential.1, 14 Additionally, consult the prescribing information for lenalidomide, pomalidomide, or thalidomide for further contraception recommendations.1, 14
Safety and efficacy of daratumumab-containing products have not been established in pediatric patients.1, 14
The safety and efficacy of IV daratumumab in combination with chemotherapy were evaluated but not established in a single open-label trial (DELPHINUS) involving 34 pediatric patients (2 to <17 years of age) with relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma.1 No new safety concerns were identified in these patients.1 The pharmacokinetic parameters observed were consistent with those previously reported in adults with multiple myeloma receiving the same weight-based dosage.1
In clinical studies, no overall differences in efficacy were observed between geriatric and younger adults.1, 14 No clinically meaningful differences in pharmacokinetics of daratumumab have been observed in geriatric patients compared to younger adult patients.14
In clinical studies, among the 2459 patients who received IV daratumumab at the recommended dosage, 38% were 65-74 years of age, while 15% were 75 years of age or older.1 Effectiveness was comparable between older and younger patients; however, serious adverse reactions were more common in older patients.1 Among the 1213 patients with relapsed or refractory multiple myeloma, pneumonia and sepsis were more frequently reported in patients 65 years of age and older.1 Within the daratumumab plus carfilzomib-dexamethasone group in the CANDOR study, fatal adverse reactions occurred in 14% of patients 65 years of age and older, compared with 6% in younger patients.1 Among 710 newly diagnosed multiple myeloma patients ineligible for autologous stem cell transplant, pneumonia was the most frequently observed serious adverse reaction in those 75 years of age and older.1
Among the 291 patients who received daratumumab/hyaluronidase-fihj as monotherapy for relapsed or refractory multiple myeloma in clinical studies, 37% were 65-74 years of age, while 19% were 75 years of age or older.14 Effectiveness was consistent across age groups, but adverse reactions such as upper respiratory and urinary tract infections, dizziness, cough, dyspnea, diarrhea, nausea, fatigue, and peripheral edema occurred more frequently (≥5% difference) in patients 65 years of age and older.14
In a separate study of 214 patients receiving daratumumab/hyaluronidase-fihj in combination with pomalidomide and dexamethasone or lenalidomide and low-dose dexamethasone, 43% were 65-74 years of age, and 18% were 75 years of age or older.14 No differences in effectiveness were noted, but older patients had higher rates of fatigue, fever, peripheral edema, urinary tract infections, GI adverse effects, dyspnea, cough, and hyperglycemia.14 Serious adverse reactions included neutropenia, thrombocytopenia, anemia, COVID-19, ischemic colitis, deep vein thrombosis, general health deterioration, pulmonary embolism, and urinary tract infections.14
In a clinical trial of 355 newly diagnosed multiple myeloma patients eligible for autologous stem cell transplant who received daratumumab/hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone, 26% were 65-70 years of age, with no patients over 70 years of age included.14 Effectiveness was similar across age groups, but older patients experienced higher rates (≥5% difference) of constipation, hemorrhoids, nausea, injection site erythema, bronchitis, nasopharyngitis, back pain, myalgia, extremity pain, dysgeusia, peripheral motor neuropathy, and insomnia.14 Serious adverse reactions included febrile bone marrow aplasia, atrial fibrillation, fever, and orthostatic hypotension.14
In a study of 193 patients receiving daratumumab/hyaluronidase-fihj for light chain amyloidosis, 35% were 65-74 years of age, and 10% were 75 years of age or older.14 Due to the limited number of older patients, differences in effectiveness could not be determined, but adverse reactions occurring more frequently in those 65 years of age and older included peripheral edema, asthenia, pneumonia, and hypotension.14
In a population pharmacokinetic analysis, no clinically meaningful differences in exposure of daratumumab were observed between patients with mild (total bilirubin concentrations 1-1.5 times the upper limit of normal [ULN] or AST concentrations exceeding the ULN)1, 14 or moderate (total bilirubin 1.5-3 times ULN and any AST) hepatic impairment and those with normal hepatic function.1 The effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) on daratumumab pharmacokinetics is unknown.1, 14
In a population pharmacokinetic analysis, no clinically meaningful differences in exposure of daratumumab were observed between patients with renal impairment (creatinine clearance [Clcr] 15-89 mL/minute) and those with normal renal function.1, 14
Common adverse effects reported in ≥20% of patients receiving daratumumab infusions in clinical trials include upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.1
Adverse effects reported in ≥20% of patients with multiple myeloma receiving daratumumab/hyaluronidase-fihj monotherapy include upper respiratory tract infection.14
