Introduction: In the phase 3 DREAMM-7 trial (NCT04246047), belantamab mafodotin (belamaf) plus bortezomib and dexamethasone (BVd) demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits vs daratumumab plus bortezomib and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma (RRMM) who had received ≥1 prior line of therapy (LOT). Minimal residual disease (MRD) negativity has been shown to be a predictor of PFS and OS in multiple myeloma. The first interim analysis of the DREAMM-7 trial (data cutoff: October 2, 2023) showed that patients in the BVd arm had a significantly higher rate of complete response (CR)–based MRD negativity vs those in the DVd arm. MRD was declared statistically significant at the second interim analysis (data cutoff: October 7, 2024) due to the prespecified testing hierarchy. The purpose of the current analysis was to evaluate the number of patients who achieved sustained MRD negativity for ≥12 months in the DREAMM-7 trial and to describe their demographics and baseline disease characteristics. Methods: As previously reported, patients treated with ≥1 prior LOT were randomized (1:1) to BVd or DVd in DREAMM-7. The primary endpoint was independent review committee–assessed PFS. OS and MRD negativity at achievement of ≥ CR were key secondary endpoints. Patients achieving ≥ CR were tested for MRD negativity by next-generation sequencing with 10−5 sensitivity and 10−6 sensitivity (exploratory analysis). Results: At data cutoff (October 7, 2024), CR–based MRD negativity rates in pts with ≥ CR were 70% (61/87) vs 59% (26/44) in the BVd vs DVd arms, respectively, at the 10−5 sensitivity threshold; rates in the intention-to-treat (ITT) population were 25% (95% CI, 19.8%-31.0%) vs 10% (95% CI, 6.9%-14.8%). At the 10−6 sensitivity threshold, rates in patients with ≥ CR were 45% (39/87) vs 23% (10/44) in the BVd vs DVd arms, respectively; rates in the ITT population were 16% (95% CI, 11.7%-21.3%) vs 4% (95% CI, 1.9%-7.2%). Median time to first CR–based MRD negativity was 11.14 months in the BVd arm vs 17.02 months in the DVd arm. Sustained ≥ CR MRD negativity was observed for ≥12 months in 57% (35/61) of patients who reached MRD negative status in the BVd arm vs 42% (11/26) of patients in the DVd arm. In patients who had sustained MRD negativity for ≥12 months, age was balanced between treatment arms. All patients had Revised International Staging System stages of I or II at screening. The DVd arm had a greater proportion of patients with 1 prior LOT (91%) vs the BVd arm (63%); the remaining patients in both arms received ≥2 prior LOTs. The proportion of patients with high-risk cytogenetics was greater in the BVd arm (40%) vs the DVd arm (27%). Conclusions: BVd demonstrated greater overall MRD negativity rates at 10−5 and 10−6 thresholds compared with DVd. In addition, for those patients achieving MRD negativity, more patients had sustained MRD-negative status for ≥12 months in BVd arm compared with DVd arm, further demonstrating the link between achieving deep and durable treatment responses. Funding: GSK (study ID, 207503). Drug-linker technology licensed from Seagen Inc; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Chronic lymphocytic leukemia, characterized by an accumulation of monoclonal B lymphocytes, is the most common adult leukemia. The disease predominantly affects older adults, with a significant proportion being asymptomatic at diagnosis. This manuscript provides a comprehensive review of chronic lymphocytic leukemia, including its epidemiology, clinical presentation, diagnostic criteria, and treatment strategies. Prognostic factors, particularly IGHV mutation status and chromosomal abnormalities, are discussed as critical determinants of disease behavior and treatment response. Recent advances in targeted therapies, such as Bruton's tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL-2i), have changed the treatment landscape by demonstrating superior efficacy to chemoimmunotherapy. However, disparities in access to care, particularly in low- and middle-income countries such as Brazil, highlight the need for equitable treatment approaches. The discussion of measurable residual disease (MRD) assessment for prognostication and treatment planning is also highlighted. This review highlights the need for continued research and integration of novel therapies to optimize patient outcomes in chronic lymphocytic leukemia.

