Darzalex

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, ATC code: L01FC01. 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 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. 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 In multiple myeloma, including smouldering multiple myeloma at high risk of developing into 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 and 8 patients tested positive for neutralising antibodies. In multiple myeloma, including smouldering multiple myeloma at high risk of developing into multiple myeloma, and AL amyloidosis patients, the incidence of treatment‑emergent anti‑rHuPH20 antibodies was 8.9% (133/1491) in patients who received either monotherapy DARZALEX subcutaneous formulation or combination DARZALEX subcutaneous formulation and 1 patient tested positive for neutralising antibodies. 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 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 (1,800 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 10) and maximum C trough at pre‑dose cycle 3 day 1, (see section 5.2) . Table 10: Key results from Study MMY3012 Subcutaneous Daratumumab (N=263) Intravenous Daratumumab (N=259) Primary endpoint Overall response (sCR+CR+VGPR+PR), n (%) a 108 (41.1%) 96 (37.1%) 95% CI (%) (35.1%, 47.3%) (31.2%, 43.3%) Ratio of response rates (95% CI) b 1.11 (0.89, 1.37) CR or better, n (%) 5 (1.9%) 7 (2.7%) Very good partial response (VGPR) 45 (17.1%) 37 (14.3%) Partial response (PR) 58 (22.1%) 52 (20.1%) Secondary endpoint Rate of infusion‑related reaction, n (%) c 33 (12.7%) 89 (34.5%) Progression‑free survival, months Median (95% CI) 5.59 (4.67, 7.56) 6.08 (4.67, 8.31) Hazard ratio (95% CI) 0.99 (0.78, 1.26) a Based on intent-to-treat population. b p-value <0.0001 from Farrington-Manning test for non-inferiority hypothesis. c Based on safety population. P-value<0.0001 from Cochran-Mantel-Haenszel Chi-Squared test 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 Combination treatment with bortezomib, lenalidomide and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma eligible for autologous stem cell transplant (ASCT) Study MMY3014 was an open‑label, randomised, active‑controlled phase III study that compared induction and consolidation treatment with DARZALEX subcutaneous formulation (1800 mg) in combination with bortezomib, lenalidomide and dexamethasone (D‑VRd), followed by maintenance with DARZALEX in combination with lenalidomide, to treatment with bortezomib, lenalidomide and dexamethasone (VRd), followed by maintenance with lenalidomide, in patients 70 years of age and younger with newly diagnosed multiple myeloma eligible for ASCT until documented disease progression or unacceptable toxicity. Patients received DARZALEX subcutaneous formulation (1800 mg) administered subcutaneously once weekly (days 1, 8, 15, and 22) for cycles 1‑2 followed by once every two weeks (days 1 and 15) for cycles 3‑6. For maintenance (cycles 7+), patients received DARZALEX subcutaneous formulation (1800 mg) once every four weeks. Patients who achieved MRD negativity that was sustained for 12 months and had been treated on maintenance for at least 24 months discontinued treatment with DARZALEX subcutaneous formulation (1800 mg). Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg/m 2 body surface area twice weekly for two weeks (days 1, 4, 8, and 11) of repeated 28‑day (4‑week) cycles 1‑6). Lenalidomide was administered orally at 25 mg daily on days 1 to 21 during cycles 1‑6. For maintenance (cycles 7+), patients received 10 mg lenalidomide daily on days 1‑28 (continuously) of each cycle until documented disease progression or unacceptable toxicity. Dexamethasone (oral or intravenous) was administered at 40 mg on days 1‑4 and days 9‑12 of cycles 1‑6. On the days of DARZALEX subcutaneous formulation (1800 mg) infusion, the dexamethasone dose was administered orally or intravenously as a