Single-agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma: Final analysis of the DREAMM-2 trial.

INTRODUCTION

The management of multiple myeloma (MM) has made much progress with the introduction of novel therapies such as proteasome inhibitors (PIs), immunomodulatory agents, and monoclonal antibodies (mAbs). 1 , 2 Bispecific T-cell engager monoclonal antibodies (BiTEs) and chimeric antigen receptor (CAR)-T–cell therapies provide additional options for patients with relapsed/refractory MM (RRMM) but have complex administration procedures and significant side effects. 3 , 4 Despite these advances in MM treatment, outcomes remain poor once the disease becomes refractory to multiple therapies. 1 , 2 , 5 , 6 In the 2019 MAMMOTH study, patients with disease refractory to anti-CD38 mAbs, PIs, and immunomodulatory agents demonstrated a median overall survival (OS) of 9.2 months, with subsequent treatment often resulting in reduced treatment duration, overall response rates (ORRs), and OS with each successive therapy. 6

Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation antigen (BCMA)-binding antibody-drug conjugate (ADC) containing monomethyl auristatin F (MMAF), 7 eliminates myeloma cells by a multimodal mechanism involving direct cell killing and activation of anti-myeloma immune responses. 8 , 9 In the primary DREAMM-2 study ( NCT03525678 ; cutoff: June 2019) and 13-month follow-up (cutoff: January 2020), single-agent belamaf demonstrated deep and durable responses, with a manageable safety profile in patients with heavily pretreated RRMM. 7 , 10 Here, we report the long-term efficacy and safety profiles of single-agent belamaf from DREAMM-2.

MATERIALS AND METHODS

Study design

Full DREAMM-2 methodology has been previously published. 7 , 10 , 11 Briefly, DREAMM-2 was a phase 2, two-arm, open-label study of single-agent belamaf in patients with RRMM who had received three or more prior therapies and were refractory to an immunomodulatory agent and a PI, and refractory/intolerant to an anti-CD38 mAb. Belamaf was dosed at 2.5 or 3.4 mg/kg every 3 weeks (Q3W) by intravenous infusion (frozen formulation) until disease progression or unacceptable toxicity. An additional independent cohort was treated with 3.4 mg/kg of a lyophilized formulation to allow assessment of the safety and efficacy of this preparation. Patient accrual to the lyophilized cohort started after enrollment in the other cohorts was complete. DREAMM-2 began in June 2018; the last patient last visit for the final report was in March 2022. Patients still receiving benefit from belamaf at the time of the final analysis were allowed to continue belamaf, and only key safety data are reported on those patients.

Outcomes and analysis

The primary end point was ORR as assessed by an independent review committee. Secondary end points included clinical benefit rate (CBR), time-to-response (TTR), duration of response (DoR), progression-free survival (PFS), OS, safety, and ocular events. Healthrelated quality of life (HRQOL), disease-related symptoms, and impact on functioning were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core module (EORTC-QLQ-C30), EORTC-QLQ-20-item Multiple Myeloma module, and the Ocular Surface Disease Index (OSDI). Exploratory end points included rate of minimal residual disease (MRD) negativity (assessed by next-generation sequencing with a threshold of 10 –5 ) measured at time of very good partial response (VGPR) and complete response (CR).

Adverse events (AEs) were graded per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 12 The GSK Keratopathy and Visual Acuity (KVA) scale was also used for grading ocular events. 13 The KVA scale incorporates ocular examination findings and reduced visual acuity into a combined scale, providing the incidence of worst case post baseline ocular events. 13 Recovery was defined as Grade 1 examination findings/no examination findings, and ≤1-line decline in best corrected visual acuity (BCVA) compared with baseline. Patients completed patient-reported outcomes (PRO) questionnaires at baseline and Q3W thereafter for PRO-CTCAE and every 6 weeks for EORTC questionnaires.

The intention-to-treat (ITT) population comprised all randomized patients regardless of treatment administration. The safety population comprised all patients receiving one or more belamaf dose. Patients with unknown or missing response data were considered nonresponders. Post hoc analyses included outcomes in patients with high-risk cytogenetics, renal impairment, and extramedullary disease, OS and PFS in patients with ≥VGPR, and the effect of dose delays on response.