Adverse reactions reported in ≥20% of patients with multiple myeloma receiving daratumumab/hyaluronidase-fihj, bortezomib, lenalidomide, and dexamethasone include peripheral neuropathy, fatigue, edema, pyrexia, upper respiratory infection, constipation, diarrhea, musculoskeletal pain, insomnia, and rash.14
Adverse reactions reported in ≥20% of patients with multiple myeloma receiving daratumumab/hyaluronidase-fihj, bortezomib, melphalan, and prednisone include upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain.14
Adverse reactions reported in ≥20% of patients with multiple myeloma receiving daratumumab/hyaluronidase-fihj, lenalidomide, and dexamethasone include fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.14
Adverse reactions reported in ≥20% of patients with multiple myeloma receiving daratumumab/hyaluronidase-fihj, pomalidomide, and dexamethasone include fatigue, pneumonia, upper respiratory tract infection, and diarrhea.14
Adverse reactions reported in ≥20% of patients with multiple myeloma receiving daratumumab/hyaluronidase-fihj, carfilzomib, and dexamethasone include upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and peripheral edema.14
Adverse reactions reported in ≥20% or more of patients with light chain amyloidosis receiving daratumumab/hyaluronidase-fihj are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.14
Additionally, the most common hematologic laboratory abnormalities (≥40%) associated with daratumumab/hyaluronidase-fihj included decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.14
Daratumumab, a recombinant humanized anti-CD38 monoclonal antibody, is an antineoplastic agent.1, 2, 5, 12, 14 The drug is an IgG1 kappa immunoglobulin produced by recombinant DNA technology in mammalian cell (Chinese hamster ovary) culture.1 Daratumumab binds specifically to antigen CD38, a glycoprotein expressed on the surface of normal and malignant hematopoietic stem cells, including multiple myeloma and other cell types and tissues of nonhematopoietic origin.1, 12, 13, 14 Following binding of daratumumab to antigen CD38, the Fc domain triggers host immune responses (i.e., antibody-dependent cell-mediated cytotoxicity [ADCC], antibody-dependent cellular phagocytosis [ADCP], complement-dependent cytotoxicity [CDC]) causing cell lysis.1, 2, 12, 13, 14 Myeloid-derived suppressor cells, a subset of regulatory T cells, and natural killer (NK) cells expressing CD38 are also susceptible to daratumumab-mediated cell lysis.1, 14
Decreased absolute counts and percentages of total NK cells (CD16+/56+) and activated NK cells (CD16+/56dim) in peripheral blood and bone marrow have been observed following daratumumab therapy.1, 14 Absolute CD4+ and CD8+ T-cell counts, including the percentage of total lymphocytes, increased in peripheral blood and bone marrow following daratumumab therapy.1, 14
Area under the concentration-time curves of daratumumab are more than dose proportional over a dosage range of 1-24 mg/kg for daratumumab monotherapy and 1-16 mg/kg as combination therapy.1 Split dosing of the first dose of daratumumab results in a different pharmacokinetic profile on the first day, but similar maximum concentrations and minimum concentrations are observed following the administration of the second split dose on day 2 of week 1.1 Clearance is decreased with increasing dose and following repeated administration, indicating target-mediated pharmacokinetics.1 Steady-state concentrations are reached in approximately 5 months following administration of daratumumab monotherapy every 4 weeks.1 The estimated terminal half-life associated with linear clearance of daratumumab is 18 days.1 No clinically important differences in the pharmacokinetics of daratumumab were observed based on sex or age (31-93 years).1
Hyaluronidase is an endoglycosidase that enhances the dispersion and absorption of co-administered drugs when given subcutaneously.14 It is a glycosylated single-chain protein derived from Chinese hamster ovary cells containing a DNA plasmid that encodes a soluble fragment of human hyaluronidase (PH20).14 In the administered doses, the hyaluronidase in daratumumab/hyaluronidase-fihj acts locally, increasing subcutaneous tissue permeability by depolymerizing hyaluronan.14 Its effects are reversible, with subcutaneous tissue permeability returning to normal within 24-48 hours.14
Absolute bioavailability of daratumumab/hyaluronidase-fihj is 69% at the recommended subcutaneous dosage (1800 mg/30,000 units).14 After administering the recommended dosage of daratumumab/hyaluronidase-fihj subcutaneously once weekly for 8 weeks, daratumumab peak concentration increased 4.8-fold, and the AUC increased 5.4-fold from the first to the eighth dose as monotherapy.14 Maximum trough concentrations are generally reached at the end of the weekly dosing period for both monotherapy and combination therapies.14 In patients with multiple myeloma, peak concentrations are reached approximately 3 days after administration, while in patients with light chain amyloidosis, peak concentrations occur around 4 days.14 Daratumumab is cleared by parallel linear and nonlinear saturable target-mediated clearances.14 The estimated mean elimination half-life for linear clearance is 20 days in multiple myeloma patients and 28 days in those with light chain amyloidosis.14 No clinically important differences in the pharmacokinetics of daratumumab