ABSTRACT:Belantamab mafodotin (belamaf) combined with standard therapies demonstrated significant progression-free survival (PFS) and overall survival benefits in DREAMM-7 and PFS benefit in DREAMM-8 in relapsed/refractory multiple myeloma. Belamaf dose modifications managed adverse events, including belamaf-related ocular events. Ocular events included ocular adverse reactions (eg, dry eyes, photophobia, eye irritation) and protocol-mandated ophthalmic examination findings. Protocol-recommended dose modifications for ocular events were driven by ophthalmic examination findings and included belamaf dose delays until resolution and reductions. We used descriptive analyses to evaluate the impact of dose modifications on managing ocular events and treatment efficacy. In patients with normal baseline vision who were receiving treatment, dose modifications extended belamaf dosing intervals to a median of 8 to 12 weeks by 9 months; the prevalences of reduced vision to bilateral 20/50 or worse and ocular adverse reactions were highest in the first 3 months and remained low at later time points. The median time to resolution after grade ≥2 ophthalmic examination findings was 12 weeks. Rates of belamaf discontinuations due to ocular events were low. Almost all responders (partial response or better) required dose modifications. Most patients achieved a response before an extended (>2 cycles) dose delay; most who had not, subsequently achieved or deepened their response. In DREAMM-7 and DREAMM-8, the median PFS in patients with ≥1 dose delay of ≥12 weeks was 36.6 months and not reached, respectively. Ocular events were common but effectively managed with dose modifications, allowing for patients to remain on treatment and derive robust efficacy benefit. The trials were registered at www.clinicaltrials.gov as #NCT04246047 (DREAMM-7) and #NCT04484623 (DREAMM-8).

Introduction: Renal impairment is a common clinical complication in patients with RRMM, and improvement in renal function is associated with better outcomes. In the ongoing phase 1 DREAMM-12 study (NCT04398745), belantamab mafodotin (belamaf) pharmacokinetics appeared to be similar in patients with normal or impaired renal function. In 2 phase 3 trials, DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623), belamaf-containing regimens showed an efficacy benefit vs standard-of-care triplets in patients with RRMM who had received ≥1 prior therapy. Here we present changes in renal function and efficacy outcomes in patients with mild/moderate renal impairment at baseline who were treated with belamaf-containing regimens in DREAMM-7 and DREAMM-8. Methods: Renal function was assessed using estimated glomerular filtration rate (eGFR) calculated from creatinine values obtained from local laboratory results at screening and throughout the study. Renal function was categorized as normal (≥90 mL/min/1.73 m2), mildly impaired (≥60 to <90 mL/min/1.73 m2), or moderately impaired (≥30 to <60 mL/min/1.73 m2). Patients with severe renal impairment (<30 mL/min/1.73 m2) at screening were ineligible for both trials. In this analysis, an improvement in renal function was defined as an improvement of ≥1 severity category for ≥2 consecutive visits at any point during the study period. PFS and response rates were analyzed in patients who showed improvement in renal function. Results: In DREAMM-7, of the 234 patients receiving belamaf, bortezomib, and dexamethasone with baseline eGFR assessments, 124 patients had mild renal impairment and 52 patients had moderate renal impairment at baseline. As of October 7, 2024, improvement in renal function was observed in 64 patients (51.6%) with baseline mild impairment and 27 (51.9%) with baseline moderate impairment. In patients with improved renal function, median PFS was 35.7 