Demographics and safety data were analyzed using descriptive statistics; ORR and CBR were summarized by number and percentages with corresponding exact 97.5% confidence intervals (CI). DoR, PFS, TTR, and OS were summarized using Kaplan–Meier methodology with 95% CIs. ORR, CBR, and PFS were calculated on confirmed responses, per International Myeloma Working Group criteria. DoR and TTR were calculated on unconfirmed visit-level responses.

RESULTS

Patients and treatment

Overall, 97 patients (ITT population) were allocated to the belamaf 2.5 mg/kg cohort, 99 patients to the 3.4 mg/kg cohort, and 25 patients to the lyophilized (3.4 mg/kg) cohort ( Figure S1 ). Full demographics and baseline characteristics have been previously reported and are summarized in Table S1 . 7 , 10 , 11 Per eligibility criteria, all patients were triple-class refractory (PI, anti-CD38mAb, immunomodulatory agent); 87%, 78%, and 96% of patients in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, respectively, were pomalidomide refractory. 7 , 11

This final analysis (data cutoff March 2022) corresponds to approximately a 3-year follow-up. Patients received a median (range) of three (1–39) cycles in the 2.5 mg/kg cohort, three (1–32) cycles in the 3.4 mg/kg cohort, and three and a half (1–35) cycles in the lyophilized cohort; patients received treatment for a median of 9.3 (2–178), 12.0 (2–186), and 16.6 (3–146) weeks, respectively. Median dose intensity is reported in Table S2 : the 2.5 mg/kg cohort decreased to 1.92 mg/kg by cycle 5 ( n = 28); the 3.4 mg/kg cohort decreased to 2.5 mg/kg by cycle 4 ( n = 45) and 1.92 mg/kg by cycle 10 ( n = 18); and the lyophilized cohort decreased to 2.5 mg/kg by cycle 4 ( n = 12) and to 1.92 mg/kg by cycle 20 ( n = 3). Median (range) duration of follow-up was 12.5 (0.1–40.4) months, 13.8 (0.1–42.8) months, and 24.5 (1.8–38.8) months. Treatment withdrawal resulted mostly from progressive disease ( Figure S1 ). At the final data cut, three patients who were still receiving benefit from treatment continued belamaf within the DREAMM-2 protocol, with a response at last study assessment of VGPR in two patients and stringent CR (sCR) in one patient.

Efficacy

ORR (97.5% CI) was 32% (21.7–43.6) and 35% (24.8, 47.0) in the 2.5 and 3.4 mg/kg cohorts, respectively; 19% and 24% of patients (58% and 69% of responders) achieved ≥VGPR ( Table 1 ). ORR for the lyophilized cohort was 52% (97.5% CI, 28.9–74.5). ORR by subgroup is shown in Figure S2 . CBR in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts were 36%, 40%, and 56%. In the 2.5 and 3.4 mg/kg cohorts, the MRD negativity rate (threshold 10 –5 ) of patients with ≥VGPR was 36% (5 of 14) and 23% (3 of 13), whereas for patients who achieved ≥CR, MRD negativity rates were 44% (4 of 9) and 67% (2 of 3), respectively. MRD negativity was not assessed for the lyophilized cohort.

Median TTR (95% CI) was 1.5 months (1.0–2.1) in the 2.5 mg/kg cohort, 1.4 months (0.9–2.1) in the 3.4 mg/kg cohort, and 0.9 months (0.8–2.3) in the lyophilized cohort. In responding patients, median TTR (best response; 95% CI) was 2.2 (1.5–5.0), 3.5 (2.8–4.3), and 1.4 (0.8–2.9) months, respectively. Median DoR (95% CI) was 12.5 (4.2–19.3) and 6.2 (4.8–18.7) months for the 2.5 and 3.4 mg/kg cohorts, and 9.0 (2.8–10.4) for the lyophilized cohort ( Figure 1 ). For patients who responded to belamaf, duration and depth of response, dose levels received, and timing of subsequent doses are shown in Figure S3 . In the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, patients with progressive disease (nonresponders/nonevaluable) discontinued treatment in a median (range) of 6 (2–18), 6 (2–21), and 9 (3–117) weeks.