pre‑injection medicinal product. Dose adjustments for bortezomib, lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. A total of 709 patients were randomised: 355 to the D‑VRd arm and 354 to the VRd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 60 (range: 31 to 70 years). The majority were male (59%), 64% had an ECOG performance score of 0, 31% had an ECOG performance score of 1 and 5% had an ECOG performance score of 2. Additionally, 51% had ISS stage I, 34% had ISS stage II, 15% had ISS stage III disease, 75% had a standard cytogenetic risk, 22% had a high cytogenetic risk (del17p, t[4;14]), t[14;16]), and 3% had an indeterminate cytogenetic risk. During maintenance treatment, 207 (59%) patients discontinued DARZALEX subcutaneous formulation (1800 mg) after completing at least 24 months of maintenance treatment and achieving MRD‑negativity that was sustained for at least 12 months. With a median follow‑up of 47.5 months, the primary analysis of PFS in study MMY3014 demonstrated an improvement in PFS in the D‑VRd arm as compared to the VRd arm (HR=0.42; 95% CI: 0.30, 0.59; p<0.0001). Figure 1: Kaplan-Meier Curve of PFS in study MMY3014 Additional efficacy results from study MMY3014 are presented in table 11 below. Table 11: Efficacy results from study MMY3014 a D-VRd (n=355) VRd (n=354) Odds ratio (95% CI) d Overall response (sCR+CR+VGPR+PR) n(%) a 343 (96.6%) 332 (93.8%) Stringent complete response (sCR) 246 (69.3%) 158 (44.6%) Complete response (CR) 66 (18.6%) 90 (25.4%) Very good partial response (VGPR) 26 (7.3%) 68 (19.2%) Partial response (PR) 5 (1.4%) 16 (4.5%) CR or better (sCR+CR) 312 (87.9%) 248 (70.1%) 3.13 (2.11, 4.65) 95% CI (%) (84.0%, 91.1%) (65.0%, 74.8%) P‑value b < 0.0001 Overall MRD negativity rate a,c 267 (75.2%) 168 (47.5%) 3.40 (2.47, 4.69) 95% CI (%) (70.4%, 79.6%) (42.2%, 52.8%) P‑value b < 0.0001 Post-consolidation MRD negativity rate 204 (57.5%) 115 (32.5%) 2.79 (2.06, 3.78) 95% CI (%) (52.1%, 62.7%) (27.6%, 37.6%) D-VRd=daratumumab-bortezomib-lenalidomide-dexamethasone; VRd=bortezomib-lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval a Based on intent-to-treat population b p-value from Cochran Mantel-Haenszel Chi-Squared test c Patients achieved both MRD negativity (threshold of 10 -5 ) and CR or better d Mantel-Haenszel estimate of the common odds ratio for stratified tables is used Combination treatment with bortezomib, lenalidomide and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma for whom ASCT is not planned as initial therapy or who are ineligible for ASCT Study MMY3019 was an open‑label, randomised, active‑controlled phase III study that compared treatment with DARZALEX subcutaneous formulation (1800 mg) in combination with bortezomib, lenalidomide and dexamethasone (D‑VRd) to treatment with bortezomib, lenalidomide and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma for whom ASCT was not planned as initial therapy or who were not eligible for ASCT. An emergency short course of corticosteroid (equivalent of dexamethasone 40 mg/day for a maximum 4 days) was permitted before treatment. Patients received DARZALEX subcutaneous formulation (1800 mg) administered subcutaneously once weekly (days 1, 8, and 15) for cycles 1 to 2 followed by once every three weeks for cycles 3 to 8, and once every four weeks in cycle 9 and beyond until documented disease progression or unacceptable toxicity. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m 2 body surface area twice weekly (days 1, 4, 8, and 11) of repeated 21‑day (3-week) cycles 1‑8. Lenalidomide was administered orally at 25 mg daily on days 1 to 14 during cycles 1‑8 and on days 1‑21 during cycle 9 and beyond. Dexamethasone was administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21‑day (3‑week) cycles 1‑8 and 40 mg on days 1, 8, 15, and 22 of each 28‑day (4‑week) during cycle 9 and beyond. On the days of DARZALEX subcutaneous formulation (1800 mg) injection, the dexamethasone dose was administered orally or intravenously as a pre‑injection medication. Dose adjustments for bortezomib, lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. A total of 395 patients were randomised: 197 to the D‑VRd arm and 198 to the VRd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 70 (range: 31 to 80 years). Fifty percent were male, 39% had an ECOG performance score of 0, 51% had an ECOG performance score of 1 and 9% had an ECOG performance score of 2. Eighteen percent were less than 70 years of age and transplant ineligible and 27% were less than 70 years of age and were transplant deferred. Additionally, 34% had ISS stage I, 38% had ISS stage II, 28% had ISS stage III disease, 75% had a standard cytogenetic risk, 13% had a high cytogenetic risk (del17p, t[4;14], t[14;16]), and 11% had an indeterminate cytogenetic risk. With a median follow‑up of 22.3 months, the primary analysis of MRD in study MMY3019 demonstrated an improvement in overall MRD negativity rate (by NGS at or below 10-5) for patients reaching CR or better in the D‑VRd arm as compared to the VRd arm. Overall MRD negativity rates were 53.3% (95% CI: 46.1, 60.4) in the D‑VRd arm and 35.4% (95% CI: 28.7, 42.4) in the VRd arm (odds ratio [D‑VRd versus VRd] 2.07 with 95% CI: 1.38, 3.10; p=0.0004). At the time of primary MRD analysis, an improvement in overall CR or better rate was observed in the D‑VRd arm as compared to the VRd arm. Overall CR or better rates were 76.6% (95% CI: 70.1, 82.4) in the D‑VRd arm and 59.1% (95% CI: 51.9, 66.0) in the VRd arm (odds ratio [D‑VRd versus VRd] 2.31; 95% CI: 1.48, 3.60; p=0.0002). With a median follow‑up of 39 months, an interim analysis of PFS in Study MMY3019 demonstrated an improvement in PFS in the D‑VRd arm as compared to the VRd arm (HR=0.61; 95% CI: 0.42, 0.90; p=0.0104). The median PFS had not been reached in either arm. With more mature PFS data at the final PFS analysis, treatment effect for PFS was improved with a hazard ratio of 0.57 (95% CI: 0.41, 0.79). The median PFS had not been reached in the D‑VRd arm and was 52.6 months in the VRd arm. Figure 2: Kaplan-Meier curve of PFS at final analysis in study MMY3019 At the time of interim PFS analysis, an improvement in 1‑year sustained MRD negativity rate (by NGS at or below 10-5) for patients reaching CR or better was observed in the D‑VRd arm as compared to the VRd arm. Sustained MRD negativity rates were 42.6% (95% CI: 35.6, 49.9) in the D‑VRd arm and 25.3% (95% CI: 19.4, 31.9) in the VRd arm (odds ratio [D‑VRd versus VRd] 2.18 with 95% CI: 1.42, 3.34; p=0.0003). Additional efficacy results from Study MMY3019 are presented in table 12 below. Table 12: Efficacy results from the final PFS analysis of study MMY3019 a D-VRd (n=197) VRd (n=198) Overall MRD negativity rate b 120 (60.9%) 78 (39.4%) Odds ratio (95% CI) c 2.37 (1.58, 3.55) Sustained MRD negativity rate d 96 (48.7%) 52 (26.3%) Odds ratio (95% CI) c 2.63 (1.73, 4.00) Overall CR or better (sCR+CR) 160 (81.2%) 122 (61.6%) Odds ratio (95% CI) c 2.73 (1.71, 4.34) Overall response (sCR+CR+VGPR+PR) n (%) a 191 (97.0%) 184 (92.9%) Stringent complete response (sCR) 128 (65.0%) 88 (44.4%) Complete response (CR) 32 (16.2%) 34 (17.2%) Very good partial response (VGPR) 23 (11.7%) 50 (25.3%) Partial response (PR) 8 (4.1%) 12 (6.1%) D‑VRd=daratumumab‑bortezomib‑lenalidomide‑dexamethasone; VRd=bortezomib‑lenalidomide‑dexamethasone; MRD=minimal residual disease; CI=confidence interval a Based on intent‑to‑treat population, median follow‑up of 59 months b Patients achieved both MRD negativity (threshold of at or below 10 -5 ) and CR or better c Mantel‑Haenszel estimate of the common ratio for stratified tables is used. The stratification factors are: ISS staging (I, II, III), age/transplant eligibility (< 70 years ineligible, or age< 70 years and refusal to transplant, or age ≥ 70 years) as randomised. An odds ratio > 1 indicates an advantage for D‑VRd. d Sustained MRD negativity is defined as MRD negative and confirmed by at least 1 year apart without MRD positive in between. Combination therapies in multiple myeloma MMY2040 was an open‑label study evaluating the efficacy and safety of DARZALEX subcutaneous formulation 1,800 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/m 2 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/m 2 , and prednisone at 60 mg/m 2 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/m 2 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 enroled. 