Elsevier

The Lancet Oncology

Volume 21, Issue 2, February 2020, Pages 207-221
The Lancet Oncology

Articles
Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study

https://doi.org/10.1016/S1470-2045(19)30788-0Get rights and content

Summary

Background

Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study.

Methods

DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0–2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov, NCT03525678, and is ongoing.

Findings

Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8–42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9–46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3–4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2·5 mg/kg cohort and 21 [21%] of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort).

Interpretation

Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.

Funding

GlaxoSmithKline.

Introduction

Treatment of patients with relapsed or refractory multiple myeloma remains challenging despite numerous therapeutic advances.1, 2, 3, 4, 5, 6 Patients with disease refractory to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a poor prognosis, with newer combination therapies such as selinexor plus dexamethasone resulting in 26% of patients achieving an overall response (median progression-free survival of 3·7 months and median overall survival of 8·6 months).7 Effective novel therapies with acceptable safety profiles are needed for patients who have exhausted available treatment options.

B-cell maturation antigen (BCMA; also known as TNFRSF17) is a cell-surface receptor that is expressed on multiple myeloma cells, but is virtually absent on naive and memory B cells, making it an ideal therapeutic target.8, 9 Belantamab mafodotin (GSK2857916) is a first-in-class, anti-BCMA immunoconjugate with an afucosylated, humanised IgG1 anti-BCMA monoclonal antibody conjugated by a protease-resistant maleimidocaproyl linker to a microtubule-disrupting agent, monomethyl auristatin F (MMAF).10 Belantamab mafodotin binds to BCMA and kills multiple myeloma cells via a multimodal mechanism, including delivery of MMAF to BCMA-expressing multiple myeloma cells, thereby inducing apoptosis; enhancing antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis; and inducing immunogenic cell death.10, 11 In the first-in-human DREAMM-1 study, single-agent belantamab mafodotin (3·4 mg/kg administered every 3 weeks) induced deep (overall response achieved in 21 [60%] of 35 patients) and durable (median duration of response 14·3 months; 95% CI 10·6–not estimable) responses in patients with heavily pre-treated relapsed or refractory multiple myeloma.12, 13 In a subgroup of 13 patients previously treated with an anti-CD38 monoclonal antibody and refractory to both proteasome inhibitors and immunomodulatory drugs, an overall response was achieved in five (38·5%) patients and median progression-free survival was 6·2 months (95% CI 0·7–7·9).13

Research in context

Evidence before this study

Effective therapies with acceptable safety profiles are needed to improve outcomes of patients with relapsed or refractory multiple myeloma, particularly for patients with disease that is refractory to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies, who have few treatment options available. Before initiating the DREAMM-1 study, we searched PubMed with the terms “relapsed”, “myeloma”, “BCMA”, and “clinical trial” for studies published from Jan 1, 1990, onwards. Although we identified multiple trials assessing B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell therapies and related adoptive cellular approaches, we found no published studies in humans of BCMA-targeting antibodies or immunoconjugates. Belantamab mafodotin (GSK2857916) is a first-in-class, anti-BCMA immunoconjugate with a multimodal mechanism of action. In the first-in-human, phase 1 DREAMM-1 study, belantamab mafodotin showed promising anti-myeloma activity, inducing responses in heavily pre-treated patients with relapsed or refractory multiple myeloma.

Added value of this study

DREAMM-2 builds on the results from DREAMM-1, showing that the responses observed with single-agent belantamab mafodotin at both the 2·5 mg/kg and 3·4 mg/kg doses (every 3 weeks) compare favourably with the responses described with other approved treatments in patients who were heavily pre-treated and refractory to immunomodulatory drugs and proteasome inhibitors and refractory or intolerant to anti-CD38 monoclonal antibodies (either alone or in combination). Results from DREAMM-2 also show that the safety profile of belantamab mafodotin is manageable, with no new safety concerns compared to DREAMM-1.

Implications of all the available evidence

Belantamab mafodotin might be a viable treatment option for patients with relapsed or refractory multiple myeloma, particularly those who are refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to anti-CD38 monoclonal antibodies as a single-agent treatment. Additional studies of belantamab mafodotin in combination with standard of care or novel agents are ongoing or planned.

The DREAMM-2 study was designed to further explore the safety, activity, and clinical benefit profile of two doses of belantamab mafodotin (2·5 mg/kg and 3·4 mg/kg every 3 weeks) in patients with relapsed or refractory multiple myeloma who were refractory to an immunomodulatory drug and proteasome inhibitor, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody.

Section snippets

Study design and participants

The open-label, two-arm, phase 2 DREAMM-2 study was done at 58 multiple myeloma specialty centres in eight countries (appendix pp 12–13). Eligible patients with relapsed or refractory multiple myeloma confirmed histologically or cytologically according to International Myeloma Working Group criteria were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status of 0–2; had undergone autologous stem cell transplantation (>100 days before enrolment) or were considered

Results

Between June 18, 2018, and Jan 2, 2019, 293 patients were screened. 221 patients were randomly assigned, of whom 196 were randomly assigned to the 2·5 mg/kg (n=97) and 3·4 mg/kg (n=99) cohorts and included in the intention-to-treat population. 30 of these patients were included in the ocular substudy (17 in the 2·5 mg/kg cohort and 13 in the 3·4 mg/kg cohort; figure 1). In the safety population (95 patients in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort), as of the data cutoff date of

Discussion

In DREAMM-2, belantamab mafodotin (2·5 mg/kg or 3·4 mg/kg) every 3 weeks showed clinically meaningful activity in patients with relapsed or refractory multiple myeloma. Overall responses were achieved in more than 30% of patients in each cohort and around 20% achieved a very good partial response or better. The depth and durability of responses seen with single-agent belantamab mafodotin in this population compares favourably with the responses described with other approved combination

Data sharing

Information about GlaxoSmithKline's data sharing commitments and access requests to anonymised individual participant data and associated documents can be requested for further research from ClinicalStudyDataRequest.com.

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