Median PFS (95% CI) was 2.8 months (1.6–3.6) in the 2.5 mg/kg cohort, 3.9 (2.0–5.8) months in the 3.4 mg/kg cohort, and 5.7 (2.2–9.7) months in the lyophilized cohort ( Figure 2 ). In patients who achieved ≥VGPR, median PFS was 14.0 (9.7, not reached [NR]) and 16.8 (7.7, NR) months for the 2.5 and 3.4 mg/kg cohorts.

Median OS (95% CI) was 15.3 (9.9–18.9), 14.0 (10.0–18.1), and 24.5 (8.7–NR) months in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, respectively ( Figure 2 ). In patients who achieved ≥VGPR, estimated OS was 30.7 (19.7–37.9) and 35.5 (14.1– NR) months in the 2.5 and 3.4 mg/kg cohorts (post hoc analysis; not analyzed for the lyophilized cohort). For patients with ≥minimal response, estimated OS (95% CI) was 35.3 (19.6–NR) and 25.7 (18.8–37.0) months for the 2.5 and 3.4 mg/kg cohorts (not analyzed for the lyophilized cohort).

ORR and CBR did not differ greatly across subgroups except for the extramedullary disease subgroup, where they were lower ( Figure S2 , Table S3 ).

Safety

The overall frequency of AEs and serious AEs (SAEs) are shown in Table 2 . In the 2.5 mg/kg cohort, 98% of patients experienced one or more AE; treatment-related AEs occurred in 88%. All patients (100%) in the 3.4 mg/kg cohort experienced one or more AE; 95% experienced treatment-related AEs. In the lyophilized cohort, 100% of patients had one or more treatment-related AE. In the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, Grade ≥3 AEs occurred in 84%, 83%, and 88% of patients, respectively; treatment-related Grade ≥3 AEs occurred in 58%, 64%, and 58%. The most common Grade 3 AEs were keratopathy, anemia, and thrombocytopenia ( Table 2 ). The most common Grade 4 AEs were thrombocytopenia, neutropenia, and decreased lymphocyte count. Fatal SAEs occurred in four patients in the 2.5 mg/kg cohort, nine patients in the 3.4 mg/kg cohort, and one patient in the lyophilized cohort ( Table 2 ).

The most commonly reported ocular events of any grade included keratopathy (71%, 75%, 96%), blurred vision (25%, 36%, 42%), BCVA reduced to 20/50 or worse (48%, 49%, 75%), and dry eye (18%, 25%, 25%) in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, respectively ( Table 2 ). The overall any-grade infection rates were 45%, 55%, and 46%. Grade ≥3 infections were observed in 20%, 44%, and 8% of patients. Upper respiratory tract infections were seen in 11%, 22%, and 17% of patients in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, whereas pneumonia was seen in 9%, 18%, and 13% of patients. Investigator-assessed hypogammaglobulinemia was reported in one patient in each of the 2.5 mg/kg and lyophilized cohorts (both Grade 2). Intravenous immunoglobulins were used in up to 7.3% of patients in the study. There were two COVID-19 infection-related deaths during the study.

AEs, including thrombocytopenia and ocular events, were managed with dose delays or reductions. In the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, dose delays due to AEs occurred in 51 (54%), 61 (62%), and 19 (79%) patients in each cohort, respectively, with keratopathy (45 [47%], 49 [49%], 18 [75%]), blurred vision (6 [6%], 13 [13%], 5 [21%]), pneumonia (3 [3%], 6 [6%], 2 [8%]), and thrombocytopenia (2 [2%], 5 [5%], 0) being the most frequently reported causes. Following any keratopathy-related dose delay, 34 (76%), 39 (80%), and 16 (89%) patients restarted treatment ( Table S4 ).

AE-related dose reductions occurred in 34 (36%), 44 (44%), and 14 (58%) patients ( Table 2 ). In all cohorts, the most frequently reported reasons for dose reductions were keratopathy (27 [28%], 30 [30%], 12 [50%]), thrombocytopenia (4 [4%], 11 [11%], 2 [8%]), blurred vision (2 [2%], 3 [3%], 2 [8%]), and in the 2.5 and 3.4 mg/kg cohorts only, decreased platelet counts (2 [2%], 2 [2%]). AE-related permanent discontinuations occurred in 12%, 12%, and 8% of patients; discontinuations due to ocular events were rare (2.5 mg/kg cohort: 5% [keratopathy, blurred vision, reduced visual acuity]; 3.4 mg/kg cohort: 3% [keratopathy]; lyophilized cohort: 4% [keratopathy]). Dose delays ≥63 days occurred in 16 of 31 (52%) and 19 of 34 (56%) responding patients who received a subsequent dose ( Table S4 ). Patients with evidence of a response had longer dose delays; median DoR in patients with dose delays >63 days was longer than patients with delays ≤63 days ( Figure S4 ). Across all responding patients with dose delays ≥63 days, clinical benefit was maintained or deepened during 14 of 16 (88%), 16 of 19 (84%) and 4 of 4 (100%) of the first dose delay >63 days ( Table S4 ).

