Blenrep

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, and antibody drug conjugates, ATC code: L01FX15. Mechanism of action Belantamab mafodotin is a humanised IgG1 kappa monoclonal antibody conjugated with a cytotoxic agent, mcMMAF.‍‍‍‍‍‍​​​‍​​​​​​ Belantamab mafodotin binds to cell surface BCMA and is rapidly internalised. Once inside the tumour cell, the cytotoxic agent (cys-mcMMAF) is released disrupting the microtubule network, leading to cell cycle arrest and apoptosis. The antibody also enhances recruitment and activation of immune effector cells, killing tumour cells by antibody-dependent cellular cytotoxicity and phagocytosis. Apoptosis induced by belantamab mafodotin is accompanied by markers of immunogenic cell death, which may contribute to an adaptive immune response to tumour cells. Pharmacodynamic effects Exposure-Response Relationship in Combination Therapies For BVd and BPd combination therapies, higher belantamab mafodotin Cycle 1 exposure was associated with higher probability of response (e.g., very good partial response [VGPR+]) and higher incidence of some adverse reactions (e.g., ≥Grade 2 corneal examination findings). For most of the range of belantamab mafodotin Cycle 1 exposure, the probability of VGPR or better was higher than the probability of ocular adverse reactions and BCVA-related endpoints. Cardiac electrophysiology Belantamab mafodotin or cys-mcMMAF had no meaningful QTc prolongation (>10 ms) at doses of up to 3.4 mg/kg once every 3 weeks. Immunogenicity The incidence of anti-belantamab mafodotin antibodies (ADAs) was consistently low in patients treated with belantamab mafodotin in combination therapies with no observed clinical impact on pharmacokinetics, safety, and efficacy. In the pivotal combination therapy studies (DREAMM-7 and DREAMM-8) and the Phase 1/2, open-label dose exploration study (DREAMM-6), 3% of patients (15/515) tested positive for treatment emergent ADAs. Two patients tested positive for neutralising anti-belantamab mafodotin antibodies (NAbs) . Clinical efficacy and safety DREAMM-7: Blenrep in combination with bortezomib and dexamethasone The efficacy and safety of Blenrep in combination with bortezomib and dexamethasone (BVd) were investigated in a multicentre, randomised (1:1), open-label, Phase 3 study conducted in patients with relapsed and/or refractory multiple myeloma (MM) who had received at least one prior line of therapy. In the BVd arm (N = 243), patients received Blenrep 2.5 mg/kg by intravenous infusion (IV) every 3 weeks on day 1 of each 21-day Cycle; bortezomib 1.3 mg/m 2 (subcutaneously) on days 1, 4, 8, and 11 of Cycles 1 to 8 (21‑day Cycles); and dexamethasone 20 mg (IV or orally) on the day of and the day after bortezomib treatment. In the daratumumab, bortezomib, and dexamethasone (DVd) arm (N = 251), patients received daratumumab 16 mg/kg (IV) in 21‑day Cycles for Cycles 1 to 8: on days 1, 8 and 15 for Cycles 1 to 3 and on day 1 for Cycles 4 to 8. Daratumumab was administered on day 1 every 4 weeks from Cycle 9 onwards. Dexamethasone and bortezomib schedules were the same in both arms. The dose level of dexamethasone in each arm was reduced by half in patients aged 75 years and older. Treatment continued in both arms until disease progression, death, unacceptable toxicity, withdrawal of consent, or study end. Patients were stratified by the Revised International Staging System (R-ISS), prior exposure to bortezomib, and the number of prior lines of therapy. The key eligibility criteria for the study were having a confirmed diagnosis of MM as defined by International Myeloma Working