Darzalex

Daratumumab.

Daratumumab is a human monoclonal IgG1κ antibody against CD38 antigen, produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.
Concentrate for solution for IV infusion: Each 5 mL vial contains 100 mg of daratumumab (20 mg daratumumab per mL).
Each 20 mL vial contains 400 mg of daratumumab (20 mg daratumumab per mL).
Excipients with known effect: Each 5 mL and 20 mL vial of DARZALEX contains 0.4 mmol and 1.6 mmol (9.3 mg and 37.3 mg) sodium, respectively.
Excipients/Inactive Ingredients: Glacial acetic acid, Mannitol (E421), Polysorbate 20, Sodium acetate trihydrate, Sodium chloride, Water for injections.
Solution for SC injection: Each 15 mL vial of solution for subcutaneous injection contains 1800 mg of daratumumab (120 mg daratumumab per mL).
Excipients with known effect: Each 15 mL vial of solution for injection contains 735.1 mg of sorbitol (E420).
Excipients/Inactive Ingredients: Recombinant human hyaluronidase (rHuPH20), L-histidine, L-histidine hydrochloride monohydrate, L-methionine, Polysorbate 20, Sorbitol (E420), Water for injections.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC24.
Pharmacology: Pharmacodynamics: Solution for SC injection: DARZALEX solution for subcutaneous injection contains recombinant human hyaluronidase (rHuPH20). rHuPH20 works locally and transiently to degrade hyaluronan ((HA), a naturally occurring glycoaminoglycan found throughout the body) in the extracellular matrix of the subcutaneous space by cleaving the linkage between the two sugars (N-acetylglucosamine and glucuronic acid) which comprise HA. rHuPH20 has a half-life in skin of less than 30 minutes. Hyaluronan levels in subcutaneous tissue return to normal within 24 to 48 hours because of the rapid biosynthesis of hyaluronan.
Mechanism of action: Concentrate for solution for IV infusion: Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.
Solution for SC injection: Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed on the surface of cells in a variety of haematological malignancies, including clonal plasma cells in multiple myeloma and AL amyloidosis, as well as other cell types and tissues. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.
Concentrate for solution for IV infusion & Solution for SC injection: Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells. Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T_regs) and B cells (CD38+B_regs) are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response.
Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour growth, are not well-understood.
Pharmacodynamic effects: Natural killer (NK) cell and T-cell count: NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56^dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. However, baseline levels of NK cells did not show an association with clinical response.
Immunogenicity: Concentrate for solution for IV infusion: In patients treated with intravenous daratumumab in clinical trials, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies.
Solution for SC injection: In multiple myeloma and AL amyloidosis patients treated with subcutaneous daratumumab in monotherapy and combination clinical studies, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies.
In multiple myeloma and AL amyloidosis patients, the incidence of treatment-emergent non-neutralizing anti-rHuPH20 antibodies was 7.3% (55/750) in patients who received either monotherapy DARZALEX subcutaneous formulation or combination DARZALEX subcutaneous formulation. The anti-rHuPH20 antibodies did not appear to impact daratumumab exposures. The clinical relevance of the development of anti-daratumumab or anti-rHuPH20 antibodies after treatment with DARZALEX subcutaneous formulation is not known.
Clinical experience with daratumumab concentrate for solution for infusion (intravenous formulation): Newly diagnosed multiple myeloma: Combination treatment with lenalidomide and dexamethasone in patients ineligible for autologous stem cell transplant: Study MMY3008, an open-label, randomised, active-controlled Phase III study, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, the dexamethasone dose was given as a pre-infusion medicinal product. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 737 patients were randomised: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age. The majority were white (92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 49.5% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.
Study MMY3008 showed an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd. Results of an updated PFS analysis approximately 9 months after the original clinical cutoff, continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was not reached in the DRd arm and was 33.8 months in the Rd arm (HR=0.56; 95% CI: 0.44, 0.71; p<0.0001). (See Figure 1.)

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Additional efficacy results from Study MMY3008 are presented in Table 1 as follows. (See Table 1.)

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In responders, the median time to response was 1.0 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.
Combination treatment with bortezomib, melphalan and prednisone (VMP) in patients ineligible for autologous stem cell transplant: Study MMY3007, an open-label, randomised, active-controlled Phase III study, compared treatment with intravenous DARZALEX 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m² body surface area twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1; 8 doses), followed by once weekly administrations at Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2-9; 4 doses per cycle). Melphalan at 9 mg/m², and prednisone at 60 mg/m² were orally administered on Days 1 to 4 of the nine 6-week cycles (Cycles 1-9). Intravenous DARZALEX treatment was continued until disease progression or unacceptable toxicity.
A total of 706 patients were randomised: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40-93) years, with 30% of the patients ≥75 years of age. The majority were white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 25% had an ECOG performance score of 2. Patients had IgG/IgA/Light chain myeloma in 64%/22%/10% of instances, 19% had ISS Stage I, 42% had ISS Stage II, 38% had ISS Stage III disease and 84% had standard risk cytogenetics. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).
With a median follow‑up of 16.5 months, the primary analysis of PFS in Study MMY3007 showed an improvement in the D-VMP arm as compared to the VMP arm; the median PFS had not been reached in the D-VMP arm and was 18.1 months in the VMP arm (HR=0.5; 95% CI: 0.38, 0.65; p<0.0001). Results of an updated PFS analysis after a median follow-up of 40 months continued to show an improvement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was 36.4 months in the D‑VMP arm and 19.3 months in the VMP arm (HR=0.42; 95% CI: 0.34, 0.51; p<0.0001), representing a 58% reduction in the risk of disease progression or death in patients treated with D‑VMP. (See Figure 2.)

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After a median follow‑up of 40 months, D‑VMP has shown an overall survival (OS) advantage over the VMP arm (HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patients treated in the D‑VMP arm. Median OS was not reached for either arm. (See Figure 3.)

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Additional efficacy results from Study MMY3007 are presented in Table 2 as follows. (See Table 2.)

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In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the D-VMP group and 0.82 months (range: 0.7 to 12.6 months) in the VMP group. The median duration of response had not been reached in the D-VMP group and was 21.3 months (range: 18.4, not estimable) in the VMP group.
A subgroup analysis was performed on patients at least 70 years old, or those 65-69 years old with ECOG performance score of 2, or aged less than 65 years of age with significant comorbidity or ECOG performance score of 2 (D-VMP: n=273, VMP: n=270). The efficacy results in this subgroup were consistent with the overall population. In this subgroup, median PFS was not reached in the D-VMP group and was 17.9 months in the VMP group (HR=0.56; 95% CI: 0.42, 0.75); p<0.0001). The overall response rate was 90% in the D-VMP group and 74% in the VMP group (VGPR rate: 29% in D-VMP group and 26% in VMP group; CR: 22% in D-VMP group and 18% in VMP group; sCR rate: 20% in D-VMP group and 7% in VMP group). The safety results of this subgroup were consistent with the overall population. Furthermore, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was also consistent with the overall population.
Combination treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients eligible for autologous stem cell transplant (ASCT): Study MMY3006 is a 2-part, open-label, randomised, active-controlled Phase III study. Part 1 compared induction and consolidation treatment with intravenous DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D-VTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. In Part 2, subjects with at least a partial response (PR) by Day 100 post-transplant were re-randomised in a 1:1 ratio to daratumumab maintenance or observation only. Only results from Part 1 are described henceforth.
Bortezomib was administered by subcutaneous injection or intravenous injection at a dose of 1.3 mg/m² body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28 day (4-week) induction treatment cycles (Cycles 1-4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles 1 and 2, and at 40 mg on Days 1-2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3-4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of intravenous DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medicinal product. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer's prescribing information.
A total of 1085 patients were randomised: 543 to the D-VTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 (range: 22 to 65) years. All patients were ≤65 years: 43% were in the age group ≥60-65 years, 41% were in the age group ≥50-60 years and 16% below age of 50 years. The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had International Staging System (ISS) Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.
Efficacy was evaluated by the stringent Complete Response (sCR) rate at Day 100 post-transplant and Progression free survival (PFS). (See Table 3.)

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With a median follow-up of 18.8 months, the primary analysis of PFS by censoring patients who were randomised to daratumumab maintenance in the second randomisation at the date of the second randomisation showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005. Results of an updated PFS analysis with a median follow-up of 44.5 months, censoring patients who were randomised to daratumumab maintenance in the second randomisation, showed HR=0.43; 95% CI: 0.33, 0.55; p < 0.0001. Median PFS was not reached in the D-VTd arm and was 37.8 months in the VTd arm. (See Figure 4.)