were observed based on sex or age (33-92 years).14 African-American patients had a 24% higher daratumumab mean maximum trough concentration after the eighth dose of daratumumab/hyaluronidase-fihj compared with white patients, and Asian patients had a 16% higher daratumumab mean maximum trough concentration after the eighth dose of daratumumab/hyaluronidase-fihj compared with white patients.14 In patients with multiple myeloma who received daratumumab/hyaluronidase-fihj 1800 mg/30,000 units as monotherapy, the mean maximum trough concentration after the eighth dose was 12% lower in patients weighing >85 kg and 81% higher in patients weighing ≤50 kg compared to the corresponding body weight groups in the IV daratumumab arm.14 In patients with light chain amyloidosis who received daratumumab/hyaluronidase-fihj 1800 mg/30,000 units in combination and had a maximum trough concentration after the eighth dose, the mean maximum trough concentration after the eighth dose was 22% lower in patients weighing >85 kg and 37% higher in patients weighing ≤50 kg compared with patients having a body weight of 51-85 kg.14
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Concentrate, for injection, for IV infusion | 20 mg/mL (100 and 400 mg) |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for subcutaneous use only | Daratumumab 1800 mg and hyaluronidase-fihj 30,000 units/15 mL (120 mg/2000 units/mL) | Darzalex Faspro® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Janssen Biotech, Inc. Darzalex® (daratumumab) injection for intravenous use prescribing information. Horsham, PA; 2025 Jan.
2. Lonial S, Weiss BM, Usmani SZ et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet . 2016; 387:1551-60. [PubMed 26778538]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
5. Lokhorst HM, Plesner T, Laubach JP et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med . 2015; 373:1207-19. [PubMed 26308596]
12. Phipps C, Chen Y, Gopalakrishnan S et al. Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Ther Adv Hematol . 2015; 6:120-7. [PubMed 26137203]
13. de Weers M, Tai YT, van der Veer MS et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol . 2011; 186:1840-8. [PubMed 21187443]
14. Janssen Biotech, Inc. Darzalex Faspro® (daratumumab and hyaluronidase-fihj) injection for subcutaneous use prescribing information. Horsham, PA; 2024 Jul.
15. Facon T, Kumar S, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med. 2019;380(22):2104-2115.
16. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596.
17. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(14):1319-1331.
18. Dimopoulos MA, Oriol A, Nahi H, et al. Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2023;41(8):1590-1599.
19. Chari A, Rodriguez-Otero P, McCarthy H, et al. Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label Phase II study. Br J Haematol. 2021;192(5):869-878.
20. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018;378(6):518-528.
21. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141.
22. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study Lancet. 2019;394(10192):29-38.
23. Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390.
24. Moreau P, Hulin C, Perrot A, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024;25(8):1003-1014.
25. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754-766.
26. Sonneveld P, Chanan-Khan A, Weisel K, et al. Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2023;41(8):1600-1609.
27. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197.
28. Usmani SZ, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022;23(1):65-76.
29. Usmani SZ, Quach H, Mateos MV, et al. Final analysis of carfilzomib, dexamethasone, and daratumumab vs carfilzomib and dexamethasone in the CANDOR study. Blood Adv. 2023;7(14):3739-3748.
30. Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019;134(5):421-431.
31. Moreau P, Chari A, Oriol A, et al. Daratumumab, carfilzomib, and dexamethasone in relapsed or refractory myeloma: final analysis of PLEIADES and EQUULEUS. Blood Cancer J. 2023;13(1):33.
32. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981.
33. Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812.
34. Dimopoulos MA, Terpos E, Boccadoro M, et al. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial. Lancet Haematol. 2023;10(10):e813-e824.
35. Mateos MV, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial Lancet Haematol. 2020;7(5):e370-e380.
36. Usmani SZ, Nahi H, Legiec W, et al. Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematologica. 2022;107(10):2408-2417.
37. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024;390(4):301-313.
38. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019;37(14):1228-1263.
39. PDQ® Adult Treatment Editorial Board. PDQ Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment. Updated February 21, 2025. [Web]
40. Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021;385(1):46-58.
41. Baker KR. Light Chain Amyloidosis: Epidemiology, Staging, and Prognostication. Methodist Debakey Cardiovasc J. 2022;18(2):27-35.
42. Wechalekar AD, Cibeira MT, Gibbs SD, et al. Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group. Amyloid. 2023;30(1):3-17.
43. Institute for Safe Medication Practices (ISMP). ISMP List of High-Alert Medications in Acute Care Settings. ISMP; 2024.