Abstract
DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.
Highlights
Despite improved outcomes with currently available therapies, including proteasome inhibitors (PIs), immunomodulatory agents and anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains a challenging disease that is incurable for most patients1–4
Belamaf binds to B-cell maturation antigen (BCMA) and eliminates myeloma cells by a multimodal mechanism, including delivering mafodotin to BCMA-expressing malignant cells thereby inhibiting microtubule polymerisation, and inducing immune-independent antibody-drug conjugate (ADC)-mediated apoptosis; immune-dependent enhancement of antibody-dependent cellular cytotoxicity and phagocytosis; and release of markers characteristic of immunogenic cell death—a form of regulated cell death involving the release of a series of damage-associated molecular patterns leading to an adaptive immune response10–13
overall response rate (ORR) were similar to those in patients with refractory MM (RRMM) who were refractory to a PI and an immunomodulatory agent and exposed to anti-CD38 monoclonal antibodies (mAbs) receiving single-agent belamaf 3.4 mg/kg Q3W in both the first-inhuman DREAMM-1 study (ORR: 38.5% in this sub-group of 13 patients) and the previously published main DREAMM-2 study (ORR: 35% at 13-month follow-up)
Summary
Despite improved outcomes with currently available therapies, including proteasome inhibitors (PIs), immunomodulatory agents and anti-CD38 monoclonal antibodies (mAbs), multiple myeloma (MM) remains a challenging disease that is incurable for most patients. B-cell maturation antigen (BCMA), a member of the tumour necrosis factor receptor family, is expressed on the surface of all normal plasma cells and late-stage B cells, as well as on all malignant cells in all patients with MM8,9. Belantamab mafodotin (belamaf; GSK2857916) is a firstin-class, BCMA-targeted antibody-drug conjugate (ADC) consisting of a humanised, afucosylated anti-BCMA mAb fused to the cytotoxic payload monomethyl auristatin F (MMAF) by a protease-resistant maleimidocaproyl linker. Belamaf binds to BCMA and eliminates myeloma cells by a multimodal mechanism, including delivering mafodotin to BCMA-expressing malignant cells thereby inhibiting microtubule polymerisation, and inducing immune-independent ADC-mediated apoptosis; immune-dependent enhancement of antibody-dependent cellular cytotoxicity and phagocytosis; and release of markers characteristic of immunogenic cell death—a form of regulated cell death involving the release of a series of damage-associated molecular patterns (such as calreticulin and high-mobility group box 1) leading to an adaptive immune response
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