months (95% CI, 29.0 months-not reached [NR]) and the 18-month PFS rate was 80%. The overall response rate (ORR) in patients with improved renal function was 98% (95% CI, 92.3%-99.7%) and included a complete response or better (≥ CR) minimal residual disease (MRD) negativity rate of 34.1% (31 of 91; 95% CI, 24.5%-44.7%). Of these patients, 64.5% (20 of 31) had sustained MRD negativity for ≥12 months. In DREAMM-8, of the 155 patients who had baseline eGFR assessments in the belamaf, pomalidomide, and dexamethasone arm, 88 patients had mild renal impairment and 29 patients had moderate renal impairment at baseline. At the January 29, 2024, data cutoff, 37 patients (42.0%) with baseline mild renal impairment and 16 (55.2%) with baseline moderate impairment showed improvement in renal function. In patients with improved renal function, the median PFS was NR (95% CI, 20.6 months-NR) and the 18-month PFS rate was 72%. The ORR in patients with improved renal function was 89% (95% CI, 77.0%-95.7%) and included a ≥ CR MRD negativity rate of 26.4% (14 of 53; 95% CI, 15.3%-40.3%). Of these patients, 35.7% (5 of 14) had sustained MRD negativity for ≥12 months. Conclusions: Renal impairment is considered a poor prognostic factor in MM, and recovery of renal function is associated with prolonged survival. Across both the DREAMM-7 and DREAMM-8 trials, a substantial proportion of patients treated with belamaf combinations had high rates of improvement in renal function and high response rates with durable PFS. Drug-linker technology licensed from Seagen Inc; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Background: There is a significant need for effective and well-tolerated therapies for patients (pts) with functional high-risk (FHR) MM. In DREAMM-7 (D7; NCT04246047), belamaf, bortezomib, and dexamethasone (BVd) demonstrated significant PFS and OS benefit vs daratumumab-Vd (DVd) in pts with RRMM with ≥1 prior line of therapy (LOT). In DREAMM-8 (D8; NCT04484623), belamaf, pomalidomide, and dexamethasone (BPd) demonstrated a significant PFS benefit vs PVd in pts with RRMM who received ≥1 prior LOT, including lenalidomide. Here, we present a subgroup analysis in pts with FHR MM treated with 1 prior LOT. Methods: Pts treated with ≥1 prior LOT were randomized (1:1) to BVd or DVd in D7 and BPd or PVd in D8. The primary endpoint of both trials was independent review committee–assessed PFS. Key secondary endpoints for both trials were OS, MRD, and DOR. In the D7 and D8 trials, FHR was defined as RRMM that progressed ≤18 mo after the start of ASCT or start of first-line therapy. Descriptive statistics were used for response rates, MRD negativity (10−5) rates, and adverse events (AEs). Hazard ratios (HRs) for PFS, OS, and DOR were estimated with the Cox model. The Kaplan-Meier method estimated median survival times. Results: Baseline disease characteristics were generally balanced between treatment arms in pts with 1 prior LOT, regardless of FHR status. In D7, 125 pts per arm who received 1 prior LOT were treated with BVd or DVd, with 43 pts in each arm having FHR MM. In D8, 82 and 77 pts who received 1 prior LOT were treated with BPd and PVd, respectively, with 28 (BPd) and 31 pts (PVd) having FHR MM. In D7, median follow-up was 28.2 mo for pts who received 1 prior LOT and 39.4 mo for pts with FHR MM. In D8, median follow-up was 21.8 mo for all pts. In D7, median PFS was longer in the BVd vs DVd arm, both in pts with 1 prior LOT (36.6 mo vs 19.1 mo; HR, 0.52; 95% CI, 0.36-0.76), and in those with FHR MM (28.4 mo vs 13.4 mo; HR, 0.65; 95% CI, 0.37-1.14). Similarly, in D8, median PFS favored the BPd vs PVd arm, both in pts with 1 prior LOT (not reached [NR] vs 18.5 mo; HR, 0.50; 95% CI, 0.30-0.85) and in those with FHR MM (NR vs 14.8 mo; HR, 0.66; 95% CI, 0.28-1.54). In pts