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 13). Table 13: Efficacy results from study MMY2040 D-VMP (n=67) D-Rd (n=65) D-VRd (n=67) Overall response (sCR+CR+VGPR+PR), n (%) a 60 (89.6%) 61 (93.8%) 65 (97.0%) 90% CI(%) (81.3%, 95.0%) (86.5%, 97.9%) (90.9%, 99.5%) Stringent complete response (sCR) 13 (19.4%) 12 (18.5%) 6 (9.0%) Complete response (CR) 19 (28.4%) 13 (20.0%) 5 (7.5%) Very good partial response (VGPR) 20 (29.9%) 26 (40.0%) 37 (55.2%) Partial response (PR) 8 (11.9%) 10 (15.4%) 17 (25.4%) VGPR or better (sCR + CR + VGPR) 52 (77.6%) 51 (78.5%) 48 (71.6%) 90% CI(%) (67.6%, 85.7%) (68.4%, 86.5%) (61.2%, 80.6%) D-VMP = Daratumumab-bortezomib-melphalan-prednisone; D-Rd = Daratumumab-lenalidomide-dexamethasone; D-VRd = Daratumumab-bortezomib-lenalidomide-dexamethasone; Daratumumab = DARZALEX subcutaneous formulation; CI=confidence interval. a Based on treated subjects 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 (1, 800 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. Figure 3 Kaplan-Meier curve of PFS in study MMY3013 An additional planned follow-up analysis of OS after a median follow-up of 39.6 months was performed. At OS maturity of 57%, the median OS was 34.4 months in the D-Pd arm and 23.7 months in the Pd arm (HR [95% CI]: 0.82 [0.61, 1.11]). Additional efficacy results from study MMY3013 are presented in table 14 below. Table 14: Efficacy results from study MMY3013 a D-Pd (n=151) Pd (n=153) Overall response (sCR+CR+VGPR+PR) n(%) a 104 (68.9%) 71 (46.4%) P-value b <0.0001 Stringent complete response (sCR) 14 (9.3%) 2 (1.3%) Complete response (CR) 23 (15.2%) 4 (2.6%) Very good partial response (VGPR) 40 (26.5%) 24 (15.7%) Partial response (PR) 27 (17.9%) 41 (26.8%) MRD negativity rate c n(%) 13 (8.7%) 3 (2.0%) 95% CI (%) (4.7%, 14.3%) (0.4%, 5.6%) P-value d 0.0102 D-Pd=daratumumab-pomalidomide-dexamethasone; Pd=pomalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval a Based on intent-to-treat population. b p-value from Cochran Mantel-Haenszel Chi-Squared test adjusted for stratification factors. c MRD Negative rate is based on the intent-to-treat population and a threshold of 10 -5 . d p-value from Fisher's exact test. 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. Monotherapy – smouldering multiple myeloma at high risk of developing into multiple myeloma SMM3001, an open-label, randomised, phase III study, compared efficacy and safety of treatment with DARZALEX subcutaneous formulation (1800 mg) to active monitoring in patients with smouldering multiple myeloma at high risk of developing multiple myeloma. For patients randomised to the treatment arm, DARZALEX subcutaneous formulation (1800 mg) was administered subcutaneously once weekly (days 1, 8, 15, and 22) for cycles 1 to 2 then every 2 weeks (days 1 and 15) for cycles 3 to 6, and thereafter every 4 weeks until 39 cycles or up to 36 months or until confirmed disease progression. A total of 390 patients were randomised: 194 to the DARZALEX subcutaneous formulation arm and 196 to the active monitoring arm. The baseline demographic and disease characteristics were similar between the two study arms. The median patient age was 64 years (range: 31-86 years); 12% were ≥75 years; 48% were male; 83% Caucasian, 8% Asian, and 3% were African American. Eighty-three percent had an ECOG performance score of 0 and 17% had an ECOG