Group (IMWG) criteria, having previously been treated with at least 1 prior line of MM therapy, and having had documented disease progression during or after their most recent therapy. Patients previously refractory to daratumumab or twice weekly bortezomib 1.3 mg/m 2 were excluded while patients refractory to weekly bortezomib were included. The primary efficacy outcome measure was progression-free survival (PFS) as evaluated by a blinded Independent Review Committee (IRC) based on the IMWG criteria for MM. A total of 494 patients were evaluated for efficacy in DREAMM-7. Baseline demographics and characteristics were similar across both arms. Baseline characteristics for the BVd arm (N = 243) were: median age: 65 years (35% aged 65-74 years and 15% aged 75 years or older); 53% male, 47% female; 85% White, 12% Asian, 3% Black; R-ISS stage at screening I (42%), II (53%), III (4%); 28% high cytogenetics risk, median number of 1 prior lines (minimum 1, maximum 7); 5% with extramedullary disease (EMD) present; and of those who received treatment (n = 242), Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 (50%), 1 (46%), or 2 (4%). In the BVd arm, 90% of patients received prior proteasome inhibitor therapy (bortezomib, carfilzomib, ixazomib), 81% of patients received prior immunomodulator therapy (lenalidomide, thalidomide, pomalidomide), 1% of patients received prior daratumumab therapy, and 67% of patients previously received autologous stem cell transplantation (ASCT). There were 9% of patients refractory to proteasome inhibitor therapy and 39% of patients refractory to immunomodulator therapy. Patients treated with Blenrep in combination with bortezomib and dexamethasone had a statistically significant improvement in PFS, overall survival (OS) and minimal residual disease (MRD) negativity rate in the overall population compared with daratumumab, bortezomib, and dexamethasone. Efficacy results at the time of the first interim analysis (data cut-off 2 October 2023, except OS where data is presented from the second interim analysis data cut-off 7 October 2024) are presented in Table 9 and Figures 1 and 2. Table 9: Efficacy results in DREAMM-7 Blenrep plus bortezomib and dexamethasone (BVd) a N = 243 Daratumumab plus bortezomib and dexamethasone (DVd) a N = 251 Progression-free survival (PFS) b Number (%) of patients with event 91 (37) 158 (63) Median in months (95% CI) c 36.6 (28.4, NR) 13.4 (11.1, 17.5) Hazard ratio (95% CI) d 0.41 (0.31, 0.53) p-value e <0.00001 Probability of PFS at 18 months, % (95% CI) f 69 (62, 75) 43 (36, 49) Overall survival (OS) Number (%) of patients with event 68 (28) 103 (41) Median in months (95% CI) c NR (NR, NR) NR (41, NR) Hazard ratio (95% CI) d 0.58 (0.43, 0.79) p-value e 0.00023 Probability of OS at 24 months, % (95% CI) f 79 (73, 84) 67 (61, 73) Probability of OS at 36 months (95% CI) f 74% (68, 79) 60% (54, 66) Duration of response (DoR) b, g Number of responders, n 201 179 Number (%) of responders: follow-up ongoing h 106 (53) 52 (29) Median in months (95% CI) d 35.6 (30.5, NR) 17.8 (13.8, 23.6) Minimal residual disease (MRD) negativity rate b, h, i Percent of patients, (95% CI) 24.7 (19.4, 30.6) 9.6 (6.2, 13.9) p-value j <0.00001 Overall response rate (ORR) b, g, k , % (95% CI) 82.7 (77.4, 87.3) 71.3 (65.3, 76.8) Stringent complete response (sCR), n (%) 34 (14) 13 (5.2) Complete response rate (CRR), n (%) 50 (20.6) 30 (12) Very good partial response (VGPR), n (%) 76 (31.3) 73 (29.1) Partial response (PR), n (%) 41 (16.9) 63 (25.1) Median time to response (TTR) in months (minimum, maximum) b 1.41 (0.7, 8.4) 0.85 (0.7, 