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Relapsed/refractory multiple myeloma: Monotherapy: The clinical efficacy and safety of intravenous DARZALEX monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who had demonstrated disease progression on the last therapy, was demonstrated in two open-label studies.
In Study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg intravenous DARZALEX until disease progression. The median patient age was 63.5 years (range, 31 to 84 years), 11% of patients were ≥ 75 years of age, 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent (IMiD), 77% were refractory to alkylating agents, 63% were refractory to pomalidomide and 48% of patients were refractory to carfilzomib.
Efficacy results of the pre-planned interim analysis based on Independent Review Committee (IRC) assessment are presented in Table 4 as follows. (See Table 4.)

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Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myeloma therapy. At a survival update with a median duration of follow-up of 14.7 months, median Overall Survival (OS) was 17.5 months (95% CI:13.7, not estimable).
In Study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg intravenous DARZALEX until disease progression. The median patient age was 64 years (range, 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% were refractory to both a PI and IMiD, 60% were refractory to alkylating agents, 36% were refractory to pomalidomide and 17% were refractory to carfilzomib.
Pre-planned interim analysis showed that treatment with daratumumab at 16 mg/kg led to a 36% ORR with 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. The median duration of response was not reached (95% CI: 5.6 months, not estimable).
At a survival update with a median duration of follow-up of 15.2 months, median OS was not reached (95% CI: 19.9 months, not estimable), with 74% of subjects still alive.
Combination treatment with lenalidomide: Study MMY3003, an open-label, randomised, active-controlled Phase III trial, compared treatment with intravenous DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose dexamethasone at 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years or BMI < 18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medicinal product and the remainder given the day after the infusion. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 569 patients were randomised; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the intravenous DARZALEX and the control arm. The median patient age was 65 years (range 34 to 89 years) and 11% were ≥ 75 years. The majority of patients (86%) received a prior PI, 55% of patients had received a prior IMiD, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and IMiD. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Patients refractory to lenalidomide were excluded from the study.
With a median follow‑up of 13.5 months, the primary analysis of PFS in study MMY3003 demonstrated an improvement in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (HR=0.37; 95% CI: 0.27, 0.52; p < 0.0001). Results of an updated PFS analysis after a median follow‑up of 55 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 45.0 months in the DRd arm and 17.5 months in the Rd arm (HR=0.44; 95% CI: 0.35, 0.54; p<0.0001), representing a 56% reduction in the risk of disease progression or death in patients treated with DRd (see Figure 5).

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Additional efficacy results from Study MMY3003 are presented in Table 5 as follows. (See Table 5.)

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Median OS was not reached for either treatment group. With an overall median follow-up of 13.5 months, the hazard ratio for OS was 0.64 (95% CI: 0.40, 1.01; p = 0.0534).
Combination treatment with bortezomib: Study MMY3004, an open-label, randomised, active-controlled Phase III trial, compared treatment with intravenous DARZALEX 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy. Bortezomib was administered by subcutaneous injection or intravenous infusion at a dose of 1.3 mg/m² body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients > 75 years, BMI < 18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of intravenous DARZALEX infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medicinal product. Intravenous DARZALEX treatment was continued until disease progression or unacceptable toxicity.
A total of 498 patients were randomised; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the intravenous DARZALEX and the control arm. The median patient age was 64 years (range 30 to 88 years) and 12% were ≥ 75 years.
Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an IMiD (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment. Thirty-three percent (33%) of patients were refractory to an IMiD only, and 28% were refractory to lenalidomide. Patients refractory to bortezomib were excluded from the study.
With a median follow‑up of 7.4 months, the primary analysis of PFS in study MMY3004 demonstrated an improvement in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value < 0.0001). Results of an updated PFS analysis after a median follow‑up of 50 months continued to show an improvement in PFS for patients in the DVd arm compared with the Vd arm. Median PFS was 16.7 months in the DVd arm and 7.1 months in the Vd arm (HR [95% CI]: 0.31 [0.24, 0.39]; p-value <0.0001), representing a 69% reduction in the risk of disease progression or death in patients treated with DVd versus Vd (see Figure 6).

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Additional efficacy results from Study MMY3004 are presented in Table 6 as follows. (See Table 6.)

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Median OS was not reached for either treatment group. With an overall median follow-up of 7.4 months (95% CI: 0.0, 14.9), the hazard ratio for OS was 0.77 (95% CI: 0.47, 1.26; p = 0.2975).
Clinical experience of DARZALEX solution for subcutaneous injection (subcutaneous formulation): Monotherapy - relapsed/refractory multiple myeloma: MMY3012, an open-label, randomised, phase III non-inferiority study, compared efficacy and safety of treatment with DARZALEX solution for subcutaneous injection (1800 mg) vs. intravenous (16 mg/kg) daratumumab in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who were double-refractory to a PI and an IMiD. Treatment continued until unacceptable toxicity or disease progression.
A total of 522 patients were randomised: 263 to the DARZALEX subcutaneous formulation arm and 259 to the intravenous daratumumab arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median patient age was 67 years (range: 33 - 92 years), 55% were male and 78% were Caucasian. The median patient weight was 73 kg (range: 29 - 138 kg) Patients had received a median of 4 prior lines of therapy. A total of 51% of patients had prior autologous stem cell transplant (ASCT), 100% of patients were previously treated with both PI(s) and IMiD(s) and most patients were refractory to a prior systemic therapy, including both PI and IMiD (49%).
The study met its co-primary endpoints of overall response rate (ORR) by the IMWG response criteria (Table 7) and maximum C_trough at pre-dose cycle 3 day 1, (see Dosage & Administration). (See Table 7.)

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After a median follow-up of 29.3 months, the median OS was 28.2 months (95% CI: 22.8, NE) in the DARZALEX subcutaneous formulation arm and was 25.6 months (95% CI: 22.1, NE) in the intravenous daratumumab arm.
Safety and tolerability results, including in lower weight patients, were consistent with the known safety profile for DARZALEX subcutaneous formulation and intravenous daratumumab.
Results from the modified-CTSQ, a patient reported outcome questionnaire that assesses patient satisfaction with their therapy, demonstrated that patients receiving DARZALEX subcutaneous formulation had greater satisfaction with their therapy compared with patients receiving intravenous daratumumab. However, open-label studies are subject to bias.
Combination therapies in multiple myeloma: MMY2040 was an open-label study evaluating the efficacy and safety of DARZALEX subcutaneous formulation 1800 mg: in combination with bortezomib, melphalan, and prednisone (D-VMP) in patients with newly diagnosed multiple myeloma (MM) who are ineligible for transplant. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m² body surface area twice weekly at weeks 1, 2, 4 and 5 for the first 6-week cycle (cycle 1; 8 doses), followed by once weekly administrations at weeks 1, 2, 4 and 5 for eight more 6-week cycles (cycles 2-9; 4 doses per cycle). Melphalan at 9 mg/m², and prednisone at 60 mg/m² were orally administered on days 1 to 4 of the nine 6-week cycles (cycles 1-9). DARZALEX subcutaneous formulation was continued until disease progression or unacceptable toxicity.
In combination with lenalidomide and dexamethasone (D-Rd) in patients with relapsed or refractory MM. Lenalidomide (25 mg once daily orally on days 1-21 of repeated 28-day [4-week] cycles) was given with low dose dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years or BMI < 18.5). DARZALEX subcutaneous formulation was continued until disease progression or unacceptable toxicity.
In combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with newly diagnosed MM who are transplant eligible. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m² body surface area twice weekly at weeks 1 and 2. Lenalidomide was administered orally at 25 mg once daily on days 1-14; low dose dexamethasone was administered 40 mg/week in 3-week cycles. Total treatment duration was 4 cycles.
A total of 199 patients (D-VMP: 67; D-Rd: 65; D-VRd: 67) were enrolled. Efficacy results were determined by computer algorithm using IMWG criteria. The study met its primary endpoint ORR for D-VMP and D-Rd and the primary endpoint VGPR or better for D-VRd (see Table 8).