performance score of 1. Median percentage of plasma cells in the bone marrow was 20% and the median time from initial diagnosis date of smouldering multiple myeloma to randomisation was 0.7 years. Eighty percent of patients had less than 3 risk factors associated with progression to multiple myeloma. Risk factors were serum M protein ≥30 g/L; IgA SMM; immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes; serum involved: uninvolved FLC ratio ≥8 and <100, clonal bone marrow plasma cells (BMPCs) >50% to <60% with measurable disease. To be eligible for enrolment in study SMM3001, patients were required to have at least one of these risk factors and BMPCs ≥10%. Nineteen percent of patients had a serum M protein ≥30 g/L, 25% had IgA SMM, 60% had immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes, 72% had serum involved: uninvolved FLC ratio ≥8 and <100, and 3% clonal BMPCs >50% to <60% with measurable disease. The primary endpoint of the study was PFS as assessed by the independent review committee (IRC). The Kaplan-Meier curve for PFS is shown in figure 4 and efficacy results from study SMM3001 are presented in table 15 below. Figure 4: Kaplan-Meier curve of PFS in study SMM3001 Table 15: Efficacy results from study SMM3001 a DARZALEX subcutaneous formulation (n=194) Active monitoring (n=196) Odds ratio (95% CI) b Progression-free survival (PFS), months c Median (95% CI) NE (66.7-NE) 41.5 (26.4-53.3) Hazard ratio (95% CI) 0.49 (0.36, 0.67) P-value d < 0.0001 Overall response (sCR+CR+VGPR+PR), n(%) a 123 (63.4%) 4 (2.0%) 83.80 (29.69, 236.54), p<0.0001 Stringent Complete Response (sCR) 5 (2.6%) 0 Complete response (CR) 12 (6.2%) 0 Very good partial response (VGPR) 41 (21.1%) 2 (1.0%) Partial response (PR) 65 (33.5%) 2 (1.0%) CI=confidence interval; NE=not evaluable a Based on intent-to-treat population. b Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. c Median follow-up was 65.2 months. d p-value based on the log-rank test stratified by the stratification factor. 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 (1,800 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 enroled in study AMY3001 had newly diagnosed AL amyloidosis with at least one affected organ, measurable haematologic 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/m 2 body surface area), cyclophosphamide (oral or IV; 300 mg/m 2 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 hypervolaemia, 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 haematologic 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 16. Table 16: Efficacy results from study AMY3001 a D-VCd (n=195) VCd (n=193) P-value Haematologic complete response (HemCR), n (%) 104 (53.3%) 35 (18.1%) <0.0001 b Very good partial response (VGPR), n (%) 49 (25.1%) 60 (31.1%) Partial response (PR), n (%) 26 (13.3%) 53 (27.5%) Haematologic VGPR or better (HemCR + VGPR), n (%) 153 (78.5%) 95 (49.2%) <0.0001 b Major organ deterioration progression-free survival (MOD-PFS), Hazard ratio with 95% CI c 0.58 (0.36, 0.93) 0.0211 d D-VCd=daratumumab-bortezomib-cyclophosphamide-dexamethasone; VCd=bortezomib-cyclophosphamide-dexamethasone; CI=confidence interval a All results from the planned analysis after a median follow-up of 11.4 months based on intent-to-treat population. b p-value from Cochran Mantel-Haenszel Chi-Squared test. c MOD-PFS defined as haematologic progression, major organ (cardiac or renal) deterioration or death. d Nominal p-value from inverse probability censoring weighted log-rank test. With a median follow-up of 11.4 months, 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. After a median follow-up of 61.4 months, the overall HemCR rates were 59.5% (95% CI: 52.2, 66.4) in the D-VCd group and 19.2% (95% CI: 13.9, 25.4) in the VCd group (odds ratio [D-VCd versus VCd] 6.03 with 95% CI: 3.80, 9.58). Results of a MOD-PFS analysis after a median follow-up of 61.4 months showed an improvement in MOD-PFS for patients