treated with 1 prior LOT in D7, ORR was similar between BVd and DVd arms (83% vs 82%), with greater depth of response in the BVd arm (≥ CR: 39% vs 24%). In pts treated with 1 prior LOT in D7, ≥ CR MRD negativity rates were 28% (35/125) with BVd vs 14% (18/125) with DVd. In D7 pts with FHR MM, both ORR (86% vs 74%) and depth of response (≥ CR: 33% vs 21%) were higher with BVd vs DVd, respectively. In D7 pts with FHR MM, ≥ CR MRD negativity rates were 21% (9/43) with BVd vs 9% (4/43) with DVd. In pts treated with 1 prior LOT in D8, ORR was higher with PVd (88%) vs BPd (79%); however, response was deeper with BPd (≥ CR: 46% vs 23%). In pts treated with 1 prior LOT in D8, ≥ CR MRD negativity rates were 33% (27/82) with BPd vs 5% (4/77) with PVd. In D8 pts with FHR MM, ORR was comparable between pts in the BPd and PVd arms (82% vs 87%, respectively), with greater depth of response seen with BPd (≥ CR: 50% vs 23%). In pts with FHR MM in D8, ≥ CR MRD negativity rates were higher with BPd (36% [10/28]) than with PVd (7% [2/31]). In both the D7 and D8 trials, mOS was NR in pts with 1 prior LOT, regardless of FHR status. Among D7 pts with FHR MM, 70% in the BVd arm and 58% in the DVd arm were alive. Among pts with FHR MM in D8, 79% in the BPd arm vs 77% in the PVd arm were alive. In D7 pts treated with 1 prior LOT and FHR MM, grade 3/4 treatment-related AEs (TRAEs) related to any study treatment occurred in 91% with BVd and 60% with DVd. In D8 pts treated with 1 prior LOT and FHR MM, grade 3/4 TRAEs related to any study treatment occurred in 78% with BPd and 71% with PVd. Conclusions: In both D7 and D8, BVd and BPd were associated with extended PFS vs standard-of-care (SOC) regimens DVd and PVd, respectively, in patients with FHR MM. Deeper responses with higher rates of ≥ CR MRD negativity were also observed vs SOC regimens in both studies. mOS was NR in both trials at the time of this analysis.Funding:GSK (study numbers: 207503; 207499). Drug linker technology licensed from Seagen Inc; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa

7548 Background: Renal impairment is a frequent complication in relapsed/refractory multiple myeloma (RRMM). Results from DREAMM-7 (NCT04246047) showed significant PFS and OS benefit favoring belantamab mafodotin (belamaf), bortezomib, and dexamethasone (BVd) vs daratumumab-Vd (DVd). DREAMM-8 (NCT04484623) showed significant PFS benefit with belamaf, pomalidomide, and dexamethasone (BPd) vs pomalidomide, bortezomib, and dexamethasone (PVd). In an ongoing phase 1 study (NCT04398745), renal impairment did not impact belamaf pharmacokinetics. We report outcomes in pts with mild/moderate renal impairment from DREAMM-7 and DREAMM-8. Methods: Renal function of eligible pts with RRMM was defined based on estimated glomerular filtration rate (eGFR) derived by local labs at screening: normal (≥90 mL/min/1.73 m 2 ), mild (≥60 to <90 mL/min/1.73 m 2 ), or moderate (≥30 to <60 mL/min/1.73 m 2 ) impairment. Pts with eGFR <30 mL/min/1.73 m 2 were ineligible for these trials. Results: Results included pts with mild/moderate renal impairment in DREAMM-7 (BVd, n=175; DVd, n=183) as of October 2, 2023, and DREAMM-8 (BPd, n=117; PVd, n=109) as of January 29, 2024. Median PFS was NR with BVd vs 12.6 mo with DVd (HR, 0.39; 95% CI, 0.29-0.53) in DREAMM-7 and 24.0 mo with BPd vs 9.7 mo with PVd (HR, 0.52; 95% CI, 0.35-0.76) in DREAMM-8. Belamaf-containing regimens in both trials had numerically higher 18-mo PFS rates, overall response rates (ORRs), and complete response or better (≥CR) rates (Table). OS benefit favored BVd vs DVd (HR, 0.58; 95% CI, 0.39-0.86) and BPd vs PVd (HR, 0.71; 95% CI, 0.46-1.09). Median OS was NR in either arm of both trials. In pts with mild/moderate renal impairment in DREAMM-7, 95% with BVd and 79% with DVd had a grade 