11.1) Median time to best response in months (min, max) b 4.5 (0.7, 32.5) 2.23 (0.7, 25.7) PFS 2 Number (%) of patients with event 70 (29) 106 (42) Median in months (95% CI) c NR 34.6 (27.6, NR) Hazard ratio (95% CI) d 0.56 (0.41, 0.76) CI = Confidence interval; NR = Not reached. a Efficacy data are based on the intent-to-treat (ITT) population, except DOR which is based on responders only. Data presented is from the first interim analysis data cut-off (2 OCT 2023) except OS, where data is from the second interim analysis data cut-off (7 OCT 2024). b Response was based on IRC per IMWG criteria. c By Brookmeyer and Crowley method. d Based on stratified Cox regression model. e One-sided p-value based on stratified log-rank test. f By Kaplan-Meier method. g For patients with a partial response or better. h For patients with a complete response or better. i Assessed by NGS at 10 -5 threshold. j Two-sided p-value based on stratified Cochran-Mantel-Haenszel test. k ORR: sCR+CR+VGPR+PR. The PFS of BVd was consistent across all pre-specified subgroups including patients with high-risk cytogenetics, and patients exposed or refractory to lenalidomide. Figure 1: Kaplan-Meier curve of progression‑free survival per IRC in DREAMM-7 Figure 2: Kaplan-Meier curve of overall survival in DREAMM-7 The median duration of follow-up was 29.2 months (Interquartile Range (IQR) 21.7 to 32.5) with a median duration of exposure of 15.9 months (range 0.69 to 40.2 months) in the BVd arm and 27.6 months (IQR 12.3 to 30.4) with a median duration of exposure of 12.9 months (range 0.23 to 40.5 months) in the DVd arm. Throughout the study, the recommended dose modifications for Blenrep, which included dose delays and reductions, managed adverse reactions and enabled patients to continue treatment. Patient received a median dose of 2.1 mg/kg Blenrep (mean dose: 2.2 mg/kg) with a median of 9 doses (IQR 4, 16), and median dosing interval of 5.7 weeks (IQR 3, 10). For patients who continued treatment after the onset of the first ≥Grade 2 corneal examination finding, they received a median of 8 additional doses (range: 1 to 52), and 93% (177/190) achieved a response to therapy of partial response or better. Exposure to Blenrep observed during DREAMM-7 is presented in Table 10. Table 10: Dose exposure of Blenrep in DREAMM-7 Time intervals 0 to ≤6 months >6 to ≤12 months >12 months Overall Total number of doses 1133 577 1122 2832 Number of doses administered by dose level (%) 2.5 mg/kg 768 (68) 198 (34) 201 (18) 1167 (41) 1.9 mg/kg 365 (32) 379 (66) 921 (82) 1665 (59) Time between doses per patient (weeks) a n 231 130 124 231 Mean 4.8 6.8 10.9 7.2 Median (IQR) 3.6 (3, 6) 4.7 (3, 8) 9.5 (5, 15) 5.7 (3, 10) IQR = Interquartile range. a Intervals for 0 to ≤ 6 months, > 6 to ≤ 12 months, and > 12 months, were calculated either by using days or days converted into months. DREAMM-8: Blenrep in combination with pomalidomide and dexamethasone The efficacy and safety of Blenrep in combination with pomalidomide and dexamethasone (BPd) were investigated in a multicentre, randomised (1:1), open-label, Phase 3 study conducted in patients with relapsed and/or refractory MM following treatment with at least one prior line of therapy, including lenalidomide. In the BPd arm (N = 155), patients received Blenrep 2.5 mg/kg IV once on day 1 in Cycle 1 (28-day Cycle) followed by Blenrep 1.9 mg/kg IV every 4 weeks on day 1 of Cycle 2 onwards (28-day Cycles); pomalidomide 4 mg (orally [PO]) administered on days 1 to 21; and dexamethasone 40 mg PO on days 1, 8, 15, and 22 in all Cycles (28-day Cycles). In the pomalidomide, bortezomib, and