in the D-VCd group compared with the VCd group. The hazard ratio (HR) for MOD-PFS was 0.44 (95% CI: 0.31, 0.63) and the p-value was <0.0001. The median MOD-PFS was not reached in the D-VCd arm and was 30.2 months in the VCd arm. The Kaplan-Meier estimated 60‑month MOD-PFS rate was 60% (95% CI: 52, 67) in the D-VCd arm and was 33% (95% CI: 23, 44) in the VCd arm. Figure 5: Kaplan-Meier curve of MOD-PFS in study AMY3001 After a median follow-up of 61.4 months, a total of 112 deaths were observed [n=46 (23.6%) D-VCd vs . n=66 (34.2%) VCd group]. The median OS was not reached for either arm; however, the HR for OS was 0.62 (95% CI: 0.42, 0.90) and the p-value was 0.0121. The 60‑month OS rate was 76% (95% CI: 69, 82) in the D-VCd arm and was 65% (95% CI: 57, 71) in the VCd arm. Figure 6: Kaplan-Meier curve of OS in study AMY3001 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 intravenous daratumumab 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 intravenous daratumumab 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 and overall survival (OS). With a median follow-up of 28 months, the primary analysis of PFS in study MMY3008 showed 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 31.9 months in the Rd arm ( 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 after a median follow-up of 64 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 61.9 months in the DRd arm and 34.4 months in the Rd arm (HR=0.55; 95% CI: 0.45, 0.67). Figure 7: Kaplan-Meier curve of PFS in study MMY3008 With a median follow-up of 56 months, DRd has shown an OS advantage over the Rd arm (HR=0.68; 95% CI: 0.53, 0.86; p=0.0013). Results of an updated OS analysis after a median of 89 months continued to show an improvement in OS for patients in the DRd arm compared to the Rd arm. Median OS was 90.3 months in the DRd arm and was 64.1 months in the Rd arm (HR= 0.67; 95% CI: 0.55, 0.82). Figure 8 Kaplan-Meier curve of OS in study MMY3008 Additional efficacy results from study MMY3008 are presented in table 17 below. Table 17: Additional efficacy results from study MMY3008 a DRd (n=368) Rd (n=369) Overall response (sCR+CR+VGPR+PR) n(%) a 342 (92.9%) 300 (81.3%) p-value b <0.0001 Stringent complete response (sCR) 112 (30.4%) 46 (12.5%) Complete response (CR) 63 (17.1%) 46 (12.5%) Very good partial response (VGPR) 117 (31.8%) 104 (28.2%) Partial response (PR) 50 (13.6%) 104 (28.2%) CR or better (sCR + CR) 175 (47.6%) 92 (24.9%) p-value b <0.0001 VGPR or better (sCR + CR + VGPR) 292 (79.3%) 196 (53.1%) p-value b <0.0001 MRD negativity rate a,c n(%) 89 (24.2%) 27 (7.3%) 95% CI (%) (19.9%, 28.9%) (4.9%, 10.5%) Odds ratio with 95% CI d 4.04 (2.55, 6.39) p-value e <0.0001 DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval a Based on intent-to-treat population. b p-value from Cochran Mantel-Haenszel Chi-Squared test. c Based on threshold of 10 -5 . d Mantel-Haenszel estimate of the odds ratio for un-stratified tables is used. An odds ratio >1 indicates an advantage for DRd. e p-value from Fisherʼs exact test. In responders, the median time to response was 1.05 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 daratumumab 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/m 2 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/m 2 , and prednisone at 60 mg/m 2 were orally administered on days 1 to 4 of the nine 6‑week cycles (cycles 1‑9). Intravenous daratumumab 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. Figure 9: Kaplan-Meier curve of PFS in study MMY3007 After a median follow‑up of 40 months, D‑VMP has shown an 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. After a median follow-up of 87 months, the median OS was 83 months (95% CI: 72.5, NE) in the D-VMP arm and 53.6 months (95% CI: 46.3, 60.9) in the VMP arm. Figure 10: Kaplan-Meier curve of OS in study MMY3007 Additional efficacy results from study MMY3007 are presented in table 18 below. Table 18: Additional