3/4 AE. AEs leading to discontinuation of any study drug occurred in 33% and 18%, respectively. Fatal serious AEs occurred in 10% with BVd and 8% with DVd. In DREAMM-8, 90% with BPd and 73% with PVd had a grade 3/4 AE. AEs leading to discontinuation of any study drug occurred in 13% with BPd and 15% with PVd. Fatal serious AEs were observed in 13% and 12%, respectively. Conclusions: In pts with mild/moderate renal impairment, belamaf-containing regimens (BVd and BPd) showed improved efficacy vs standard triplets, indicating they are an efficacious alternative SOC in a broad range of pts with RRMM. Safety results in this pt population were consistent with the ITT populations. ITT population with mild/moderate renal impairment BVd n=175 DVd n=183 BPd n=117 PVd n=109 18-mo PFS rate(95% CI) 0.69 (0.61-0.75) 0.41 (0.33-0.48) 0.61 (0.51-0.70) 0.40 (0.29-0.50) ORR (95% CI), % 86 (79.6-90.5) 74 (67.4-80.5) 76 (67.3-83.5) 72 (62.1-79.8) ≥CR (95%CI), % 34 (26.8-41.2) 15 (10.4-21.3) 38 (29.6-47.9) 13 (7.2-20.6) Safety population with mild/moderate renal impairment BVd n=175 DVd n=183 BPd n=112 PVd n=107 Grade 3/4 AE, % 95 79 90 73 AEs leading to discontinuation of any study drug, % 33 18 13 15 Serious fatal AEs, % 10 8 13 12

Background:The Brazilian Group of CLL (BGCLL) has proposed a more restrictive approach for treatment initiation compared to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines. Here, we report on the safety and efficacy of this strategy. Methods:We performed a retrospective analysis of patients with CLL registered in the Brazilian CLL Registry between January 2009 and July 2023 who met the minimum data availability criteria for analysis. The BGCLL criteria employ stricter thresholds for cytopenias, defining them as hemoglobin levels below 9.5 g/dL or platelet counts below 50,000/mm3, as opposed to the IWCLL criteria of below 10 g/dL and below 100,000/mm3, respectively. Furthermore, the BGCLL criteria do not consider progressive lymphocytosis or disease-related symptoms to be criteria for treatment initiation when cytopenias or symptomatic masses are absent. Survival outcomes were estimated using the Kaplan-Meier method and compared with log-rank tests. Cox proportional hazards models were used for multivariable analysis, with results expressed as hazard ratios and 95% confidence intervals. A P-value <0.05 was considered statistically significant. Findings:A total of 2511 patients were enrolled from 41 centers. Of these, 1404 patients (56%) met the IWCLL criteria for treatment initiation (liberal criteria), whereas only 788 patients (31%) met the BGCLL criteria (restrictive criteria). Patients with liberal criteria had a better overall survival than those with restrictive criteria (85% vs. 68%, respectively), suggesting that restrictive criteria were more predictive of prognosis than liberal criteria. In addition, patients treated for cytopenias had significantly worse overall survival (69%) compared to those treated for any other indication (97%, P < 0.0001). Patients with disease-related symptoms, progressive lymphocytosis, and extranodal involvement as isolated indications for treatment had similar overall survival to those with no indication for treatment. Interpretation:Our results demonstrate that a more restrictive approach to treatment initiation in CLL, as proposed by the BGCLL, better identifies patients with higher disease burden and poorer outcomes, while sparing others unnecessary therapy. Funding:Brazilian Registry of CLL-Brazilian Association of Hematology and Hemotherapy (ABHH)/Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