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Combination treatment with pomalidomide and dexamethasone (Pd): Study MMY3013 was an open-label, randomised, active-controlled phase III study that compared treatment with DARZALEX subcutaneous formulation (1800 mg) in combination with pomalidomide and low-dose dexamethasone (D-Pd) to treatment with pomalidomide and low-dose dexamethasone (Pd) in patients with multiple myeloma who had received at least one prior line of therapy with lenalidomide and a proteasome inhibitor (PI). Pomalidomide (4 mg once daily orally on days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years). On DARZALEX subcutaneous formulation administration days, 20 mg of the dexamethasone dose was given as a pre-administration medicinal product and the remainder given the day after the administration. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX subcutaneous formulation pre-administration medicinal product. Dose adjustments for pomalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 304 patients were randomised: 151 to the D-Pd arm and 153 to the Pd arm. Patients with documented evidence of disease progression on or after the last regimen were included in the study. Patients who had ≥ grade 3 rash during prior therapy were excluded as per the pomalidomide Summary of Product Characteristics. The baseline demographic and disease characteristics were similar between the two treatment groups. The median patient age was 67 years (range 35 to 90 years), 18% were ≥ 75 years, 53% were male, and 89% Caucasian. Patients had received a median of 2 prior lines of therapy. All patients received a prior treatment with a proteasome inhibitor (PI) and lenalidomide, and 56% of patients received prior stem cell transplantation (ASCT). Ninety-six percent (96%) of patients received prior treatment with bortezomib. The majority of patients were refractory to lenalidomide (80%), a PI (48%), or both an immunomodulator and a PI (42%). Eleven percent of patients received 1 prior line of therapy; all were refractory to lenalidomide and 32.4% were refractory to both lenalidomide and a PI. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.
With a median follow-up of 16.9 months, the primary analysis of PFS in study MMY3013 showed a statistically significant improvement in the D-Pd arm as compared to the Pd arm; the median PFS was 12.4 months in the D-Pd arm and 6.9 months in the Pd arm (HR [95% CI]: 0.63 [0.47, 0.85]; p-value = 0.0018), representing a 37% reduction in the risk of disease progression or death for patients treated with D-Pd versus Pd. Median OS was not reached for either treatment group. (See Figure 7.)

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Additional efficacy results from study MMY3013 are presented in Table 9 as follows. (See Table 9.)

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In responders, the median time to response was 1 month (range: 0.9 to 9.1 months) in the D-Pd group and 1.9 months (range: 0.9 to 17.3 months) in the Pd group. The median duration of response had not been reached in the D-Pd group (range: 1 to 34.9+ months) and was 15.9 months (range: 1+ to 24.8 months) in the Pd group.
Combination treatment with bortezomib, cyclophosphamide and dexamethasone in patients with AL amyloidosis: Study AMY3001, an open-label, randomised, active-controlled phase III study, compared treatment with DARZALEX subcutaneous formulation (1800 mg) in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd) to treatment with bortezomib, cyclophosphamide and dexamethasone (VCd) alone in patients with newly diagnosed systemic AL amyloidosis. Randomisation was stratified by AL amyloidosis Cardiac Staging System, countries that typically offer autologous stem cell transplant (ASCT) for patients with AL amyloidosis, and renal function.
All patients enrolled in study AMY3001 had newly diagnosed AL amyloidosis with at least one affected organ, measurable hematologic disease, cardiac stage I-IIIA (based on European Modification of Mayo 2004 cardiac stage), and NYHA class I-IIIA. Patients with NYHA class IIIB and IV were excluded.
Bortezomib (SC; 1.3 mg/m² body surface area), cyclophosphamide (oral or IV; 300 mg/m² body surface area; max dose 500 mg), and dexamethasone (oral or IV; 40 mg or a reduced dose of 20 mg for patients > 70 years or body mass index [BMI] < 18.5 or those who have hypervolemia, poorly controlled diabetes mellitus or prior intolerance to steroid therapy) were administered weekly on days 1, 8, 15, and 22 of repeated 28-day [4-week] cycles. On the days of DARZALEX dosing, 20 mg of the dexamethasone dose was given as a pre-injection medicinal product and the remainder given the day after DARZALEX administration. Bortezomib, cyclophosphamide and dexamethasone were given for six 28-day [4-week] cycles in both treatment arms, while DARZALEX treatment was continued until disease progression, start of subsequent therapy, or a maximum of 24 cycles (~2 years) from the first dose of study treatment. Dose adjustments for bortezomib, cyclophosphamide and dexamethasone were applied according to manufacturer's prescribing information.
A total of 388 patients were randomised: 195 to the D-VCd arm and 193 to the VCd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The majority (79%) of patients had lambda free light chain disease. The median patient age was 64 years (range: 34 to 87); 47% were ≥ 65 years; 58% were male; 76% Caucasian, 17% Asian, and 3% African American; 23% had AL amyloidosis Clinical Cardiac stage I, 40% had stage II, 35% had stage IIIA, and 2% had stage IIIB. All patients had one or more affected organs and the median number of organs involved was 2 (range: 1-6) and 66% of patients had 2 or more organs involved. Vital organ involvement was: 71% cardiac, 59% renal and 8% hepatic. Patients with grade 2 sensory or grade 1 painful peripheral neuropathy were excluded. The primary efficacy endpoint was hematologic complete response (HemCR) rate as determined by the Independent Review Committee assessment based on International Concensus Criteria. Study AMY3001 demonstrated an improvement in HemCR in the D-VCd arm as compared to the VCd arm. Efficacy results are summarised in Table 10. (See Table 10.)