efficacy results from study MMY3007 a D-VMP (n=350) VMP (n=356) Overall response (sCR+CR+VGPR+PR) [n(%)] 318 (90.9) 263 (73.9) p-value b <0.0001 Stringent complete response (sCR) [n(%)] 63 (18.0) 25 (7.0) Complete response (CR) [n(%)] 86 (24.6) 62 (17.4) Very good partial response (VGPR) [n(%)] 100 (28.6) 90 (25.3) Partial response (PR) [n(%)] 69 (19.7) 86 (24.2) MRD negativity rate (95% CI) c (%) 22.3 (18.0, 27.0) 6.2 (3.9, 9.2) Odds ratio with 95% CI d 4.36 (2.64, 7.21) p-value e <0.0001 D-VMP=daratumumab-bortezomib-melphalan-prednisone; VMP=bortezomib-melphalan-prednisone; MRD=minimal residual disease; CI=confidence interval a Based on intent-to-treat population. b p-value from Cochran Mantel-Haenszel Chi-Squared test. c Based on threshold of 10 -5 . d A Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. An odds ratio >1 indicates an advantage for D-VMP. e p-value from Fisherʼs exact test. 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 daratumumab 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/m 2 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 daratumumab 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 1 085 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 PFS. Table 19: Efficacy results from study MMY3006 a D-VTd (n=543) VTd (n=542) P value b Response assessment Day 100 post‑transplant Stringent complete response (sCR) 157 (28.9%) 110 (20.3%) 0.0010 CR or better (sCR+CR) 211 (38.9%) 141 (26.0%) <0.0001 Very good partial response or better (sCR+CR+VGPR) 453 (83.4%) 423 (78.0%) MRD negativity c, d n(%) 346 (63.7%) 236 (43.5%) <0.0001 95% CI (%) (59.5%, 67.8%) (39.3%, 47.8%) Odds ratio with 95% CI e 2.27 (1.78, 2.90) MRD negativity in combination with CR or better c n(%) 183 (33.7%) 108 (19.9%) <0.0001 95% CI (%) (29.7%, 37.9%) (16.6%, 23.5%) Odds ratio with 95% CI e 2.06 (1.56, 2.72) D-VTd=daratumumab-bortezomib-thalidomide-dexamethasone; VTd=bortezomib-thalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval a Based on intent-to-treat population. b p-value from Cochran Mantel-Haenszel Chi-Squared test. c Based on threshold of 10 -5 . d Regardless of response per IMWG. e Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. 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. Figure 11: Kaplan-Meier curve of PFS in sstudy MMY3006 Relapsed/Refractory multiple myeloma Monotherapy: The clinical efficacy and safety of intravenous daratumumab 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 daratumumab 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, aPI and 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 20 below. Table 20: IRC assessed efficacy results for study MMY2002 Efficacy endpoint Intravenous daratumumab 16 mg/kg N=106 Overall response rate 1 (ORR: sCR+CR+VGPR+PR) [n (%)] 31 (29.2) 95% CI (%) (20.8, 38.9) Stringent complete response (sCR) [n (%)] 3 (2.8) Complete response (CR) [n] 0 Very good partial response (VGPR) [n (%)] 10 (9.4) Partial response (PR) [n (%)] 18 (17.0) Clinical benefit rate (ORR+MR) [n (%)] 36 (34.0) Median duration of response [months (95% CI)] 7.4 (5.5, NE) Median time to response [months (range)] 1 (0.9; 5.6) 1 Primary efficacy endpoint (International Myeloma Working Group criteria) CI=confidence interval; NE=not estimable; MR=minimal response 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 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 daratumumab 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 study, compared treatment with intravenous daratumumab 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 intravenous daratumumab 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 daratumumab 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 12). Figure 12: Kaplan-Meier curve of PFS in study MMY3003 After a median follow-up of 80 months, DRd has shown an OS advantage over the Rd arm (HR=0.73; 95% CI: 0.58, 0.91; p=0.0044). The median OS was 67.6 months in the DRd