7544 Background: Belamaf combinations were evaluated for RRMM in the phase 3 DREAMM-7 (belamaf + bortezomib + dexamethasone [BVd]; NCT04246047) and DREAMM-8 (belamaf + pomalidomide + dexamethasone [BPd]; NCT04484623) trials, and significant progression-free survival benefits were reported over standard of care, with significant overall survival benefit reported for BVd. Ocular events (e.g., ocular adverse events [oAEs], blurred vision, dry eye) occurred with belamaf and most resolved with dose holds and modifications. We examined the baseline eye health of pts with RRMM receiving BVd or BPd, and whether baseline ocular conditions affected rates of treatment-emergent (TE) oAEs. Methods: Pts with ≥1 prior therapy were eligible for DREAMM-7/8; pts with ocular conditions were eligible except for corneal epithelial disease (mild punctate keratopathy was allowed). Mandatory ophthalmic examinations (best corrected visual acuity [BCVA], slit lamp, and funduscopic exams) were performed in both arms of the trials at baseline and routinely during treatment. oAEs were graded by Common Terminology Criteria for Adverse Events. Regardless of presence/absence of baseline ocular conditions, the same protocol-defined strategies were used for ocular event management during the studies. Results: In 392 pts treated with belamaf (n=242 DREAMM-7 and n=150 DREAMM-8), baseline ocular conditions were reported in 62% of pts (n=135 and 106); baseline conditions included cataract 50% (n=101 and 96), keratopathy 14% (n=33 and 23), dry eye 14% (n=31 and 24), visual acuity of 20/50 or worse 6% (n=18 and 7), glaucoma 6% (n=11 and 13), blepharitis 2% (n=4 and 3), age-related macular degeneration 1% (n=3 and 2), and diabetic retinopathy <1% (n=0 and 2). Any TE oAE was reported in 74% (n=100/135) and 87% (n=92/106) of pts with baseline ocular conditions in DREAMM-7 and DREAMM-8, respectively, compared with 79% (n=85/107) and 91% (n=40/44) of pts without baseline ocular conditions (Table). Conclusions: The safety profiles of belamaf combinations for oAEs were similar between patients with vs without baseline ocular conditions, suggesting that these baseline ocular conditions did not increase the risk of TE oAEs. The effect of each baseline ocular condition on TE oAEs, as well as TE corneal exam findings and visual acuity changes, will be presented. Clinical trial information: NCT04246047 , NCT04484623 . TE ocular events in patients receiving a belamaf combination in DREAMM-7/8. DREAMM-7 DREAMM-8 With any baseline ocular condition, n=135 No baseline ocular condition, n=107 With any baseline ocular condition, n=106 No baseline ocular condition, n=44 Any oAE, n (%) 100 (74) 85 (79) 92 (87) 40 (91)

As treatments for multiple myeloma (MM) evolve, there is a need for real-world insights into treatment patterns and outcomes. The treatment practices and clinical outcomes in patients with MM (TOTEMM) was a database study (2018-2024) of newly diagnosed transplant-ineligible patients with MM in Argentina (TOTEMM-A) and Brazil (TOTEMM-B) in a private healthcare setting. In TOTEMM-A (n = 72) and TOTEMM-B (n = 892), 37 and 92 different drug regimens were reported, respectively. In each country, treatment duration reduced across lines of therapy (LOT) (TOTEMM-A: range, 6.2-3.4 months; TOTEMM-B: range, 4.4-3.5 months); attrition rates increased across LOT (TOTEMM-A: range, 52.8-86.1%; TOTEMM-B: range, 41.9-88.0%); triplet regimens (mainly bortezomib based) were used most frequently in first-line (1L); >75% relapsed within 12 months, regardless of the drug prescribed; over 90% of relapses occurred between 1L and second-line, and up to half of patients were rechallenged with the same drug; >65% of patients experienced disease progression after 1L; and the 1- to 5-year adjusted cumulative risk of progression or death increased across LOT (TOTEMM-A: range, 47.1-88.5%; TOTEMM-B: range, 40.4-91.7%). The rapid and marked progression underscores the urgent need for novel treatments and regimens.