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In responders, the median time to HemCR was 60 days (range: 8 to 299 days) in the D-VCd group and 85 days (range: 14 to 340 days) in the VCd group. The median time to VGPR or better was 17 days (range: 5 to 336 days) in the D-VCd group and 25 days (range: 8 to 171 days) in the VCd group. The median duration of HemCR had not been reached in either arm.
The median follow-up for the study is 11.4 months. The median major organ deterioration progression-free survival (MOD-PFS) was not reached for patients in either arm.
Overall survival (OS) data were not mature. A total of 56 deaths were observed [n=27 (13.8%) D-VCd vs. n=29 (15%) VCd group].
Cardiac electrophysiology: Daratumumab as a large protein has a low likelihood of direct ion channel interactions. The effect of daratumumab on the QTc interval was evaluated in an open-label study for 83 patients (Study GEN501) with relapsed and refractory multiple myeloma following daratumumab infusions (4 to 24 mg/kg). Linear mixed PK-PD analyses indicated no large increase in mean QTcF interval (i.e. greater than 20 ms) at daratumumab C_max.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with DARZALEX in all subsets of the paediatric population in multiple myeloma (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Concentrate for solution for IV infusion: The pharmacokinetics (PK) of daratumumab following intravenous administration of daratumumab monotherapy were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg.
In the 1 to 24 mg/kg cohorts, peak serum concentrations (C_max) after the first dose increased in approximate proportion to dose and volume of distribution was consistent with initial distribution into the plasma compartment. Following the last weekly infusion, C_max increased in a greater than dose-proportional manner, consistent with target mediated drug disposition. Increases in AUC were more than dose-proportional and clearance (CL) decreased with increasing dose. These observations suggest CD38 may become saturated at higher doses, after which the impact of target binding clearance is minimised and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumour burden decreases.
Terminal half-life increases with increasing dose and with repeated dosing. The mean (standard deviation [SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was 9 (4.3) days. The estimated terminal half-life of daratumumab following the last 16 mg/kg dose increased, but there are insufficient data for a reliable estimation. Based on population PK analysis, the mean (SD) half-life associated with non-specific linear elimination was approximately 18 (9) days; this is the terminal half-life that can be expected upon complete saturation of target mediated clearance and repeat dosing of daratumumab.
At the end of weekly dosing for the recommended monotherapy schedule and dose of 16 mg/kg, the mean (SD) serum C_max value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (331.5) micrograms/mL.
Four population PK analyses were performed to describe the PK characteristics of daratumumab and to evaluate the influence of covariates on the disposition of daratumumab in patients with multiple myeloma; Analysis 1 (n=223) in patients receiving DARZALEX monotherapy while Analysis 2 (n=694), Analysis 3 (n=352) and Analysis 4 (n=355) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Analysis 2 included 694 patients (n=326 for lenalidomide-dexamethasone; n=246 for bortezomib-dexamethasone; n=99 for pomalidomide-dexamethasone; n=11 for bortezomib-melphalan-prednisone; and n=12 for bortezomib-thalidomide-dexamethasone) and Analysis 3 included 352 patients (bortezomib-melphalan-prednisone) and Analysis 4 included 355 patients (lenalidomide-dexamethasone).
Based on the population PK analysis of daratumumab monotherapy (Analysis 1), daratumumab steady state is achieved approximately 5 months into the every 4-week dosing period (by the 21^st infusion), and the mean (SD) ratio of C_max at steady-state to C_max after the first dose was 1.6 (0.5). The mean (SD) central volume of distribution is 56.98 (18.07) mL/kg.
Three additional population PK analyses (Analysis 2, Analysis 3 and Analysis 4) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Daratumumab concentration-time profiles were similar following the monotherapy and combination therapies. The mean estimated terminal half-life associated with linear clearance in combination therapy was approximately 15-23 days.
Based on the population PK analyses (Analyses 1-4) body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the multiple myeloma patients.
Simulation of daratumumab pharmacokinetics was conducted for all recommended dosing schedules in 1,309 patients with multiple myeloma. The simulation results confirmed that the split and single dosing for the first dose provide similar PK, with the exception of the PK profile in the first day of the treatment.
Special populations: Age and gender: Based on four individual population PK analyses (1-4) in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-4), age (range: 31-93 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged < 65 years, n = 518) and older (aged ≥ 65 to <75 years, n = 761; aged ≥ 75 years, n = 334) patients.
Gender did not affect exposure of daratumumab to a clinically relevant degree in the population PK analyses.
Renal impairment: No formal studies of daratumumab in patients with renal impairment have been conducted. Four individual population PK analyses were performed based on pre-existing renal function data in patients receiving daratumumab monotherapy, or various combination therapies (Analyses 1-4), and included a total of 441 patients with normal renal function (creatinine clearance [CRCL] ≥ 90 mL/min), 621 with mild renal impairment (CRCL < 90 and ≥ 60 mL/min), 523 with moderate renal impairment (CRCL < 60 and ≥ 30 mL/min), and 27 with severe renal impairment or end stage renal disease (CRCL < 30 mL/min). No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.
Hepatic impairment: No formal studies of daratumumab in patients with hepatic impairment have been conducted. Changes in hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1 molecules such as daratumumab are not metabolised through hepatic pathways.
Four individual population PK analyses were performed in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-4), and included a total of 1404 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]), 189 with mild hepatic impairment (TB 1.0 x to 1.5 x ULN or AST > ULN) and 8 patients with moderate (TB > 1.5 x to 3.0 x ULN; n=7), or severe (TB > 3.0 x ULN; n=1) hepatic impairment. No clinically important differences in the exposure to daratumumab were observed between patients with hepatic impairment and those with normal hepatic function.
Race: Based on four individual population PK analyses in patients receiving either daratumumab monotherapy, or various combination therapies (Analyses 1-4), the exposure to daratumumab was similar between white (n=1371) and non-white subjects (n=242).
Solution for SC injection: In patients with multiple myeloma, daratumumab exposure in a monotherapy study following the recommended 1800 mg administration of DARZALEX subcutaneous formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter) as compared to 16 mg/kg intravenous daratumumab for the same dosing schedule, showed non-inferiority for the co-primary endpoint of maximum C_trough (cycle 3 day 1 pre-dose), with mean ± SD of 593 ± 306 μg/mL compared to 522 ± 226 μg/mL for intravenous daratumumab, with a geometric mean ratio of 107.93% (90% CI: 95.74-121.67).
In a combination study, AMY3001, in patients with AL amyloidosis, the maximum C_trough (cycle 3 day 1 pre-dose) was similar to that in multiple myeloma with mean ± SD of 597 ± 232 μg/mL following the recommended 1800 mg administration of DARZALEX subcutaneous formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter).
Following the recommended dose of 1800 mg DARZALEX solution for subcutaneous injection, peak concentrations (C_max) increased 4.8-fold and total exposure (AUC_{0-7 days}) increased 5.4-fold from first dose to last weekly dose (8th dose). Highest trough concentrations for DARZALEX solution for subcutaneous injection are typically observed at the end of the weekly dosing regimens for both monotherapy and combination therapy.
In patients with multiple myeloma, the simulated trough concentrations following 6 weekly doses of 1800 mg DARZALEX solution for subcutaneous injection for combination therapy were similar to 1800 mg DARZALEX solution for subcutaneous injection monotherapy.
In patients with multiple myeloma, daratumumab exposure in a combination study with pomalidomide and dexamethasone (study MMY3013) was similar to that in monotherapy, with the maximum C_trough (cycle 3 day 1 pre-dose) mean ± SD of 537 ± 277 μg/mL following the recommended 1800 mg administration of DARZALEX solution for subcutaneous injection (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter).
Absorption and distribution: At the recommended dose of 1800 mg in multiple myeloma patients, the absolute bioavailability of DARZALEX solution for subcutaneous injection is 69%, with an absorption rate of 0.012 hour^-1, with peak concentrations occurring at 70 to 72 h (T_max). At the recommended dose of 1800 mg in AL amyloidosis patients, the absolute bioavailability was not estimated, the absorption rate constant was 0.77 day^-1 (8.31% CV) and peak concentrations occurred at 3 days.
The model predicted mean estimate of the volume of distribution for the central compartment was 5.25 L (36.9% CV) and peripheral compartment (V2) was 3.78 L in daratumumab monotherapy, and the modeled mean estimate of the volume of distribution for V1 was 4.36 L (28.0% CV) and V2 was 2.80 L when daratumumab was administered in combination with pomalidomide and dexamethasone in multiple myeloma patients. In AL amyloidosis patients, the model estimated apparent volume of distribution after subcutaneous administration is 10.8 L (3.1% CV). These results suggest that daratumumab is primarily localised to the vascular system with limited extravascular tissue distribution.
Metabolism and elimination: Daratumumab exhibits both concentration and time-dependent pharmacokinetics with parallel linear and nonlinear (saturable) elimination that is characteristic of target-mediated clearance. The population PK model estimated mean clearance value of daratumumab is 4.96 mL/h (58.7% CV) in daratumumab monotherapy and 4.32 mL/h (43.5% CV) when daratumumab is administered in combination with pomalidomide and dexamethasone in multiple myeloma patients. In AL amyloidosis patients, the apparent clearance after subcutaneous administration is 210 mL/day (4.1% CV). The model-based geometric mean for half-life associated with linear elimination is 20.4 days (22.4% CV) in daratumumab monotherapy and 19.7 days (15.3% CV) when daratumumab was administered in combination with pomalidomide and dexamethasone in multiple myeloma patients and 27.5 days (74.0% CV) in AL amyloidosis patients. For the monotherapy and combination regimens, the steady state is achieved at approximately 5 months into every 4 weeks dosage at the recommended dose and schedule (1800 mg; once weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks thereafter).
A population PK analysis was conducted using data from DARZALEX solution for subcutaneous injection monotherapy and combination therapy multiple myeloma studies, and the predicted PK exposures are summarised in Table 11. (See Table 11.)

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A population PK analysis, using data from DARZALEX solution for subcutaneous injection combination therapy in AL amyloidosis patients, was conducted with data from 211 patients. At the recommended dose of 1800 mg, predicted daratumumab concentrations were slightly higher, but generally within the same range, in comparison with multiple myeloma patients. (See Table 12.)