In the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, more than three blurred vision events occurred during treatment in 17%, 8%, and 10% of patients, respectively. The first blurred vision event resolved in 79% (19 of 24), 89% (32 of 36), and 50% (5 of 10) of affected patients ( Table 3 ). The first blurred vision event resolved in a median of 43, 85, and 43 days, respectively. At the time of this analysis, considering all occurrences of blurred vision, 6%, 6%, and 21% of patients in each cohort had not resolved. BCVA reduction to 20/50 or worse recurred (having three or more events) in affected patients in 0%, 5%, and 11% of patients. The first event resolved in 89% (16 of 18), 95% (20 of 21), and 100% (9 of 9) of patients. In patients without resolution, two (11%), one (5%), and zero patients discontinued the study and follow-up ended. Median time from occurrence to resolution of the first BCVA event was 21.5, 23.5, and 23.5 days ( Table 3 ). Within the follow-up period, no patient had <20/200 on the Snellen visual acuity scale or had permanent complete vision loss. The last event of reduced BCVA remained unresolved in 11%, 10%, and 0% of patients in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts.

Keratopathy also sometimes occurred multiple times: three or more events occurred in 12%, 16%, and 4% of patients in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, respectively. The first keratopathy event resolved in 73% (49 of 67), 64% (47 of 74), and 52% (12 of 13) of patients ( Table 3 ). All patients with unresolved keratopathy discontinued treatment and follow-up ended. Median time to resolution of the first event was 120, 106, and 228 days, respectively. When all incidents of keratopathy were considered, 23%, 26%, and 50% of patients in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts had unresolved keratopathy at this final analysis.

Corneal events graded by the KVA scale were reported in 72%, 77%, and 96% of patients in the 2.5 mg/kg, 3.4 mg/kg, and lyophilized cohorts, with Grade 3 being the most common severity reported in 46%, 47%, and 75%. The first corneal event (Grade ≥2) occurred at a median of 63, 45, and 43 days from start of treatment and had a median duration of 54, 87, and 80 days. At the end of treatment 36 (38%), 37 (37%), and 14 (58%) patients had a corneal event worse than baseline, of which 50%, 41%, and 43% had resolved by the last follow-up. Median time to resolution of these events was 113, 113, and 196 days after treatment ended. The cumulative incidence, and recovery of, corneal events is shown in Figure 3 . Additional details of corneal events graded by the KVA scale are shown in Table S5 .

PROs

Global Health Status/QoL remained stable over time for both the 2.5 and 3.4 mg/kg cohorts and group-level trends toward improvements in Fatigue and Pain scores were noted as early as week 7 ( Figure S5 ). Disease symptoms also trended toward improvement over time in both cohorts ( Figure S5 ). PRO analyses were not done for the lyophilized cohort.

A ≥12.5-point worsening from baseline in OSDI vision-related functioning (VRF) occurred in 48 (51%) patients in the 2.5 mg/kg cohort, 61 (62%) patients in the 3.4 mg/kg cohort, and 18 (75%) patients in the lyophilized cohort ( Table S5 ). Median time to onset of worsening VRF was 45, 44, and 43 days, respectively. A high proportion of patients (73%, 72%, and 83%) recovered from their worsening VRF, similar to outcomes with eye examination findings and symptoms. Median time to improvement from a worst-case score on the OSDI VRF domain was 25, 22, and 22 days, respectively. No change in overall patient-reported Global Health Status/QoL, or Physical Functioning domain scores were reported, even among patients with reductions in OSDI VRF.

Summaries of outcomes for patients who gave up reading or driving due to impaired vision are shown in Tables S6 and S7 , respectively.