arm and 51.8 months in the Rd arm. Figure 13: Kaplan-Meier curve of OS in study MMY3003 Additional efficacy results from study MMY3003 are presented in table 21 below. Table 21: Additional efficacy results from study MMY3003 Response evaluable patient number DRd (n=281) Rd (n=276) Overall response (sCR+CR+VGPR+PR) n(%) 261 (92.9) 211 (76.4) p-value a <0.0001 Stringent complete response (sCR) 51 (18.1) 20 (7.2) Complete response (CR) 70 (24.9) 33 (12.0) Very good partial response (VGPR) 92 (32.7) 69 (25.0) Partial response (PR) 48 (17.1) 89 (32.2) Median time to response [months (95% CI)] 1.0 (1.0, 1.1) 1.3 (1.1, 1.9) Median duration of response [months (95% CI)] NE (NE, NE) 17.4 (17.4, NE) MRD negative rate (95% CI) b (%) 21.0 (16.4, 26.2) 2.8 (1.2, 5.5) Odds ratio with 95% CI c 9.31 (4.31, 20.09) P-value d <0.0001 DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval; NE=not estimable. a p-value from Cochran Mantel-Haenszel Chi-Squared test. b Based on Intent-to-treat population and threshold of 10 -5 . c Mantel‑Haenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for DRd. d p-value is from a Fisher's exact test. Combination treatment with bortezomib: Study MMY3004, an open‑label, randomised, active‑controlled phase III study, compared treatment with intravenous daratumumab 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 injection at a dose of 1.3 mg/m 2 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 daratumumab infusion, 20 mg of the dexamethasone dose was administered as a pre‑infusion medicinal product. intravenous daratumumab 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 daratumumab 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 14). Figure 14: Kaplan-Meier curve of PFS in study MMY3004 After a median follow-up of 73 months, DVd has shown an OS advantage over the Vd arm (HR=0.74; 95% CI: 0.59, 0.92; p=0.0075). The median OS was 49.6 months in the DVd arm and 38.5 months in the Vd arm. Figure 15: Kaplan-Meier curve of OS in study MMY3004 Additional efficacy results from study MMY3004 are presented in table 22 below. Table 22: Additional efficacy results from study MMY3004 Response evaluable patient number DVd (n=240) Vd (n=234) Overall response (sCR+CR+VGPR+PR) n(%) 199 (82.9) 148 (63.2) P-value a <0.0001 Stringent complete response (sCR) 11 (4.6) 5 (2.1) Complete response (CR) 35 (14.6) 16 (6.8) Very good partial response (VGPR) 96 (40.0) 47 (20.1) Partial response (PR) 57 (23.8) 80 (34.2) Median time to response [months (range)] 0.9 (0.8, 1.4) 1.6 (1.5, 2.1) Median duration of response [months (95% CI)] NE (11.5, NE) 7.9 (6.7, 11.3) MRD negative rate (95% CI) b 8.8% (5.6%, 13.0%) 1.2% (0.3%, 3.5%) Odds ratio with 95% CI c 9.04 (2.53, 32.21) P-value d 0.0001 DVd=daratumumab- bortezomib-dexamethasone; Vd=bortezomib-dexamethasone; MRD=minimal residual disease; CI=confidence interval; NE=not estimable. a p-value from Cochran Mantel-Haenszel Chi-Squared test. b Based on Intent-to-treat population and threshold of 10 -5 . c Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for DVd. d p-value is from Fisher's exact test. 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 Study ALL2005 was an open-label, multicentre, phase II study in which 46 paediatric and young adult patients (ages 1 to 30 years) with relapsed or refractory B‑cell ALL or T‑cell ALL/LL received DARZALEX intravenous formulation (16 mg/kg) in combination with vincristine and prednisone for B‑cell ALL/LL patients and in combination with vincristine, doxorubicin, prednisone and PEG‑asparaginase for T‑cell ALL/LL patients. Based on the limited results of this study, DARZALEX efficacy was not established in the population studied. The licensing authority has waived the obligation to submit the results of studies with DARZALEX in all subsets of the paediatric population in mature B-cell neoplasms, and systemic AL amyloidosis (see section 4.2 for information on paediatric use).