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Special populations: Age and gender: Based on population PK analyses in patients (33-92 years) receiving monotherapy or various combination therapies, age had no statistically significant effect on the PK of daratumumab. No individualisation is necessary for patients on the basis of age.
Gender had a statistically significant effect on PK parameters in patients with multiple myeloma but not in patients with AL amyloidosis. Slightly higher exposure in females were observed than males, but the difference in exposure is not considered clinically meaningful. No individualisation is necessary for patients on the basis of gender.
Renal impairment: No formal studies of DARZALEX subcutaneous formulation in patients with renal impairment have been conducted. Population PK analyses were performed based on pre-existing renal function data in patients with multiple myeloma receiving DARZALEX subcutaneous formulation monotherapy or various combination therapies in patients with multiple myeloma or AL amyloidosis. No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.
Hepatic impairment: No formal studies of DARZALEX subcutaneous formulation in patients with hepatic impairment have been conducted.
Population PK analyses were performed in patients with multiple myeloma receiving DARZALEX subcutaneous formulation monotherapy or various combination therapies in patients with multiple myeloma and in AL amyloidosis. No clinically important differences in the exposure to daratumumab were observed between patients with normal hepatic function and mild hepatic impairment. There were very few patients with moderate and severe hepatic impairment to make meaningful conclusions for these populations.
Race: Based on the population PK analyses in patients receiving either DARZALEX subcutaneous formulation monotherapy or various combination therapies, the daratumumab exposure was similar across races.
Body weight: The flat-dose administration of DARZALEX subcutaneous formulation 1800 mg as monotherapy achieved adequate exposure for all body-weight subgroups. In patients with multiple myeloma, the mean cycle 3 day 1 C_trough in the lower body-weight subgroup (≤ 65 kg) was 60% higher and in the higher body weight (> 85 kg) subgroup, 12% lower than the intravenous daratumumab subgroup. In some patients with body weight > 120 kg, lower exposure was observed which may result in reduced efficacy. However, this observation is based on limited number of patients.
In patients with AL amyloidosis, no meaningful differences were observed in C_trough across body weight.
Toxicology: Preclinical safety data: Toxicology data have been derived from studies with daratumumab in chimpanzees and with a surrogate anti-CD38 antibody in cynomolgus monkeys. No chronic toxicity testing has been conducted.
Carcinogenicity and mutagenicity: No animal studies have been performed to establish the carcinogenic potential of daratumumab.
Reproductive toxicology: No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development.
Fertility: No animal studies have been performed to determine potential effects on fertility in males or females.
Solution for SC injection: No carcinogenicity, genotoxicity, or fertility studies were conducted for recombinant human hyaluronidase. There were no effects on reproductive tissues and function and no systemic exposure of hyaluronidase in monkeys given 22000 U/kg/week subcutaneously (12 times higher than the human dose) for 39 weeks. As hyaluronidase is a recombinant form of the endogenous human hyaluronidase, no carcinogenicity, mutagenesis, or effects on fertility are expected.

Concentrate for solution for IV infusion: DARZALEX is indicated: in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy; as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.
Solution for SC injection: Multiple myeloma: DARZALEX is indicated: in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one prior therapy containing a proteasome inhibitor and lenalidomide and were lenalidomide-refractory, or who have received at least two prior therapies that included lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or after the last therapy (see Pharmacology: Pharmacodynamics under Actions); as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.
Light chain (AL) amyloidosis: DARZALEX is indicated in combination with cyclophosphamide, bortezomib and dexamethasone for the treatment of adult patients with newly diagnosed systemic AL amyloidosis.

Concentrate for solution for IV infusion: DARZALEX should be administered by a healthcare professional, in an environment where resuscitation facilities are available.
Pre- and post-infusion medicinal products should be administered to reduce the risk of infusion-related reactions (IRRs) with daratumumab. See Recommended concomitant medicinal products, Management of infusion-related reactions as follows and Precautions.
Posology: Dosing schedule in combination with lenalidomide and dexamethasone (4‑week cycle regimen) and for monotherapy: The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 13. (See Table 13.)

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Dexamethasone should be administered at 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years).
For dose and schedule of medicinal products administered with DARZALEX, see Pharmacology: Pharmacodynamics under Actions and the corresponding product insert.
Dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle regimens): The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 14. (See Table 14.)

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Bortezomib is given twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by once weekly at Weeks 1, 2, 4 and 5 for eight more 6-week cycles. For information on the VMP dose and dosing schedule when administered with DARZALEX, see Pharmacology: Pharmacodynamics under Actions.
Dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle regimens) for treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT): The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 15. (See Table 15.)

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Dexamethasone should be administered at 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and 2, and at 40 mg on days 1-2 and 20 mg on subsequent dosing days (days 8, 9, 15, 16) of cycles 3-4. Dexamethasone 20 mg should be administered on days 1, 2, 8, 9, 15, 16 in cycles 5 and 6.
For dose and schedule of medicinal products administered with DARZALEX, see Pharmacology: Pharmacodynamics under Actions and the corresponding product insert.
Dosing schedule in combination with bortezomib and dexamethasone (3‑week cycle regimen): The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 16. (See Table 16.)

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Dexamethasone should be administered at 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 bortezomib treatment cycles or a reduced dose of 20 mg/week for patients >75 years, underweight (BMI <18.5), poorly controlled diabetes mellitus or prior intolerance to steroid therapy.
For dose and schedule of medicinal products administered with DARZALEX, see Pharmacology: Pharmacodynamics under Actions and the corresponding package insert.
Infusion rates: Following dilution the DARZALEX infusion should be intravenously administered at the initial infusion rate presented in Table 17 as follows. Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions.
To facilitate administration, the first prescribed 16 mg/kg dose at Week 1 may be split over two consecutive days i.e. 8 mg/kg on Day 1 and Day 2 respectively, see Table 17 as follows.

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Management of infusion-related reactions: Pre-infusion medicinal products should be administered to reduce the risk of infusion-related reactions (IRRs) prior to treatment with DARZALEX.
For IRRs of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms.
Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined as follows (see Precautions).
Grade 1-2 (mild to moderate): Once reaction symptoms resolve, the infusion should be resumed at no more than half the rate at which the IRR occurred. If the patient does not experience any further IRR symptoms, infusion rate escalation may be resumed at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 17).
Grade 3 (severe): Once reaction symptoms resolve, restarting of the infusion may be considered at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, infusion rate escalation may be resumed at increments and intervals as appropriate (Table 17). The procedure previously mentioned should be repeated in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion reaction.
Grade 4 (life-threatening): Permanently discontinue DARZALEX treatment.
Solution for SC injection: DARZALEX subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified.
DARZALEX should be administered by a healthcare professional, and the first dose should be administered in an environment where resuscitation facilities are available.
It is important to check the vial labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and dose is being given to the patient as prescribed.
For patients currently receiving daratumamab intravenous formulation, DARZALEX solution for subcutaneous injection may be used as an alternative to the intravenous daratumumab formulation starting at the next scheduled dose.
Pre- and post-injection medicinal products should be administered to reduce the risk of infusion-related reactions (IRRs) with daratumumab. See "Recommended concomitant medicinal products" as follows and Precautions.
Posology: Multiple myeloma: Dosing schedule in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone (4-week cycle regimen) and for monotherapy: The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in Table 18. (See Table 18.)

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Dexamethasone should be administered at 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years). For dose and schedule of medicinal products administered with DARZALEX solution for subcutaneous injection, see Pharmacology: Pharmacodynamics under Actions and the corresponding package insert.
Dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle regimens): The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in Table 19. (See Table 19.)

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Bortezomib is given twice weekly at weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by once weekly at weeks 1, 2, 4 and 5 for eight more 6-week cycles. For information on the VMP dose and dosing schedule when administered with DARZALEX solution for subcutaneous injection, see Pharmacology: Pharmacodynamics under Actions.
Dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle regimens) for treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT): The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in Table 20. (See Table 20.)

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Dexamethasone should be administered at 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and 2, and at 40 mg on days 1-2 and 20 mg on subsequent dosing days (days 8, 9, 15, 16) of cycles 3-4. Dexamethasone 20 mg should be administered on days 1, 2, 8, 9, 15, 16 in cycles 5 and 6.
For dose and schedule of medicinal products administered with DARZALEX solution for subcutaneous injection, see Pharmacology: Pharmacodynamics under Actions and the corresponding package insert.
Dosing schedule in combination with bortezomib and dexamethasone (3-week cycle regimen): The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in Table 21. (See Table 21.)

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Dexamethasone should be administered at 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 bortezomib treatment cycles or a reduced dose of 20 mg/week for patients > 75 years, underweight (BMI < 18.5), poorly controlled diabetes mellitus or prior intolerance to steroid therapy.
For dose and schedule of medicinal products administered with DARZALEX solution for subcutaneous injection, see Pharmacology: Pharmacodynamics under Actions and the corresponding package insert.
AL amyloidosis: Dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle regimens): The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in Table 22. (See Table 22.)