Background: In DREAMM-7 (NCT04246047), belantamab mafodotin (belamaf) plus bortezomib and dexamethasone (BVd) demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit vs the standard-of-care triplet daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma who had received ≥1 prior line of treatment. MRD negativity has been shown to be a predictor of PFS and overall survival (OS) in multiple myeloma. Here, we aimed to understand if MRD negativity translated to improvements in PFS and OS in the DREAMM-7 trial. Methods: In DREAMM-7,patients with ≥1 prior line of treatment were randomized (1:1) to BVd or DVd. The primary endpoint was independent review committee (IRC)-assessed PFS. OS and aMRD negative status by next-generation sequencing with 10-5 sensitivity; follow-up testing was performed every 6 months thereafter until progressive disease. An exploratory MRD analysis was also performed in patients who achieved a very good partial response or better (≥VGPR). Post hoc subgroup analyses of PFS (IRC assessed) and OS were performed based on IRC-assessed response (≥CR or ≥ VGPR) and MRD- negative status and evaluated using the Kaplan-Meier method; CIs were estimated using the Brookmeyer-Crowley method. Results: In total, 494 patients (BVd, n=243; DVd, n=251) were randomized in the intention-to-treat population. As previously reported, at the first interim analysis (data cutoff: October 2, 2023; median follow-up, 28.2 months), a higher proportion of patients in the BVd arm had CR-based MRD-negative status vs the DVd arm (60 of 243 [25%] vs 24 of 251 [10%] patients). A higher proportion of patients achieved sustained MRD negativity for ≥12 months (≥CR) with BVd (10%) vs DVd (2%) by the data cutoff. Rates of CR-based MRD negativity favored BVd vs DVd in prespecified subgroups of patients with disease refractory to lenalidomide (25% vs 6%) and patients with ≥1 high-risk cytogenetic abnormality (31% vs 7%); this is consistent with findings from the intention-to-treat analysis. A similar trend was observed in an exploratory analysis of patients with ≥VGPR, with 94 of 243 (39%) patients achieving VGPR-based MRD negativity in the BVd arm vs 43 of 251 (17%) patients in the DVd arm. Inability to achieve MRD-negative status was associated with lower PFS and OS outcomes compared with the intention-to-treat population. Among patients who did not achieve CR-based MRD negativity, median PFS was 15.3 months (95% CI, 12.7-18.0 months; BVd, 25.0 months; DVd, 11.8 months), with an 18-month PFS rate of 45% (95% CI, 40%-50%; BVd, 57%; DVd, 36%); median OS was not reached at the data cutoff, and the 18-month OS rate was 74% (95% CI, 69%-78%; BVd, 79%; DVd, 70%). In patients who achieved CR-based MRD-negative status, median PFS and OS were not reached; by the data cutoff, 13% (BVd, 10%; DVd, 21%) of patients had PFS events, and 5% (BVd, 5%; DVd, 4%) had OS events. Conclusions: In the DREAMM-7 trial, patients in the BVd arm achieved MRD-negative status at more than double the rate observed in the DVd arm, and more patients achieved sustained MRD-negative status for ≥12 months with BVd. MRD negativity was associated with durable PFS and OS benefits, which is consistent with previous reports; this highlights the importance of the greater response depth that is achieved with BVd. Funding statement: GSK (Study # 207503) Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

BACKGROUND:In the primary (first interim) analysis of the DREAMM-7 trial (median follow-up 28·2 months), belantamab mafodotin, bortezomib, and dexamethasone (BVd) showed a statistically significant and clinically meaningful progression-free survival benefit versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM) after at least one line of therapy. The aim of this study is to report overall survival from the second interim analysis, with extended follow-up. METHODS:In the ongoing global, open-label, randomised, phase 3 DREAMM-7 trial done at 142 study centres (research facilities, hospitals, and institutions) in 20 countries across North America, South America, Europe, and