DISCUSSION

This final analysis of DREAMM-2 evaluating single-agent belamaf in patients with heavily pretreated RRMM confirms the meaningful clinical efficacy reported earlier. 7 , 10 In the 2.5 mg/kg cohort, ORR for the total patient population was 32% at 3 years of follow-up compared with the 31% reported earlier. 7 , 10 Responses were typically seen soon after cycle one and were sustained for a median of 1 year. Patients with minimal response also maintained their responses for long durations. ORR was comparable between the 2.5 and 3.4 mg/kg cohorts (32% and 35%), as was median PFS (2.8 and 3.9 months for the full cohorts; 14.0 and 16.8 months in patients with ≥VGPR).

As is typical in patients with triple-class refractory RRMM, progressive disease was the leading cause of early discontinuation. However, some patients were able to remain on treatment for a prolonged period of time, receiving up to 39 cycles of belamaf at the 2.5 mg/kg dose. The median OS achieved in this cohort was 15.3 months, which doubled in patients achieving ≥VGPR, reaching 30.7 months, with similar results in the 3.4 mg/kg cohort.

These outcomes are favorable when compared with those typically seen in heavily pretreated patients with RRMM. In a real-world study of older patients (median age, 69 years) treated with belamaf, an ORR of 45% was reported, with treatment-related AEs also managed using dose delays. 14 In this real-world study, patients who were refractory to anti-CD38 mAbs had a median OS of 8.6 months, with OS ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory agent and a PI, to 5.6 months for penta-refractory patients. 6 Additional real-world studies have demonstrated similar findings, consistent with the clinical trial setting. 15 – 19

Despite having similar ORR and PFS, the shorter DoR reported here for the 3.4 mg/kg cohort may be due to tolerability issues requiring more frequent dose modifications. AEs such as thrombocytopenia and ocular events were frequently managed with dose delays that allowed for event resolution before recommencing treatment. These dose modifications decrease the median dose intensity received by patients over time; however, patients who responded to belamaf and had dose delays >63 days (three cycles) still experienced long DoR, indicating that dose modifications do not negatively impact response duration.

The lyophilized cohort had more patients with International Staging System stage I disease, fewer patients with high-risk cytogenetics or extramedullary disease, and had received fewer prior lines of therapy than the other cohorts ( Table S1 ), which potentially explains the higher ORR (52% vs. 32% and 35%) and CBR (56% vs. 36% and 40%) in this cohort. Additionally, the median number of belamaf cycles received was higher for patients in the lyophilized cohort, which may also explain the higher ORR, CBR, and DoR, but also the higher rates of keratopathy and blurred vision.

Additional BCMA-targeting therapies, such as CAR-T or BiTE-based regimens, have recently become available and have demonstrated promising efficacy in patients with RRMM (idecabtagene vicleucel, median OS 19.4 months, mPFS 20.0 months in patients with CR/sCR [≥VGPR not given] 20 ; ciltacabtagene autoleucel, ORR 97%, PFS and DoR NR 3 ). Single-agent belamaf demonstrated a 32% ORR, 14 months mPFS and 31 months median OS in patients with ≥VGPR, suggesting comparable efficacy in responding patients. Additionally, belamaf treatment (at 2.5 mg/kg) is not associated with cytokine release syndrome, neurotoxicity, prolonged cytopenia, or high rates of severe 4 or fatal 3 infections as observed with CAR-T therapies or BiTEs. T-cell redirection therapy availability may also be limited in some countries outside of the United States and China, which have the largest number of CAR-T clinical trials. 21 Belamaf is available “off-the-shelf,” can be given with or without corticosteroids and has a dosing schedule and side effect profile that may provide additional utility for elderly patients who are unable to tolerate more aggressive treatment options or who have limited access to clinic or hospital care.