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For dose and schedule of medicinal products administered with DARZALEX solution for subcutaneous injection, see Pharmacology: Pharmacodynamics under Actions and the corresponding package insert.
Missed dose: If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.
Dose modifications: No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity (see Precautions). For information concerning medicinal products given in combination with DARZALEX, see corresponding package insert.
Recommended concomitant medicinal products: Prophylaxis for herpes zoster virus reactivation: Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.
Concentrate for solution for IV infusion: Pre-infusion medicinal product: Pre-infusion medicinal products should be administered to reduce the risk of IRRs to all patients 1-3 hours prior to every infusion of DARZALEX as follows: Corticosteroid (long-acting or intermediate-acting): Monotherapy: Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg).
Combination therapy: Dexamethasone 20 mg (or equivalent), administered prior to every DARZALEX infusion. When dexamethasone is the background‑regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre‑infusion medicinal product on DARZALEX infusion days (see Pharmacology: Pharmacodynamics under Actions).
Dexamethasone is given intravenously prior to the first DARZALEX infusion and oral administration may be considered prior to subsequent infusions. Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on DARZALEX infusion days when patients have received dexamethasone as a pre-infusion medicinal product.
Antipyretics (oral paracetamol 650 to 1,000 mg).
Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).
Post-infusion medicinal product: Post-infusion medicinal products should be administered to reduce the risk of delayed IRRs as follows: Monotherapy: Oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) should be administered on each of the two days following all infusions (beginning the day after the infusion).
Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent the day after the DARZALEX infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional post-infusion medicinal products may not be needed (see Pharmacology: Pharmacodynamics under Actions).
Additionally, for patients with a history of chronic obstructive pulmonary disease, the use of post-infusion medicinal products including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four infusions, if the patient experiences no major IRRs, these inhaled post-infusion medicinal products may be discontinued at the discretion of the physician.
Solution for SC injection: Pre-injection medicinal product: Pre-injection medicinal products (oral or intravenous) should be administered to reduce the risk of IRRs to all patients 1-3 hours prior to every administration of DARZALEX solution for subcutaneous injection as follows: Corticosteroid (long-acting or intermediate-acting): Monotherapy: Methylprednisolone 100 mg, or equivalent. Following the second injection, the dose of corticosteroid may be reduced to methylprednisolone 60 mg.
Combination therapy: Dexamethasone 20 mg (or equivalent), administered prior to every DARZALEX solution for subcutaneous injection. When dexamethasone is the background-regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre-injection medicinal product on DARZALEX administration days (see Pharmacology: Pharmacodynamics under Actions). Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on DARZALEX administration days when patients have received dexamethasone (or equivalent) as a pre-injection medicinal product.
Antipyretics (paracetamol 650 to 1000 mg).
Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).
Post-injection medicinal product: Post-injection medicinal products should be administered to reduce the risk of delayed IRRs as follows: Monotherapy: Oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) should be administered on each of the two days following all injections (beginning the day after the injection).
Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent the day after the DARZALEX injection. However, if a background regimen specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX injection, additional post-injection medicinal products may not be needed (see Pharmacology: Pharmacodynamics under Actions).
If the patient experiences no major IRRs after the first three injections, post-injection corticosteroids (excluding any background regimen corticosteroids) may be discontinued.
Additionally, for patients with a history of chronic obstructive pulmonary disease, the use of post-injection medicinal products including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four injections, if the patient experiences no major IRRs, these inhaled post-injection medicinal products may be discontinued at the discretion of the physician.
Special populations: Renal impairment: No formal studies of daratumumab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses no dosage adjustment is necessary for patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No formal studies of daratumumab in patients with hepatic impairment have been conducted.
Based on population PK analyses, no dosage adjustments are necessary for patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Elderly: No dose adjustments are considered necessary (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of DARZALEX in children aged below 18 years of age have not been established.
No data are available (see Pharmacology: Pharmacodynamics under Actions).
Body weight (> 120 kg): Solution for SC injection: Limited number of patients with body weight > 120 kg have been studied using flat-dose (1800 mg) DARZALEX solution for subcutaneous injection and efficacy in these patients has not been established. No dose adjustment based on body weight can currently be recommended (see Precautions and Dosage & Administration).
Method of administration: Concentrate for solution for IV infusion: DARZALEX is for intravenous use. It is administered as an intravenous infusion following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection. For instructions on dilution of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.
Solution for SC injection: DARZALEX subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. See Cautions for Usage for special precautions prior to administration.
To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.
Inject 15 mL DARZALEX solution for subcutaneous injection into the subcutaneous tissue of the abdomen approximately 7.5 cm to the right or left of the navel over approximately 3-5 minutes. Do not inject DARZALEX solution for subcutaneous injection at other sites of the body as no data are available.
Injection sites should be rotated for successive injections.
DARZALEX solution for subcutaneous injection should never be injected into areas where the skin is red, bruised, tender, hard or areas where there are scars.
Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by slowing down the injection, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.
During treatment with DARZALEX solution for subcutaneous injection, do not administer other medicinal products for subcutaneous use at the same site as DARZALEX.

Symptoms and signs: There has been no experience of overdose in clinical studies. Doses up to 24 mg/kg have been administered intravenously in a clinical study.
Treatment: There is no known specific antidote for daratumumab overdose. In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment should be instituted immediately.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Traceability: In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.
Infusion-related reactions: Concentrate for solution for IV infusion: DARZALEX can cause serious IRRs, including anaphylactic reactions (see Adverse Reactions).
All patients should be monitored throughout the infusion for IRRs. For patients that experience any Grade IRRs, continue monitoring post-infusion until symptoms resolve.
In clinical studies, IRRs were reported in approximately half of all patients treated with DARZALEX.
The majority of IRRs occurred at the first infusion and were Grade 1-2 (see Adverse Reactions). Four percent of all patients had an IRR at more than one infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, laryngeal oedema and pulmonary oedema. Symptoms predominantly included nasal congestion, cough, throat irritation, chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus and hypotension (see Adverse Reactions).
Patients should be pre-medicated with antihistamines, antipyretics and corticosteroids to reduce the risk of IRRs prior to treatment with DARZALEX. DARZALEX infusion should be interrupted for IRRs of any severity and medical management/supportive treatment for IRRs should be instituted as needed. For patients with Grade 1, 2, or 3 IRRs, the infusion rate should be reduced when re-starting the infusion. If an anaphylactic reaction or life-threatening (Grade 4) infusion reaction occurs, appropriate emergency resuscitation should be initiated immediately. DARZALEX therapy should be discontinued immediately and permanently (see Dosage & Administration and Contraindications).
To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX infusions. Additionally the use of post-infusion medicinal products (e.g. inhaled corticosteroids, short and long acting bronchodilators) should be considered for patients with a history of chronic obstructive pulmonary disease to manage respiratory complications should they occur (see Dosage & Administration).
Solution for SC injection: DARZALEX solution for subcutaneous injection can cause severe and/or serious IRRs, including anaphylactic reactions. In clinical studies, approximately 9% (74/832) of patients experienced an IRR. Most IRRs occurred following the first injection and were grade 1-2. IRRs occurring with subsequent injections were seen in 1% of patients (see Adverse Reactions).
The median time to onset of IRRs following DARZALEX injection was 3.2 hours (range 0.15-83 hours). The majority of IRRs occurred on the day of treatment. Delayed IRRs have occurred in 1% of patients.
Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension and tachycardia (see Adverse Reactions).
Patients should be pre-medicated with antihistamines, antipyretics, and corticosteroids as well as monitored and counselled regarding IRRs, especially during and following the first and second injections. If an anaphylactic reaction or life-threatening (grade 4) reactions occur, appropriate emergency care should be initiated immediately. DARZALEX therapy should be discontinued immediately and permanently (see Dosage & Administration and Contraindications).
To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX injection (see Dosage & Administration). Patients with a history of chronic obstructive pulmonary disease may require additional post-injection medicinal products to manage respiratory complications. The use of post-injection medicinal products (e.g. short- and long-acting bronchodilators and inhaled corticosteroids) should be considered for patients with chronic obstructive pulmonary disease (see Dosage & Administration).
Neutropenia/Thrombocytopenia: DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy (see Adverse Reactions).
Complete blood cell counts should be monitored periodically during treatment according to prescribing information for background therapies. Patients with neutropenia should be monitored for signs of infection. DARZALEX delay may be required to allow recovery of blood cell counts. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions or growth factors.
Solution for SC injection: In lower body weight patients receiving DARZALEX subcutaneous formulation, higher rates of neutropenia were observed; however, this was not associated with higher rates of serious infections.
Interference with indirect antiglobulin test (indirect Coombs test): Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive indirect Coombs test. Daratumumab-mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab infusion. It should be recognised that daratumumab bound to RBCs may mask detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type are not impacted.
Patients should be typed and screened prior to starting daratumumab treatment. Phenotyping may be considered prior to starting daratumumab treatment as per local practice. Red blood cell genotyping is not impacted by daratumumab and may be performed at any time.
In the event of a planned transfusion blood transfusion centres should be notified of this interference with indirect antiglobulin tests (see Interactions). If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.
Interference with determination of complete response: Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein (see Interactions). This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.
Hepatitis B virus (HBV) reactivation: Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with DARZALEX. HBV screening should be performed in all patients before initiation of treatment with DARZALEX.
For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of DARZALEX treatment. Manage patients according to current clinical guidelines. Consider consulting a hepatitis disease expert as clinically indicated.
In patients who develop reactivation of HBV while on DARZALEX, suspend treatment with DARZALEX and institute appropriate treatment. Resumption of DARZALEX treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.
Body weight (> 120 kg): Solution for SC injection: There is a potential for reduced efficacy with DARZALEX solution for subcutaneous injection in patients with body weight > 120 kg (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Excipients: Concentrate for solution for IV infusion: Each 5 mL and 20 mL vial of DARZALEX contains 0.4 mmol and 1.6 mmol (9.3 mg and 37.3 mg) sodium, respectively. This corresponds to 0.46% and 1.86% of the WHO recommended maximum daily intake of 2 g sodium for an adult, respectively.
Solution for SC injection: This medicinal product contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) should not be given this medicinal product.
This medicinal product also contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: DARZALEX has no or negligible influence on the ability to drive and use machines. However, fatigue has been reported in patients taking daratumumab and this should be taken into account when driving or using machines.