the Asia-Pacific region, eligible patients were aged at least 18 years and had confirmed multiple myeloma (according to International Myeloma Working Group criteria), an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and progression on or after at least one previous line of therapy. Patients were randomly assigned (1:1) by use of a central interactive response technology system to receive BVd, which comprised belantamab mafodotin 2·5 mg/kg intravenously every 3 weeks plus bortezomib 1·3 mg/m2 subcutaneously (twice weekly in 21-day cycles, for up to eight cycles) plus dexamethasone 20 mg orally or intravenously (on the day of, and after, bortezomib; for up to eight cycles), or DVd, which comprised daratumumab 16 mg/kg intravenously (21-day cycles; once weekly in cycles 1-3, every 3 weeks in cycles 4-8, and every 4 weeks in cycle 9 and beyond) plus bortezomib and dexamethasone; bortezomib and dexamethasone doses and schedules were the same as those in the BVd group. Randomisation was stratified by number of previous lines of therapy, previous bortezomib, and Revised International Staging System stage. Treatment assignments were unmasked for study personnel and patients; however, they were masked to the independent review committee. Patients received treatment until progressive disease, death, unacceptable toxicity, withdrawal of consent, or loss to follow-up, whichever occurred first. The primary endpoint was progression-free survival; key secondary endpoints were overall survival, minimal residual disease negativity in patients with a complete response or better, duration of response to treatment, and safety. Analysis of efficacy endpoints was based on assessments in all patients who were randomly assigned (ie, the intention-to-treat population). The safety population included all randomly assigned patients who received one or more doses of study treatment. This trial is registered with ClinicalTrials.gov, NCT04246047, and is ongoing. FINDINGS:From May 7, 2020, to June 28, 2021, of 623 patients assessed for eligibility, 494 were randomly assigned to receive BVd (n=243) or DVd (n=251); 272 (55%) were male, and 409 (83%) were White. The median age of the patients was 64·5 years (IQR 57·0-71·0). At the updated data cutoff (Oct 7, 2024) and median follow-up (39·4 months [IQR 14·6-42·9]), early, sustained, and significant overall survival benefit was observed with BVd versus DVd. Median overall survival was not reached (NR; 95% CI NR-NR) with BVd and NR (41·0 months-NR) with DVd (hazard ratio [HR] 0·58; 95% CI 0·43-0·79; p=0·0002). BVd versus DVd led to greater than double the minimal residual disease-negativity rates in patients with a complete response or better (25% [95% CI 19·8%-31·0%] vs 10% [6·9%-14·8%]) and median duration of response (40·8 months [95% CI 30·5 months-NR] vs 17·8 months [13·8-23·6]). Analysis of progression-free survival 2 showed that the treatment benefit favouring BVd versus DVd was maintained following subsequent antimyeloma therapy; median progression-free survival 2 was NR with BVd (95% CI 45·6-NR) versus 33·4 months (95% CI 26·7-44·9) with DVd (HR, 0·59; 95% CI, 0·45-0·77). The most common grade 3 or 4 adverse event was thrombocytopenia (135 [56%] of 242 with BVd vs 87 [35%] of 246 with DVd). Serious adverse events occurred in 129 (53%) of 242 patients receiving BVd and 94 (38%) of 246 patients receiving DVd; the most common events were pneumonia (29 [12%] vs 11 [4%]), pyrexia (12 [5%] vs 10 [4%]), and COVID-19 (11 [5%] vs 10 [4%]). Treatment-related serious adverse events that led to death occurred in seven (3%) of 242 patients receiving BVd (pneumonia [n=4], gastrointestinal haemorrhage [n=1], subdural haemorrhage [n=1], or mesenteric vessel thrombosis [n=1]) and two (1%) of 246 receiving DVd (COVID-19 [n=2]). INTERPRETATION:DREAMM-7 showed significant and clinically meaningful overall survival, progression-free survival, minimal residual disease negativity, and duration of response benefits with BVd versus DVd. BVd could be a new standard of care for RRMM. FUNDING:GSK.