dexamethasone (PVd) arm (N = 147), pomalidomide 4 mg PO was administered every 3 weeks on days 1 to 14 in all Cycles (21-day Cycles); bortezomib 1.3 mg/m 2 was administered subcutaneously on days 1, 4, 8, and 11 in Cycles 1 to 8, and on days 1 and 8 in Cycle ≥9 (21-day Cycles). Dexamethasone 20 mg PO was administered on the day of and the day after bortezomib. The dose level of dexamethasone in each arm was reduced by half in patients aged 75 years and older. Treatment in both arms continued until disease progression, unacceptable toxicity, withdrawal of consent, initiation of another anticancer therapy, or end of study/death. Patients were stratified by the number of prior lines of treatment, prior exposure to bortezomib, prior anti-CD38 treatment, and International Staging System (ISS) status. The key eligibility criteria included having confirmed diagnosis of multiple myeloma (MM) as defined by IMWG criteria, having previously been treated with at least 1 prior line of MM therapy, including lenalidomide, and having had documented disease progression during or after their most recent therapy. Patients intolerant of, or refractory to bortezomib; or previously treated, or were intolerant to pomalidomide were excluded. Additionally, patients must have been deemed ineligible for prior ASCT, or must have received ASCT at least 100 days prior to first dose of Blenrep, to be considered eligible. The primary efficacy outcome measures were PFS as evaluated by a blinded IRC based on the IMWG criteria for MM. A total of 302 patients were evaluated for efficacy in DREAMM-8. Baseline demographics and characteristics were similar across both arms. Baseline characteristics for the BPd arm (N = 155) were: median age: 67 years (46% aged 65-74 years and 12% aged 75 years or older); 64% male, 36% female; 86% White, 13% Asian; ISS stage at screening I (60%), II (25%), III (14%); 34% high cytogenetic risk, median number of 1 prior line of therapy (minimum 1, maximum 6); 13% with EMD present; and of those who received treatment (n = 150), ECOG PS 0 (53%), 1 (45%), or 2 (3%). In the BPd arm, 100% of patients received prior immunomodulator therapy (lenalidomide, thalidomide), 90% of patients received prior proteasome inhibitor therapy (bortezomib, carfilzomib, ixazomib), 25% of patients received prior anti-CD38 therapy (daratumumab, isatuximab), and 64% of patients previously received ASCT. There were 81% of patients refractory to lenalidomide therapy, 26% of patients refractory to proteasome inhibitor therapy, and 23% of patients refractory to anti-CD38 therapy. Patients treated with Blenrep in combination with pomalidomide and dexamethasone had a statistically significant improvement in PFS in the overall population compared with pomalidomide, bortezomib and dexamethasone. Efficacy results at the time of the first interim analysis (data cut-off 29 January 2024) are presented in Table 11 and Figures 3 and 4. Table 11: Efficacy results in DREAMM-8 Blenrep plus pomalidomide and dexamethasone (BPd) a N = 155 Pomalidomide plus bortezomib and dexamethasone (PVd) a N = 147 Primary endpoint Progression-free survival (PFS) b Number (%) of patients with event 62 (40) 80 (54) Median in months (95% CI) c, d, e NR (20.6, NR) 12.7 (9.1, 18.5) Hazard ratio (95% CI) f 0.52 (0.37, 0.73) p-value g <0.001 Probability of PFS at 12 months, % (95% CI) h 71 (63, 78) 51 (42, 60) Secondary endpoints Overall survival (OS) Number (%) of patients with event 49 (32) 56 (38) Median in months (95% CI) c NR (33, NR) NR (25.2, NR) Hazard ratio (95% CI) f 0.77 (0.53, 1.14) Probability of OS at 12 months, % (95% CI) h 