Women of child-bearing potential/Contraception: Women of child-bearing potential should use effective contraception during, and for 3 months after cessation of daratumumab treatment.
Pregnancy: There are no or limited amount of data from the use of daratumumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). DARZALEX is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding: It is not known whether daratumumab is excreted into human or animal milk.
A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from DARZALEX therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: No data are available to determine potential effects of daratumumab on fertility in males or females (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Concentrate for solution for IV infusion: Summary of the safety profile: The most frequent adverse reactions of any grade ≥20% were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, dyspnoea, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, asthenia, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were sepsis, pneumonia, bronchitis, upper respiratory tract infection, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.
Tabulated list of adverse reactions: Table 23 summarises the adverse reactions that occurred in patients receiving DARZALEX. The data reflects exposure to DARZALEX (16 mg/kg) in 2066 patients with multiple myeloma including 1910 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. Post-marketing adverse reactions are also included.
In Study MMY3006, the number of CD34+ cell yield was numerically lower in the D-VTd arm compared with the VTd arm (Median: D-VTd: 6.3 x 10⁶/kg; VTd 8.9 x 10⁶/kg) and among those who completed mobilisation, more patients in the D-VTd group received plerixafor compared to those in the VTd arm (D-VTd: 21.7%; VTd: 7.9%). The rates of engraftment and haematopoietic reconstitution was similar among the transplanted subjects in the D-VTd and VTd arms (D-VTd: 99.8%; VTd: 99.6%; as measured by the recovery of neutrophils > 0.5 x 10⁹/L, leukocytes > 1.0 x 10⁹/L, and platelets > 50 x 10⁹/L without transfusion).
Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness. (See Table 23.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Infusion-related reactions (IRRs): In clinical studies (monotherapy and combination treatments; N = 2066) the incidence of any grade IRRs was 37% with the first (16 mg/kg, Week 1) infusion of DARZALEX, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 IRR with the Week 2 or subsequent infusions.
The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 hours). The incidence of infusion modifications due to reactions was 36%. Median durations of 16 mg/kg infusions for the 1^st Week, 2^nd Week and subsequent infusions were approximately 7, 4 and 3 hours respectively.
Severe IRRs included bronchospasm, dyspnoea, laryngeal oedema, pulmonary oedema, hypoxia, and hypertension. Other adverse IRRs included nasal congestion, cough, chills, throat irritation, vomiting and nausea (see Precautions).
When DARZALEX dosing was interrupted in the setting of ASCT (Study MMY3006) for a median of 3.75 (range: 2.4; 6.9) months, upon re-initiation of DARZALEX the incidence of IRRs was 11% at first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption due to ASCT. IRRs occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3/4: <1%) with those reported in previous studies at Week 2 or subsequent infusions.
In Study MMY1001, patients receiving daratumumab combination treatment (n=97) were administered the first 16 mg/kg daratumumab dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2 respectively. The incidence of any grade IRRs was 42%, with 36% of patients experiencing IRRs on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 h for Week 1-Day 1, 4.2 h for Week 1-Day 2, and 3.4 hours for the subsequent infusions.
Infections: In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported as follows: Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd: 28%.
Newly diagnosed patient studies: D‑VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; D-VTd: 22%, VTd: 20%.
Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In active controlled studies, discontinuations from treatment due to infections occurred in 1-4% of patients. Fatal infections were primarily due to pneumonia and sepsis.
In patients receiving DARZALEX combination therapy, fatal infections (Grade 5) were reported as follows: Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%.
Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.
Key: D=daratumumab; Vd=bortezomib-dexamethasone; Rd=lenalidomide-dexamethasone; Pd=pomalidomide-dexamethasone; VMP=bortezomib-melphalan-prednisone; VTd=bortezomib-thalidomide-dexamethasone.
Haemolysis: There is a theoretical risk of haemolysis. Continuous monitoring for this safety signal will be performed in clinical studies and post-marketing safety data.
Other special populations: In the Phase III study MMY3007, which compared treatment with D-VMP to treatment with VMP in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was consistent with the overall population (see Pharmacology: Pharmacodynamics under Actions).
Elderly patients: Of the 2459 patients who received DARZALEX at the recommended dose, 38% were 65 to 75 years of age, and 15% were 75 years of age or older. No overall differences in effectiveness were observed based on age. The incidence of serious adverse reactions was higher in older than in younger patients. Among patients with relapsed and refractory multiple myeloma (n=1213), the most common serious adverse reactions that occurred more frequently in elderly (≥65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the most common serious adverse reaction that occurred more frequently in elderly (≥75 years of age) was pneumonia.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Solution for SC injection: Summary of the safety profile: The most frequent adverse reactions of any grade (≥ 20% patients) with daratumumab (either intravenous or subcutaneous formulations) when administered either as monotherapy or combination treatment were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea, atrial fibrillation and syncope.
The safety profile of the DARZALEX subcutaneous formulation was similar to that of intravenous formulation with the exception of a lower rate of IRRs. In the phase III study MMY3012, neutropenia was the only adverse reaction reported at ≥ 5% higher frequency for DARZALEX subcutaneous formulation compared to intravenous daratumumab (grade 3 or 4: 13% vs 8%, respectively).
Tabulated list of adverse reactions: Table 24 summarises the adverse reactions that occurred in patients receiving DARZALEX subcutaneous formulation or intravenous formulation of daratumumab.
The data reflects exposure to DARZALEX subcutaneous formulation (1800 mg) in 639 patients with multiple myeloma (MM). The data includes 260 patients from a phase III active-controlled study (MMY3012) who received DARZALEX solution for subcutaneous injection as monotherapy and 149 patients from a phase III active-controlled study (MMY3013) who received DARZALEX subcutaneous formulation in combination with pomalidomide and dexamethasone (D-Pd). The data also reflects three open-label, clinical studies in which patients received DARZALEX solution for subcutaneous injection either as monotherapy (N=31, MMY1004 and MMY1008) and MMY2040 in which patients received DARZALEX solution for subcutaneous injection in combination with either bortezomib, melphalan and prednisone (D-VMP, n=67), lenalidomide and dexamethasone (D-Rd, n=65) or bortezomib, lenalidomide and dexamethasone (D-VRd, n=67). Additionally, data reflect exposure to 193 patients with newly diagnosed AL amyloidosis from a phase III active-controlled study (AMY3001) in which patients received DARZALEX subcutaneous formulation in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd).
The safety data also reflects exposure to intravenous daratumumab (16 mg/kg) in 2324 patients with multiple myeloma including 1910 patients who received intravenous daratumumab in combination with background regimens and 414 patients who received intravenous daratumumab as monotherapy. Post-marketing adverse reactions are also included.
Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. (See Table 24.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Infusion-related reactions (IRRs): In clinical studies (monotherapy and combination treatments; N=832) with DARZALEX subcutaneous formulation, the incidence of any grade IRRs was 8.2% with the first injection of DARZALEX (1800 mg, week 1), 0.4% with the week 2 injection, and 1.1% with subsequent injections. Grade 3 IRRs were seen in 0.8% of patients. No patients had grade 4 IRRs.
Signs and symptoms of IRR may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritis, chills, vomiting, nausea, and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension and tachycardia (see Precautions).
Injection site reactions (ISRs): In clinical studies (N=832) with DARZALEX subcutaneous formulation, the incidence of any grade injection site reaction was 7.7%. There were no grade 3 or 4 ISRs. The most common (> 1%) ISR at the site of injection was erythema.
Infections: In patients with multiple myeloma receiving daratumumab as monotherapy, the overall incidence of infections was similar between DARZALEX subcutaneous formulation (52.9%) versus intravenous daratumumab groups (50.0%). Grade 3 or 4 infections also occurred at similar frequencies between DARZALEX subcutaneous formulation (11.7%) and intravenous daratumumab (14.3%). Most infections were manageable and rarely led to treatment discontinuation. Pneumonia was the most commonly reported grade 3 or 4 infection across studies. In active-controlled studies, discontinuations from treatment due to infections occurred in 1-4% of patients. Fatal infections were primarily due to pneumonia and sepsis.
In patients with multiple myeloma receiving intravenous daratumumab combination therapy, the following were reported: Grade 3 or 4 infections: Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%.
Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; D-VTd: 22%, VTd: 20%.
Grade 5 (fatal) infections: Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%.
Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.
In patients with multiple myeloma receiving DARZALEX subcutaneous formulation combination therapy, the following were reported: Grade 3 or 4 infections: DPd: 28%, Pd: 23%.
Grade 5 (fatal) infections: DPd: 5%, Pd: 3%.
Key: D=daratumumab; Vd=bortezomib-dexamethasone; Rd=lenalidomide-dexamethasone; Pd=pomalidomide-dexamethasone; VMP=bortezomib-melphalan-prednisone; VTd=bortezomib-thalidomide-dexamethasone.
In patients with AL amyloidosis receiving DARZALEX subcutaneous formulation combination therapy, the following were reported: Grade 3 or 4 infections: D-VCd: 17%, VCd:10%.
Grade 5 infections: D-VCd: 1%, VCd: 1%.
Key: D=daratumumab; VCd=bortezomib-cyclophosphamide-dexamethasone.
Haemolysis: There is a theoretical risk of haemolysis. Continuous monitoring for this safety signal will be performed in clinical studies and post-marketing safety data.
Cardiac disorders and AL amyloidosis-related cardiomyopathy: The majority of patients in AMY3001 had AL amyloidosis-related cardiomyopathy at baseline (D-VCd 72% vs. VCd 71%). Grade 3 or 4 cardiac disorders occurred in 11% of D-VCd patients compared to 10% of VCd patients, while serious cardiac disorders occurred in 16% vs. 13% of D-VCd and VCd patients, respectively. Serious cardiac disorders occurring in ≥ 2% of patients included cardiac failure (D-VCd 6.2% vs. VCd 4.3%), cardiac arrest (D-VCd 3.6% vs. VCd 1.6%) and atrial fibrillation (D-VCd 2.1% vs. VCd 1.1%). All D-VCd patients who experienced serious or fatal cardiac disorders had AL amyloidosis-related cardiomyopathy at baseline. The longer median duration of treatment in the D-VCd arm compared to the VCd arm (9.6 months vs. 5.3 months, respectively) should be taken into consideration when comparing the frequency of cardiac disorders between the two treatment groups. Exposure-adjusted incidence rates (number of patients with the event per 100 patient-months at risk) of overall grade 3 or 4 cardiac disorders (1.2 vs. 2.3), cardiac failure (0.5 vs. 0.6), cardiac arrest (0.1 vs. 0.0) and atrial fibrillation (0.2 vs. 0.1) were comparable in the D-VCd arm vs. the VCd arm, respectively.
With a median follow-up of 11.4 months, overall deaths (D-VCd 14% vs. VCd 15%) in study AMY3001 were primarily due to AL amyloidosis-related cardiomyopathy in both treatment arms.
Other special populations: In the phase III study MMY3007, which compared treatment with D-VMP to treatment with VMP in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was consistent with the overall population (see Pharmacology: Pharmacodynamics under Actions).
Elderly patients: Of the 3549 patients who received daratumumab (n=832 subcutaneous; n=2717 intravenous) at the recommended dose, 38% were 65 to less than 75 years of age, and 16% were 75 years of age or older. No overall differences in effectiveness were observed based on age. The incidence of serious adverse reactions was higher in older than in younger patients. Among patients with relapsed and refractory multiple myeloma (n=1976), the most common serious adverse reactions that occurred more frequently in elderly (≥ 65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=777), the most common serious adverse reaction that occurred more frequently in elderly (≥ 75 years of age) was pneumonia. Among patients with newly diagnosed AL amyloidosis (n=193), the most common serious adverse reaction that occurred more frequently in elderly (≥ 65 years of age) was pneumonia.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