Along with these considerations, determining the optimal sequence within the current MM treatment landscape is critical, as the effectiveness of subsequent BCMA-directed therapies may be dependent on the baseline expression of BCMA or overall T-cell fitness. 22 – 25 Notably, recent data suggest that surface BCMA expression is not completely lost following belamaf treatment, 26 allowing possible subsequent treatment with other BCMA-targeting therapies, including other T-cell redirection therapies. 5 , 22 , 23 , 25

This final analysis of DREAMM-2 demonstrates a consistent and manageable safety profile over time for patients treated with belamaf. The AE frequency was consistent with earlier reports 7 , 10 ; no new safety signals were noted. The grade of AEs remained unchanged with longer follow-up. Keratopathy was the most common AE overall and was mostly Grade 1–2, with 29% of patients having Grade 3 and no patients having Grade 4 keratopathy in the 2.5 mg/kg cohort. Incidents of thrombocytopenia and other hematologic AEs were consistent with the previous reports and did not increase over time. The overall infection rates of 45%–55% in this study were lower in comparison to those for teclistamab (76% infection, 45% Grade 3–4), 4 although the mPFS and duration of teclistamab treatment (11.3 and 8.5 months) are longer than belamaf in the overall study population. 4 Hypogammaglobulinemia may have been under-reported by investigators in this study as up to 7.3% of patients were treated with intravenous immunoglobulins. It is worth noting that in this study, few patients were treated through the COVID-19 pandemic; two COVID-related deaths occurred.

Ocular events reported with belamaf treatment are a known class effect of MMAF-containing ADCs. 27 , 28 These comprise eye examination findings of keratopathy including superficial punctate keratopathy and microcyst-like epithelial changes, with a decrease in visual acuity and patient-reported symptoms such as blurred vision and dry eye. 7 , 10 , 13 , 27 , 29 In the DREAMM-2 trial, dose modification was used to manage ocular events and allowed continuation of treatment with belamaf. By the final analysis, corneal events graded by the KVA scale (encompassing both ocular examination findings and decreases in visual acuity) had not resolved to baseline in 22% of patients across the whole trial. Clinical experience gained in real-world settings has provided more insight into the occurrence and impact of ocular events with belamaf, and guidance is available on how to recognize and manage these events. 10 , 13 , 27 , 29 , 30

Patient’s HRQOL was maintained or improved across cohorts despite changes in ocular symptoms. QoL is as important as “quantity of life” in patients with RRMM, in whom the number and side-effect burden of previous therapies can be high. 31 Changes in OSDI VRF, which measures changes in visual acuity were transient, and ≥72% of the patients with a decline in VRF recovered within 25 days across all cohorts. Importantly, patients experiencing worsening vision while on study treatment reported no overall change in Global Health Status/QoL, or Physical Functioning domain scores. As in other studies, improvements in fatigue, pain, and disease symptoms correlate with clinical findings during responses 32 and support the use of belamaf in patients with RRMM.

This single-arm phase 2 study included no active control/comparator arm, making it unsuitable to assess noninferiority to standard-of-care treatments. DREAMM-3 ( NCT04162210 ) was designed with that aim, but primary analysis demonstrated that the study did not meet its primary end point of superiority to pomalidomide/dexamethasone. Subsequently, belamaf has been withdrawn from the US market. Additional DREAMM trials are ongoing examining alternative belamaf regimens including combinations with other anti-myeloma treatments and in different lines of therapy with encouraging early results. 33 – 37 Overall, the results of DREAMM-2 have meaningfully informed ongoing and future studies of belamaf: patients who respond demonstrate rapid responses that are sustained for long durations. These results have translated into clinical practice, where similar real-world results have been reported. 14 , 19 , 38

In conclusion, single-agent belamaf at 2.5 or 3.4 mg/kg Q3W resulted in rapid, durable, and clinically meaningful responses with a manageable safety profile in patients who have received three or more prior therapies for RRMM, including an anti-CD38 mAb, a PI, and an immunomodulatory agent. This is a patient population with otherwise poor prognosis and limited treatment options.

Supplementary Material

ACKNOWLEDGMENTS

The study investigators ( Table S8 ) would like to acknowledge the ophthalmology and optometry colleagues who provided ophthalmic examinations to patients enrolled in the study, as well as Sumita RoyGhanta for her contributions to manuscript development and revision. Editorial support (in the form of writing assistance, including preparation of the draft manuscript under the direction and guidance of the authors, collating and incorporating authors’ comments for each draft, assembling tables and figures, grammatical editing, and referencing) was provided by Elisabeth Walsby, PhD, Rebecca L. Crepeau, PhD, and Richard Fay, PhD, CMPP at Fishawack Indicia UK, Ltd, part of Fishawack Health and was funded by GSK. Drug linker technology was licensed from Seagen, Inc (Bothell, Washington) and monoclonal antibody was produced using POTELLIGENT Technology licensed from BioWa, Inc (Princeton, New Jersey). DREAMM-2 was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines after approval by ethics committees and institutional review boards at each study site. All patients provided written informed consent. This study was funded by GSK (GSK study 205678). Rakesh Popat is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and this trial was supported in part by the NIHR UCLH Clinical Research Facility and the Cancer Research UK Experimental Cancer Medicine Centre. Medical writing support was funded by GSK.