83 (76, 88) 76 (68, 82) Duration of response (DOR) b, k Number of responders 120 106 Number (%) of responders: follow-up ongoing e 66 (55) 33 (31) Median in months (95% CI) c NR (24.9, NR) 17.5 (12.1, 26.4) Minimal residual disease (MRD) negativity rate b, i, j Percent of patients (95% CI) 23.9 (17.4, 31.4) 4.8 (1.9, 9.6) Overall response rate (ORR) b, k, l , % (95% CI) 77 (70, 83.7) 72 (64.1, 79.2) Stringent complete response (sCR), n (%) 14 (9) 4 (3) Complete response rate (CRR), n (%) 48 (31) 20 (14) Very good partial response (VGPR), n (%) 37 (24) 32 (22) Partial response (PR), n (%) 21 (14) 50 (34) Median time to response (TTR) in months (minimum, maximum) b 1.07 (0.9, 9.3) 1.05 (0.7, 11.2) Median time to best response in months (min, max) b 5.59 (0.9, 26.1) 2.5 (0.7, 25.7) PFS 2 Number (%) of patients with event 56 (36) 73 (50) Median in months (95% CI) c NR (33, NR) 22.4 (13.8, NR) Hazard ratio (95% CI) f 0.61 (0.43, 0.86) CI = Confidence interval; NR = Not reached. a Efficacy data are based on the intent-to-treat (ITT) population, except DOR which is based on responders only. b Response was based on IRC per IMWG criteria. c By Brookmeyer and Crowley method. d Median follow-up of 21.8 months. e At the time of the data cut-off (29 JAN 2024). f Based on stratified Cox regression model. g One-sided p-value based on stratified log-rank test. h By Kaplan-Meier method. i For patients with a complete response or better. j Assessed by NGS at 10-5 threshold. k For patients with a partial response or better. l ORR: sCR+CR+VGPR+PR. The PFS of BPd was consistent across all pre-specified subgroups including patients with high-risk cytogenetics, those refractory to lenalidomide, or refractory to anti-CD38 agents. Figure 3: Kaplan-Meier curve of progression-free survival per IRC in DREAMM-8 Figure 4: Kaplan-Meier curve of overall survival in DREAMM-8 The median duration of follow-up was 22.4 months (IQR 13.8 to 27.8) with a median duration of exposure of 16.5 months (range 0.92 to 35.1 months) in the BPd arm and 20.5 months (IQR 11.2 to 27.3) with a median duration of exposure of 8.5 months (range 0.26 to 39.9 months) in the PVd arm. Throughout the study, the recommended dose modifications for Blenrep, which included dose delays and reductions, managed adverse reactions and enabled patients to continue treatment. Patients received a median dose of 2 mg/kg (mean dose:2 mg/kg) with a median of 6 doses of Blenrep (IQR 4, 10), and median dosing interval of 8.7 weeks (IQR 5, 13). For patients who continued treatment after the onset of the first ≥Grade 2 corneal examination finding, they received a median of 5 additional doses (range: 1 to 21), and 88% (106/120) achieved a response to therapy of partial response or better. Exposure to Blenrep observed during DREAMM-8 is presented in Table 12. Table 12: Dose exposure of Blenrep in DREAMM-8 Time intervals 0 to ≤ 6 months >6 to ≤ 12 months >12 months Overall Total number of doses 570 242 286 1098 Number of doses administered by dose level, (%) 2.5 mg/kg 151 (26) – – 151 (14) 1.9 mg/kg 415 (73) 235 (97) 267 (93) 917 (84) 1.4 mg/kg 4 (<1) 7 (3) 19 (7) 30 (3) Time between doses per patient (weeks) a n 129 79 77 142 Mean 5.3 11.9 14.2 9.5 Median (IQR) 4.1 (4,5) 11.8 (5,16) 14.1 (10,18) 8.7 (5,13) IQR = Interquartile range. a. Intervals for 0 to ≤ 6 months, > 6 to ≤ 12 months, and > 12 months, were calculated either by using days or days converted into months. Paediatric population The licensing authority has waived the obligation to submit the results of studies with Blenrep in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).