No interaction studies have been performed.
As an IgG1κ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact daratumumab are unlikely to represent major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of daratumumab. Due to the high affinity to a unique epitope on CD38, daratumumab is not anticipated to alter drug-metabolising enzymes.
Clinical pharmacokinetic assessments of daratumumab in combination with lenalidomide, pomalidomide, thalidomide, bortezomib and dexamethasone indicated no clinically-relevant drug-drug interaction between daratumumab and these small molecule medicinal products.
Interference with indirect antiglobulin test (indirect Coombs test): Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching (see Precautions). Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or other locally validated methods. Since the Kell blood group system is also sensitive to DTT treatment, Kell-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs. Alternatively, phenotyping or genotyping may also be considered (see Precautions).
Interference with serum protein electrophoresis and immunofixation tests: Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a validated daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response.

Special precautions for disposal and other handling: Concentrate for solution for IV infusion: This medicinal product is for single-use only.
Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient weight.
Check that the DARZALEX solution is colourless to yellow. Do not use if opaque particles, discolouration or other foreign particles are present.
Using aseptic technique, remove a volume of sodium chloride 9 mg/mL (0.9%) solution for injection from the infusion bag/container that is equal to the required volume of DARZALEX solution.
Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to an infusion bag/container containing sodium chloride 9 mg/mL (0.9%) solution for injection (see Dosage & Administration). Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.
Gently invert the bag/container to mix the solution. Do not shake.
Visually inspect parenteral medicinal products for particulate matter and discolouration prior to administration. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discolouration or foreign particles are observed.
Since DARZALEX does not contain a preservative, diluted solutions should be administered within 15 hours (including infusion time) at room temperature (15°C - 25°C) and in room light.
If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions (2°C - 8°C) and protected from light. Do not freeze.
Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometre). Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE administration sets must be used.
Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.
Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.
Solution for SC injection: DARZALEX solution for subcutaneous injection is for single use only and is ready to use.
DARZALEX solution for subcutaneous injection should be a clear to opalescent and colourless to yellow solution. Do not use if opaque particles, discolouration or other foreign particles are present.
DARZALEX solution for subcutaneous injection is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles.
Unopened vial: Remove the DARZALEX solution for subcutaneous injection vial from refrigerated storage (2°C-8°C) and equilibrate to ambient temperature (15°C-30°C). The unpunctured vial may be stored at ambient temperature and ambient light for a maximum of 24 hours in the original carton to protect from light. Keep out of direct sunlight. Do not shake.
Prepared syringe: Prepare the dosing syringe in controlled and validated aseptic conditions. Once transferred from the vial into the syringe, store DARZALEX solution for subcutaneous injection for up to 24 hours refrigerated conditions (2°C-8°C) protected from light, followed by up to 7 hours at 15°C-30°C and ambient light (see Shelf life under Storage). If stored in the refrigerator, allow the solution to reach ambient temperature before administration.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except those previously mentioned in Special precautions for disposal and other handling.

Store in a refrigerator (2°C - 8°C).
Do not freeze.
Store in the original package in order to protect from light.
Shelf life: Concentrate for solution for IV infusion: After dilution: From a microbiological point of view, unless the method of opening/ dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should be no more than 24 hours at refrigerated conditions (2°C - 8°C) protected from light, followed by 15 hours (including infusion time) at room temperature (15°C - 25°C) and room light.
Solution for SC injection: Unopened vial: During the shelf-life, the product in unpunctured vials may be stored at ambient temperature (15°C - 30°C) for a single period of up to 24 hours. Once the product has been taken out of the refrigerator, it must not be returned to the refrigerator (see Special precautions for disposal and other handling under Cautions for Usage).
Prepared syringe: Chemical and physical in-use stability in syringe has been demonstrated for 24 hours at refrigerated conditions (2°C-8°C) protected from light, followed by no more than 7 hours at 15°C-30°C and ambient light. From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Targeted Cancer Therapy

L01FC01 - daratumumab ; Belongs to the class of CD38 (Clusters of Differentiation 38) inhibitors. Used in the treatment of cancer.

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