CONFLICT OF INTEREST STATEMENT

Ajay K. Nooka reports grant funding and personal fees from GSK, Janssen, Bristol-Myers Squibb, Takeda, Pfizer, Karyopharm, and Amgen, and personal fees from Beyond Springs, Adaptive, SecuraBio, Sanofi, and Oncopeptides. Adam D. Cohen reports grant funding and personal fees from GSK, Janssen, Celgene, Novartis, Amgen, Genentech/Roche, Seagen Inc, and Millenium/Takeda; personal fees from Bristol-Myers Squibb, Karyopharm, Sanofi, AstraZeneca, AbbVie, Pfizer, Oncopeptides, Ichnos, and Arcellx. Hans C. Lee reports consulting fees from Allogene Therapeutics, Bristol-Myers Squibb, Celgene, Genentech, GSK, Karyopharm, Legend Biotech, Monte Rosa Therapeutics, Oncopetides, Pfizer, Sanofi, and Takeda Pharmaceuticals and research funding from Amgen, Bristol-Myers Squibb, Janssen, GSK, Regeneron, and Takeda Pharmaceuticals. Attaya Suvannasankha reports grant funding and personal fees from GSK, Janssen Oncology, and Karyopharm, and grant funding from Bristol-Myers Squibb and Celgene. NC and A-OA have nothing to disclose. Suzanne Trudel reports grant funding and personal fees from Amgen, Celgene, Janssen, and GSK, and personal fees from Takeda, Novartis, Sanofi, and Karyopharm. Ajai Chari reports grant funding and personal fees from Janssen, Celgene, Novartis, Amgen, Seagen Inc, and Millenium/Takeda; personal fees from Bristol-Myers Squibb, Karyopharm, Sanofi, Oncopeptides, and Antengene, and grant funding from Pharmacyclics. Edward N. Libby reports personal fees from AbbVie and Janssen, and research funding from Celgene, Genentech, Amgen, and GSK. Maria Chaudhry reports consulting fees from Sanofi. Malin Hultcrantz reports consulting fees from Curio Science LLC, GSK, and Intellisphere LLC; research funding from Amgen, Daiichi Sankyo, and GSK; and speakers bureau fees from Bristol-Myers Squibb and GSK. K. Martin Kortüm reports grant funding and personal fees from AbbVie, Bristol-Myers Squibb, Celgene, GSK, Pfizer, and Takeda. Paul G. Richardson reports grant funding from Bristol-Myers Squibb, Celgene, Takeda, and Oncopeptides and served on advisory committees for Celgene, Takeda, and Oncopeptides, Amgen, Janssen, Karyopharm, and Sanofi. Rakesh Popat reports grant funding, personal fees and nonfinancial support from Takeda; personal fees and nonfinancial support from Janssen, Celgene, and GSK; and personal fees from AbbVie. Douglas Sborov reports personal fees from Celgene, Janssen, and Amgen. Shawn Hakim holds stock/shares in GSK. Eric Lewis holds stock/shares in GSK. Boris Gorsh holds stock/shares in GSK. Bharat Bhushan holds stock/shares in GSK. Astrid McKeown holds stock/shares in GSK. Joanna Opalinska holds stock/shares in GSK. Ira Gupta holds stock/shares in GSK and Novartis. Sagar Lonial reports grant funding and personal fees from Celgene and Takeda and personal fees from Novartis, Bristol-Myers Squibb, GSK, Amgen, Merck, and Janssen. The other authors declare no conflicts of interest.

Maria Chaudhry was affiliated with George Washington University at the time of the study. The trial registration is ClinicalTrials.gov identifier NCT03525678 .

SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

DATA AVAILABILITY STATEMENT

Information on GSK’s data sharing commitments and access requests to anonymized individual participant data and associated documents can be requested for further research from https://www.gsk-study-register.com/en/ .

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